Compound for treating cancer

Abstract

The present invention relates to a compound for treating cancer, and in particular to a use of the following compound or a pharmaceutically acceptable salt thereof in preparation of a drug which is used for treating cancer: formula (1), wherein R1 is (C1-C6) alkyl optionally substituted by hydroxy; R2 is independently halogen, (C1-C6) alkyl or halogen-substituted (C1-C6) alkyl; R3 is independently (C1-C6) alkyl; m is 0, 1, 2, 3 or 4; and n is 0, 1, 2, 3, 4 or 5. The compound can be used for treating cancer, particularly a solid tumor, and can inhibit the growth of the tumor.

Description

Compounds used to treat cancer Technical Field

[0001] The present invention relates to the field of pharmaceutical compounds, in particular compounds for treating cancer. Background Art

[0002] Adenosine receptors are a class of purinergic G protein-coupled receptors that include four subtypes: A1, A2a, A2b, and A3. Adenosine signaling may be an important compensatory immunosuppressive mechanism. In solid tumors, the hypoxic environment and cellular tissue breakdown generate large amounts of adenosine triphosphate (ATP).

[0003] CN110446712B discloses a 2A Triazolopyrimidine derivatives as receptor inhibitors can be used to treat A 2A Receptor-related diseases, which is incorporated herein by reference.

[0004] CN112105617B discloses the crystal form of the compound.

[0005] There remains a need for compounds useful in the treatment of cancer, particularly solid tumors.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide compounds for treating cancer, especially solid tumors.

[0008] The present invention relates to the use of the following compound or a pharmaceutically acceptable salt thereof in preparing a medicament for treating cancer:

[0009] in,

[0010] R1 is (C1-C6)alkyl optionally substituted with hydroxy;

[0011] R2 is independently halogen, (C1-C6)alkyl or (C1-C6)alkyl substituted by halogen;

[0012] R3 is independently (C1-C6)alkyl;

[0013] m is 0, 1, 2, 3, or 4;

[0014] n is 0, 1, 2, 3, 4 or 5.

[0015] The compound can be used to treat cancer, especially solid tumors, and can inhibit tumor growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG1 is a graph showing the number of days of treatment for subjects;

[0017] Figure 2 is a graph showing adverse events associated with the trial drug;

[0018] FIG3 is a graph showing the occurrence of adverse events related to the test drug in each dose group;

[0019] FIG4 is an X-ray powder diffraction pattern of the crystalline form of Compound A. DETAILED DESCRIPTION

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In the event of conflict, the present document, including definitions, will prevail. Preferred methods and materials are described below, but methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. The materials, methods, and examples disclosed herein are illustrative only and are not intended to limit the present invention.

[0021] The present invention provides the use of the following compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer:

[0022] in,

[0023] R1 is (C1-C6)alkyl optionally substituted with hydroxy;

[0024] R2 is independently halogen, (C1-C6)alkyl or (C1-C6)alkyl substituted by halogen;

[0025] R3 is independently (C1-C6)alkyl;

[0026] m is 0, 1, 2, 3, or 4;

[0027] n is 0, 1, 2, 3, 4 or 5.

[0028] In one embodiment, R1 is (C1-C6)alkyl substituted by hydroxy, preferably (C1-C3)alkyl substituted by hydroxy, preferably hydroxymethyl.

[0029] In one embodiment, R2 is independently trifluoromethyl or (C1-C6)alkyl, said (C1-C6)alkyl is preferably methyl.

[0030] In one embodiment, m is 2.

[0031] In one embodiment, n is 0.

[0032] In one embodiment, the compound is

[0033] (No. ILB-2109).

[0034] Compound ILB-2109 can be prepared according to the method described in CN110446712B or CN112105617B, both of which are incorporated herein by reference.

[0035] In one embodiment, the cancer is a solid tumor.

[0036] In one embodiment, the cancer is selected from gastric cancer, esophageal cancer, urothelial carcinoma, prostate cancer, renal cancer, colorectal cancer, non-small cell lung cancer, triple-negative breast cancer, liver cancer, pancreatic cancer, head and neck squamous cell carcinoma, melanoma, cervical cancer, ovarian cancer, endometrial cancer, sarcoma, glioma, rectal cancer, lung cancer, adenoid cystic carcinoma, spindle cell sarcoma, lung adenocarcinoma, colon cancer, fallopian tube cancer, esophageal squamous cell carcinoma, rectal adenocarcinoma, lung squamous cell carcinoma, malignant pleomorphic adenocarcinoma, intrahepatic bile duct carcinoma, or nasopharyngeal carcinoma.

[0037] In one embodiment, the compound has a crystalline form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.08±0.2°, 11.30±0.2°, 14.00±0.2°, 16.90±0.2°, 18.30±0.2°, 22.52±0.2°, 23.15±0.2°, and 25.26±0.2°.

[0038] In one embodiment, the compound has a crystal form A, and its X-ray powder diffraction pattern is shown in FIG4 .

[0039] The crystal form A of the compound can be prepared according to the method described in CN112105617B, which is incorporated herein by reference.

[0040] In one embodiment, the compound is a deuterated compound.

[0041] The compound can replace hydrogen with heavy hydrogen to form a deuterated compound. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated compounds, deuterated compounds have the advantages of reducing toxic side effects, increasing compound stability, enhancing therapeutic effects, and extending the half-life of the compound.

[0042] In one embodiment, the deuterated compound is selected from:

[0043] In one embodiment, the medicament further comprises an anti-CTLA-4 monoclonal antibody. Preferably, the weight ratio of the compound to the anti-CTLA-4 monoclonal antibody is 5:1 to 50:1, for example, 10:1 to 20:1. Preferably, the medicament is used to treat colon cancer. The compound and the anti-CTLA-4 monoclonal antibody have a synergistic effect in treating cancer, for example, solid tumors, such as colon cancer.

[0044] The compound can be prepared with commonly used adjuvants, carriers or excipients into conventional formulations in the art for administration to individuals, including tablets, capsules, injections, powders, granules, inhalants, suppositories, solutions, emulsions, suspensions, ointments, films, etc.

[0045] Example 1. Preclinical studies

[0046] Preclinical pharmacodynamic studies

[0047] In vitro activity assays showed that ILB-2109 effectively inhibited the binding of A2aR to its isotope-labeled ligand, with an IC50 of 2.92 nM. Furthermore, ILB-2109 exhibited high selectivity for A2aR (18.9-, 40.7-, and 3424.7-fold selectivity relative to A1, A2b, and A3 receptors, respectively). ILB-2109 also effectively antagonized A2aR activity at the cellular level, with an IC50 of 0.43 nM. Under physiologically equivalent tumor conditions (NECA 5 μM), the IC50 was 1.08 nM, also demonstrating highly potent A2aR antagonism. The antagonistic activity and selectivity of ILB-2109 against A2aR were comparable to those of the reference compound AZD4635, currently in Phase II clinical studies.

[0048] In the in vivo pharmacodynamic evaluation of the mouse colon cancer MC38 tumor model, ILB-2109 (50 and 100 mg / kg) combined with anti-CTLA-4 monoclonal antibody (5 mg / kg) also showed significant tumor inhibitory effects (TGI were 70.97% and 84.38%, respectively).

[0049] Experimental methods

[0050] The study included six groups: a vehicle control group, low- and high-dose ILB-2109 monotherapy groups, an anti-CTLA-4 antibody monotherapy group, and two combined doses of ILB-2109 and anti-CTLA-4. Details of the doses and groups are shown in Table 1.

[0051] Table 1 Experimental dosage and grouping

[0052] Note:

[0053] a: The vehicle control group consisted of vehicle 1 + vehicle 2 (vehicle 1: 1% tween 80 + 9% PEG 400 + 90% ddwater; vehicle 2: DPBS). b: Vehicle 1 and ILB-2109 were administered starting on the day of vaccination, twice daily, with a 6-hour interval. Vehicle 2 and anti-CTLA-4 antibody were administered on days 9, 13, 16, and 20 after vaccination.

[0054] Compound formulation

[0055] Anti-CTLA-4 antibody was sterilely diluted to 0.5 mg / mL with DPBS. Prepare immediately before administration.

[0056] ILB-2109 is diluted to 10 mg / mL using a solvent consisting of 1% tween 80, 9% PEG 400, and 90% dd-water. The specific preparation method is as follows: Prepare solvent 1 (10 mL tween 80, 90 mL PEG 400, and 900 mL dd-water). Weigh 1120 mg of ILB-2109 and add it to 112 mL of solvent 1. Grind until nearly homogeneous, then sonicate for approximately 2-3 minutes to obtain a uniform suspension. Then, take an appropriate amount of the solution and add solvent 1 (1% tween 80, 9% PEG 400, and 90% dd-water) at a 1:1 ratio to dilute to 5 mg / mL. Aliquot 4 mL into 5 mL EP tubes and store at 4°C.

[0057] Prepare once a week.

[0058] Construction of MC38 tumor transplantation model

[0059] Forty-eight female C57BL / 6 mice were subaxillary inoculated with 2×10⁵ MC38 cells in 0.1 mL of DPBS. On the day of inoculation, the mice were randomly assigned based on body weight to a vehicle control group, a low-dose ILB-2109 group, or a high-dose ILB-2109 group, with 16 animals per group. The day of inoculation was designated Day 1. By Day 9 after inoculation, the mean tumor volume in the vehicle control group reached approximately 64 mm³. Based on tumor volume and body weight, the original vehicle control group was subdivided into a vehicle control group and an anti-CTLA-4 antibody monotherapy group. The original low-dose ILB-2109 group was subdivided into a low-dose ILB-2109 monotherapy group and a low-dose ILB-2109 combined with an anti-CTLA-4 antibody group. The original high-dose ILB-2109 group was subdivided into a high-dose ILB-2109 monotherapy group and a high-dose ILB-2109 combined with an anti-CTLA-4 antibody group. On the day of reassignment, the animals in each group were administered the prescribed dose.

[0060] Tumor volume and body weight were measured three times a week.

[0061] Sample collection

[0062] All animals were euthanized on day 23 after inoculation, and tumor samples were collected and weighed.

[0063] Observation indicators

[0064] Tumor volume

[0065] Tumor volume was measured three times a week, and the tumor inhibition rate TGITV (%) was calculated. The calculation formula of tumor volume (TV) is:

[0066] TV=1 / 2×a×b2

[0067] Where a and b represent the long and short diameters of the tumor mass, respectively.

[0068] Tumor inhibition rate TGITV (%) = [(1-average tumor volume of the treated group at the end of drug administration) / (average tumor volume of the solvent control group at the end of treatment)] × 100%.

[0069] Tumor weight

[0070] When the samples were collected, the tumor weight of the animals was measured and the tumor inhibition rate of the animals was calculated according to the following formula:

[0071] Tumor weight inhibition rate TGITW (%) = (TWc-TWt) / TWc×100%.

[0072] TWt is the average tumor weight of the treatment group, and TWc is the average tumor weight of the vehicle control group.

[0073] Data processing and statistical analysis

[0074] All data are expressed as mean ± SEM.

[0075] In this experiment, the data from day 21 after inoculation were statistically analyzed using PRISM software. T test was used for analysis of the comparison between two groups, and one-way ANOVA was used for analysis of the comparison between three or more groups.

[0076] Experimental results

[0077] Tumor volume

[0078] This study evaluated the efficacy of ILB-2109 alone and in combination with an anti-CTLA-4 antibody (clone 9D9) in an MC38 mouse colon cancer xenograft model. At 21 days of dosing, the T / C ratio (T / C) ratio in the high-dose ILB-2109 combined with CTLA-4 antibody group was 15.62%, and the TGI (Tg) ratio was 84.38%. (See Tables 2 and 3 for details.) Tumor volumes in all animals in the high-dose combined with antibody group were less than 250 mm³. In the antibody monotherapy group, only five mice had tumors less than 250 mm³, and in the vehicle group, only one animal had a tumor less than 250 mm³.

[0079] Table 2 Tumor inhibition effect of ILB-2109 on MC38 mouse transplant tumor model

[0080] Note: a. Mean ± SEM.

[0081] b. Tumor growth inhibition was calculated from T / C and TGI (TGI (%) = [1-(T20) / (V20)] x 100).

[0082] Table 3 p values ​​for comparison of tumor volume (TV) among groups in MC38 mouse transplant tumor model

[0083] Note: p values ​​were obtained by one-way ANOVA analysis of tumor volume, and Tukey's method was used for comparison between groups.

[0084] a. The analysis value is the tumor volume data of each group on the 21st day of administration

[0085] G1: vehicle control (n=8)

[0086] G2: ILB-2109-50 mg / kg (n=8)

[0087] G3: Anti-CTLA-4 antibody-5mg / kg (n=8)

[0088] G4:ILB-2109+Anti-CTLA-4-(50+5)mg / kg(n=8)

[0089] G5: ILB-2109-100 mg / kg (n=8)

[0090] G6:ILB-2109+Anti-CTLA-4-(100+5)mg / kg(n=8)

[0091] Table 4 Tumor volume of each group at different time points

[0092] Tumor weight

[0093] At the end of the experiment, tumor tissue was collected and weighed, and the tumor weight inhibition rate (TGITW) was calculated based on the tumor weight data. The results showed that the TGITW in the low-dose ILB-2109 monotherapy group was 31%; the TGITW in the anti-CTLA-4 antibody group was 83%, demonstrating significant tumor inhibition compared to the vehicle control group (p=0.0001). The TGITW in the low-dose ILB-2109 combined with the anti-CTLA-4 antibody group reached 74%, demonstrating significant tumor inhibition compared to the vehicle control group (p=0.0001), demonstrating superior efficacy to either drug alone.

[0094] The TGITW in the high-dose ILB-2109 monotherapy group reached 38%, while the TGITW in the high-dose ILB-2109 combined with anti-CTLA-4 antibody group reached 89%. These results demonstrated significant tumor inhibition compared to the vehicle control group (p=0.0001), and were superior to those in the low-dose combination group and the antibody monotherapy group. See Table 5 for detailed results.

[0095] Table 5 Antitumor effects of the test substances on the mouse colon cancer MC38 cell transplanted tumor model

[0096] Note: a. Mean ± SEM.

[0097] BP values ​​were analyzed using one-way ANOVA to determine tumor weight. The anti-CTLA-4 antibody monotherapy group vs. the low-dose combination group (p = 0.7595); the anti-CTLA-4 antibody monotherapy group vs. the high-dose combination group (p = 0.9090); the low-dose ILB-2109 monotherapy group vs. the low-dose combination group (p = 0.0100); and the high-dose ILB-2109 monotherapy group vs. the high-dose combination group (p = 0.0007).

[0098] Experimental Conclusion

[0099] In this MC38 mouse colon cancer transplant tumor model experiment, ILB-2109 showed anti-tumor efficacy when combined with Anti-CTLA-4 antibody at doses of 50 mg / kg and 100 mg / kg.

[0100] At a dose of 100 mg / kg, ILB-2109 combined with an anti-CTLA-4 antibody showed a trend toward smaller tumor volumes compared to the anti-CTLA-4 antibody alone group, but this difference was not statistically significant. Further analysis revealed that the proportion of mice with tumor volumes >250 mm³ in the combination group (0 / 8) was significantly lower than in the anti-CTLA-4 antibody alone group (3 / 8).

[0101] Example 2. Preclinical pharmacokinetic studies

[0102] Based on the "Technical Guidelines for Nonclinical Pharmacokinetic Studies of Drugs" and the results of in vitro species-specific metabolic studies, this pharmacokinetic study fully validated the analytical method for ILB-2109 in Sprague-Dawley rat and cynomolgus monkey plasma (anticoagulated with EDTA-K2) using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The method demonstrated a linear range of 20.0 to 20,000 nM. The method's precision, accuracy, and other parameters were confirmed to meet relevant regulations for biological sample testing.

[0103] absorb

[0104] According to the existing classification criteria, ILB-2109 showed high permeability in Caco-2 cells, and the test article was highly likely to be a substrate for efflux transporters.

[0105] SD rat absorption test

[0106] This study investigated the pharmacokinetic properties of ILB-2109 in male and female Sprague-Dawley rats, including 1) a single intravenous injection study at 2 mg / kg; 2) an oral dose escalation study at 12, 40, and 120 mg / kg; and 3) a repeated oral dosing study at 40 mg / kg, BID for 7 consecutive days.

[0107] After a single intravenous injection of 2 mg / kg in female and male SD rats, the plasma clearance (CL) of ILB-2109 was 1.33±0.135 mL / min / kg and 6.30±1.04 mL / min / kg, respectively. The apparent volume of distribution at steady state (Vdss) was 0.526±0.0558 L / kg and 0.681±0.0975 L / kg, respectively. The elimination half-life (T1 / 2) and the area under the time-plasma concentration curve from time 0 to the last quantifiable time point (AUC0-last) were 5.71±1.25 h and 60300±5180 nM·h, 1.26±0.361 h and 13300±2260 nM·h, respectively.

[0108] Following single oral administration of ILB-2109 at 12, 40, and 120 mg / kg to male SD rats, the AUC0-last values ​​were 58,900 ± 19,200, 296,000 ± 54,100, and 792,000 ± 167,000 nM·h, respectively. Peak concentrations (Cmax) were 23,800 ± 2,230, 63,300 ± 1,650, and 118,000 ± 19,800 nM, respectively, occurring at 0.667 ± 0.289, 1.33 ± 0.577, and 2.67 ± 1.15 h after administration, respectively. At a 12 mg / kg oral dose, the bioavailability of ILB-2109 was 73.0%.

[0109] Following single oral administration of ILB-2109 to female SD rats at 12, 40, and 120 mg / kg, the AUC0-last values ​​were 247,000±22,100, 915,000±169,000, and 1,560,000±205,000 nM·h, respectively. Peak concentrations (Cmax) were 33,700±2,800, 124,000±17,500, and 155,000±24,300 nM, respectively, occurring at 2.33±1.53, 3.33±1.15, and 2.67±1.15 h after administration, respectively. At a 12 mg / kg oral dose, the bioavailability of ILB-2109 was 67.8%.

[0110] At single oral doses of 12, 40, and 120 mg / kg, the AUC0-last ratios for female and male rats were 4.19, 3.09, and 1.97, respectively, indicating significant differences in systemic exposure between female and male rats at low and medium doses. Within the 12 to 40 mg / kg dose range, systemic exposure (AUC0-last) and Cmax increased approximately proportionally with dose in both male and female rats. Following oral administration of 40 mg / kg ILB-2109 for seven consecutive days, the Cmax ratios for female and male rats on day 7 to day 1 were 0.899 and 0.673, respectively, and the AUC0-last ratios for female and male rats on day 7 to day 1 were 0.669 and 0.584, respectively.

[0111] All animals tolerated the compound well and showed no abnormal symptoms.

[0112] Cynomolgus monkey absorption study

[0113] This study investigated the pharmacokinetic properties of ILB-2109 in male and female cynomolgus monkeys, including 1) a single intravenous injection study at 3 mg / kg; 2) an oral dose escalation study at 3, 15, and 60 mg / kg; and 3) oral administration at a dose of 15 mg / kg for 7 consecutive days, BID.

[0114] After a single intravenous injection of 3 mg / kg in male and female cynomolgus monkeys, the plasma clearance (CL) of ILB-2109 was 3.13±0.361 mL / min / kg, the apparent volume of distribution (Vd) at steady state was 0.867±0.141 L / kg, the elimination half-life (T1 / 2) and the area under the time-plasma concentration curve from point 0 to the last quantifiable time point (AUC0-last) were 4.33±0.750 h and 39500±5270 nM·h, respectively.

[0115] Following single oral administration of ILB-2109 at 3, 15, or 60 mg / kg to male and female cynomolgus monkeys, peak concentrations (Cmax) were 8190±1810, 33900±9660, and 59300±33300 nM, respectively, occurring at 1.33±0.516, 2.00±1.10, and 4.00±2.19 hours post-dose. AUC0-last values ​​were 35200±6870, 192000±51600, and 571000±254000 nM·h, respectively. Bioavailability was 89.1% in the 3 mg / kg oral dose group.

[0116] In male and female cynomolgus monkeys, oral administration of 15 mg / kg of ILB-2109 twice daily for 7 consecutive days resulted in peak concentrations (Cmax) of 18,200 ± 4,000 and 28,300 ± 4,780 nM on day 1 and day 7, respectively, with peaks occurring 3.00 ± 1.10 hours after administration. AUC0-last values ​​were 172,000 ± 34,400 and 268,000 ± 42,500 nM·h, respectively.

[0117] As the oral dose increased from 3 to 60 mg / kg, the systemic exposure (AUC0-last) of the drug in male and female cynomolgus monkeys increased in almost the same proportion as the dose.

[0118] There were no significant gender differences in systemic exposure (AUC0-last and Cmax) between male and female cynomolgus monkeys at any oral dose.

[0119] Following oral administration of 15 mg / kg ILB-2109 twice daily for 7 consecutive days, there was no significant accumulation of systemic exposure in males and females.

[0120] distributed

[0121] ILB-2109 tablets showed high binding in human plasma (95.1-95.8%) and moderate binding in the plasma of CD-1 mice, Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys (87.3%-95.0%), without showing a clear concentration-dependency.

[0122] Following a single oral administration of 30 mg / 100 μCi / kg of [14C]ILB-2109 to both male and female rats, total radioactivity was widely distributed throughout the body, primarily in the liver, kidneys, lungs, and gastrointestinal tract wall. It was also present to some extent in all tissues tested, including the mesenteric, submandibular, and axillary lymph nodes and thymus. The Tmax for most tissues and plasma in female rats was 4 hours, while that in male rats was 0.25 hours, indicating slightly faster uptake of total radioactivity in male rats. Following a single oral administration of 30 mg / 100 μCi / kg of [14C]ILB-2109 to both male and female rats, total radioactivity was rapidly eliminated. Four hours after administration, levels in most tissues and plasma of male rats decreased to some extent, indicating that male rats entered the elimination phase earlier. Twenty-four hours after dosing, radioactivity was still detectable in most tissues and plasma of female rats, while it was below the limit of detection in most tissues and plasma of male rats. At the final collection time point (72 hours), only the liver, intestinal wall, and plasma of female rats remained with a small amount of radioactivity, representing approximately 0.09% of the dose. Total radioactivity in the remaining tissues and plasma was below the limit of detection.

[0123] metabolism

[0124] ILB-2109 is metabolized at a moderate rate in CD-1 mice and SD rats, and at a slow or no rate in beagle dogs, cynomolgus monkeys, and human liver microsomes. The primary biotransformation pathways of ILB-2109 in liver microsomes and hepatocytes in vitro include oxidation, dehydrogenation, and glucuronidation (hepatocyte biotransformation pathway). No human-specific metabolites were detected.

[0125] In vivo metabolism experiments in SD rats showed that the major clearance pathway for [14C]ILB-2109 in rats was direct binding to glucuronic acid to form M576a / b, or monooxidation followed by binding to glucuronic acid to form M592a / b / c. The drug was primarily metabolized in the liver and excreted in the feces, with a small amount excreted through the kidneys. The glucuronic acid conjugation products in the feces could be partially converted back to the monooxidation products M416a / b and the parent drug form. The secondary clearance pathway was monooxidation and dehydrogenation to form M414, which was excreted through the liver and kidneys.

[0126] In in vivo metabolism studies in cynomolgus monkeys, parent drug ILB-2109 was found at a relative abundance of >83% in plasma samples from both male and female monkeys, making it the predominant component in plasma. ILB-2109 is metabolized in monkey plasma primarily through oxidation, dehydrogenation, and glucuronidation. CYP3A is the primary metabolizing enzyme for the production of the ILB-2109 metabolite M4, while CYP2B6, CYP2C8, and CYP2C9 may play a minor role. Other isoenzymes (CYP1A2, CYP2C19, and CYP2D6) play little or no role in the production of M4.

[0127] excretion

[0128] After a single oral dose in male and female rats, the average recovery of total radioactivity within 0-168 hours was 91.74%. Excretion in urine accounted for 13.81% of the dose, in feces 75.17%, and in cage washing and cleaning fluids 2.75%. Excretion primarily occurred within 48 hours of dosing, accounting for approximately 88.01% of the dose.

[0129] Following a single oral dose in male and female bile cannulated (BDC) rats, the average recovery of total radioactivity within 0-72 hours was 93.63%. Total excretion into bile accounted for 66.17% of the dose, followed by urine (12.16%), feces (14.45%), and cage wash and cleaning fluids (0.85%). Based on the total radioactivity excretion into bile and urine in BDC rats, the oral absorption rate of ILB-2109 is estimated to be at least 78.33%.

[0130] Drug interactions

[0131] In vitro, ILB-2109 weakly inhibited CYP2C8 (IC50: 33.9 μM) in human liver microsomes, had no inhibitory effect on CYP2C9 (IC50: 57.2 μM) and CYP2C19 (IC50: 91.6 μM), and had no inhibitory effect on CYP1A2, CYP2B6, CYP2D6, CYP3A4 (with midazolam as a substrate), or CYP3A4 (with testosterone as a substrate) (IC50>100 μM). ILB-2109 had no time-dependent inhibitory effect on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

[0132] The time-dependent inhibitory effect of ILB-2109 on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was determined using a non-dilution method. An IC50 shift of 1.5 or greater is generally used as the criterion for determining a time-dependent inhibitor. The results showed that ILB-2109 had no time-dependent inhibitory effect on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

[0133] In vitro hepatocyte induction assays evaluated the effects of ILB-2109 on the enzymatic activity and gene expression levels of the cytochrome P450 isoenzymes CYP1A2, CYP2B6, and CYP3A4. In vitro enzyme activity data demonstrated that ILB-2109 was not an inducer of CYP1A2, CYP2B6, and CYP3A4 at concentrations of 0.200, 2.00, and 20.0 μM. In vitro gene expression data demonstrated that ILB-2109 was an inducer of the cytochrome P450 isoenzyme CYP3A4 at a concentration of 2.00 μM for both donors 1 and 3. When the concentration of ILB-2109 was 20.0 μM, the results of donor 1 showed that ILB-2109 was an inducer of cytochrome P450 isoenzymes CYP1A2 and CYP2B6; the results of donors 1, 2 and 3 showed that ILB-2109 was an inducer of hepatic cytochrome P450 isoenzyme CYP3A4.

[0134] Example 3. Preclinical toxicology studies

[0135] In accordance with the relevant requirements of the "Good Manufacturing Practice for Nonclinical Drug Research" of the State Food and Drug Administration of the People's Republic of China, and in compliance with the experimental plan and its revisions, ILB-2109 safety pharmacology experiments, single-dose toxicity, and genotoxicity were explored.

[0136] Single-dose toxicity studies

[0137] SD rats were observed for 14 days after a single oral gavage administration of ILB-2109 at doses of 0 (vehicle), 500, 1000, and 2000 mg / kg. Results showed that all animals survived until planned autopsy, with no signs of dying or death, and no obvious clinical signs. Body weight, food consumption, clinical examination, or gross anatomy were normal. Under these experimental conditions, the maximum tolerated dose (MTD) of ILB-2109 in rats was 2000 mg / kg.

[0138] Crab-eating macaques were given a single oral dose of ILB-2109 at doses of 0 (vehicle), 250, 500 and 1000 mg / kg and observed for 14 consecutive days after the single dose. The results showed that all animals survived until the planned autopsy, and no animals were dying or dying. On the day of administration, mild vomiting (a small amount of food-like vomitus) occurred in the medium and high-dose groups within 30 minutes to 4 hours after administration. No abnormalities were found in body weight, food consumption, body temperature, respiration, electrocardiogram, blood, ophthalmology, clinical examination, bone marrow, and gross anatomy. Under the conditions of this experiment, the maximum tolerated dose (MTD) of ILB-2109 in crab-eating macaques after a single oral administration within 24 hours was 1000 mg / kg. The test article has an effect on the digestive system (gastrointestinal function, liver function).

[0139] Repeated dose toxicity study

[0140] SD rats were orally gavaged with ILB-2109 at 0 (vehicle), 60, 200, and 600 mg / kg for 28 consecutive days. Results showed no test article-related clinical symptoms, changes in body weight, or food consumption across all dose groups. WBC and #LYMPH increased or showed an increasing trend in the medium- and high-dose groups; GLU decreased or showed a decreasing trend in the medium- and high-dose groups; CREA and UREA increased or showed an increasing trend in the female high-dose group; and GLOB increased and A / G decreased in female animals across all dose groups. Histopathological findings revealed only centrilobular hepatocyte hypertrophy in the female livers of the medium- and high-dose groups. All of these changes fully resolved during the recovery period. Significant gender differences were observed in the AUC0-24h in the low-dose group, but no significant gender differences were observed in the other dose groups in terms of systemic exposure. There was no significant accumulation of systemic exposure across all dose groups, and the proportion of increase in systemic exposure was less than the proportion of increase in dose. Under these experimental conditions, the NOAEL for repeated oral administration of ILB-2109 to SD rats for four weeks was 60 mg / kg (at this dose, female AUC0-24h = 295.88 h*μg / mL, Cmax = 22.16 μg / mL; male AUC0-24h = 114.50 h*μg / mL, Cmax = 15.86 μg / mL), and the MTD was 600 mg / kg (at this dose, female AUC0-24h = 724.86 h*μg / mL, Cmax = 69.40 μg / mL; male AUC0-24h = 481.00 h*μg / mL, Cmax = 36.34 μg / mL). ILB-2109 may have toxic effects on the digestive system (liver function), hematologic system (granulocyte system), and urinary system (renal function) of SD rats, which are reversible after the recovery period.

[0141] Forty cynomolgus macaques (half male and half female) were randomly divided into four groups, with five animals per group per sex, and administered ILB-2109 by oral gavage once daily for 28 consecutive days at doses of 0 (vehicle), 20, 60, and 200 mg / kg / day. Results showed that one male animal in the high-dose group was found moribund 2 hours after dosing on Day 3. Prior to moribundity, the animal began to exhibit decreased respiratory rate, abnormal respiratory sounds, prone position, abnormal feces, and vomiting. Gross observations revealed diffuse dark red lungs and white froth in the trachea. Combined with gross observations and histopathological findings, lung damage was suspected to be the cause of death. No test article-related clinical symptoms, body weight, or food consumption changes were observed across the dose groups. In the mid-dose group, male animals showed decreased %LYMPH and increased %NEUT. In the high-dose group, there was a trend toward decreased %LYMPH and increased %NEUT in both males and females. Histopathological examination revealed only a decrease in adrenal cortical vacuoles in the mid- and high-dose groups. These changes fully resolved during the recovery period. No other drug-related changes were observed in body temperature, respiration, electrocardiogram, ophthalmology, or bone marrow. There were no gender differences in systemic exposure across all dose groups; there was no significant accumulation; and the proportion of increase in systemic exposure was lower than the proportion of increase in dose.

[0142] Therefore, under the conditions of this study, a 4-week repeat-dose toxicity study of ILB-2109 administered orally to cynomolgus monkeys showed a HNSTD of 60 mg / kg (at this dose, females had AUC0-24h = 148.56 h*μg / mL, Cmax = 11.92 μg / mL; males had AUC0-24h = 205.78 h*μg / mL, Cmax = 14.32 μg / mL), and a NOAEL of 20 mg / kg (at this dose, females had AUC0-24h = 60.97 h*μg / mL, Cmax = 5.01 μg / mL; males had AUC0-24h = 80.19 h*μg / mL, Cmax = 6.58 μg / mL). During clinical use, attention should be paid to the potential effects of ILB-2109 on the respiratory, hematological, and endocrine systems.

[0143] Genotoxicity test

[0144] AMES: This test examines the ability of ILB-2109 to induce reverse mutations in histidine-deficient Salmonella Typhimurium (TA97a, TA98, TA100, TA102, and TA1535) with and without the addition of an exogenous metabolic activation system. Results showed that ILB-2109 tablets at doses ranging from 128 to 5000 μg / dish were non-mutagenic against the five strains, TA1535, TA102, TA100, TA98, and TA97a, with and without the addition of the S9 metabolic activation system. Therefore, the Ames test results were negative under the conditions of this study.

[0145] Chromosome aberration test: The test observed the effect of ILB-2109 on the chromosome structure and number of mammalian cells (CHL cells). The results showed that the chromosome aberration test results of CHL cells were negative when treated with 3.2, 16.0 and 80.0 μg / mL of ILB-2109.

[0146] Micronucleus test: SD rats were given 500-2000 mg / kg of ILB-2109 by gavage. All doses of ILB-2109 had no micronucleus-inducing effect on the polychromatic erythrocytes in the bone marrow of SD rats.

[0147] Example 4. Multicenter, open-label, Phase Ia clinical study: Dose-finding and dose-expansion clinical study of ILB-2109 tablets in patients with advanced solid tumors

[0148] Test drug: A2aR antagonist ILB-2109

[0149] ILB-2109 is granulated and tableted with conventional cellulose excipients to prepare ILB-2109 tablets.

[0150] Research stage: Phase Ia

[0151] Number of subjects: A maximum of 78 subjects are expected to be enrolled (27 to 54 subjects for dose escalation and 12 to 24 subjects for dose expansion).

[0152] Research period:

[0153] Screening period (day -28 to day -1);

[0154] single-dose period (3 days);

[0155] Continuous administration period (ILB-2109 tablets were taken orally on an empty stomach, QD, continuously, with 21 days as one cycle);

[0156] Safety follow-up after treatment completion (within 28 days after the last dose);

[0157] Survival follow-up (follow-up every 3 months after the safety follow-up until the end of the study).

[0158] End of treatment: All patients will continue treatment until disease progression, intolerable toxicity, death, investigator's decision, or patient's voluntary withdrawal from the study.

[0159] Study End: It is expected to be one year after the last enrolled subject received the first dose or when the trial is completed (whichever occurs first). Completion of the trial refers to when the subject completes the last study-related phone call or visit, terminates the trial, or is lost to follow-up (i.e., the researcher is unable to contact the subject).

[0160] Study Objectives

[0161] Main Purpose:

[0162] To observe the safety and tolerability of single and continuous oral administration of ILB-2109 tablets in patients with advanced solid tumors;

[0163] Determine the maximum tolerated dose (MTD) of ILB-2109 tablets and the appropriate recommended dose (RD) for subsequent studies;

[0164] Secondary objectives:

[0165] To evaluate the pharmacokinetic characteristics of ILB-2109 tablets;

[0166] Preliminary evaluation of the effect of food on the PK characteristics and safety and tolerability of ILB-2109 tablets (only in the extension phase);

[0167] Preliminary evaluation of the effectiveness of ILB-2109 tablets in the treatment of patients with advanced solid tumors;

[0168] Exploratory purpose:

[0169] Describe the pharmacodynamic (PD) characteristics of ILB-2109 tablets, including phosphorylated c-AMP response element binding protein (pCREB), cytokine TNF-α, IFN-γ, and IL-2 signaling levels (dose-escalation phase only);

[0170] To evaluate potential biomarkers of ILB-2109 tablets in peripheral blood and tumor specimens of patients with advanced solid tumors that: (1) may correlate with biological activity (pharmacodynamics); and (2) may pre-identify subjects who are most likely to respond to ILB-2109 tablets (predictive).

[0171] Study Design

[0172] This is an open-label, non-randomized, multicenter clinical study that includes dose escalation and dose expansion phases of ILB-2109 tablets alone; a maximum of 78 subjects are expected to be enrolled.

[0173] Dose escalation phase:

[0174] Patients with advanced solid tumors who have no standard effective treatment options, have failed standard treatment, or are not suitable for standard treatment at this stage are planned to be enrolled. The dose escalation will be carried out using the traditional "3+3" rule.

[0175] The ILB-2109 tablets dosing plan has approximately 9 dose groups, as shown in Table 6 below. Subjects take the drug on an empty stomach (at least 2 hours before or after meals) and must not eat for 1 hour after taking the drug. After a single dose on Day 1 of each subject, PK blood samples will be collected and safety monitored for 3 days (Cycle 0). If no DLT occurs during the observation period, the patient will enter the continuous dosing phase (Cycle 1) and start taking the drug once a day. A dosing cycle of 21 days will be established until the subject develops disease progression, intolerable toxicity, withdrawal of informed consent, death, or other conditions requiring termination of treatment. The trial will determine the dose group to enter the extension phase based on the safety, preliminary efficacy, and PK characteristics of the ILB-2109 tablets.

[0176] Table 6

[0177] Note: With the exception of dose groups 1-4, for which dosing has been completed and the fifth dose group currently underway, subsequent dose groups are tentatively scheduled for dose and frequency. Adjustments will be made based on safety, efficacy, and pharmacokinetics data from previous dose groups. The total number of dose groups will also be adjusted based on actual conditions.

[0178] Definition and Assessment of DLT:

[0179] DLT is defined as: DLT observation period (24 days in total), including single-dose DLT observation period (single-dose 3 days) and continuous-dose DLT observation period (21 days of the first cycle of continuous dosing), DLT assessment is performed on C2D1, and all toxicities are graded using the NCI-CTCAE (version 5.0) criteria. Any of the following adverse events related to the trial drug during the observation period is considered a DLT:

[0180] Table 7

[0181] Tumor assessment:

[0182] Tumor assessment will use the RECIST 1.1 evaluation criteria for solid tumors. Subjects will be assessed every 6 weeks until disease progression, study withdrawal or death, initiation of new anti-tumor treatment, or end of the study, whichever occurs first. At the completion of C1, if the investigator determines that the subject will not benefit from continuing to receive the study drug, the subject will be required to withdraw from the trial.

[0183] Determination of RD:

[0184] SRC will determine the RD comprehensively by combining the MTD and PK data from the dose escalation phase and the efficacy data observed in each dose group during the dose expansion study phase.

[0185] SRC:

[0186] During the study, a Pharmaceutical Science Review Committee consisting of the coordinating investigator, the principal investigator of the enrolling center, the sponsor and / or CRO medical monitor, PK experts and biostatisticians will be established to review the safety data generated in the study, determine the allocation and dose level of subjects in each dose group in the dose escalation study, and recommend the dose and RD selected for the expansion study.

[0187] This study includes a screening period, a treatment period, a safety follow-up period (28 days after the last dose), and a survival follow-up period. During the survival follow-up period, the subjects' survival status and other anti-tumor treatment status will be monitored.

[0188] All patients will receive study drug until disease progression (based on RECIST 1.1 criteria), death, intolerable toxicity, or other circumstances requiring treatment discontinuation.

[0189] Study subjects:

[0190] This study included subjects with advanced malignant solid tumors (such as gastric cancer, esophageal cancer, urothelial cancer, prostate cancer, renal cancer, colorectal cancer, non-small cell lung cancer, triple-negative breast cancer, liver cancer, pancreatic cancer, head and neck squamous cell carcinoma, melanoma, cervical cancer, ovarian cancer, nasopharyngeal carcinoma, etc.).

[0191] Eligibility criteria

[0192] Inclusion criteria

[0193] Subjects must meet all of the following criteria:

[0194] The subjects must give their informed consent to this study before the trial and voluntarily sign a written informed consent form;

[0195] 18-80 years old (inclusive), no gender restrictions;

[0196] Patients with histologically and / or cytologically confirmed advanced solid tumors who have no standard treatment options, have failed standard treatment, or are not currently suitable for standard treatment;

[0197] At least one evaluable tumor lesion in the dose-escalation phase and at least one measurable tumor lesion according to RECIST version 1.1 in the dose-expansion phase;

[0198] ECOG score 0-1;

[0199] Expected survival time ≥ 3 months;

[0200] The major organ functions are basically normal, and the laboratory test values ​​during the screening period meet the following standards:

[0201] Table 8

[0202] Female subjects of childbearing age whose serum pregnancy test results are negative;

[0203] The subjects agreed to use reliable contraceptive methods from the time they signed the informed consent form until 90 days after the last dose, including but not limited to: abstinence, vasectomy for males, sterilization for females, effective intrauterine devices, and effective contraceptive medications.

[0204] Exclusion criteria

[0205] Subjects must be excluded from the trial if they meet any of the following criteria:

[0206] Received chemotherapy, radiotherapy, biological therapy, endocrine therapy, targeted therapy, immunotherapy and other anti-tumor treatments within 4 weeks before the first use of study drugs, excluding the following:

[0207] Nitrosourea or mitomycin C within 6 weeks before the first use of study drugs;

[0208] For oral fluorouracils and small molecule targeted drugs, the duration is 2 weeks before the first use of the study drug or within 5 half-lives of the drug (whichever is longer);

[0209] For Chinese medicine with anti-tumor indications, the treatment should be within 2 weeks before the first use of the study drug;

[0210] Received other unapproved clinical investigational drugs or treatments within 4 weeks before the first dose;

[0211] Patients who have received immunotherapy and developed grade ≥3 irAE or grade ≥2 immune-related myocarditis;

[0212] Patients with clinically uncontrollable third space effusion were judged by the investigator to be unsuitable for inclusion;

[0213] Acute coronary syndrome within the past 6 months, including myocardial infarction, unstable angina, symptomatic congestive heart failure (New York Heart Association grade II-IV), aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events;

[0214] Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, II-III degree atrioventricular block, etc.

[0215] Any factors that increase the risk of QTc prolongation or arrhythmia, such as congenital long QT syndrome, family history of long QT syndrome, or use of any concomitant medication known to prolong the QT interval;

[0216] Uncontrolled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg after optimal medical treatment) or a history of hypertensive crisis or hypertensive encephalopathy;

[0217] Patients with clinical symptoms of brain parenchymal metastasis or meningeal metastasis are judged by the researchers to be unsuitable for inclusion;

[0218] Unable to swallow the drug orally, or having a condition that seriously affects gastrointestinal absorption as determined by the researcher;

[0219] People infected with human immunodeficiency virus (HIV) (HIV antibody positive);

[0220] Active hepatitis B (HBsAg positive and HBV-DNA > 500 IU / ml or the lower limit of detection of the research center [only when the lower limit of detection of the research center is higher than 500 IU / ml]), active hepatitis C (patients with positive HCV antibodies but HCV-RNA < the lower limit of detection of the research center are allowed to be included), and patients receiving preventive antiviral treatment other than interferon are allowed to be included;

[0221] Patients with active infection and currently requiring intravenous anti-infective treatment;

[0222] Received systemic glucocorticoids (prednisone > 10 mg / day or equivalent dose of similar drugs) or other immunosuppressive therapy within 14 days before the first dose, excluding the following:

[0223] Treatment with topical, ocular, intra-articular, intranasal, and inhaled corticosteroids;

[0224] Short-term use of glucocorticoids for prophylaxis (e.g., to prevent contrast agent allergy);

[0225] Received live attenuated vaccine within 4 weeks before the first dose or planned to receive it during the study;

[0226] Patients who have undergone major organ surgery (excluding puncture biopsy) or significant trauma within 4 weeks before the first dose, or need to undergo elective surgery during the trial;

[0227] Those who have received allogeneic hematopoietic stem cell transplantation or organ transplantation in the past;

[0228] Known alcohol or drug dependence;

[0229] People with mental disorders or poor compliance;

[0230] Adverse reactions from previous anti-tumor treatment have not recovered to CTCAE 5.0 grade ≤ 1 (excluding toxicities that the investigator judges to be without safety risks, such as alopecia, grade 2 peripheral neuropathy, and hypothyroidism that has been stabilized by hormone replacement therapy);

[0231] Use of strong CYP3A4 inhibitors or inducers within 7 days before the first dose (topical medications are not restricted);

[0232] Pregnant or breastfeeding patients;

[0233] The researcher believes that the subject is not suitable to participate in this clinical study due to other reasons.

[0234] Research evaluation

[0235] Safety evaluation:

[0236] Safety was evaluated by adverse events (graded using NCI-CTCAE version 5.0), laboratory tests, vital signs, physical examinations, electrocardiograms, etc. Adverse events were recorded from the time the subject signed the informed consent until 28 days after the last dose.

[0237] Pharmacokinetic evaluation:

[0238] PK blood samples were collected within the planned timeframe to determine ILB-2109 plasma concentrations and estimate pharmacokinetic parameters. The pharmacokinetic profile of ILB-2109 monotherapy after single and multiple doses was evaluated.

[0239] Pharmacodynamic evaluation:

[0240] PD blood samples will be collected at each PD blood sampling point during the dose-escalation phase of ILB-2109 monotherapy in this study and at baseline to measure the levels of pCREB, TNF-α, IFN-γ, and IL-2 signaling in blood cells for pharmacodynamic analysis. The time of blood sample collection will be recorded in the source file and eCRF.

[0241] Efficacy evaluation:

[0242] Baseline confirmation and efficacy assessment should be performed through imaging examinations (enhanced CT / CT plain scan, MRI, PET-CT). The same imaging assessment method (including instrument parameters, operating standards, imaging planes, etc.) should be used for the same subject during the trial.

[0243] The evaluation criteria used were the Response Evaluation Criteria for Solid Tumors (RECIST 1.1).

[0244] Baseline assessments should be performed within 28 days before the first dose of the drug. Imaging evaluations should be performed every 6±1 weeks after the start of treatment. After 13 treatment cycles, subjects who are still receiving treatment will undergo imaging evaluations every 12±4 weeks. Imaging examinations should be performed on calendar days and should not be adjusted due to treatment delays. Imaging examinations should be performed continuously until disease progression, withdrawal from the study, death, initiation of new anti-tumor treatment, or end of the study, whichever occurs first.

[0245] Study endpoints

[0246] Primary End Point

[0247] The incidence of dose-limiting toxicity (DLT) within 3 days of single-dose administration and within 21 days of continuous administration;

[0248] Determine the maximum tolerated dose (MTD) of ILB-2109 tablets and the appropriate recommended dose (RD) for subsequent studies;

[0249] Secondary End Points

[0250] Safety endpoints:

[0251] The incidence, type, and toxicity of treatment-emergent adverse events (TEAEs) during treatment were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

[0252] Treatment Emergent Serious Adverse Events (TESAE) and toxic reactions leading to permanent discontinuation of treatment;

[0253] Safety laboratory tests graded according to NCI-CTCAE (version 5.0);

[0254] Vital signs, 12-lead electrocardiogram, physical examination, and Eastern Cooperative Oncology Group (ECOG) score;

[0255] To evaluate the PK parameters of ILB-2109 tablets, including drug exposure (AUC0-last, AUC0-inf, AUC0-24), peak concentration (Cmax), time to peak concentration (Tmax), terminal elimination half-life (t1 / 2), apparent clearance (CL / F), and apparent volume of distribution (V / F);

[0256] The effect of food on the PK parameters of ILB-2109 tablets (only in the expansion phase) was preliminarily evaluated, including total drug exposure (AUC0-∞, AUC0-t), peak concentration (Cmax), time to peak concentration (Tmax), lag time (tlag), terminal phase elimination half-life (t1 / 2), apparent clearance (CL / F), and apparent volume of distribution (V / F);

[0257] Safety and tolerability indicators in the food effect study phase (only in the expansion phase): vital signs, 12-lead electrocardiogram, clinical laboratory test indicators (blood routine, urine routine, blood biochemistry, etc.), physical examination, ECOG score, adverse events and serious adverse events;

[0258] Efficacy endpoints: objective response rate (ORR), progression-free survival (PFS), overall survival (OS), 1-year OS rate, time to tumor response (TTR), duration of response (DOR), and clinical benefit rate (CBR);

[0259] Exploratory endpoints

[0260] To explore the relationship between the drug concentration of ILB-2109 tablets and the levels of pCREB, TNF-α, IFN-γ, and IL-2 signaling in blood cells during ILB-2109 monotherapy;

[0261] Explore tumor markers related to ILB-2109 tablets;

[0262] Statistical methods

[0263] Security Analysis:

[0264] Safety analyses will be based on the safety analysis set (SS). Descriptive statistics will be used to analyze adverse events, laboratory values, vital signs, and electrocardiograms. The incidence of adverse events, serious adverse events, and adverse events leading to discontinuation will be summarized by dose group.

[0265] For the dose escalation phase, the incidence of DLTs will be calculated for each dose group and presented as point estimates and two-sided 95% confidence intervals using the exact binomial method. The maximum tolerated dose (MTD) will be determined according to the traditional "3+3" dose escalation design.

[0266] Pharmacokinetic Analysis / Pharmacodynamics:

[0267] Pharmacokinetic analysis will be based on the PK analysis set (PKS). The drug concentration in plasma of ILB-2109 tablets will be determined, key PK parameters (Cmax, AUC, etc.) will be estimated, drug clearance pathways will be analyzed, and descriptive summary analyses will be provided by dose group.

[0268] For all subjects with evaluable PD blood samples, the levels of pCREB, TNF-α, IFN-γ, and IL-2 signals in blood cells from each PD blood collection point during the dose escalation phase and the baseline blood samples will be calculated, and descriptive statistics will be summarized.

[0269] Efficacy analysis:

[0270] Efficacy analyses will be primarily based on the full analysis set (FAS). The per-protocol set (PPS) may be used as a supportive supplement if necessary. Efficacy data will include the objective response rate (ORR) and disease control rate (DCR) and their 95% confidence intervals (CIs). Descriptive statistics for progression-free survival (PFS), duration of response (DOR), and overall survival (OS) will be presented using the Kaplan-Meier method with 95% CIs provided using the Greenwood method, and survival curves will be plotted. Waterfall, spider, and swimmer plots will be drawn to present the maximum change from baseline in the sum of the long diameters of target lesions for each patient, the change in tumor size over time, and the occurrence of each clinical endpoint over time.

[0271] Recommended dose (RD):

[0272] RD is determined based on safety evaluation, preliminary efficacy and PK data, combined with preclinical efficacy model data and in vitro study data.

[0273] Table 9: Preliminary efficacy results of subjects

[0274] Note: PD: Progressive disease (PD), defined as a ≥20% increase in the sum of the largest diameters of target lesions or the appearance of new lesions. SD: Stable disease (SD), defined as a decrease in the sum of the largest diameters of target lesions that does not achieve a PR or an increase that does not achieve a PD. PR: Partial response (PR), defined as a ≥30% decrease in the sum of the largest diameters of target lesions that persists for at least 4 weeks. Subject 03001 with esophageal cancer did not have target lesions, and SD was assessed using non-target lesions; therefore, no value is available.

[0275] Deadline: July 20, 2023

[0276] *Still undergoing treatment

[0277] Table 10: Potential efficacy signals were detected starting with the 100 mg dose group

[0278] 100mg: 1 case of rectal cancer SD, 1 case of lung cancer SD; 200mg: 1 case of cervical cancer PR, 1 case of adenoid cystic carcinoma SD

[0279] 300 mg: 1 case of spindle cell sarcoma, 1 case of esophageal cancer, and 1 case of adenoid cystic carcinoma

[0280] Overview of adverse events related to trial drugs

[0281] A total of 85 AEs related to the trial drug occurred in 19 subjects. Common AEs related to the trial drug were vomiting, increased bilirubin, proteinuria, increased aspartate aminotransferase, anemia, increased alanine aminotransferase, decreased appetite, etc., which were comparable to the AEs of similar products.

[0282] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. Use of the following compounds or their pharmaceutically acceptable salts in the preparation of medicaments for treating cancer: in, R1 is (C1-C6)alkyl optionally substituted by hydroxy; R2 is independently halogen, (C1-C6)alkyl or (C1-C6)alkyl substituted by halogen; R3 is independently (C1-C6) alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4 or 5.

2. The use according to claim 1, wherein R1 is a (C1-C6) alkyl group substituted by a hydroxy group, preferably a (C1-C3) alkyl group substituted by a hydroxy group, preferably a hydroxymethyl group.

3. The use according to claim 1, wherein R2 is independently trifluoromethyl or (C1-C6)alkyl.

4. The use according to claim 1, wherein The compound is The use according to claim 1 , wherein the cancer is a solid tumor.

6. The method of claim 1, wherein the cancer is selected from gastric cancer, esophageal cancer, urothelial carcinoma, prostate cancer, renal cancer, colorectal cancer, non-small cell lung cancer, triple-negative breast cancer, liver cancer, pancreatic cancer, head and neck squamous cell carcinoma, melanoma, cervical cancer, ovarian cancer, endometrial cancer, sarcoma, glioma, rectal cancer, lung cancer, adenoid cystadenocarcinoma, spindle cell sarcoma, lung adenocarcinoma, colon cancer, fallopian tube cancer, esophageal squamous cell carcinoma, rectal adenocarcinoma, lung squamous cell carcinoma, malignant pleomorphic adenocarcinoma, intrahepatic bile duct carcinoma or nasopharyngeal carcinoma.

7. The use according to claim 4, wherein The compound has a crystal form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.08±0.2°, 11.30±0.2°, 14.00±0.2°, 16.90±0.2°, 18.30±0.2°, 22.52±0.2°, 23.15±0.2°, and 25.26±0.2°.

8. The use according to claim 4, wherein The compound has a crystal form A, and its X-ray powder diffraction pattern is shown in FIG4 .

9. The use according to claim 1, wherein The compound is a deuterated compound, preferably, the deuterated compound is selected from:

10. The use according to claim 1, wherein The drug further comprises anti-CTLA-4 monoclonal antibody. Preferably, the weight ratio of the compound to the anti-CTLA-4 monoclonal antibody is 5:1 to 50:1, such as 10:1 to 20:

1. Preferably, the drug is used to treat colon cancer.

Images