Compounds for treatment of cancer

Abstract

The present invention relates to compounds for the treatment of cancer. The present invention relates inter alia to the use of a compound, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer: # imgabs0 # wherein R1 is a (C1-C6) alkyl group optionally substituted by a hydroxyl group; r2 is independently halogen, (C1-C6) alkyl or (C1-C6) alkyl substituted by halogen; r3 is independently a (C1-C6) alkyl group; 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 cancers, especially solid tumors, and can inhibit tumor growth.

Description

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, including four subtypes: A1, A2a, A2b, and A3. Adenosine signaling pathways may be an important compensatory immunosuppression mechanism. In solid tumors, the hypoxic environment and the decomposition of cell tissues can produce a large amount 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 crystalline form of the compound.

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

[0006] The object of the present invention is to provide compounds for treating cancer, especially solid tumors.

[0007] The present invention relates to the use of the following compounds or pharmaceutically acceptable salts thereof in preparing a medicament for treating cancer:

[0008]

[0009] in,

[0010] R 1 is optionally substituted with hydroxyl groups (C 1 -C 6 )alkyl;

[0011] R 2 are independently halogen, (C 1 -C 6 ) alkyl or halogen-substituted (C 1 -C 6 )alkyl;

[0012] R 3 Independently (C 1 -C 6 )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] Figure 1 is a graph showing the number of days the subjects were treated;

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

[0018] Figure 3 It is a graph showing the occurrence of adverse events related to the trial drug in each dose group;

[0019] Figure 4 is the X-ray powder diffraction pattern of Compound A crystalline form. DETAILED DESCRIPTION

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as are commonly understood by those skilled in the art. In the event of a conflict, the present document, including definitions, shall prevail. Preferred methods and materials are described below, but methods and materials similar or equivalent to those described herein can be used to implement or test 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 preparing a medicament for treating cancer:

[0022]

[0023] in,

[0024] R 1 is optionally substituted with hydroxyl groups (C 1 -C 6 )alkyl;

[0025] R 2 are independently halogen, (C 1 -C 6 ) alkyl or halogen-substituted (C 1 -C 6 )alkyl;

[0026] R 3 Independently (C 1 -C 6 )alkyl;

[0027] m is 0, 1, 2, 3, or 4;

[0028] n is 0, 1, 2, 3, 4 or 5.

[0029] In one embodiment, R 1is substituted by hydroxyl (C 1 -C 6 ) alkyl, preferably substituted with hydroxyl (C 1 -C 3 ) alkyl, preferably hydroxymethyl.

[0030] In one embodiment, R 2 are independently trifluoromethyl or (C 1 -C 6 ) alkyl, said (C 1 -C 6 )Alkyl is preferably methyl.

[0031] In one embodiment, m is 2.

[0032] In one embodiment, n is 0.

[0033] In one embodiment, the compound is

[0034] (No. ILB-2109).

[0035] Compound ILB-2109 can be prepared according to the method described in CN110446712B or CN112105617B, both of which are incorporated herein by reference.

[0036] In one embodiment, the cancer is a solid tumor.

[0037] 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 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.

[0038] 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°.

[0039] In one embodiment, the compound has a crystalline form A, and its X-ray powder diffraction pattern is as follows Figure 4 shown.

[0040] The A crystal form of the compound can be prepared according to the method described in CN112105617B, which is incorporated herein by reference.

[0041] In one embodiment, the compound is a deuterated compound.

[0042] 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.

[0043] In one embodiment, the deuterated compound is selected from:

[0044]

[0045]

[0046]

[0047] In one embodiment, the drug 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, such as 10:1 to 20:1, preferably, the drug is used to treat colon cancer. The compound and the anti-CTLA-4 monoclonal antibody have a synergistic effect in treating cancer, such as solid tumors, such as colon cancer.

[0048] The compound can be prepared into conventional preparations in the art with common auxiliary materials, carriers or excipients for administration to individuals, including tablets, capsules, injections, powders, granules, inhalants, suppositories, solutions, emulsions, suspensions, ointments, films, etc.

[0049] Example 1. Preclinical studies

[0050] Preclinical pharmacodynamic studies

[0051] The results of in vitro activity tests showed that ILB-2109 can effectively inhibit the binding of A2aR to its isotope-labeled ligand, with an IC50 of 2.92nM. At the same time, ILB-2109 has high selectivity for A2aR (relative to A1, A2b and A3 receptors, its selectivity is 18.9, 40.7 and 3424.7 times, respectively). At the cellular level, ILB-2109 can also effectively antagonize the activity of A2aR, with an IC50 of 0.43nM; under tumor physiological conditions (NECA 5μM), the IC50 is 1.08nM, and it also shows high antagonism activity against A2aR. The antagonistic activity and selectivity of ILB-2109 against A2aR are comparable to those of the reference compound AZD4635 in Phase II clinical studies.

[0052] 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 was 70.97% and 84.38%, respectively).

[0053] Experimental methods

[0054] The experiment included 6 groups: vehicle control group, low-dose and high-dose ILB-2109 monotherapy groups, anti-CTLA-4 antibody monotherapy group, and two dose groups of ILB-2109 combined with anti-CTLA-4. The doses and groups are detailed in Table 1.

[0055] Table 1 Experimental dosage and grouping

[0056]

[0057] Note:

[0058] a: The vehicle control group was vehicle 1 + vehicle 2 (vehicle 1 was 1% tween80 + 9% PEG400 + 90% ddwater, and vehicle 2 was DPBS). b: Vehicle 1 and ILB-2109 were administered on the day of inoculation, twice a day with an interval of 6 hours; vehicle 2 and anti-CTLA-4 antibody were administered on D9, D13, D16 and D20 after inoculation.

[0059] Compound formulation

[0060] Anti-CTLA-4 antibody was aseptically diluted to 0.5 mg / mL with DPBS and prepared immediately before administration.

[0061] ILB-2109 is prepared to 10mg / mL with 1% tween80+9% PEG400+90% ddwater solvent. The specific preparation method is: prepare solvent 1 (10mL tween80, 90mL PEG400, 900mL ddwater), weigh 1120mg ILB-2109, add 112mL solvent 1, grind until basically uniform, and then ultrasonicate for about 2-3min to obtain a uniform suspension. Then take an appropriate amount of solution and add solvent 1 (1% tween80+9% PEG400+90% ddwater) in a ratio of 1:1 to dilute to 5mg / ml. After preparation, divide into 5mL EP tubes, 4mL per tube, and store at 4℃.

[0062] Prepare once a week.

[0063] Construction of MC38 tumor transplantation model

[0064] 48 female C57BL / 6 mice were inoculated with 0.1 mL DPBS containing 2×105 MC38 cells in the armpit. On the day of inoculation, the mice were randomly divided into a vehicle control group, a low-dose ILB-2109 group, and a high-dose ILB-2109 group according to their body weight, with 16 animals in each group. The day of inoculation was defined as D1. On D9 after inoculation, the mean tumor volume of the vehicle control group reached about 64 mm3. According to the tumor volume and body weight of the animals, the original vehicle control group was divided into a vehicle control group and an Anti-CTLA-4 antibody monotherapy group; the original ILB-2109 low-dose group was divided into an ILB-2109 low-dose monotherapy group and an ILB-2109 low-dose combined with Anti-CTLA-4 antibody group; the original ILB-2109 high-dose group was divided into an ILB-2109 high-dose monotherapy group and an ILB-2109 high-dose combined with Anti-CTLA-4 antibody group. On the day of regrouping, the animals in each group were given the drug according to the set dose.

[0065] Tumor volume and body weight were measured 3 times a week.

[0066] Sample collection

[0067] All animals were euthanized on D23 after inoculation and tumor samples were collected and weighed.

[0068] Observation indicators

[0069] Tumor volume

[0070] The tumor volume was measured three times a week, and the tumor inhibition rate TGITV (%) was calculated. The calculation formula of tumor volume (TV) is:

[0071] TV=1 / 2×a×b2

[0072] Wherein, a and b represent the long and short diameters of the tumor mass, respectively.

[0073] Tumor inhibition rate TGITV (%) = [(1-average tumor volume of the treatment group at the end of drug administration) / (average tumor volume of the solvent control group at the end of treatment)] × 100%.

[0074] Tumor weight

[0075] When collecting samples, the tumor weight of the animal was measured. The animal tumor inhibition rate was calculated according to the following formula:

[0076] Tumor weight inhibition rate TGITW (%) = (TWc-TWt) / TWc×100%.

[0077] Where TWt is the average tumor weight of the treatment group, and TWc is the average tumor weight of the vehicle control group.

[0078] Data processing and statistical analysis

[0079] All data are expressed as mean ± SEM.

[0080] In this experiment, the data from day 21 after inoculation were used for statistical analysis using PRISM software. Ttest was used for analysis between two groups, and one-way ANOVA was used for analysis between three or more groups.

[0081] Experimental Results

[0082] Tumor volume

[0083] This experiment evaluated the efficacy of ILB-2109 alone and in combination with anti-CTLA-4 antibody (clone 9D9) in the MC38 mouse colon cancer transplant model. At 21 days of administration, the T / C of the high-dose ILB-2109 combined with CTLA-4 antibody treatment group was 15.62%, and the TGI was 84.38%. (See Table 2 and Table 3 for details). Among them, the tumor volume of all animals in the high-dose combined with antibody group was less than 250mm3, only 5 mice in the antibody monotherapy group had a tumor volume less than 250mm3, and 1 animal in the vehicle group had a tumor volume less than 250mm3.

[0084] Table 2 Antitumor effect of ILB-2109 on MC38 mouse transplant tumor model

[0085]

[0086] Note: a. Mean ± SEM.

[0087] b. Tumor growth inhibition was calculated by T / C and TGI (TGI (%) = [1-(T20) / (V20)] x 100).

[0088] Table 3 p value of comparison of tumor volume (TV) among groups in MC38 mouse transplant tumor model

[0089]

[0090] Note: p value was obtained by one-way ANOVA analysis of tumor volume, and Tukey's method was used for comparison between groups.

[0091] a. The analysis value is the tumor volume data of each group on the 21st day of administration

[0092] G1: vehicle control (n=8)

[0093] G2: ILB-2109-50 mg / kg (n=8)

[0094] G3: Anti-CTLA-4 antibody-5mg / kg (n=8)

[0095] G4:ILB-2109+Anti-CTLA-4-(50+5)mg / kg(n=8)

[0096] G5: ILB-2109-100 mg / kg (n=8)

[0097] G6:ILB-2109+Anti-CTLA-4-(100+5)mg / kg(n=8)

[0098] Table 4 Tumor volume of each group at different time points

[0099]

[0100] Tumor weight

[0101] At the end of the experiment, tumor tissues were collected and weighed, and the tumor weight inhibition rate (TGITW) was calculated based on the tumor weight data. The results showed that the TGITW of the low-dose ILB-2109 monotherapy group was 31%; the TGITW of the Anti-CTLA-4 antibody group was 83%, which had a significant tumor inhibition effect compared with the vehicle control group (p = 0.0001); the TGITW of the low-dose ILB-2109 combined with the Anti-CTLA-4 antibody group reached 74%, which had a significant tumor inhibition effect compared with the vehicle control group (p = 0.0001), and the efficacy was better than any single drug.

[0102] The TGITW of the high-dose ILB-2109 monotherapy group reached 38%, and the TGITW of the high-dose ILB-2109 combined with Anti-CTLA-4 antibody group reached 89%, which had a significant tumor inhibition effect compared with the vehicle control group (p=0.0001), and the results were better than the low-dose combination group and the antibody monotherapy group. The results are shown in Table 5.

[0103] Table 5 Antitumor effects of the test substances on the mouse colon cancer MC38 cell transplanted tumor model

[0104]

[0105] Note: a. Mean ± SEM.

[0106] BP values ​​were obtained by analyzing tumor weight using ONE-WAY ANOVA. Anti-CTLA-4 antibody monotherapy group vs low-dose combination group, p = 0.7595; Anti-CTLA-4 antibody monotherapy group vs high-dose combination group, p = 0.9090, ILB-2109 low-dose monotherapy group vs low-dose combination group, p = 0.0100, ILB-2109 high-dose monotherapy group vs high-dose combination group, p = 0.0007.

[0107] Experimental conclusion

[0108] In this MC38 mouse colon cancer transplant model experiment, ILB-2109 showed anti-tumor efficacy at doses of 50 mg / kg and 100 mg / kg in combination with Anti-CTLA-4 antibody.

[0109] The tumor volume of the ILB-2109 combined with Anti-CTLA-4 antibody group at a dose of 100 mg / kg tended to decrease compared with the tumor volume of the Anti-CTLA-4 antibody group alone, but there was no statistical difference. Further analysis found that the proportion of mice with tumor volume >250 mm3 in the combined group (0 / 8) was significantly reduced compared with the Anti-CTLA-4 antibody group alone (3 / 8).

[0110] Example 2. Preclinical pharmacokinetic studies

[0111] According to the Technical Guidelines for Nonclinical Pharmacokinetic Studies of Drugs and the results of in vitro metabolic species differences studies, this pharmacokinetic study used liquid chromatography-tandem mass spectrometry (LC-MS / MS) to fully validate the analytical method for the content of ILB-2109 in SD rats (Sprague-Dawley rats) and cynomolgus monkey plasma (EDTA-K2 anticoagulation). The linear range of this method is 20.0-20000nM. The precision, accuracy and other indicators of the method have been confirmed and meet the relevant regulations for biological sample testing.

[0112] absorb

[0113] 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.

[0114] SD rat absorption test

[0115] This study investigated the pharmacokinetic properties of ILB-2109 in male and female SD 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.

[0116] 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 distribution volume at steady state (Vdss) was 0.526±0.0558 L / kg and 0.681±0.0975 L / kg, respectively, and 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 5.71±1.25 h and 60300±5180 nM·h, 1.26±0.361 h and 13300±2260 nM·h, respectively.

[0117] After a single oral administration of 12, 40 and 120 mg / kg of ILB-2109 to male SD rats, the AUC0-last was 58900±19200, 296000±54100 and 792000±167000 nM·h, respectively, and the peak concentration (Cmax) was 23800±2230, 63300±1650 and 118000±19800 nM, respectively, and the peak time appeared at 0.667±0.289, 1.33±0.577 and 2.67±1.15 h after administration, respectively. When 12 mg / kg of ILB-2109 was orally administered, its bioavailability was 73.0%.

[0118] After a single oral administration of 12, 40 and 120 mg / kg of ILB-2109 to female SD rats, the AUC0-last was 247000±22100, 915000±169000 and 1560000±205000 nM·h, respectively, and the peak concentration (Cmax) was 33700±2800, 124000±17500 and 155000±24300 nM, respectively, and the peak time appeared at 2.33±1.53, 3.33±1.15 and 2.67±1.15h after administration, respectively. When 12 mg / kg of ILB-2109 was taken orally, its bioavailability was 67.8%.

[0119] At each oral dose of 12, 40, and 120 mg / kg, the AUC0-last ratios of female and male rats were 4.19, 3.09, and 1.97, respectively, indicating that there were significant differences in the systemic exposure of female and male rats at low and medium doses. In the dose range of 12 to 40 mg / kg, the systemic exposure (AUC0-last) and Cmax of male and female rats increased in the same proportion as the dose. After oral administration of 40 mg / kg of ILB-2109 for 7 consecutive days, the Cmax ratios of female and male rats on the seventh day to the first day were 0.899 and 0.673, respectively, and the AUC0-last ratios of female and male rats on the seventh day to the first day were 0.669 and 0.584, respectively.

[0120] All animals tolerated the compound well and no abnormal symptoms were observed.

[0121] Absorption study in cynomolgus monkeys

[0122] 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.

[0123] After a single intravenous injection of 3 mg / kg in male and female crab-eating 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.

[0124] After a single oral administration of 3, 15 or 60 mg / kg of ILB-2109 to male and female cynomolgus monkeys, the peak concentration (Cmax) was 8190±1810, 33900±9660 and 59300±33300 nM, respectively, and the peak time appeared at 1.33±0.516, 2.00±1.10 and 4.00±2.19 h after administration. AUC0-last was 35200±6870, 192000±51600 and 571000±254000 nM·h, respectively. The bioavailability of the drug in the 3 mg / kg oral dose group was 89.1%.

[0125] After male and female cynomolgus monkeys were orally administered 15 mg / kg of ILB-2109 twice a day for 7 consecutive days, the peak concentrations (Cmax) on the first and seventh days were 18200±4000 and 28300±4780 nM, respectively, and the peak time appeared at 3.00±1.10 h after administration. AUC0-last was 172000±34400 and 268000±42500 nM·h, respectively.

[0126] 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.

[0127] At all oral doses, there were no significant gender differences in systemic exposure (AUC0-last and Cmax) between male and female cynomolgus monkeys.

[0128] After oral administration of 15 mg / kg of ILB-2109 twice daily for 7 consecutive days, there was no significant accumulation of systemic exposure in males and females.

[0129] distributed

[0130] 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, beagles, and cynomolgus monkeys (87.3%-95.0%), without showing obvious concentration dependence.

[0131] After a single oral administration of 30 mg / 100 μCi / kg of [14C]ILB-2109 to male and female rats, the total radioactivity was widely distributed in the rats, mainly in the liver, kidneys, lungs and gastrointestinal wall, and to a certain extent in all tested tissues, including mesenteric lymph nodes, submandibular lymph nodes, axillary lymph nodes and thymus. The Tmax of most tissues and plasma of female rats was 4 hours, and the Tmax of most tissues and plasma of male rats was 0.25 hours, indicating that the total radioactivity absorption of male rats was slightly faster than that of female rats. After a single oral administration of 30 mg / 100 μCi / kg of [14C]ILB-2109 to male and female rats, the total radioactivity was eliminated rapidly in the body. Four hours after administration, most tissues and plasma of male rats decreased to a certain extent, indicating that male rats entered the elimination stage earlier. 24 hours after administration, radioactivity was still detectable in most tissues and plasma of female rats, while in most tissues and plasma of male rats, it was below the detection limit. At the last collection time point (72 hours), only the liver, intestinal wall and plasma of female rats still had a small amount of radioactivity, accounting for about 0.09% of the dose, and the total radioactivity of the remaining detected tissues and plasma was below the detection limit.

[0132] metabolism

[0133] ILB-2109 is metabolized at a moderate rate in CD-1 mice and SD rats, and is metabolized at a slow rate or not metabolized in beagle dogs, cynomolgus monkeys, and human liver microsomes. The main biotransformation pathways of ILB-2109 in liver microsomes and hepatocytes in vitro are oxidation, dehydrogenation, and glucuronic acid conjugation (hepatocyte biotransformation pathway), and no human-specific metabolites were detected.

[0134] Metabolism experiments in SD rats showed that the main clearance pathway of [14C]ILB-2109 in rats is direct binding to glucuronic acid to form M576a / b, or monooxidation followed by binding to glucuronic acid to form M592a / b / c. It is mainly metabolized by the liver and excreted in the feces, and a small amount is excreted by the kidneys. The glucuronic acid binding products in the feces can be partially converted back to monooxidation products M416a / b and the original drug form; the secondary clearance pathway is monooxidation dehydrogenation to form M414, which is excreted from the liver and kidneys.

[0135] In the in vivo metabolism experiment of cynomolgus monkeys, the relative abundance of parent drug ILB-2109 in plasma samples of male and female monkeys was >83%, and it was the main component in plasma samples. ILB-2109 is metabolized in monkey plasma mainly through oxidation, dehydrogenation and glucuronic acid conjugation. For the production of ILB-2109 metabolite M4, CYP3A is the main metabolic enzyme, CYP2B6, CYP2C8 and CYP2C9 may play a minor role in the production of M4, and other isoenzymes (CYP1A2, CYP2C19 and CYP2D6) play little or no role.

[0136] excretion

[0137] The average recovery rate of total radioactivity in male and female rats within 0-168 hours after a single oral administration was 91.74%, of which the total excretion in urine accounted for 13.81% of the dose, in feces for 75.17%, and in cage flushing and cleaning fluid for 2.75%. Excretion mainly occurred within 48 hours after administration, accounting for about 88.01% of the dose.

[0138] After a single oral administration in male and female bile cannulated (BDC) rats, the average total radioactivity recovery rate was 93.63% within 0-72 hours; the total excretion in bile accounted for 66.17% of the dose, urine was 12.16%, feces was 14.45%, and cage flushing and cleaning fluid was 0.85%. Based on the total radioactivity excretion in the bile and urine of BDC rats, the oral absorption rate of ILB-2109 is at least 78.33%.

[0139] Drug interactions

[0140] ILB-2109 has a weak inhibitory effect on CYP2C8 (IC50 is 33.9μM) in human liver microsomes in vitro, no inhibitory effect on CYP2C9 (IC50 is 57.2μM) and CYP2C19 (IC50 is 91.6μM), no inhibitory effect on CYP1A2, CYP2B6, CYP2D6, CYP3A4 (with midazolam as substrate) and CYP3A4 (with testosterone as substrate) (IC50>100μM). ILB-2109 has no time-dependent inhibitory effect on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

[0141] 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 by the non-dilution method. Usually, the IC50 shift multiple greater than or equal to 1.5 is used as the criterion for judging time-dependent inhibitors. The results showed that ILB-2109 had no time-dependent inhibitory effect on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

[0142] In vitro hepatocyte induction assays were used to evaluate the effects of ILB-2109 on the enzyme activities and gene expression levels of cytochrome P450 isoenzymes CYP1A2, CYP2B6, and CYP3A4. In vitro enzyme activity data showed 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 level data showed that ILB-2109 was an inducer of cytochrome P450 isoenzyme CYP3A4 at a concentration of 2.00 μM for 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.

[0143] Example 3. Preclinical toxicology studies

[0144] According to the relevant requirements of the Good Practice for Nonclinical Drug Research, and in compliance with the experimental plan and its revisions, the safety pharmacology experiments, single-dose toxicity, and genetic toxicity of ILB-2109 were explored.

[0145] Single-dose toxicity studies

[0146] SD rats were observed for 14 days after a single oral gavage of ILB-2109, with a single dose of 0 (vehicle), 500, 1000 and 2000 mg / kg of ILB-2109. The results showed that all animals survived until the planned autopsy, without dying or death, and no obvious clinical symptoms. No abnormalities were found in body weight, food consumption, clinical examination, and gross anatomy. Under the conditions of this experiment, the maximum tolerated dose (MTD) of ILB-2109 in rats is 2000 mg / kg.

[0147] The cynomolgus monkeys were given a single oral dose of 0 (vehicle), 250, 500 and 1000 mg / kg of ILB-2109 and observed for 14 consecutive days after the single administration. The results showed that all animals survived until the planned dissection, and no dying or death occurred. 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 given to cynomolgus monkeys by single oral administration within 24 hours was 1000 mg / kg. The test product has an effect on the digestive system (gastrointestinal function, liver function).

[0148] Repeated dose toxicity study

[0149] SD rats were continuously given ILB-2109 by oral gavage at 0 (solvent), 60, 200 and 600 mg / kg of ILB-2109 for 28 consecutive days. The results showed that no clinical symptoms, body weight and food consumption changes related to the test product were observed in each dose group. WBC and #LYMPH of animals in the medium and high dose groups increased or showed an increasing trend; GLU of animals in the medium and high dose groups decreased or showed a decreasing trend, CREA and UREA of female high dose group animals increased or showed an increasing trend; GLOB of female animals in each dose group increased and A / G decreased. Histopathological examination showed only hypertrophy of central hepatocytes in the liver lobules of female animals in the medium and high dose groups. The above changes were completely recovered during the recovery period. There was a significant gender difference in AUC0-24h in the low dose group, and there was no significant gender difference in systemic exposure in the other dose groups; there was no significant accumulation in systemic exposure in each dose group; the increase ratio of systemic exposure was lower than the increase ratio of dose. Under the conditions of this experiment, the NOAEL of the 4-week repeated-dose toxicity test of ILB-2109 administered orally to SD rats was 60 mg / kg (at this dose, female AUC0-24h=295.88h*μg / mL, Cmax=22.16μg / mL; male AUC0-24h=114.50h*μg / mL, Cmax=15.86μg / mL), and the MTD was 600 mg / kg (at this dose, female AUC0-24h=724.86h*μg / mL, Cmax=69.40μg / mL; male AUC0-24h=481.00h*μg / mL, Cmax=36.34μg / mL). ILB-2109 may have toxic effects on the digestive system (liver function), blood system (granulocyte system), and urinary system (renal function) of SD rats, which can be recovered after the recovery period.

[0150] 40 cynomolgus monkeys (half male and half female) were randomly divided into 4 groups, 5 per sex in each group, and were given 0 (vehicle), 20, 60 and 200 mg / kg / day of ILB-2109 by oral gavage once a day for 28 consecutive days. The results showed that one male animal in the high-dose group was found to be dying 2 hours after administration on D3. Before dying, the animal began to have symptoms of decreased respiratory rate, abnormal breathing sounds, prone position, abnormal feces and vomiting. Gross observation revealed diffuse dark red lungs and white foam in the trachea. Combined with the results of gross observation and histopathological examination, it is considered that the cause of animal death may be related to lung damage. No clinical symptoms, body weight and food consumption related to the test product were observed in each dose group. In the middle-dose group, the %LYMPH of male animals decreased and the %NEUT increased. In the high-dose group, the %LYMPH of male and female animals showed a decreasing trend and the %NEUT showed an increasing trend. Histopathological observation only showed a decrease in adrenal cortical vacuoles in animals in the middle and high-dose groups. All the above changes were completely recovered during the recovery period. In addition, no drug-related changes were observed in body temperature, respiration, electrocardiogram, ophthalmology and bone marrow. There was no gender difference in systemic exposure in each dose group; there was no obvious accumulation; the increase in systemic exposure was lower than the increase in dose.

[0151] Therefore, under the conditions of this experiment, the HNSTD of the 4-week repeated-dose toxicity test of ILB-2109 given by oral gavage to cynomolgus monkeys was 60 mg / kg (at this dose, female AUC0-24h=148.56h*μg / mL, Cmax=11.92μg / mL; male AUC0-24h=205.78h*μg / mL, Cmax=14.32μg / mL), and the NOAEL was 20 mg / kg (at this dose, female AUC0-24h=60.97h*μg / mL, Cmax=5.01μg / mL; male AUC0-24h=80.19h*μg / mL, Cmax=6.58μg / mL). In clinical use, attention should be paid to the possible effects of ILB-2109 on the respiratory system, blood system, endocrine system, etc.

[0152] Genotoxicity test

[0153] AMES: This test detects 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. The results showed that 128-5000 μg / dish of ILB-2109 tablets had no mutagenicity against the five strains of TA1535, TA102, TA100, TA98, and TA97a under the conditions of the addition / without the S9 metabolic activation system. Therefore, the Ames test result was negative under the conditions of this study.

[0154] 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 under the action of 3.2, 16.0 and 80.0 μg / mL of ILB-2109.

[0155] Micronucleus test: SD rats were given 500-2000 mg / kg of ILB-2109 by oral gavage. All doses of ILB-2109 had no micronucleus-inducing effect on the polychromatic erythrocytes in the bone marrow of SD rats.

[0156] Example 4. Multicenter, open, Phase Ia clinical study: Dose exploration and dose expansion clinical study of ILB-2109 tablets in patients with advanced solid tumors

[0157] Drug under investigation: A2aR antagonist ILB-2109

[0158] ILB-2109 and conventional cellulose auxiliary materials are granulated and tableted to prepare ILB-2109 tablets.

[0159] Research phase: Phase Ia

[0160] 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).

[0161] Research period:

[0162] Screening period (day -28 to day -1);

[0163] Single-dose period (3 days);

[0164] Continuous dosing period (ILB-2109 tablets were taken orally on an empty stomach, QD, continuously, 21 days as a cycle);

[0165] Safety follow-up after treatment completion (within 28 days after the last dose);

[0166] Survival follow-up (follow-up every 3 months after the safety follow-up until the end of the study).

[0167] 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.

[0168] End of study: It is expected that the last enrolled subject will receive the first dose of the drug for 1 year or complete the trial (whichever occurs earlier). Completion of the trial means that the subject completes the last study-related telephone contact or visit, terminates the trial, or is lost to follow-up (i.e., the researcher cannot contact the subject).

[0169] Purpose

[0170] Main purpose:

[0171] To observe the safety and tolerability of single and continuous oral administration of ILB-2109 tablets in patients with advanced solid tumors;

[0172] Determine the maximum tolerated dose (MTD) of ILB-2109 tablets and the appropriate recommended dose (RD) for subsequent studies;

[0173] Secondary Purpose:

[0174] To evaluate the pharmacokinetic characteristics of ILB-2109 tablets;

[0175] Preliminary evaluation of the effect of food on the PK characteristics and safety tolerability of ILB-2109 tablets (only in the extension phase);

[0176] Preliminary evaluation of the effectiveness of ILB-2109 tablets in the treatment of patients with advanced solid tumors;

[0177] Exploratory purpose:

[0178] To characterize 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);

[0179] To evaluate ILB-2109 tablets in peripheral blood and tumor specimens of patients with advanced solid tumors for potential biomarkers 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).

[0180] Study Design

[0181] This is an open, non-randomized, multicenter clinical study, including dose escalation and dose expansion phases of ILB-2109 tablets alone; a maximum of 78 subjects are expected to be enrolled.

[0182] Dose escalation phase:

[0183] The group plans to enroll 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. The dose escalation will be carried out using the traditional "3+3" rule.

[0184] The ILB-2109 tablets dosing plan has about 9 dose groups, see Table 6 below. Subjects take the medicine on an empty stomach (at least 2 hours before or after meals), and must not eat for 1 hour after taking the medicine. After a single dose on the first day 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 period (Cycle 1), starting with a daily dose, 21 days as a dosing cycle, until the subject has disease progression, intolerable toxicity, withdrawal of informed consent, death or other situations that require termination of treatment. The trial will determine the dose group entering the extension period based on the safety, preliminary efficacy and PK characteristics of ILB-2109 tablets.

[0185] Table 6

[0186]

[0187]

[0188] Note: Except for the doses of dose groups 1-4, which have been completed and the 5th dose group is being tested, the subsequent dose groups are tentative doses and frequencies, and the decision on whether to adjust will be made based on the safety, efficacy, pharmacokinetics and other data of the previous dose groups. The total number of dose groups will also be increased or decreased according to actual conditions.

[0189] Definition and Assessment of DLT:

[0190] DLT is defined as: DLT observation period (24 days in total), including single-dose DLT observation period (single-dose 3 days), continuous-dose DLT observation period (21 days in the first cycle of continuous dosing period), dose-limiting toxicity events that occur, 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 that occur during the observation period is considered a DLT:

[0191] Table 7

[0192]

[0193]

[0194] Tumor Assessment:

[0195] Tumor assessment will be based on RECIST 1.1 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.

[0196] Determination of RD:

[0197] SRC will determine the RD comprehensively by combining the MTD and PK data in the dose escalation phase and the efficacy data observed in each dose group in the dose expansion study phase.

[0198] SRC:

[0199] During the study, a Pharmaceutical Science Review Committee consisting of the coordinating investigator, the principal investigator of the enrolling center, the medical monitor of the sponsor and / or CRO, 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 extension study.

[0200] 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 survival status and other anti-tumor treatment conditions of the subjects will be followed up.

[0201] All patients will receive study drug treatment until disease progression (based on RECIST 1.1 criteria), death, intolerable toxicity, or other circumstances requiring discontinuation of treatment.

[0202] Study subjects:

[0203] This study included subjects with advanced malignant solid tumors (such as 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, nasopharyngeal carcinoma, etc.).

[0204] Entry criteria

[0205] Inclusion Criteria

[0206] Subjects must meet all of the following criteria:

[0207] The subjects must give their informed consent to this study before the trial and voluntarily sign a written informed consent form;

[0208] 18-80 years old (inclusive), regardless of gender;

[0209] Patients with advanced solid tumors confirmed by histology and / or cytology who have no standard treatment options, have failed standard treatment, or are not currently suitable for standard treatment;

[0210] 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;

[0211] ECOG score 0-1;

[0212] Expected survival time ≥ 3 months;

[0213] The major organ functions are basically normal, and the laboratory test values ​​during the screening period meet the following standards:

[0214] Table 8

[0215]

[0216] The results of serum pregnancy test for female subjects of childbearing age are negative;

[0217] The subjects agreed to use reliable contraceptive methods from the signing of the informed consent form to 90 days after the last administration, including but not limited to: abstinence, vasectomy for men, sterilization for women, effective intrauterine devices, and effective contraceptive drugs.

[0218] Exclusion criteria

[0219] Subjects shall be excluded from the trial if they meet any of the following criteria:

[0220] Received chemotherapy, radiotherapy, biological therapy, endocrine therapy, targeted therapy, immunotherapy and other anti-tumor treatments within 4 weeks before the first use of the study drug, excluding the following:

[0221] Nitrosourea or mitomycin C within 6 weeks before the first use of study drugs;

[0222] For oral fluorouracil and small molecule targeted drugs, the period is 2 weeks before the first use of the study drug or within 5 half-lives of the drug (whichever is longer);

[0223] For Chinese medicine with anti-tumor indications, the application period is within 2 weeks before the first use of the study drug;

[0224] Received other unapproved clinical research drugs or treatments within 4 weeks before the first dose;

[0225] Those who have received immunotherapy and developed ≥ grade 3 irAE or ≥ grade 2 immune-related myocarditis;

[0226] Patients with clinically uncontrollable third space effusion were judged by the investigator to be unsuitable for inclusion;

[0227] 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;

[0228] Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, II-III degree atrioventricular block, etc.

[0229] Any factors that increase the risk of QTc prolongation or arrhythmias, such as congenital long QT syndrome, family history of long QT syndrome, use of any concomitant medications known to prolong the QT interval;

[0230] 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;

[0231] Patients with clinical symptoms of brain parenchymal metastasis or meningeal metastasis are judged by the researchers to be unsuitable for inclusion;

[0232] Unable to swallow the drug orally, or having a condition that seriously affects gastrointestinal absorption as determined by the investigator;

[0233] People infected with human immunodeficiency virus (HIV) (HIV antibody positive);

[0234] Patients with active hepatitis B (HBsAg positive and HBV-DNA>500IU / 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 500IU / ml]), active hepatitis C (patients with positive HCV antibody 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;

[0235] Those with active infection and currently requiring intravenous anti-infection treatment;

[0236] Patients who have received systemic glucocorticoids (prednisone > 10 mg / day or equivalent doses) or other immunosuppressive drugs within 14 days before the first dose, except for the following:

[0237] Treatment with topical, ocular, intra-articular, intranasal, and inhaled corticosteroids;

[0238] Short-term use of glucocorticoids for prophylaxis (e.g., to prevent contrast agent allergy);

[0239] Receiving live attenuated vaccines within 4 weeks before the first dose or planning to receive them during the study;

[0240] 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;

[0241] Those who have received allogeneic hematopoietic stem cell transplantation or organ transplantation in the past;

[0242] Known alcohol or drug dependence;

[0243] People with mental disorders or poor compliance;

[0244] The adverse reactions of previous anti-tumor treatment have not recovered to CTCAE 5.0 grade ≤ 1 (except for toxicities that the researchers judge to have no safety risks, such as alopecia, grade 2 peripheral neuropathy, and hypothyroidism that has been stabilized by hormone replacement therapy, etc.);

[0245] Use of strong CYP3A4 inhibitors or inducers within 7 days before the first dose (topical medications are not restricted);

[0246] Patients who are pregnant or breastfeeding;

[0247] The researcher believes that the subject is not suitable to participate in this clinical study due to other reasons.

[0248] Research evaluation

[0249] Safety evaluation:

[0250] Safety was evaluated by adverse events (graded using NCI-CTCAE version 5.0), laboratory tests, vital signs, physical examination, electrocardiogram, etc. Adverse events were recorded from the time the subject signed the informed consent until 28 days after the last dose.

[0251] Pharmacokinetic evaluation:

[0252] PK blood samples were collected within the planned time to determine the plasma drug concentration of ILB-2109 tablets and estimate the pharmacokinetic parameters. The pharmacokinetic characteristics of ILB-2109 tablets after single and multiple administrations were evaluated.

[0253] Pharmacodynamic evaluation:

[0254] PD blood samples will be collected at each PD blood sampling point and baseline during the dose-escalation phase of ILB-2109 monotherapy in this study to measure the levels of pCREB, TNF-α, IFN-γ, and IL-2 signals in blood cells for pharmacodynamic analysis. The time of blood sample collection will be recorded in the source file and eCRF.

[0255] Efficacy evaluation:

[0256] Baseline confirmation and efficacy evaluation are performed through imaging examinations (enhanced CT / CT plain scan, MRI, PET-CT). The same imaging evaluation method (including instrument parameters, operating standards, imaging planes, etc.) should be used for the same subject during the trial.

[0257] The evaluation criteria used were the response evaluation criteria for solid tumors (RECIST 1.1).

[0258] Baseline assessments will be performed within 28 days before the first dose, and imaging evaluations will be performed every 6±1 weeks after the start of treatment. After 13 treatment cycles, subjects who are still receiving treatment will be evaluated every 12±4 weeks. The timing of imaging examinations should follow the calendar day and should not be adjusted due to treatment delays. Imaging examinations should be performed continuously until disease progression, withdrawal from the study or death, the start of new anti-tumor treatment, or the end of the study, whichever occurs first.

[0259] Study End Points

[0260] Primary End Point

[0261] The incidence of dose-limiting toxicity (DLT) within 3 days of single-dose administration and within 21 days of continuous administration;

[0262] Determine the maximum tolerated dose (MTD) of ILB-2109 tablets and the appropriate recommended dose (RD) for subsequent studies;

[0263] Secondary End Points

[0264] Safety endpoints:

[0265] 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.

[0266] Serious adverse events (TESAE) during treatment and toxic reactions leading to permanent discontinuation of treatment;

[0267] Safety laboratory tests graded according to NCI-CTCAE (version 5.0);

[0268] Vital signs, 12-lead electrocardiogram, physical examination, and Eastern Cooperative Oncology Group (ECOG) score;

[0269] 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 phase elimination half-life (t1 / 2), apparent clearance (CL / F), and apparent volume of distribution (V / F);

[0270] Preliminary evaluation of the effect of food on PK parameters of ILB-2109 tablets (only in the extension phase), total drug exposure (AUC0-∞, AUC0-t), peak concentration (Cmax), time to peak (Tmax), lag time (tlag), terminal phase elimination half-life (t1 / 2), apparent clearance (CL / F), and apparent volume of distribution (V / F);

[0271] Safety and tolerability indicators in the food effect study phase (only in the extension 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;

[0272] 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 response (CBR);

[0273] Exploratory End Points

[0274] To explore the relationship between the drug concentration of ILB-2109 tablets and the levels of pCREB, TNF-α, IFN-γ, and IL-2 signals in blood cells during ILB-2109 tablets monotherapy;

[0275] Explore tumor markers related to ILB-2109 tablets;

[0276] Statistical methods

[0277] Security Analysis:

[0278] Safety analysis will be based on the safety analysis set (SS). Descriptive statistics will be used to analyze adverse events, laboratory test indicators, vital signs, electrocardiograms, etc. The incidence of adverse events, serious adverse events, adverse events leading to discontinuation, etc. will be summarized according to the dose group.

[0279] For the dose escalation phase, the DLT incidence rate for each dose group will be calculated and presented as a point estimate and a two-sided 95% confidence interval using the exact binomial method. The maximum tolerated dose (MTD) will be determined according to the traditional "3+3" dose escalation design rule.

[0280] Pharmacokinetic Analysis / Pharmacodynamics:

[0281] Pharmacokinetic analysis will be based on the PK analysis set (PKS). The drug concentration in plasma of ILB-2109 tablets will be determined, the main PK parameters (Cmax, AUC, etc.) will be estimated, the drug clearance pathway will be analyzed, and a descriptive summary analysis will be provided according to the dose group.

[0282] 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 sampling point during the dose escalation phase and the baseline blood samples will be calculated, and descriptive statistics will be summarized.

[0283] Efficacy analysis:

[0284] The efficacy analysis will be mainly based on the full analysis set (FAS). If necessary, the per-protocol set (PPS) can be used as a supportive supplement. For the efficacy data, the objective response rate (ORR) and disease control rate (DCR) and their 95% confidence intervals will be calculated. For progression-free survival (PFS), duration of response (DOR) and overall survival (OS), the Kaplan-Meier method will be used for descriptive statistics and the Greenwood method will be used to provide 95% confidence intervals, and survival curves will be drawn. Waterfall plots, spider plots, and swimmer plots will be drawn to respectively present the maximum change in the sum of the long diameters of target lesions of each patient from baseline, the change in tumor size over time, and the occurrence of each clinical endpoint over time.

[0285] Recommended Dose (RD):

[0286] RD is determined based on safety evaluation, preliminary efficacy and PK data, combined with preclinical efficacy model data and in vitro study data.

[0287] Table 9: Preliminary efficacy results of subjects

[0288]

[0289] Note: PD: progressive disease, the sum of the maximum diameters of target lesions increases by at least 20%, or new lesions appear. SD: stable disease, the sum of the maximum diameters of target lesions decreases but does not reach PR, or increases but does not reach PD. PR: partial response, the sum of the maximum diameters of target lesions decreases by 30% or more, and lasts for at least 4 weeks. 03001 Esophageal cancer subjects do not have target lesions, and SD is assessed by non-target lesions, so there is no value.

[0290] Deadline: July 20, 2023

[0291] * Still under treatment

[0292] Table 10: Potential efficacy signals were detected starting from the 100 mg dose group

[0293]

[0294] 100mg: 1 case of rectal cancer SD, 1 case of lung cancer SD; 200mg: 1 case of cervical cancer PR, 1 case of adenoid cystadenocarcinoma SD

[0295] 300 mg: 1 case of spindle cell sarcoma SD, 1 case of esophageal cancer SD, 1 case of adenoid cystadenocarcinoma SD

[0296] Overview of adverse events related to trial drugs

[0297] 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 AEs of similar products.

[0298] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope 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, R 1 is optionally substituted with hydroxyl groups (C 1 -C 6 )alkyl; R 2 are independently halogen, (C 1 -C 6 ) alkyl or halogen-substituted (C 1 -C 6 )alkyl; R 3 Independently (C 1 -C 6 )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, in, R 1 is a (C 1 -C 6 ) alkyl group substituted by a hydroxyl group, preferably a (C 1 -C 3 ) alkyl group substituted by a hydroxyl group, preferably hydroxymethyl.

3. The use according to claim 1, in, R 2 are independently trifluoromethyl or (C 1 -C 6 )alkyl.

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

10. The use according to claim 1, in, 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.

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