Use of an atr inhibitor in combination with a pi3k alpha inhibitor

Abstract

Disclosed are methods of treating a cancer in a subject using an ATR inhibitor and a phosphatidylinositol 3-kinase alpha (PI3Ka) inhibitor, wherein the cancer has one or more mutations in PIK3CA Also disclosed are methods of inducing cell death in abnormal cancer cells having one or more mutations in PIK3CA by contacting the cells with an effective amount of an ATR inhibitor and a PI3Ka inhibitor.

Description

Technical Field

[0001] This disclosure relates to at least one ataxia-telangiectasia and Rad-3-related protein (ATR) kinase inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the thereof, in combination with at least one phosphatidylinositol 3-kinase α (PI3Kα) inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the thereof, and their use in the treatment of diseases or conditions such as cancer. Background Technology

[0002] DNA damage occurs continuously in cells due to environmental damage (including ultraviolet radiation and X-rays) and endogenous stress factors (such as reactive oxygen species and alkaline hydrolysis). Cancer cells experience a higher rate of DNA damage, which is essentially induced by the higher rate of DNA replication in these cells. Several DNA damage response (DDR) pathways have evolved in a highly coordinated manner to help repair DNA damage and act as cellular checkpoints to stop the replication of DNA-damaged cells, thus allowing repair functions to occur before the damaged DNA is passed on to daughter cells. Each identified DNA repair pathway can sense and repair different but overlapping types of DNA damage.

[0003] One major DDR protein acting as a key cell cycle checkpoint is the ataxia-capillary vasculopathy mutant and Rad-3-associated (ATR) kinase, which is associated with the phosphatidylinositol 3-kinase-associated protein kinase (PIKK) family. ATR is activated by single-stranded (ss) DNA damage caused by stalled replication forks or during nucleotide excision repair, but also by double-strand breaks following DNA end excision during homologous recombination. ATR is recruited to DNA damage sites by binding to an RPA protein that coats ssDNA with a cofactor called an ATR interacting protein (ATRIP). The ATR / ATRIP complex is then activated by recruiting additional factors from the 9-1-1 complex (RAD9, RAD1, and HUS1), which subsequently recruits the TOPBP1 protein and represents a key step in the activation of the downstream phosphorylation cascade leading to cell cycle arrest. The main target of ATR kinase is CHK1. When CHK1 is phosphorylated, it targets both cdc25 and Wee1, leading to inhibition of cyclin-dependent kinase activity and cell cycle arrest at S phase or G2 / M phase.

[0004] ATR has been identified as an important cancer target because it is crucial for cell division. ATR-deficient mice are embryonic lethal; however, adult mice with conditionally knocked-out ATR are viable and have an impact on rapidly proliferating tissues and stem cell populations. Embryonic stem cells in ATR-deficient mice double only 1-2 times before dying, indicating that ATR is necessary to maintain cell division. Interestingly, mice carrying hypomorphic ATR mutations (which reduce ATR expression to 10% of normal levels) show reduced H-rasG12D-induced tumor growth with minimal impact on proliferating normal cells (e.g., bone marrow or intestinal epithelial cells). Cancer cells with high levels of replication stress due to oncogenic mutations, dysfunctional G1 / S checkpoint controls (e.g., p53 loss of function), defects in other DNA repair pathways (e.g., ATM), or those affected by DNA-damaging agents (e.g., radiotherapy or chemotherapy) are therefore more dependent on ATR for DNA repair and survival. In summary, these results highlight the fundamental principles of the selective sensitivity of proliferating tumor cells to ATR inhibition and the potential of a therapeutic window on healthy proliferating cells.

[0005] PIK3CA is a gene encoding the α isoform of the catalytic subunit of phosphatidylinositol 4,5-bisphosphate 3-kinase. The p110α subunit of PIK3CA is frequently mutated and amplified in various cancers (approximately 30%). (See Mishra, R. et al., "PI3K inhibitors in cancer: clinical implications and adverse effects." International Journal of Molecular Sciences 22.7 (2021):3464.) Recent studies have shown that deletion of the C2 domain in PIK3CA significantly activates PI3K signaling and also enhances sensitivity to PI3Kα inhibitors. Croessmann S. et al., PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kalpha Inhibitors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2018;24:1426–1435. Dysregulation of PI3K signaling leads to several oncogenic activities that regulate tumor progression, such as cancer cell proliferation, invasion, migration, glucose transport, and angiogenesis. Levine DA et al., Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2005;11:2875–2878. Inhibitors of phosphatidylinositol 3-kinase α (PI3Kα inhibitors) target the p110α catalytic subunit of PI3K. Several PI3Kα inhibitors are being investigated for the treatment of various cancers, including but not limited to solid tumors, advanced solid tumors, ovarian cancer, breast cancer, and colorectal cancer. The toxicity of small molecule PI3K inhibitors depends on their PI3K isoenzyme specificity. For example, side effects associated with PI3Kα inhibitors are primarily rash and hyperglycemia, while side effects associated with the δ subunit are primarily gastrointestinal, elevated transaminase levels, and bone marrow suppression.Mishra, R. et al. "PI3K inhibitors in cancer: clinical implications and adverse effects." International Journal of Molecular Sciences 22.7 (2021): 3464.

[0006] To date, five PI3K inhibitors (copanlisib, edelalisib, umbralisib, duvelisib, and alpelisib) have been approved by the U.S. Food and Drug Administration (FDA). Mishra, R. et al., "PI3K inhibitors in cancer: clinical implications and adverse effects." International Journal of Molecular Sciences 22.7 (2021):3464. Alpelisib, a PI3Kα inhibitor, has been approved by the FDA for adult and pediatric patients aged two years and older with severe presentations of the PIK3CA-related overgrowth spectrum (PROS) requiring systemic therapy. Singh, S. et al., "FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum." Clinical Cancer Research (2023):OF1-OF6. Summary of the Invention

[0007] One aspect of this disclosure is a method of treating a subject with cancer, the method comprising administering to the subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the cancer is identified as having one or more mutations in PIK3CA.

[0008] In another aspect, the PI3Kα inhibitor disclosed herein is a compound of formula (III): , (III) and its stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, wherein: R 1 Selected from -CH3, -CH2CH3, cyclopropyl, and cyclobutyl; R2 Selected from —CH3, —CHF2, —CH2F and —CF3.

[0009] On the one hand, R 1 It is -CH3 or cyclopropyl.

[0010] On the one hand, R 2 It is -CHF2.

[0011] In another respect, PI3Kα inhibitors are compounds with the following structures: .

[0012] In another respect, PI3Kα inhibitors are compounds with the following structures: .

[0013] In another respect, PI3Kα inhibitors are compounds with the following structures: .

[0014] In another respect, PI3Kα inhibitors are compounds with the following structures: .

[0015] In another respect, PI3Kα inhibitors are compounds with the following structures: .

[0016] In another respect, PI3Kα inhibitors are compounds with the following structures: .

[0017] In another respect, PI3Kα inhibitors are compounds with the following structures: .

[0018] In some aspects, this disclosure provides a method for treating cancer in a subject of this disclosure, the method comprising: (i) The cancer is identified as having one or more mutations in PIK3CA; and (ii) Administer a therapeutically effective dose of a combination of an ATR inhibitor and a PI3Kα inhibitor to the subject in need.

[0019] In all respects, ATR inhibitors are administered before PI3Kα inhibitors.

[0020] In all respects, ATR inhibitors are administered after PI3Kα inhibitors.

[0021] In all aspects, ATR inhibitors are used in combination with PI3Kα inhibitors.

[0022] In some respects, the effective therapeutic dose is a sub-therapeutic dose regimen of an ATR inhibitor.

[0023] In some respects, the effective therapeutic dose is a sub-therapeutic dose regimen of PI3Kα inhibitors.

[0024] In another aspect, subtherapy dosing regimens include a starting dose that is at least 50% less than the minimum standard starting dose for monotherapy.

[0025] In all respects, the subtherapy dosing regimen includes a maintenance dose that is at least 50% less than the minimum standard maintenance dose for monotherapy.

[0026] In all respects, maintenance dose includes the first dose reduction.

[0027] In all respects, maintenance dose includes a second reduction dose.

[0028] In all respects, maintenance dose includes a third dose reduction.

[0029] In some cases, the route of administration is oral.

[0030] In some other respects, ATR inhibitors are administered for 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0031] In some cases, PI3Kα inhibitors are administered for 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0032] In an additional aspect, this disclosure provides a method for inducing cell death in aberrant cancer cells having one or more mutations in PIK3CA, the method comprising contacting the cells with an effective amount of an ATR inhibitor and an effective amount of a PI3Kα inhibitor, the effective amounts being sufficient to induce cell death in the aberrant cancer cells.

[0033] In all respects, PI3Kα inhibitors are compounds of formula (III): , (III) and its stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, wherein: R 1 Selected from -CH3, -CH2CH3, cyclopropyl, and cyclobutyl; R 2Selected from —CH3, —CHF2, —CH2F and —CF3.

[0034] In all respects, cancer refers to any type of cancer that carries a PIK3CA mutation.

[0035] In all respects, the patient is any patient with a PIK3CA mutation.

[0036] In various aspects, the cancers include ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or advanced solid tumors.

[0037] In all respects, cancers with one or more mutations in PIK3CA are solid tumors.

[0038] In all respects, cancers with one or more mutations in PIK3CA are advanced solid tumors.

[0039] In all respects, ATR inhibitors are compounds of formula (I): , (I) Or its pharmaceutically acceptable salt. in It is a double bond, and each Y is independently either N or CR. 4 ;or It is a single bond, and each Y is independently NR. Y carbonyl or C(R) Y )2; where each R Y H or C, independently substituted. 1-6 alkyl; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B Hydroxyl group, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms.2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

[0040] In an additional aspect, this disclosure provides a method wherein the ATR inhibitor is a compound of formula (II): , (II) Or its pharmaceutically acceptable salt. in Each Y is independently N or CR 4 ; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B Hydroxyl group, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

[0041] In all aspects, R 2 It is a 5- to 10-membered bicyclic [pqr] heterocyclic group.

[0042] In all aspects, R 2 for , , or .

[0043] In all aspects, R 2 for .

[0044] In addition, ATR inhibitors are selected from the group consisting of compounds 43, 57, 62, 87, 93, 94, 95, 99, 100, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 135, 147, 148 and their pharmaceutically acceptable salts.

[0045] In all respects, the ATR inhibitor is compound 43 or a pharmaceutically acceptable salt thereof. In all respects, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In all respects, compound 121 is a bisulfate salt. In all respects, compound 121 is carmenselotib.

[0046] In all respects, the ATR inhibitor is compound 122 or a pharmaceutically acceptable salt thereof. In all respects, the pharmaceutically acceptable salt is the hydrogen sulfate salt.

[0047] In an additional aspect, this disclosure provides a method for treating cancer, wherein the cancer is renal cell carcinoma, mature B-cell tumor, endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, colorectal cancer, skin cancer, small bowel cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, esophageal and gastric cancer, solid tumor, single tumor type, or triple-negative breast cancer.

[0048] In all respects, PI3Kα inhibitors are compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0049] In all aspects, PI3Kα inhibitors are: (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide, (S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazo-2-yl)pyrrolidine-1,2-dicarboxamide), Or its pharmaceutically acceptable salt.

[0050] In all respects, the PI3Kα inhibitor is (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide or a pharmaceutically acceptable salt thereof.

[0051] In all respects, PI3Kα inhibitors are inavolisib, apelix, serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511, buparlisib, dactolisib, pictilisib, taselisib, their pharmaceutically acceptable salts, or any combination thereof.

[0052] In an additional aspect, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the cancer has been previously identified as cancer having one or more mutations in PIK3CA, and wherein the PI3Kα inhibitor is inalipse, apelelis, threlisse, HH-CYH33, BAY1082439, ON 146040, AMG 511, buppanisi, datolisi, pitilis, and teselixi, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0053] In another aspect, this disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the cancer has one or more mutations in PIK3CA; and wherein the PI3Kα inhibitor is enoxacillin, apelelis, threliscillin, HH-CYH33, BAY1082439, ON 146040, AMG 511, bupanicillin, datoliscillin, pitilis, and teselicillin, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0054] In various respects, this disclosure further provides a method for treating cancer in a subject, the method comprising: (i) The cancer is identified as having one or more mutations in PIK3CA; and (ii) Administer to a subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the PI3Kα inhibitor is an enalixetine, apelelisetine, threlisetine, HH-CYH33, BAY1082439, ON 146040, AMG 511, bupanisic, datolisic, pitilis, and teselisic, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0055] In all cases, ATR inhibitors are administered before PI3Kα inhibitors. In all cases, ATR inhibitors are administered after PI3Kα inhibitors. In all cases, ATR inhibitors are administered concurrently with PI3Kα inhibitors.

[0056] In all respects, the effective therapeutic dose includes subtherapeutic dose regimens for ATR inhibitors. In all respects, the effective therapeutic dose includes subtherapeutic dose regimens for PI3Kα inhibitors. In all respects, the subtherapeutic dose regimen includes a starting dose that is at least 50% less than the minimum standard starting dose for monotherapy. In all respects, the subtherapeutic dose regimen includes a maintenance dose that is at least 50% less than the minimum standard maintenance dose for monotherapy.

[0057] In all respects, the maintenance dose includes a first reduction dose. In all respects, the maintenance dose includes a second reduction dose. In all respects, the maintenance dose includes a third reduction dose.

[0058] In all aspects, the route of administration is oral.

[0059] In all aspects, ATR inhibitors are administered for 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0060] In all aspects, PI3Kα inhibitors are administered for 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0061] In various respects, this disclosure provides a method for inducing cell death in aberrant cancer cells having one or more mutations in PIK3CA, the method comprising contacting the cells with an effective amount of an ATR inhibitor and an effective amount of a PI3Kα inhibitor sufficient to induce cell death in the aberrant cancer cells; wherein the PI3Kα inhibitor is inalipase, apelelis, threlisase, HH-CYH33, BAY1082439, ON 146040, AMG 511, buppanisil, datolisil, pitilis, and teselisi, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0062] In various respects, this disclosure provides a method wherein the ATR inhibitor is a compound of formula (I): , (I) Or its pharmaceutically acceptable salt. in It is a double bond, and each Y is independently either N or CR. 4 ;or It is a single bond, and each Y is independently NR. Y carbonyl or C(R) Y )2; where each R Y H or C, independently substituted. 1-6 alkyl; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B Hydroxyl group, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

[0063] In all respects, ATR inhibitors are compounds of formula (II): , (II) Or its pharmaceutically acceptable salt. in Each Y is independently N or CR 4 ; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B Hydroxyl group, optionally substituted C 1-6 Alkyl, optionally substituted C6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

[0064] In all aspects, R 2 It is a 5- to 10-membered bicyclic [pqr] heterocyclic group.

[0065] In all aspects, R 2 for , , or .

[0066] In all aspects, R 2 for .

[0067] In all respects, ATR inhibitors are selected from the group consisting of compounds 43, 57, 62, 87, 93, 94, 95, 99, 100, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 135, 147, 148 and their pharmaceutically acceptable salts.

[0068] In all respects, the ATR inhibitor is compound 43 or a pharmaceutically acceptable salt thereof. In all respects, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In all respects, compound 121 is a bisulfate. In all respects, the ATR inhibitor is carmenxetine or a pharmaceutically acceptable salt thereof. In all respects, the ATR inhibitor is compound 122 or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0069] Figure 1 shows ATP-based percentage of cell viability (y-axis) versus different dose levels of carmenereol and enoxaparin in p110α wild-type and mutant MCF7 cells. Each line represents a different dose level of enoxaparin. The y-axis shows the proportion of increased carmenereol dose.

[0070] Figure 2 shows a contour plot of the synergistic effect score (y-axis) of icoplanin doses versus the dose levels of carmenereol and icoplanin in combination in p110α wild-type and mutant MCF7 cells. Areas marked with "+" are indicated at the center or maximum value of areas with positive synergistic effects; unmarked areas indicate negative effects. The results in Figure 2 show that similar patterns of drug synergism were observed in the combination of carmenereol and icoplanin in both wild-type and mutant MCF7 cells.

[0071] Figure 3 shows an ATP-based percentage of cell survival (y-axis) plotted against different dose levels of carmenereol and enoxaparin in p110α wild-type and mutant HCC1954 cells. Each line with different shades represents a unique dose level of enoxaparin. The y-axis shows the proportion of increased carmenereol dose.

[0072] Figure 4 shows a contour plot of the synergistic effect score (y-axis) of icoplanin doses with the dose levels of carmenereol and icoplanin in p110a wild-type and mutant HCC1954 cells. Areas marked with "+" are marked at the center or maximum value of areas with positive synergistic effects; unmarked areas indicate negative effects. The results in Figure 4 show that the combination of carmenereol and icoplanin exhibits a similar pattern of drug synergistic effect in both BRCA1 mutant / p110a wild-type and BRCA1 mutant / p110a mutant cells.

[0073] Figure 5 shows Western blot images of the expression of relevant DNA damage repair proteins in untreated and treated (carmenextete and inalipe) MCF7 and HCC1954 cells. Inalipe + carmenextete treatment induced DNA damage in both p110α mutant and wild-type cells, but particularly induced increased γH2AX in the PIK3CA mutant (PIK3Cam) cell line compared to wild-type cells. The data in Figure 5 are consistent with the expected combined mechanism of increased cellular DNA damage (supported by increased γH2AX expression) when PI3K and ATR signaling are inhibited.

[0074] Figure 6 illustrates the study protocol for the combined administration of carmenxetine and enoxaphene. This study protocol includes both dose escalation and dose expansion. Abbreviations: DL = Dose Level; SRC = Safety Review Committee.

[0075] Figure 7 illustrates the individual participant regimen for Phase I dose escalation. Abbreviations: ATRi = ataxia-telangiectasia-mutant and rad-3-related inhibitor; DNA-PKi = DNA-dependent protein kinase inhibitor; PO = oral, via oral cavity; Q90D = every 90 days; RECIST = criteria for evaluating response in solid tumors. Note: Dosage and / or schedule for each agent may vary depending on the open cohort at the time of participant allocation. a The starting dose is carmenxetine 120 mg PO, administered for 3 days and stopped for 4 days, followed by 2 weeks of treatment and 1 week of treatment, combined with enoxacillin 6 mg PO QD.

[0076] Figure 8 is a schematic diagram outlining the dose escalation rule. Detailed Implementation

[0077] Generally, this disclosure relates to combinations of ATR inhibitors or pharmaceutically acceptable salts thereof with phosphatidylinositol 3-kinase (PI3Kα) inhibitors or pharmaceutically acceptable salts thereof, and their use in treating cancer or inducing cell death in cancer cells. Cancers included herein may be, for example, cancers carrying one or more mutations in PIK3CA. In embodiments, cancers carrying one or more mutations in PIK3CA are advanced solid tumors.

[0078] All features of ATR inhibitors disclosed in this specification (including any appended claims, abstract, and drawings) and / or all steps of any methods or processes disclosed herein may be combined in any combination, except for at least some mutually exclusive combinations of these features and / or steps. The invention is not limited to the details of any embodiments of ATR inhibitors explicitly disclosed herein. Any embodiment of an ATR inhibitor described in this application may be combined with any other embodiment. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any appended claims and abstract), or to any novel embodiment or step of any method or process disclosed herein, or any novel combination thereof, of any embodiment of an ATR inhibitor.

[0079] Advantageously, ATR inhibitors and PI3Kα inhibitors can act synergistically to induce cell death in cancer cells with one or more mutations in PIK3CA. Advantageously, combination cancer therapy including ATR inhibitors and PI3Kα inhibitors can exhibit reduced morbidity because the doses of the ATR inhibitors and PI3Kα inhibitors can be reduced, for example, relative to the doses administered in the corresponding monotherapy. Therefore, in the methods of this disclosure, ATR and PI3Kα inhibitors can be used in subtherapeutic dosing regimens. This disclosure demonstrates that combination cancer therapy including ATR inhibitors and PI3Kα inhibitors can synergistically induce cell death in cancer cells through the combination of ATR inhibitors and PI3Kα inhibitors (optionally close to the cancer cells). Therefore, this disclosure examines the advantages and disadvantages of treating cancer with ATR inhibitors or PI3Kα inhibitors and identifies that the combination of the two therapies will induce cell death in cancer cells while reducing side effects due to the use of subtherapeutic doses of the agents relative to the doses administered in the corresponding monotherapy. Post-publication evidence may still be needed to confirm the plausibility of these synergistic effects (based on the U.S. Rule 132 statement or evidence in EPO decision G2 / 21).

[0080] Furthermore, it should be understood that, based on this disclosure, those skilled in the art will find that a synergistic active combination therapy for prostate cancer is provided, as covered by the technical teachings and embodied in this disclosure. In particular, it is a synergistic active combination therapy of carmenxetine and enoxaparin for the treatment of prostate cancer.

[0081] Ataxia-telangiectasia mutations and Rad-3-related (ATR) inhibitors (ATRi) induce cell death in rapidly growing tumor cells by exacerbating endogenous replication stress and replication fork collapse, and by disabling cell cycle checkpoints. Carmenxetine, as a single agent, has shown antitumor activity in several xenograft models of cancer. Pharmacokinetic (PK) and pharmacodynamic (PD) biomarker analyses from tumor xenografts confirmed dose-dependent increases in target binding and double-strand DNA breaks, leading to in vivo tumor cell death.

[0082] Preclinical studies have indicated that PI3K pathway inhibition induces replication stress by reducing the activity of the spindle assembly checkpoint protein Aurora kinase B and by depleting the nucleotides required for DNA synthesis and repair (Huang et al. 2020; Juvekar et al. 2016). Therefore, the combination of DNA damage repair inhibition and PI3K pathway inhibition may lead to synthetic lethality and could potentially provide additional benefits for patients with advanced solid tumors.

[0083] Phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) are key nodes in the PI3K / AKT / mTOR intracellular signaling pathway, mediating critical cellular processes including cell cycle regulation, growth, metabolism, motility, and survival (Cantrell 2001; Hanahan and Weinberg 2011; Vanhaesebroeck et al. 2012). The PI3K / AKT / mTOR pathway is typically activated following ligand-receptor tyrosine kinase (RTK) interactions. Under physiological conditions, PI3K phosphorylates membrane-bound 4,5-phosphatidylinositol diphosphate (PIP2) to 3,4,5-phosphatidylinositol triphosphate (PIP3), which is required for intracellular signal transduction.

[0084] There are three classes of PI3K, with class I exhibiting the strongest response to external stimuli. Class I PI3K consists of two subunits: the p110 catalytic subunit and the p85 regulatory adaptor subunit. Four isoforms of the p110 catalytic subunit of PI3K exist: α, β, γ, and δ. These four isoforms are the corresponding products of the genes PIK3CA, PIK3CB, PIK3CG, and PIK3CD. PIK3CA and PIK3CB are expressed in all cells, while PIK3CD is primarily expressed in leukocytes, and PIK3CG is expressed in various tissues, including the pancreas, skeletal muscle, liver, and heart.

[0085] Dysregulation of the PI3K / AKT / mTOR signaling pathway has been described in a variety of solid tumor malignancies (e.g., glioblastoma, colorectal cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, prostate cancer, head and neck cancer, breast cancer [Gustin et al. 2008; Marquard and Jücker 2020]). Activation of the pathway may occur through a variety of mechanisms.

[0086] Activating mutations in the PIK3CA gene primarily occur in exons 9 and 20 (“hotspot” regions), which encode the helical and kinase domains of the p110α protein, respectively (Samuels et al. 2004; Nichols et al. 2013; Feldman et al. 2015). PIK3CA mutations are among the most frequently observed oncogenic alterations in solid tumors (The Cancer Genome Atlas Network 2012; Kandoth et al. 2013; Lui et al. 2013) and lead to abnormal growth and proliferation of cancer cells. These effects can be eliminated by PI3K inhibitors. Therefore, inhibiting PI3K represents an attractive strategy for treating solid tumor malignancies with dysregulated PI3K / AKT / mTOR pathways, and numerous agents targeting this pathway have been tested in clinical trials (Janku et al. 2018). However, since mutated p110α may not induce aggressive cancer progression on its own (Hanker et al. 2019), and the PI3K / AKT / mTOR pathway interacts with several other signaling pathways, leading to adaptive feedback mechanisms (Carracedo and Pandolfi 2008), it is suggested that PI3K inhibitors be combined with mechanistically appropriate therapeutic agents to improve their efficacy (Hanker et al. 2019).

[0087] It is hypothesized that the metabolic effects of p110α inhibitors synergize with those of DNA damage repair inhibitors. This disclosure is based on the synergistic effect between ATR inhibitors and PI3Kα inhibitors. Consecutive combination therapy has been well tolerated in preclinical models, and potential overlapping toxicities may exist for each drug class observed clinically. Until this disclosure, the specific population of cancer patients who could benefit from the combination of ATR inhibitors and PI3Kα inhibitors was limited, particularly those who could benefit from dose reductions of ATR inhibitors and / or PI3Kα inhibitors.

[0088] ATR inhibitors ATR inhibitors are compounds that, when exposed to ATR kinase in vitro, in cell culture, or in vivo in animals, reduce the activity of ATR kinase, thereby decreasing the measured IC50 value of ATR kinase.50 The concentration is 10 µM or lower (e.g., 5 µM or lower, or 1 µM or lower). For some ATR inhibitors, the ATR kinase IC50 is... 50 It can be 100 nM or lower (e.g., 10 nM or lower or 1 nM or lower) and can be as low as 100 pM or 10 pM. Preferably, ATR kinase IC 50 The range is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0089] Non-limiting examples of ATR inhibitors include, for example: Non-limiting examples of ATR inhibitors include, for example, those described in: international applications PCT / US2019 / 022727 and PCT / US2018 / 034729, each of which is incorporated herein by reference; U.S. Patents 9,663,535, 9,549,932, 8,552,004 and 8,841,308, each of which is incorporated herein by reference; and U.S. Patent Application Publication No. 2019 / 0055240, which is incorporated herein by reference.

[0090] In one embodiment, the ATR inhibitor is a compound of formula (I): , (I) Or its pharmaceutically acceptable salt. in It is a double bond, and each Y is independently either N or CR. 4 ;or It is a single bond, and each Y is independently NR. Y carbonyl or C(R) Y )2; where each R Y H or C, independently substituted. 1-6 alkyl; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B Hydroxyl group, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

[0091] ATR inhibitors may be, for example, compounds of formula (II): , (II) Or its pharmaceutically acceptable salt. in Each Y is independently N or CR 4 ; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B Hydroxyl group, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

[0092] In some embodiments, in compounds of formula (II), (I), or (Ib): Each Y is independently N or CR 4 ; R 1 H or C with optional substitution 1-6 alkyl; R 2 C is an optional replacement 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2 or –SO2R 5A ; R 3 C is an optional replacement 1-9 Mixed aromatics; Each R 4 H or C, independently substituted. 1-6 alkyl; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A , where each R 5A C can be substituted independently. 1-6 Alkyl or optionally substituted C 3-8 cycloalkyl; or two R 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl or optionally substituted C 3-8 cycloalkyl; and Each R 6Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic group.

[0093] The method for preparing the compound of formula (I) is described, for example, in international application number PCT / US2019 / 022727, which is hereby incorporated by reference.

[0094] ATR inhibitors may be, for example, compounds of formula (Ia): , (Ia) Or a pharmaceutically acceptable salt thereof, wherein Y, R 1 R 2 R 3 and R 4 As described for formula (I).

[0095] ATR inhibitors may be, for example, compounds of formula (Ib): , (Ib) Or a pharmaceutically acceptable salt thereof, wherein Y, R 1 R 2 R 3 and R 4 As described for formula (I).

[0096] ATR inhibitors may be, for example, compounds of formula (IA): , (IA) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As described for formula (I).

[0097] ATR inhibitors may be, for example, compounds of formula (IA-a): , (IA-a) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3and R 4 As described for formula (I).

[0098] ATR inhibitors may be, for example, compounds of formula (IB): , (IB) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As described for formula (I).

[0099] ATR inhibitors may be, for example, compounds of formula (IB-a): , (IB-a) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As described for formula (I).

[0100] ATR inhibitors may be, for example, compounds of formula (IC): (IC) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As described for formula (I).

[0101] ATR inhibitors may be, for example, compounds of formula (IC-a): (IC-a) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As described for formula (I).

[0102] ATR inhibitors may be, for example, compounds of formula (ID): (ID) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As described for formula (I).

[0103] ATR inhibitors may be, for example, compounds of formula (ID-a): (ID-a) Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As described for formula (I).

[0104] R 1 It can be methyl.

[0105] In some embodiments, R 2 C can be, for example, arbitrarily substituted. 3-8 Cycloalkyl groups. For example, R 2 Groups that can be in formula (A): , (A) in n is 0, 1, 2, or 3; and R 7 Hydrogen, alkylsulfonyl, cyano, –CON(R) A )2、–SON(R A 2. Optional substitution of C 1-9 Heteroaryl, hydroxyl, or alkoxy, wherein each R A Independently H or alkyl; or two R A They combine with the atoms they are attached to to form C 2-9 Heterocyclic group.

[0106] In some embodiments, R 2 C can be, for example, arbitrarily substituted. 1-6 Alkyl groups (e.g., optionally substituted tertiary C) 3-6 Alkyl groups). For example, R 2 Groups that can be in formula (B): , (B) Where R 7 Hydrogen, alkylsulfonyl, cyano, –CON(R) A )2、–SON(R A 2. Optional substitution of C 1-9 Heteroaryl, hydroxyl, or alkoxy, wherein each R A Independently H or alkyl; or two R A They combine with the atoms they are attached to to form C 2-9 Heterocyclic group.

[0107] In some embodiments, R 2 For example, non-aromatic C can be substituted by any choice. 2-9 Heterocyclic group.

[0108] In some embodiments, R 2 For example: , , , , , , , , , , , , , , , , , , , , , , , , , , –I, –SO2Me, , 、–SO2Ph、 –OMe , , –OCH2CF3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0109] In some embodiments, R 2 It can be a 5- to 10-membered bicyclic [pqr] heterocyclic group.

[0110] In some embodiments, R 2 Can be , , or .

[0111] In some embodiments, R 2 Can be .

[0112] In some embodiments, R 3 It can be a monocyclic C that has been optionally substituted, for example, including at least one nitrogen atom (e.g., two nitrogen atoms). 1-9 heteroaryl. For example, R 3 Groups that can be of formula (C): , (C) Where A is an optionally substituted monocyclic C 1-9 Mixed aromatic rings.

[0113] In some embodiments, A may be a group of, for example, formula (C1): , (C1) Where R 8 C is hydrogen, halogen, or optionally substituted. 1-6 alkyl.

[0114] In some embodiments, R 3 For example: , , , , , , , , , , , , , , , or .

[0115] In some embodiments, R 3 For example: .

[0116] In some embodiments, R 4 It can be, for example, hydrogen.

[0117] ATR inhibitors may be exemplified by the compounds listed in Table 1 below or their pharmaceutically acceptable salts.

[0118] Table 1 ATR inhibitors can be isotope-enriched (e.g., deuterium-enriched).

[0119] In some embodiments, the ATR inhibitors of this disclosure may be present in the form of a salt. In some embodiments, the ATR inhibitors may be present in the form of a pharmaceutically acceptable salt.

[0120] Carmenseti In some embodiments, the ATR inhibitor is carmenxetine. In some embodiments, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In some embodiments, the ATR inhibitor is the bisulfate salt of compound 121. In some embodiments, carmenxetine is compound 121. In the examples, carmenxetine is also referred to as RP-3500, and these terms are used interchangeably herein. In some embodiments, carmenxetine may be present in the form of a bisulfate salt.

[0121] Carmenxetine is a novel, orally bioavailable, clinical-stage ATR kinase inhibitor. Carmenxetine exhibits high potency, with significant IC50 values ​​in both biochemical and cell-based assays. 50 The values ​​were 1.0 and 0.33 nmol / L, respectively. Carmenxetine exhibits high selectivity for ATR, with 30-fold selectivity compared to mammalian target of rapamycin (mTOR), and more than 2,000-fold selectivity compared to ataxia-telangiectasia mutant (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase α (PI3Kα) kinase. In vivo, carmenxetine treatment at the lowest effective dose (MED) of 5 to 7 mg / kg once daily produced potent single-agent efficacy and / or tumor regression in multiple xenograft models. Pharmacodynamic assessment was performed via phosphorylation checkpoint kinase 1 (pCHK1) (IC50). 80The tumor inhibition was proportional to a dose of 18.6 nmol / L, and target binding was validated by the induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunits (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). MED-guided carmenxetine exposure demonstrated that, over a continuous timeframe, circulating free plasma concentrations exceeded the in vivo tumor IC50. 80 A duration of 10 to 12 hours is sufficient to produce efficacy. However, short-duration intermittent (3 days a week, 4 days off) dosing schedules, as monotherapy or concomitant with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing red blood cell consumption, highlighting the reversibility of carmenseline toxicities and demonstrating superior efficacy compared to sequential therapy. See Roulston, Anne et al., “RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors.” Molecular Cancer Therapeutics, Vol. 21, 2 (2022): 245-256; and NCT04497116.

[0122] Carmenxetine is being developed for the treatment of solid tumors. In some embodiments, solid tumors are selected from ovarian cancer, breast cancer, pancreatic cancer, head and neck cancer, squamous cell carcinoma, melanoma, hormone-refractory (castration-resistant, androgen-independent) prostate cancer, and relapsed and refractory chronic lymphocytic leukemia (CLL). Carmenxetine can be administered orally. In some embodiments, carmenxetine is being developed for the treatment of various diseases. In embodiments, various diseases include, but are not limited to, cancer. In embodiments, cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or advanced solid tumors. In some embodiments, cancer is prostate cancer. In some embodiments, cancer is breast cancer. In some embodiments, cancer is ovarian cancer. Carmenxetine works by targeting ataxia-telangiectasia and Rad-3-related protein (ATR).

[0123] Carmenxetine, as a single agent, has demonstrated antitumor activity in several xenograft models of cancer. Preclinical analysis of PK and PD biomarkers from tumor xenografts confirmed a dose-dependent increase in target binding and double-strand DNA breaks, leading to tumor cell death in vivo.

[0124] In the examples, carmenxetine at doses ≥120 mg QD exhibits pharmacological activity. In the examples, this disclosure provides a bisulfate of carmenxetine. In the examples, this disclosure provides a crystalline form of the bisulfate of carmenxetine. The bisulfate form of carmenxetine was previously described as Example 121 in International Application PCT / CA2022 / 050892, which is incorporated herein by reference in its entirety.

[0125] PI3Kα inhibitors The PIK3CA gene encodes the p110α catalytic subunit of PI3K, and its mutations are highly prevalent in endometrial cancer, breast cancer, bladder cancer, cervical cancer, and colorectal cancer. PIK3CA activating mutations are the most common oncogenic mutations described to date in breast cancer. (Arafeh, R. and Samuels, Y. "PIK3CA in cancer: the past 30 years." Seminars in Cancer Biology. Vol. 59. Academic Press, 2019.)

[0126] p110α is a widely expressed PI3K isoform in vivo and a key intermediate in insulin-like growth factor-1 (IGF-1), insulin, and leptin signaling. It plays a crucial role in growth factor and metabolic signaling by highly selectively recruiting and activating the insulin receptor substrate (IRS) signaling complex. p110α is significantly expressed in endothelial cells, and its activity is essential for angiogenesis.

[0127] In this embodiment, the PIK3CA mutation is selected from: ■ R88Q ■ G106A / D / R / S / V ■ K111N / R / E ■ G118D ■ N345D / H / I / K / S / T / Y ■ C420R ■ E453A / D / G / K / Q / V ■ E542A / D / G / K / Q / R / V ■ E545A / D / G / K / L / Q / R / V ■ Q546E / H / K / L / P / R ■ M1043I / T / V ■ H1047D / I / L / N / P / Q / R / T / Y ■ G1049A / C / D / R / S As used throughout this disclosure, the term "PI3Kα inhibitor" refers to any PI3K inhibitor that targets the p110α catalytic subunit of PI3K. In some embodiments, the PI3Kα inhibitor specifically targets only p110α. In some embodiments, the PI3Kα inhibitor specifically targets p110α in addition to targeting one or more other subunits (i.e., p110β and p110δ). In some embodiments, the PI3Kα inhibitor is apelelis. Apelelis is a known PI3K inhibitor that targets only the p110α subunit. In some embodiments, the PI3Kα inhibitor is enoxacillin. Enalix is ​​a known PI3K inhibitor that targets only the p110α subunit. In some embodiments, the PI3Kα inhibitor is threlixise. Threlixise is a known PI3K inhibitor that targets only the p110α subunit. In some embodiments, the PI3Kα inhibitor is teselixise. Tacelicillin is a known PI3K inhibitor targeting the p110α, p110β, and p110δ subunits. In some embodiments, the PI3Kα inhibitor is AZD8835. AZD8835 is a known PI3K inhibitor targeting the p110α and p110δ subunits.

[0128] The importance and high frequency of PIK3CA mutations in solid tumors have drawn attention to the development of selective inhibitors of PI3Kα.

[0129] In the embodiments, the PI3Kα inhibitor of this disclosure is a compound of formula (III): , (III) and its stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, wherein: R 1 Selected from -CH3, -CH2CH3, cyclopropyl, and cyclobutyl; R 2 Selected from —CH3, —CHF2, —CH2F and —CF3.

[0130] In the embodiment, R 1 It is -CH3 or cyclopropyl.

[0131] In the embodiment, R 2It is -CHF2.

[0132] In the embodiments, the compounds of formula (III) are selected from: Or its pharmaceutically acceptable salt.

[0133] The inarizole name is (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide and has the following structure: .

[0134] In the embodiments, the compounds of formula (III) are selected from: In the examples, the compound of formula (III) is (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide.

[0135] PI3Kα inhibitors may include: (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide, (S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazo-2-yl)pyrrolidine-1,2-dicarboxamide), Or its pharmaceutically acceptable salt.

[0136] PI3Kα inhibitors may be (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide or a pharmaceutically acceptable salt thereof.

[0137] PI3Kα inhibitors may be (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide.

[0138] PI3Kα inhibitors may be (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazolyl)pyrrolidine-1,2-dicarboxamide) or a pharmaceutically acceptable salt thereof.

[0139] PI3Kα inhibitors may be (S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazolyl)pyrrolidine-1,2-dicarboxamide).

[0140] PI3Kα inhibitors can be isotope-enriched (e.g., deuterium-enriched).

[0141] PI3Kα inhibitors can be prepared as described, for example, in U.S. Patent Nos. 9,650,393, 8,227,462, 8,476,268 and 9,085,560, the disclosures of which are incorporated herein by reference in their entirety.

[0142] Alternatively, the PI3Kα inhibitor used in the methods of this disclosure may be enoxacillin, apelelis, threliscillin, HH-CYH33, BAY1082439, ON 146040, AMG 511, bupanicillin, datoliscillin, pitilis, and tacelilis, a pharmaceutically acceptable salt thereof, or a combination thereof. In the examples, the PI3Kα inhibitor used in the methods of this disclosure is tacelilis, a pharmaceutically acceptable salt thereof, or a combination thereof. In the examples, the PI3Kα inhibitor used in the methods of this disclosure is pitilis, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0143] Apellis In some embodiments, the PI3Kα inhibitor is apelelis.

[0144] The compound known as apelips (BYL719) is an orally selective inhibitor of the PI3Kα isotype and is currently undergoing clinical trials for potential treatment of various tumor types, including a phase III study in combination with fulvestrant for second-line hormone receptor-positive, HER2-advanced metastatic breast cancer (Furet, P. et al. (2013) Bioorg. Med. Chem. Lett. 23:3741-3748; US Patent Nos. 8,227,462, 8,476,268, and 8,710,085). Apelips is named (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazolyl)pyrrolidine-1,2-dicarboxamide) and has the following structure: .

[0145] Activating mutations in PIK3CA increase sensitivity to the antiproliferative effects of PI3Kα inhibition in cell lines and tumor samples from breast cancer patients treated with apegliflozin (Vanhaesebroeck et al. 2021). This has been clinically validated in patients with HR-positive / HER2-negative advanced breast cancer who also have PIK3CA mutations in the SOLAR-1 and BYLieve trials (André F et al. 2019; Rugo et al. 2021).

[0146] Apellis was previously described in U.S. Patent Nos. 8,227,462 and 8,476,268, which are incorporated herein by reference in their entirety.

[0147] Threlice In some embodiments, the PI3Kα inhibitor is threlixetine.

[0148] Threcil is also known as INK-1117, MLN-1117, or TAK-117, each of which is used interchangeably throughout this disclosure. Threcil is a potent oral PI3K inhibitor, effective against PI3Kα isotypes of IC50. 50The concentration was 21 nmol / L. The first human phase I study evaluated the safety and efficacy of threlixetine in patients with advanced solid tumors. Juric D. et al., A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kalpha Isoform Inhibitor, in Patients with Advanced Solid Malignancies. Clin. Cancer Res. 2017;23:5015–5023. A phase II study is investigating threlixetine in combination with the oral mTORC1 / 2 inhibitor sapanisertib (TAK-228) to target DNA repair pathways in patients with TNBC breast cancer. A phase II study evaluated the efficacy and safety of MLN0128 and MLN0128 in combination with threlixetine and everolimus in patients with metastatic clear cell renal cell carcinoma (mccRCC) who had progressed on VEGF-targeted therapy. A phase I study tested thresher with the mTORC1 / 2 inhibitor sarpasite (TAK-228) in patients with advanced non-hematologic malignancies to determine the DLT, MTD, and / or RP2D of the drug combination. (Mishra, R. et al., "PI3K inhibitors in cancer: clinical implications and adverse effects." International Journal of Molecular Sciences 22.7 (2021):3464.)

[0149] Threlise has the following structure: .

[0150] Threllis was previously described as compound 54 in U.S. Patent No. 9,085,560, which is incorporated herein by reference in its entirety.

[0151] Inarise In some embodiments, the PI3Kα inhibitor is inaglithi.

[0152] As described in this article, enallixetine is a benzo[a]oxazolidinone-ATP competitive inhibitor of PI3Kα, which also induces selective degradation of the mutant p110α protein. Enallixetine is a highly selective inhibitor and degrader of the PI3Kα mutant. Enallixetine is a potent selective inhibitor of PI3Kα, with an IC50 concentration of [missing information]. 50 The selectivity for PI3Kα is 0.038 nM. Inalice exhibits >300-fold selectivity for PI3Kα compared to other class I PI3K isoforms (β, δ, and γ), and >2000-fold selectivity compared to PIK family members. Inalice binds to the ATP-binding site of PI3K and inhibits phosphorylation from PIP2 to PIP3.

[0153] The terms “inalixe” and “GDC-0077” refer to the same PI3Kα inhibitor, and the terms are used interchangeably throughout this disclosure.

[0154] Small molecule inhibitors targeting the phosphatidylinositol 3-kinase (PI3K) signaling pathway have generated considerable interest in cancer therapy. Class I PI3Kα is most commonly associated with solid tumors via gene amplification or activating mutations. However, inhibitors exhibiting PI3K isotype and mutation specificity remain elusive. Enallix is ​​a benzo[a]oxazolidinone-ATP competitive inhibitor of PI3Kα. Enallix also induces selective degradation of the mutant p110α protein (the catalytic subunit of PI3Kα). Enallix is ​​generated by informed isotype-specific interactions based on a structure-designed framework within its binding site, resulting in a potent inhibitor with greater than 300-fold selectivity compared to other Class I PI3K isotypes. Further optimization of its pharmacokinetic properties led to excellent in vivo exposure and efficacy, and the clinical candidate enallix was identified and is currently being evaluated in a Phase III clinical trial as a treatment for patients with PIK3CA-mutant breast cancer. Hanan, EJ et al. “Discovery of GDC-0077 (Inavolisib), a Highly SelectiveInhibitor and Degrader of Mutant PI3Kα.” Journal of Medicinal Chemistry 65, 24 (2022): 16589-16621.

[0155] Non-clinical studies have confirmed that enoxacillin promotes the specific degradation of mutant but not wild-type p110α (a characteristic that appears to be RTK activity-dependent) (Song et al. 2022). Furthermore, enoxacillin reduces the expression of downstream PI3K pathway markers, including AKT, a 40 kDa proline-rich AKT substrate, and S6 phosphorylation, leading to inhibition of proliferation and apoptosis in PIK3CA mutant breast cancer cell lines, as well as inhibition of tumor growth in xenograft models of breast cancer carrying PIK3CA mutations.

[0156] Results from completed nonclinical toxicity and safety pharmacology studies to date provide a robust characterization of the toxicological profile of enoxacillin and support its administration to patients with advanced cancer. Nonclinical findings (dose-limiting toxicities [DLT]) identified in nonclinical toxicology studies are consistent with the expected pharmacological effects of PI3K inhibition and include hyperglycemia, weight loss in rats and dogs, and inflammation in dogs. Additionally, myelocytopenia, glandular and reproductive tissue atrophy, and lens degeneration were observed in rats; and lymphoid consumption and swelling of the lens fibers in the eye were observed in dogs. Findings were generally dose-dependent and reversible, and considered clinically monitorable and / or manageable. In vitro and in vivo safety pharmacology studies of enoxacillin confirmed a low risk of cardiovascular, neurological, and respiratory adverse reactions in clinically relevant exposures. Enallix does not pose a genotoxic risk in humans and is not considered to have phototoxic potential. Enallix has been shown to be teratogenic in nonclinical studies. The fetal malformations and variations observed in rats ensure the continued use of highly effective contraceptive methods in clinical trials utilizing inalilese.

[0157] To date, clinical results using enoxaparin as a single agent and in various combinations with approved therapies have been encouraging. A global, blinded, randomized phase III clinical trial is currently underway to register enoxaparin in combination with palbociclib and fulvestrant at a fully labeled dose for first-line treatment of metastatic PIK3CA-mutated hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer (NCT04191499). Many other cancer types are also being investigated in earlier-stage trials (e.g., NCT04931342, NCT04486352, and NCT04929223).

[0158] Because enoxaparin is a highly potent and selective inhibitor of the p110a isotype that promotes the degradation of mutant p110α (Song et al. 2022), it is expected to have less off-target toxicity and a better therapeutic window compared to other PI3K inhibitors. This is further supported by non-clinical and safety data from the Phase I / Ib study GO39374, which only involved enoxaparin in combination with targeted therapies (i.e., endocrine therapy, CDK4 / 6 inhibitors) (Juric et al. 2020; Juric et al. 2022).

[0159] The inarizole name is (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide and has the following structure: .

[0160] Inalice was previously described as compound 101 in U.S. Patent No. 9,650,393, which is incorporated herein by reference in its entirety.

[0161] Isomers and their compositions This disclosure includes, where possible, individual diastereomers, enantiomers, epiomers, and transisomers of the compounds disclosed herein, as well as mixtures of diastereomers and / or enantiomers, including racemic mixtures. While certain stereochemistry disclosed herein is preferred, other stereoisomers, including diastereomers, enantiomers, epiomers, transisomers, and mixtures thereof, may also be used for the treatment of diseases. Inactive or less active diastereomers and enantiomers may be used, for example, in scientific research related to receptors and activation mechanisms.

[0162] It should be understood that some molecules can exist in multiple tautomer forms. This disclosure includes all tautomers, even if only one tautomer may be indicated in an example.

[0163] This disclosure also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers. The compounds are particularly useful, for example, in certain types of cancer, and are used to slow the progression of cancer once it has developed in a patient.

[0164] The compounds disclosed herein can be used in pharmaceutical compositions comprising (a) a compound or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. The compounds can be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients. The compounds can also be used in pharmaceutical compositions wherein the compound disclosed herein or a pharmaceutically acceptable salt thereof is the sole active ingredient.

[0165] Optical isomers - diastereomers - geometric isomers - tautomers The compounds disclosed herein may contain, for example, one or more stereocenters, and may occur as racemates, racemic mixtures, single enantiomers, single diastereomers, and mixtures of diastereomers and / or enantiomers. This disclosure includes all such isomers of the compounds disclosed herein. It is intended to include all possible stereoisomers (e.g., enantiomers and / or diastereomers) in mixtures, as well as compounds as pure or partially purified compounds, within the scope of this disclosure (i.e., all possible combinations of stereocenters as pure compounds or mixtures).

[0166] Some of the compounds described herein may contain rotationally hindered bonds, which can be advantageous as two separate rotational isomers or trans-isomers can be isolated and found to have different biological activities. It is intended that all possible trans-isomers be included within the scope of this disclosure.

[0167] Some of the compounds described herein may contain olefinic double bonds, and unless otherwise stated, this means that E and Z geometric isomers are included.

[0168] Some of the compounds described herein can have different hydrogen bonding sites, referred to as tautomers. Examples are ketones and their enol forms, referred to as keto-enol tautomers. This disclosure covers single tautomers and mixtures thereof.

[0169] The compounds disclosed herein that have one or more asymmetric centers can be isolated into diastereomers, enantiomers, etc., by methods well known in the art.

[0170] Alternatively, enantiomers and other compounds with chiral centers can be synthesized through stereospecific synthesis using optically pure starting materials and / or reagents with known configurations.

[0171] Pharmaceutically acceptable salts This disclosure also includes pharmaceutically acceptable salts of compounds, and pharmaceutical compositions comprising compounds (e.g., but not limited to carmenxetine) and pharmaceutically acceptable carriers. This disclosure provides pharmaceutically acceptable salts of the various compounds disclosed herein. In examples, carmenxetine is presented as a pharmaceutically acceptable salt. In examples, carmenxetine is present as a bisulfate. Although carmenxetine can be effective in various forms (including, but not limited to, as a free base), it can actually be administered in the form of a salt of a pharmaceutically acceptable acid or base. In examples, the bisulfate form of carmenxetine is significantly more effective than other known forms. In examples, the bisulfate form of carmenxetine is significantly more effective than the free base form. The bisulfate form of carmenxetine was previously described as Example 121 in International Application PCT / CA2022 / 050892, which is incorporated herein by reference in its entirety.

[0172] Metabolites – Prodrugs This disclosure includes therapeutically active metabolites, wherein the metabolites themselves fall within the scope of the claims. This disclosure also includes prodrugs, which are compounds that are converted into the claimed compound upon or after administration to a patient. In some cases, the chemical structure claimed in this application may itself be a prodrug.

[0173] Isotope enrichment derivatives This disclosure includes molecules enriched with isotopes at one or more sites within the molecule. Therefore, deuterium-rich compounds fall within the scope of the claims.

[0174] Methods for preparing ATR inhibitors and PI3Kα inhibitors ATR inhibitors can be prepared using reactions and techniques known in the art. For example, certain ATR inhibitors can be prepared using techniques and methods disclosed, for example, in: International Applications PCT / US2019 / 022727 and PCT / US2018 / 034729, each of which is incorporated herein by reference; U.S. Patents 9,663,535, 9,549,932, 8,552,004 and 8,841,308, each of which is incorporated herein by reference; and U.S. Patent Application Publication No. 2019 / 0055240, which is incorporated herein by reference in its entirety.

[0175] PI3Kα inhibitors can be prepared using reactions and techniques known in the art. For example, certain PI3Kα inhibitors can be prepared using techniques and methods disclosed, for example, in U.S. Patent Nos. 9,650,393, 8,227,462, 8,476,268, and 9,085,560, each of which is incorporated herein by reference in its entirety.

[0176] How to use ATR inhibitors and PI3Kα inhibitors can be used together to treat diseases or conditions characterized by excessive cell proliferation. For example, the disclosures described herein are applicable to treating various tumor conditions carrying one or more mutations in the PIK3CA gene. Specifically, mutations in the PIK3CA gene can be found in the following tumor types: renal cell carcinoma, mature B-cell tumors, endometrial cancer, ovarian cancer, colorectal cancer, skin cancer (non-melanoma), small bowel cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, and esophageal and gastric cancer. Therefore, the methods disclosed herein can be used to treat these cancers. In any and every aspect of the disclosure herein, where therapeutic methods are described, the equivalent use of the compound in treatment, as well as the use of the compound in the manufacture of a medicament for therapeutic use and treatment, are covered. Furthermore, the combination of an ATR inhibitor and a PI3Kα inhibitor for treating diseases or conditions characterized by excessive cell proliferation is not intended to be bound by a specific theory that subsequently leads to cell death. In addition, the combination of ATR inhibitors and PI3Kα inhibitors, which are used to treat diseases or conditions with symptoms of excessive cell proliferation, can be used to manufacture drugs for treating diseases or conditions with symptoms of excessive cell proliferation that subsequently lead to cell death.

[0177] The treatment method disclosed herein includes the step of administering a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor to a subject in need. The therapeutically effective amount of the PI3Kα inhibitor may be, for example, a subtherapeutic dose regimen of a PI3Kα inhibitor. The therapeutically effective amount of the ATR inhibitor may be, for example, a subtherapeutic dose regimen of an ATR inhibitor.

[0178] The diseases or conditions treated using the methods of this disclosure may present with symptoms of excessive cell proliferation. For example, the disease or condition may be cancer. Cancer may be, for example, carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, or melanoma. Cancer may be, for example, a solid tumor.

[0179] Non-limiting examples of cancer include prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain cancer, glioma, lung cancer, salivary cancer, stomach cancer, thymic carcinoma, thyroid cancer, leukemia, melanoma, lymphoma, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, and liver cancer.

[0180] The methods disclosed herein can be used to treat renal cell carcinoma, mature B-cell tumors, endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, colorectal cancer, skin cancer (non-melanoma), small bowel cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, or esophageal and gastric cancer.

[0181] Non-limiting examples of cancer include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenoma-like carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma (carcinoma basocellulare), basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, body carcinoma, cribriform carcinoma, armored carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, tubular carcinoma, sclerosing carcinoma, embryonal carcinoma, cerebral carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gel carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma (carcinoma gigantocellulare), adenocarcinoma, granular cell carcinoma, pilostromal carcinoma, polycythemia vera, hepatocellular carcinoma, Hurthle... Cellular carcinoma, clear carcinoma, adrenal carcinoma, infantile embryonic carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipoma carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma muciparum, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, papillary carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatous carcinoma, Schneiderian carcinoma, scleroderma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma. Carcinoma, spherical cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, filamentous carcinoma, telangiectatic carcinoma, telangiectasia carcinoma, transitional cell carcinoma, nodular carcinoma, tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0182] Non-limiting examples of sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multichromosomal hemorrhage sarcoma, B-cell immunoblastic sarcoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, and Kupffer cell sarcoma. Sarcoma, angiosarcoma, leukemic sarcoma, malignant stromal sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and capillary dilatational sarcoma.

[0183] Non-limiting examples of leukemia include acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonic leukemia, eosinophilic leukemia, Gross's leukemia, hairy cell leukemia, hematopoietic leukemia, blood cell leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, cellular leukemia, and lymphoblastic leukemia. Leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, microcytic leukemia, monocytic leukemia, myeloblastic leukemia, granulocytic leukemia, myeloid granulocytic leukemia, chronic myeloid monocytic leukemia, Negri leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Reed cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0184] Non-limiting examples of melanoma include acral lentigines melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, fungal melanoma, and superficial diffuse melanoma.

[0185] In some embodiments, carmenxetine is being developed for the treatment of various diseases. In these embodiments, the various diseases include, but are not limited to, cancer. In these embodiments, the cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or advanced solid tumors. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer.

[0186] Pharmaceutical Composition The compounds used in the methods described herein are preferably formulated as pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration. Pharmaceutical compositions typically comprise compounds as described herein and pharmaceutically acceptable excipients. Some pharmaceutical compositions may contain one or more additional pharmaceutically active agents as described herein.

[0187] The compounds described herein may also be used in the form of free bases, salts, zwitterions, solvates, or as prodrugs or pharmaceutical compositions thereof. All forms are within the scope of this disclosure. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof may be administered to the patient in various forms, depending on the chosen route of administration, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, orally, parenterally, orally, sublingually, nasally, rectally, via patch, pump, or transdermally, and in correspondingly formulated pharmaceutical compositions. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local administration modalities. Parenteral administration may be performed by continuous infusion over a selected time period.

[0188] For human use, the compounds of this disclosure may be administered alone or in combination with a drug carrier selected according to the intended route of administration and standard pharmaceutical practice. Therefore, pharmaceutical compositions used according to this disclosure may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the compounds of this disclosure into pharmaceutically acceptable preparations.

[0189] This disclosure also includes pharmaceutical compositions that may contain one or more pharmaceutically acceptable carriers. In preparing the pharmaceutical compositions of this disclosure, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it may be a solid, semi-solid, or liquid substance (e.g., physiological saline) serving as a mediator, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, powders, lozenges, sachets, vials, elixirs, suspensions, emulsions, solutions, syrups, and soft or hard gelatin capsules. As is known in the art, the type of diluent may vary depending on the intended route of administration. The resulting compositions may contain additional agents, such as preservatives.

[0190] The excipient or carrier is selected based on the route and method of administration. Suitable drug carriers, as well as essential pharmaceutical ingredients for drug formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Edition, edited by Gennaro, Lippincott Williams & Wilkins (2005), a well-known reference in the field and in the USP / NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, edited by Rowe et al., Pharmaceutical Press (2009).

[0191] These pharmaceutical compositions can be manufactured in conventional ways, such as, but not limited to, conventional mixing, dissolving, granulating, tableting, grinding, emulsifying, encapsulating, or lyophilizing processes. Methods well known in the art for preparing formulations can be found, for example, in *Remington: The Science and Practice of Pharmacy*, 21st edition, edited by Gennaro, Lippincott Williams & Wilkins (2005) and *Encyclopedia of Pharmaceutical Technology*, edited by J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York. A suitable formulation depends on the chosen route of administration. Formulations and preparations of such compositions are well known to those skilled in the art of pharmaceutical formulation. In preparing formulations, the active compound may be ground to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, 40 mesh.

[0192] Application of carmenseline and / or inalice The compounds disclosed herein can be administered via any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, local (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal. It should be understood that preferred routes may vary depending on, for example, the recipient's condition. In the case of oral administration of the compounds, they can be formulated with pharmaceutically acceptable carriers or excipients into pills, capsules, tablets, etc. When administered orally, pills, capsules, or tablets can be taken daily or at a less frequent frequency over a specified period of time. This regimen can be repeated for several treatment cycles.

[0193] In this example, carmenxetine is administered orally. In this example, enoxacillin is administered orally. In this example, a combination of carmenxetine and enoxacillin is administered orally. An oral formulation refers to a medicine developed and manufactured for oral delivery. In this example, carmenxetine and enoxacillin are administered as an oral formulation.

[0194] dose The dosage of the compounds used in the methods described herein, or their pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions thereof, may vary depending on a number of factors, such as the pharmacodynamic properties of the compound; the administration modality; the recipient's age, health status, and weight; the nature and severity of symptoms; the frequency of treatment and the type of concurrent treatment (if present); and the clearance of the compound in the animal being treated. Those skilled in the art can determine an appropriate dosage based on the above factors. The compounds used in the methods described herein may initially be administered at a suitable dosage, which may be adjusted as needed based on clinical response. Generally, the appropriate daily dose of the compounds disclosed herein will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose typically depends on the factors described above.

[0195] ATR inhibitors can be administered to patients in single or multiple doses. When multiple doses are administered, these doses can be spaced apart from each other, for example, 1–24 hours, 1–7 days, 1–4 weeks, or 1–12 months. The compound can be administered according to a schedule or without a predetermined schedule. The active compound can be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily; once every 2, 3, 4, 5, or 6 days; once, 1, 2, 3, 4, 5, 6, or 7 times weekly; once, 2, 3, 4, 5, or 6 times monthly; or once, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times annually. It should be understood that for any particular subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0196] While the attending physician will ultimately determine the appropriate amount and dosage regimen of the ATR inhibitor, the effective amount of the compounds disclosed herein may be a total daily dose between 0.05 mg and 3000 mg of any of the compounds described herein. Alternatively, the dosage may be calculated using the patient's weight. Such dosage ranges may include, for example, 0.05–1000 mg (e.g., 0.25–800 mg). In some embodiments, the compound is administered in doses of 0.05, 0.1, 0.25, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

[0197] Preferably, the subtherapeutic dose regimen of the ATR inhibitor is a low dose (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95% lower than the lowest standard recommended dose of the ATR inhibitor for a given route of administration).

[0198] ATR inhibitors may be administered once daily, 1 day / week, 2 days / week, 3 days / week, or 4 days / week. Preferably, the starting dose frequency of an ATR inhibitor (e.g., but not limited to carmenxetine) in a 21-day cycle is 3 days dosing / 4 days off, 2 weeks dosing / 1 week off (i.e., participants will take carmenxetine on days 1–3 [week 1] and days 8–10 [week 2]).

[0199] The dosage of PI3Kα inhibitors can be low (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95% lower than the lowest standard recommended dose of PI3Kα inhibitor for a given route of administration). PI3Kα inhibitors (e.g., but not limited to enoxalide) can be administered orally once daily, once a week, once a week, once a week, once a week, once a week, once a week, or once a week. Preferably, PI3Kα inhibitors (e.g., but not limited to enoxalide) have a daily dosing frequency.

[0200] In the methods of this disclosure, the time period for administering multiple doses of the disclosed compound to a patient can vary. For example, in some embodiments, the dose of the disclosed compound is administered to the patient over a time period of 1-7 days, 1-12 weeks, or 1-3 months. In other embodiments, the compound is administered to the patient over a time period of, for example, 4-11 months or 1-30 years. In other embodiments, the compound is administered to the patient at the onset of symptoms. In any of these embodiments, the amount of the compound administered can vary during the time period of administration. When the compound is administered daily, administration may occur, for example, once, two, or three times daily.

[0201] In this embodiment, the treatment cycle for carmenxetine consists of 3 weeks, and carmenxetine will be administered on specific dates as required for each dose level or extended cohort. In this embodiment, the starting dose and schedule for carmenxetine are as follows: 120 mg orally (PO) administered over a 21-day cycle, starting on day 1 of each week, with 3 days of treatment / 4 days off, followed by 2 weeks of treatment / 1 week off (i.e., participants will take carmenxetine on days 1–3 [week 1] and days 8–10 [week 2]). In this embodiment, alternative carmenxetine doses and schedules may be explored based on emerging data.

[0202] In this embodiment, enoxacillin was administered orally at home by the participants (except on research center visit days). In this embodiment, enoxacillin was administered orally once daily (QD) on days 1-21 of each 21-day cycle, starting at a dose of 6 mg.

[0203] In this embodiment, the maximum planned dose of the combination therapy will consist of a 21-day cycle of carmenxetine 160 mg PO for 3 days / 4 days off, 2 weeks on / 1 week off, and enoxacillin 9 mg PO daily.

[0204] preparation Compounds identified using any of the methods described herein as capable of treating any of the conditions described herein may be administered in unit dosage form to a patient or animal with a pharmaceutically acceptable diluent, carrier, or excipient. Compounds for such therapies may be produced and isolated using any standard techniques known in the field of medicinal chemistry. Suitable formulations or compositions may be provided using routine pharmaceutical practices to administer the identified compound to a subject in need. Administration may be initiated before the onset of symptoms in the patient.

[0205] Exemplary routes of administration for the compounds used in this disclosure (e.g., the compounds of this disclosure) or pharmaceutical compositions thereof include oral, sublingual, oral, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intravenous, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds are ideally administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein for the treatment of the conditions described herein are also part of this disclosure. Oral administration is a preferred route of administration in the methods of this disclosure.

[0206] Formulations for oral administration The pharmaceutical compositions covered by this disclosure include pharmaceutical compositions formulated for oral administration (“oral dosage forms”). Oral dosage forms may be in the form of, for example, tablets, capsules, liquid solutions or suspensions, powders, liquids, or solid crystals, and contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch (including potato starch), calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch (including potato starch), croscarmellose sodium, alginate, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-sticking agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0207] Formulations intended for oral administration may also be presented as chewable tablets, hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pellets may be prepared using conventional methods, such as mixers, fluidized bed apparatus, or spray drying equipment, in tablet and capsule form with the aforementioned ingredients.

[0208] Controlled-release compositions for oral administration can be constructed to release the active pharmaceutical ingredient by controlling the dissolution and / or diffusion of the active pharmaceutical substance. Any of a variety of strategies can be employed to obtain controlled release and targeted plasma concentration-time profiles. In one example, controlled release is achieved by appropriately selecting various formulation parameters and components, including, for example, various types of controlled-release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In some embodiments, the composition comprises a biodegradable pH- and / or temperature-sensitive polymer coating.

[0209] Controlled release of a compound can be achieved through appropriate coating of the compound into tablets, capsules, granules, or pellets, or by incorporating the compound into a suitable matrix. Controlled release coatings may include one or more of the coating substances described above and / or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3-butanediol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled release matrix formulations, matrix materials may also include, for example, hydrated methyl cellulose, carnauba wax and stearyl alcohol, carboplatin 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0210] The compounds and compositions disclosed herein can be incorporated into liquid forms for oral administration, including aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils, such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0211] In this embodiment, the maximum planned dose of the combination therapy will consist of a 21-day cycle of carmenxetine 160 mg PO for 3 days / 4 days off, 2 weeks on / 1 week off, and enoxacillin 9 mg PO daily.

[0212] Preparations for parenteral administration The compounds described herein for use in the methods of this disclosure can be administered in pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations as described herein. Pharmaceutical formulations may also be administered parenterally (intravenous, intramuscular, subcutaneously, etc.) in dosage forms or formulations containing conventionally non-toxic, pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes to make the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. For example, to prepare such compositions, the compounds of this disclosure can be dissolved or suspended in parenteral-acceptable liquid media. Acceptable media and solvents that can be used are water, water adjusted to a suitable pH by adding appropriate amounts of hydrochloric acid, sodium hydroxide, or suitable buffers, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives (e.g., methylparaben, ethylparaben, or n-propylparaben). Additional information about parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

[0213] The parenteral preparation may be any one of the five general types of preparations suitable for parenteral administration as identified by USP-NF: (1) "Drug injection": a liquid preparation or solution of a drug substance (e.g., a compound disclosed herein); (2) "Injectable drug": a drug substance (e.g., a compound disclosed herein) that is a dry solid and will be used in combination with a suitable sterile medium for parenteral administration as a drug injection; (3) "Injectable pharmaceutical emulsion": a liquid formulation of a pharmaceutical substance (e.g., a compound disclosed herein) dissolved or dispersed in a suitable emulsion medium; (4) "Injectable drug suspension": a liquid formulation of a drug substance (e.g., a compound of this disclosure) suspended in a suitable liquid medium; and (5) "Pharmaceutical for use in injectable suspension": A pharmaceutical substance (e.g., a compound of the present disclosure) as a dry solid will be combined with a suitable sterile mediator for parenteral administration as an injectable suspension of the pharmaceutical.

[0214] Exemplary parenteral formulations comprise solutions of compounds prepared in water appropriately mixed with surfactants such as hydroxypropyl cellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and oils. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth. Routine procedures and ingredients for selecting and preparing suitable formulations are described, for example, in: Remington: The Science and Practice of Pharmacy, 21st edition, edited by Gennaro, Lippincott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0215] Formulations for parenteral administration may contain, for example, excipients, sterile water or saline, polyalkylene glycols (e.g., polyethylene glycol), vegetable oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems for the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycolates, and deoxycholates, or may be oily solutions for administration in nasal drops or gel form.

[0216] Parenteral formulations can be formulated for immediate or sustained / delayed release of compounds. Exemplary formulations for parenteral release of compounds include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymer gels.

[0217] definition As used herein, the terms “carmenxetine,” “RP-3500,” or “compound 121” refer to a novel, potent, and selective inhibitor of an ATR. Carmenxetine is a potential candidate for the treatment of certain cancers. See, for example, NCT04497116. In some embodiments, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In some embodiments, the ATR inhibitor is the bisulfate salt of compound 121. In some embodiments, carmenxetine is the bisulfate salt of an ATR inhibitor.

[0218] As used herein, the terms “co-administered,” “administered together with,” “administered in combination with,” etc., encompass the administration of a selected therapeutic agent to a single patient and are intended to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times.

[0219] The term “progression-free survival (PFS)” refers to the time from the initiation of therapy to the first occurrence of disease progression or death from any cause (whichever occurs first). For the purposes of the clinical trials described in the examples, PFS is defined as the time from randomization of the study population to the first recorded disease progression or death from any cause. In some embodiments, administration of an ATR inhibitor and a PI3Kα inhibitor provides an increase in progression-free survival (e.g., but not limited to, cancer carrying one or more mutations in the PIK3CA gene) in subjects with cancer compared to subjects treated with an ATR inhibitor alone or without any inhibitor. An increase in progression-free survival refers to an increase in PFS in cancer patients treated with an ATR inhibitor and a PI3Kα inhibitor (e.g., but not limited to, patients with advanced solid tumors) relative to the PFS of cancer patients treated with an ATR inhibitor alone or without any inhibitor. In some embodiments, the increase in progression-free survival compared to that of subjects receiving an ATR inhibitor alone or without any inhibitor is an increase of approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 13 months, approximately 14 months, approximately 15 months, approximately 16 months, approximately 17 months, approximately 18 months, approximately 19 months, approximately 20 months, approximately 21 months, approximately 22 months, approximately 23 months, approximately 24 months, approximately 25 months, approximately 26 months, approximately 27 months, approximately 28 months, approximately 29 months, approximately 30 months, approximately 31 months, approximately 32 months, approximately 33 months, approximately 34 months, approximately 35 months, approximately 36 months, or approximately 36 months.

[0220] As used herein, the term “abnormal” means different from normal. When used to describe enzyme activity, abnormality refers to activity that is greater than or less than the average of normal or disease-free control samples. Abnormal activity can refer to a level of activity that causes disease, where restoring abnormal activity to a normal or non-disease-related level (e.g., by administering a compound or using methods as described herein) results in disease or a reduction in symptoms of one or more diseases. Abnormal activity can be measured by measuring modifications to the enzyme’s substrate; a difference in activity that is greater than or equal to 2-fold can be considered abnormal. Abnormal activity can also refer to an increased dependence on a specific signaling pathway due to defects in a single complementary pathway.

[0221] As used herein, the term "acyl" signifies a group –C(=O)–R, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclic group. The acyl group may optionally replace each respective R group as described herein.

[0222] As used herein, the term "adenocarcinoma" refers to a malignant tumor caused by glandular cells arranged in organs within an organism. Non-limiting examples of adenocarcinoma include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.

[0223] As used herein, the term "alkanoyl" refers to a hydrogen or alkyl group attached to a parent molecule group via a carbonyl group, and is exemplified by formyl (i.e., a carboxyl aldehyde group), acetyl, propionyl, butyryl, and isobutyryl. An unsubstituted alkanoyl group contains 1 to 7 carbons. The alkanoyl group may be unsubstituted or substituted (e.g., optionally substituted C1-7 alkanoyl), as described herein with respect to alkyl groups. A terminal "-acyl" may be added to another group defined herein, such as aryl, cycloalkyl, and heterocyclic groups, to define "aromatic acyl," "cycloalkanoyl," and "(heterocyclic)acyl." These groups represent carbonyl groups substituted with aryl, cycloalkyl, or heterocyclic groups, respectively. Each of "aromatic acyl," "cycloalkanoyl," and "(heterocyclic)acyl" may optionally be substituted, as defined herein with respect to "aryl," "cycloalkyl," or "heterocyclic."

[0224] As used herein, the term "alkenyl" refers to a non-cyclic, monovalent, straight-chain or branched hydrocarbon group containing one, two, or three carbon-carbon double bonds. Non-limiting examples of alkenyl groups include vinyl, propenyl, propenyl-2-enyl, 1-methylphenyl, butenyl, butenyl-2-enyl, butenyl-3-enyl, 1-methylpropenyl, 2-methylpropenyl, and 1-methylpropenyl-2-enyl. Alkenyl groups may optionally be substituted, as defined herein with respect to alkyl groups.

[0225] Unless otherwise stated, the term "alkoxy" as used herein refers to a chemical substituent of the formula – OR, where R is C 1-6 Alkyl groups. In some embodiments, alkyl groups may be further substituted as defined herein. The term “alkoxy” may be combined with other terms defined herein, such as aryl, cycloalkyl, or heterocyclic, to define “arylalkoxy,” “cycloalkylalkoxy,” and “(heterocyclic)alkoxy” groups. These groups represent alkoxy groups substituted with aryl, cycloalkyl, or heterocyclic groups, respectively. Each of “arylalkoxy,” “cycloalkylalkoxy,” and “(heterocyclic)alkoxy” may optionally be substituted as defined herein for each individual part.

[0226] As used herein, the term "alkoxyalkyl" denotes a chemical substituent of the formula –L–O–R, where L is C. 1-6 Alkylene, and R is C 1-6 Alkyl. Optionally substituted alkoxyalkyl is an Optionally substituted alkoxyalkyl, as described herein with respect to alkyl.

[0227] As used herein, the term "alkyl" refers to a non-cyclic straight-chain or branched saturated hydrocarbon group that, unless otherwise stated, has 1 to 12 carbons when unsubstituted. In some preferred embodiments, the unsubstituted alkyl group has 1 to 6 carbons. Examples of alkyl groups are methyl; ethyl; n-propyl and isopropyl; n-butyl, sec-butyl, isobutyl and tert-butyl; neopentyl, etc., and may be optionally substituted by one, two, three, or, for alkyl groups containing two or more carbon atoms, four or more substituents, where the valence state permits. These substituents are independently selected from the group consisting of: amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halogen; heterocyclic; (heterocyclic)oxy; heteroaryl; hydroxyl; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylthio; =O; =S; -SO2R (where R is amino or cycloalkyl); =NR' (where R' is H, alkyl, aryl or heterocyclic). Each substituent may itself be unsubstituted, or, where the valence state permits, substituted by an unsubstituted substituent as defined herein for each corresponding group.

[0228] As used herein, the term "alkylene" refers to a divalent alkyl group. Optionally substituted alkylenes are substituted alkylenes as described herein with respect to alkyl groups.

[0229] As used herein, the term "alkylamino" refers to an amino group having the formula -N(R N1 )2 or –NHR N1 The group, wherein R N1Alkyl groups are defined herein as such. The alkyl moiety of an alkylamino group may optionally be substituted, as defined herein for alkyl groups. Each optional substituent on a substituted alkylamino group may be unsubstituted itself, or, where the valence state permits, substituted with an unsubstituted substituent as defined herein for each corresponding group.

[0230] As used herein, the term "alkylthio" denotes a group of the formula –S–(alkyl). Alkylthio groups may optionally be substituted, as defined for alkyl groups.

[0231] As used herein, the term "alkylsulfinyl" denotes a group of the formula –S(O)–(alkyl). Alkylsulfinyl groups may optionally be substituted, as defined for alkyl groups.

[0232] As used herein, the term "alkylsulfonyl" denotes a group of the formula -S(O)2–(alkyl). Alkylsulfonyl groups may optionally be substituted, as defined for alkyl groups.

[0233] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched hydrocarbon group containing two to six carbon atoms with at least one carbon-carbon triple bond, and is exemplified by ethynyl, 1-propynyl, etc. The alkynyl group may be unsubstituted or substituted (e.g., optionally substituted alkynyl), as defined with respect to alkyl.

[0234] As used herein, the term "amino" represents –N(R N1 )2, where if the amino group is unsubstituted, then the two R groups are... N1 All are H; or if the amino group is substituted, then each R N1 Independently, it can be H, -OH, -NO2, or -N(R) N2 )2、-SO2OR N2 -SO2R N2 -SOR N2 -COOR N2 N-protecting group, alkyl, alkenyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl or heterocyclic group, provided that at least one R N1 Not H, and each of R N2 Independently, it can be H, alkyl, or aryl. Each substituent may be unsubstituted or substituted with an unsubstituted substituent as defined herein for each respective group. In some embodiments, the amino group is an unsubstituted amino group (i.e., -NH2) or a substituted amino group (e.g., NHR). N1 ), where R N1 Independently -OH, -SO2OR N2 -SO2R N2 -SOR N2 -COOR N2Optionally substituted alkyl or Optionally substituted aryl, and each R N2 The amino group may be an optionally substituted alkyl or an optionally substituted aryl group. In some embodiments, the substituted amino group may be an alkylamino group, wherein the alkyl group is optionally substituted as described herein with respect to alkyl. In some embodiments, the amino group is –NHR. N1 , where R N1 The alkyl group can be optionally substituted.

[0235] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic system having one or two aromatic rings. An aryl group may comprise 6 to 10 carbon atoms. All atoms within an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indene, indene, etc. An aryl group may be unsubstituted or substituted by one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylthio; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halogen; heteroalkyl; heterocyclic; (heterocyclic)oxy; hydroxyl; nitro; thiol; silyl; and cyano. Each substituent may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each corresponding group.

[0236] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. The aryl and alkyl moiety may optionally be substituted with individual groups as described herein.

[0237] As used herein, the term "arylene" refers to a divalent aryl group. Optionally substituted arylene groups are those that are optionally substituted, as described herein with respect to aryl groups.

[0238] Unless otherwise stated, the term “aryloxy” as used herein refers to a chemical substituent of the formula – OR, where R is an aryl group. In optionally substituted aryloxy groups, the aryl group is optionally substituted, as described herein with respect to the aryl group.

[0239] As used in this article, the term "ATM" refers to ATM serine / threonine kinase.

[0240] As used herein, the term "ATR inhibitor" or "ATRi" refers to a compound that, when exposed to ATR kinase in vitro, in cell culture, or in vivo in animals, reduces the activity of ATR kinase, thereby reducing the measured IC50 of ATR kinase. 50The concentration is 10 µM or lower (e.g., 5 µM or lower, or 1 µM or lower). For some ATR inhibitors, the ATR kinase IC50 is... 50 It can be 100 nM or lower (e.g., 10 nM or lower or 1 nM or lower) and can be as low as 100 pM or 10 pM. Preferably, ATR kinase IC 50 The range is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0241] As used in this article, the term "ATR kinase" refers to ataxia-telangiectasia and Rad-3-related protein kinase.

[0242] As used herein, the term "azido" refers to the -N3 group.

[0243] As used in this article, the term "BRCA2" refers to a gene or protein that makes individuals susceptible to type 2 breast cancer.

[0244] As used herein, the term "cancer" refers to all types of cancer, tumors, or malignant tumors found in mammals, such as humans, including leukemia, carcinoma, and sarcoma. Non-limiting examples of cancers that can be treated with the compounds or methods provided herein include prostate cancer, thyroid cancer, endocrine system cancers, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, and pancreatic cancer. Additional non-limiting examples may include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid tumor, urobladder cancer, malignant prostomy lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, and prostate cancer.

[0245] As used herein, the term "carbocyclic" refers to an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the ring, which may be aromatic or non-aromatic, is formed from carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloynyl, and certain aryl groups.

[0246] As used herein, the term "carbonyl" refers to a –C(O)– group.

[0247] As used in this article, the term “cancer” refers to a malignant new growth consisting of epithelial cells that tend to infiltrate surrounding tissues and cause metastasis. Non-limiting examples of cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenoma-like carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, body carcinoma, cribriform carcinoma, armored carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, tubular carcinoma, sclerosing carcinoma, embryonal carcinoma, cerebral carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gel carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma (carcinoma gigantocellulare), adenocarcinoma, granular cell carcinoma, pilostromal carcinoma, polycythemia carcinoma, hepatocellular carcinoma, Hurthle Cellular carcinoma, clear carcinoma, adrenal carcinoma, infantile embryonic carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipoma carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma muciparum, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, papillary carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatous carcinoma, Schneiderian carcinoma, scleroderma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma. Carcinoma, spherical cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, filamentous carcinoma, telangiectatic carcinoma, telangiectasia carcinoma, transitional cell carcinoma, nodular carcinoma, tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0248] As used herein, the term "cyano" refers to the –CN group.

[0249] Unless otherwise stated, the term "cycloalkenyl" as used herein refers to a non-aromatic carbocyclic group having at least one double bond in a ring and having three to ten carbons (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C60 3-10 (Cycloalkenyl). Non-limiting examples of cycloalkenyl groups include cyclopropenyl-1-enyl, cyclopropenyl-2-enyl, cyclobutenyl-1-enyl, cyclobutenyl-1-enyl, cyclobutenyl-2-enyl, cyclopentenyl-1-enyl, cyclopentenyl-2-enyl, cyclopentenyl-3-enyl, norbornenyl-1-enyl, norbornenyl-2-enyl, norbornenyl-5-enyl, and norbornenyl-7-enyl. The cycloalkenyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl), as described with respect to cycloalkyl groups.

[0250] As used herein, the term "cycloalkenylalkyl" refers to an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl moieties may be substituted with individual groups as defined herein.

[0251] Unless otherwise stated, the term "cycloalkoxy" as used herein refers to a chemical substituent of the formula – OR, where R is a cycloalkyl group. In some embodiments, the cycloalkyl group may be further substituted as defined herein.

[0252] Unless otherwise stated, the term "cycloalkyl" as used herein refers to a cycloalkyl group having three to ten carbons (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C60 3-C10Cycloalkyl groups can be monocyclic or bicyclic. Bicyclic cycloalkyl groups can be of the bicyclic [pq0]alkyl type, wherein each of p and q is independently 1, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, bicyclic cycloalkyl groups can include bridged cycloalkyl structures, such as bicyclic [pqr]alkyl, wherein r is 1, 2, or 3, and each of p and q is independently 1, 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. Cycloalkyl groups can be spirocyclic groups, such as spiro[pq]alkyl, wherein each of p and q is independently 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1.]heptyl, 2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1.]heptyl, 7-bicyclo[2.2.1.]heptyl and decahydronaphthyl. The cycloalkyl group may be unsubstituted or substituted by one, two, three, four or five independently selected substituents from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylthio; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halogen; heteroalkyl; heterocyclic; (heterocyclic)oxy; heteroaryl; hydroxyl; nitro; thiol; silyl; cyano; =O; =S; -SO2R, where R is amino or cycloalkyl; =NR', where R' is H, alkyl, aryl or heterocyclic; or -CON(R A )2, where each R A Independently H or alkyl, or two R A Together with the atoms to which they are attached, they form a heterocyclic group. Each substituent may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each corresponding group.

[0253] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl moiety may optionally be substituted with the individual groups described herein.

[0254] As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl group. Optionally substituted cycloalkylene groups are substituted cycloalkylene groups as described herein with respect to cycloalkylene groups.

[0255] Unless otherwise stated, the term "cycloynyl" as used herein refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having eight to twelve carbons. A cycloynyl group may include a transcyclic bond or bridge. Non-limiting examples of cycloynyl groups include cyclooctyynyl, cyclononyynyl, cyclodecynyl, and cyclodecadiynyl. The cycloynyl group may be unsubstituted or substituted (e.g., optionally substituted cycloynyl), as defined for cycloalkyl groups.

[0256] As used in this article, the term "halogenated" refers to a halogen selected from bromine, chlorine, iodine, and fluorine.

[0257] As used herein, the term "heteroalkyl" refers to an alkyl, alkenyl, or alkynyl group that is interrupted once by one or two heteroatoms; interrupted twice independently by one or two heteroatoms each time; interrupted three times independently by one or two heteroatoms each time; or interrupted four times independently by one or two heteroatoms each time. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. None of the heteroalkyl groups includes two consecutive oxygen or sulfur atoms. The heteroalkyl group may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When a heteroalkyl group is substituted and a substituent is bonded to a heteroatom, the substituent is selected according to the nature and valence state of the heteroatom. Thus, where the valence state allows, the substituent bonded to the heteroatom is selected from the group consisting of: =O, -N(R N2 )2、-SO2OR N3 -SO2R N2 -SOR N3 -COOR N3 N protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic or cyano, wherein each R N2 Independently H, alkyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, or heterocyclic, and each R N3 Independently, they are alkyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, or heterocyclic groups. Each of these substituents may be unsubstituted itself or substituted by an unsubstituted substituent as defined herein for each respective group. When a heteroalkyl group is substituted and the substituent is bonded to a carbon atom, the substituent is selected from those described for the alkyl group, provided that the substituent bonded to the carbon atom of the heteroatom is not Cl, Br, or I. It should be understood that the carbon atom is found at the end of the heteroalkyl group.

[0258] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl moieties may optionally be substituted with individual groups as described herein.

[0259] As used herein, the term "hybrid aryl" refers to a divalent heteroaryl. Optionally substituted heteroaryl is an optionally substituted heteroaryl, as described herein with respect to heteroaryl.

[0260] As used herein, the term "heteroaryloxy group" refers to the structure –OR, where R is a heteroaryl group. Heteroaryloxy groups may optionally be substituted, as defined for heterocyclic groups.

[0261] Unless otherwise stated, the term "heterocyclic group" as used herein refers to a monocyclic, bicyclic, tricyclic, or tetracyclic system having fused, bridged, and / or spirocyclic 3-, 4-, 5-, 6-, 7-, or 8-membered rings, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, "heterocyclic group" is a monocyclic, bicyclic, tricyclic, or tetracyclic system having fused or bridged 5-, 6-, 7-, or 8-membered rings, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless otherwise stated. Heterocyclic groups can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclic groups have zero or one double bond, non-aromatic 6- and 7-membered heterocyclic groups have zero to two double bonds, and non-aromatic 8-membered heterocyclic groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Unless otherwise specified, heterocyclic groups comprise 1 to 16 carbon atoms. Some heterocyclic groups may comprise up to 9 carbon atoms. Non-aromatic heterocyclic groups include pyrrolinyl, pyrrolylalkyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, thiomorpholinyl, thiazolinyl, isothiazolyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, dihydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyranyl, dihydropyranyl, dithiazolinyl, etc. If the heterocyclic system has at least one aromatic resonance structure or at least one aromatic tautomer, then such a structure is an aromatic heterocyclic group (i.e., a heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophene, furanyl, imidazolyl, indolyl, isoyindolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purine, pyrroleyl, pyridyl, pyrazinyl, pyrimidinyl, quinazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazolyl), thiazolyl, thiophene, triazolyl, tetrazolyl, etc. The term "heterocyclic group" also refers to a heterocyclic compound having a bridging polycyclic structure in which one or more carbons and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as quinine ring, tropane, or diazabicyclo[2.2.2]octane. The term "heterocyclic group" includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the aforementioned heterocycles is fused to one, two, or three carbon rings, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, or another monocyclic heterocycle. Examples of fused heterocyclic groups include 1,2,3,5,8,8a-hexahydroindoleazine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene.The heterocyclic group may be unsubstituted or substituted by one, two, three, four, five, or six independently selected substituents from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylthio; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halogen; heteroalkyl; heterocyclic; (heterocyclic)oxy; hydroxyl; nitro; thiol; silyl; cyano; =O; =S; =NR', where R' is H, alkyl, aryl, or heterocyclic. Each substituent may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each corresponding group.

[0262] As used herein, the term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, each as defined herein. The heterocyclic and alkyl moieties may optionally be substituted with individual groups as described herein.

[0263] As used herein, the term "subheterocyclic group" refers to a divalent heterocyclic group. Optionally substituted subheterocyclic groups are optionally substituted subheterocyclic groups, as described herein with respect to heterocyclic groups.

[0264] Unless otherwise stated, the term “(heterocyclic)oxy group” as used herein refers to a chemical substituent of the formula – OR, where R is a heterocyclic group. The (heterocyclic)oxy group may optionally be substituted in the manner described for heterocyclic groups.

[0265] As can be used interchangeably in this article, the terms "hydroxyl" and "hydroxyl" refer to the -OH group.

[0266] As used herein, the term "isotopically enriched" refers to a pharmaceutically active agent having an isotopic abundance of an isotope at a predetermined position within the molecule, which is at least 100 times the natural abundance of that isotope. For example, a composition isotopically enriched for deuterium comprises an active agent having at least one hydrogen atom position, having a deuterium abundance at least 100 times the natural deuterium abundance. Preferably, the isotopic enrichment of deuterium is at least 1000 times the natural deuterium abundance. More preferably, the isotopic enrichment of deuterium is at least 4000 times (e.g., at least 4750 times, e.g., up to 5000 times) the natural deuterium abundance.

[0267] As used herein, the term “leukemia” refers to a progressive malignant disease of the hematopoietic organs and is typically characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is clinically classified based on: (1) the duration and characteristics of the disease: acute or chronic; (2) the cell type involved: myeloid, lymphoid, or monocytic; and (3) whether the number of abnormal cells in the blood leukemia or leukemia (subleukemia) is increased or not increased. Leukemias treatable with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, and adult T-cell leukemia. Leukemia, Leukemia, Leukocytic Leukemia, Basophilic Leukemia, Leukemia of the Bacteroidetes, Bovine Leukemia, Chronic Myeloid Leukemia, Cutaneous Leukemia, Embryonic Leukemia, Eosinophilic Leukemia, Gross Leukemia, Hairy Cell Leukemia, Hematopoietic Leukemia, Hematologic Leukemia, Histiocytic Leukemia, Stem Cell Leukemia, Acute Monocytic Leukemia, Leukopenic Leukemia, Lymphocytic Leukemia, Lymphoblastic Leukemia, Cellular Leukemia, Lymphoblastic Leukemia Leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, microcytic leukemia, monocytic leukemia, myeloblastic leukemia, granulocytic leukemia, myeloid granulocytic leukemia, chronic myeloid monocytic leukemia, Negri leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Reed cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0268] As used herein, the term “lymphoma” refers to cancer arising from immune-derived cells. Non-limiting examples of T-cell and B-cell lymphomas include non-Hodgkin's lymphoma and Hodgkin's disease, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, small cell lymphocytic lymphoma-chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma-Waldenstrom macroglobulinemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL) / follicular T-cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), or extranodal nasal NK / T-cell lymphoma.

[0269] As used herein, the term "melanoma" refers to a tumor arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentigines melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, fungal melanoma, and superficial diffuse melanoma.

[0270] As used in this article, the term "nitro" refers to the -NO2 group.

[0271] As used herein, the term “oxo” refers to a divalent oxygen atom (e.g., the structure of an oxo atom can be shown as =O).

[0272] As used herein, the term "PI3Kα inhibitor" refers to any PI3K inhibitor that targets the p110α catalytic subunit of PI3K. In some embodiments, the PI3Kα inhibitor specifically targets only p110α. In some embodiments, the PI3Kα inhibitor specifically targets p110α in addition to targeting one or more other subunits (i.e., p110β and p110δ). In some embodiments, the PI3Kα inhibitor is selected from the group consisting of: enoxacillin, apelelis, threliscillin, HH-CYH33, BAY1082439, ON 146040, AMG 511, bupanicillin, datoliscillin, pitilis, and taceliliscillate. In some embodiments, the PI3Kα inhibitor is represented by compound (III): , (III) and its stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, wherein: R 1 Selected from -CH3, -CH2CH3, cyclopropyl, and cyclobutyl; R 2 Selected from —CH3, —CHF2, —CH2F and —CF3.

[0273] As used herein, the term "inalilex" refers to a specific PI3K inhibitor targeting the p110α catalytic subunit of PI3K. Inalilex is named (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide and has the following structure: .

[0274] Inalice was previously described as compound 101 in U.S. Patent No. 9,650,393, which is incorporated herein by reference in its entirety.

[0275] As used in this article, the term "Ph" refers to phenyl.

[0276] As used herein, the term "pharmaceutical composition" means a composition comprising a compound described herein formulated with pharmaceutically acceptable excipients. It may be manufactured or marketed as part of a therapeutic dosage regimen for the treatment of mammalian diseases, subject to approval by a regulatory authority. For example, the pharmaceutical composition may be formulated for oral administration in unit dosage forms (e.g., tablets, capsules, small capsules, gels, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.

[0277] As may be used interchangeably herein, the terms "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" refer to any component other than the compounds described herein (e.g., a mediator capable of suspending or dissolving the active compound) and have non-toxic and non-inflammatory properties in patients. Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydrates. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0278] As used herein, the term "pharmaceutically acceptable salt" means that, within reasonable medical judgment, it is suitable for contact with human and animal tissues without excessive toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutical salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (edited by PHStahl and CGWermuth), Wiley-VCH, 2008. Salts may be prepared in situ during the final isolation and purification of the compounds described herein, or prepared separately by reacting a free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, gluconate, glyceryl phosphate, guanidine sesquisulfate, heptarate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. In the examples, carmenxetine is presented in the form of a pharmaceutically acceptable salt as described herein. In the examples, carmenxetine is present in the form of a hydrogen sulfate. The hydrogen sulfate form of carmenxetine was previously described as Example 121 in International Application PCT / CA2022 / 050892, which is incorporated herein by reference in its entirety.

[0279] As used herein, the term "protecting group" refers to a group intended to protect a hydroxyl, amino, or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. As used herein, the term "O-protecting group" refers to a group intended to protect a hydroxyl or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. As used herein, the term "N-protecting group" refers to a group intended to protect a nitrogen-containing group (e.g., amino, amide, heterocyclic NH, or hydrazine) from participating in one or more undesirable reactions during chemical synthesis. Commonly used O-protecting and N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O-protecting groups and N-protecting groups include alkyl, aromatic, or carbamoyl groups, such as formyl, acetyl, propionyl, neopentyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, tert-butyldimethylsilyl, triisopropylsilyloxymethyl, 4,4'-dimethoxytrimethylyl, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylformamide, and 4-nitrobenzoyl.

[0280] Exemplary O-protecting groups for protecting carbonyl groups include, but are not limited to: acetals, carbonyl acetals, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolane, and 1,3-dithiopentane.

[0281] Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl-alkyl ethers (e.g., triphenylmethyl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; tert-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., Trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; tert-butyldimethylsilyl; tert-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenylmethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).

[0282] Other N-protecting groups include, but are not limited to: chiral auxiliaries, such as protected or unprotected D, L, or D, L-amino acids, such as alanine, leucine, phenylalanine, etc.; sulfonyl groups, such as benzyl sulfonyl, p-toluenesulfonyl, etc.; carbamate forming groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 Trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, etc.; aryl-alkyl groups, such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, etc.; silylalkyl acetal groups, such as [2-(trimethylsilyl)ethoxy]methyl and silyl groups, such as trimethylsilyl, etc. Useful N-protecting groups include formyl, acetyl, benzoyl, neopentyl, tert-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), tert-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0283] The term "sarcoma" generally refers to a tumor composed of material such as embryonic connective tissue, and typically consists of tightly packed cells embedded in fibrils or homogeneous material. Non-limiting examples of sarcomas that can be treated with the compounds or methods provided herein include, for example, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multichromosomal hemorrhage sarcoma, B-cell immunoblastic sarcoma, T... Cellular immunoblastic sarcoma, Janson's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant stromal tumor sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and capillary dilatational sarcoma.

[0284] The term "tautomer" refers to structural isomers that readily interconvert, typically through proton repositioning. Tautomers are distinct chemical substances that can be identified by their different spectroscopic properties but are generally not separable individually. Non-limiting examples of tautomers include keto-enols, enamine-imines, amide-imines, nitroso-oximes, keto-alkynols, and amino acid-carboxylic acids.

[0285] As used herein, the term "therapeutic effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt thereof sufficient to treat cancer in a combination of an ATR inhibitor and a PI3Kα inhibitor. Typically, a therapeutic effective amount is a subtherapeutic dose regimen.

[0286] As used herein, the term "subject" means a person or non-human animal (e.g., a mammal) suffering from or at risk of a disease or symptom, as determined by a qualified professional (e.g., a physician or nurse practitioner) with or without laboratory testing of a subject sample known in the art. Preferably, the subject is a human. Non-limiting examples of diseases and symptoms include diseases with symptoms of excessive cell proliferation, such as cancer.

[0287] As used herein, the term "subtherapeutic dose regimen" refers to a dosing regimen that is at least 5% (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) lower than the lowest standard recommended dosing regimen for a specific compound formulated for a given route of administration for the treatment of cancer. A subtherapeutic dose regimen of a compound may be therapeutically ineffective for the compound in a monotherapy regimen. In the methods of this disclosure, a therapeutically effective amount of a PI3Kα inhibitor is preferably a subtherapeutic dose regimen (e.g., a regimen ineffective for a PI3Kα inhibitor in a monotherapy regimen). A subtherapeutic dose regimen for formulating a PI3Kα inhibitor for oral administration may differ from a subtherapeutic dose regimen for formulating the same agent for intratumoral administration. Subtherapeutic dose regimens may include a "subtherapeutic starting dose regimen" and a "subtherapeutic maintenance dose regimen." A "subtherapeutic starting dose regimen" of a compound (e.g., a PI3Kα inhibitor) is lower than the lowest standard starting dose of the same compound (e.g., a PI3Kα inhibitor). Similarly, a "subtherapy maintenance dose regimen" for a compound (e.g., a PI3Kα inhibitor) is lower than the minimum standard maintenance dose regimen for the same compound (e.g., a PI3Kα inhibitor). Typically, a subtherapy maintenance dose regimen is at least 1% of the minimum standard subtherapy maintenance dose regimen.

[0288] As used herein, “treatment / treating” refers to the medical management of a subject with the intent to improve, alleviate, stabilize, prevent, or cure a disease or symptom. This term includes active treatment (treatment aimed at improving a disease or symptom); causal treatment (treatment addressing the cause of the related disease or symptom); palliative treatment (treatment aimed at relieving the symptoms of a disease or symptom); preventative treatment (treatment aimed at minimizing or partially or completely suppressing the development of a related disease or symptom); and supportive treatment (treatment used to complement another therapy). A disease or symptom can be cancer. Non-limiting examples of cancer include, for example, renal cell carcinoma, mature B-cell tumors, endometrial cancer, ovarian cancer, colorectal cancer, skin cancer (non-melanoma), small bowel cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, and esophageal and gastric cancer.

[0289] The terms “uM” or “µM” are used interchangeably throughout this disclosure, including in the accompanying drawings and / or illustrations. The term “uM” or “µM” stands for “micromolar (micromolars per liter)”.

[0290] If any publication incorporated herein by reference contains a definition that is inconsistent with the definition presented herein, the latter definition shall prevail.

[0291] The following examples are intended to illustrate this disclosure. They are not intended to limit this disclosure in any way.

[0292] Example Example 1: Synergistic effects of ATR inhibitors and PI3Kα inhibitors in various cancer cell lines ATR inhibitors (e.g., compound 121) can synergize with PI3Kα inhibitors (e.g., enoxaparin) in cancer cell lines (e.g., wild-type MCF7 and HCC1954 p110α, and mutant MCF7 p110α E545K and HCC1954 H1074R p110α cell lines). Therefore, the epigenetic IC50 of PI3Kα inhibitors... 50 It may change in the presence of an ATR inhibitor (e.g., compound 121). The ATR inhibitor mentioned herein and throughout this disclosure may be the hydrogen sulfate salt of compound 121.

[0293] In addition to selecting a genetic background for sensitization, optimizing the dosing schedule can improve tolerability of combination therapy with ATR inhibitors and PI3Kα inhibitors. To guide the combination dosing of an ATR inhibitor (e.g., compound 121) with a PI3Kα inhibitor (e.g., enallixetine), longer consecutive concomitant treatments of both compounds can be compared to shorter treatments, followed by removal of the compounds and growth in drug-free medium. The presence of an ATR inhibitor (e.g., compound 121) reduces the apparent IC50 of the PI3Kα inhibitor (e.g., enallixetine) during longer consecutive dosing periods (e.g., 168 h). 50 Value. When treatment is shortened, epigenetic IC may not be observed. 50 The significant difference in values ​​suggests that the intermittent dosing schedule of the combination of an ATR inhibitor (e.g., compound 121) and a PI3Kα inhibitor (e.g., inalipse), along with the subsequent recovery period, can be effective. If the above results are observed, they would indicate that, compared to standard treatment regimens, reduced doses of PI3Kα and ATR inhibitors can treat tumor cells with specific genetic makeup for a shorter duration while maintaining efficacy.

[0294] Example 2: Inhibitory and synergistic effects of the combination of inaglithioprine and carmenecitabine The metabolic effects of p110α inhibitors are hypothesized to synergize with DNA damage repair inhibitors. p110α inhibits depleted nucleotide pools, thereby increasing replication stress and susceptibility to DNA damage repair inhibitors (e.g., ATRi and PARPi). Additionally, promising results have been observed in EPIK-O / ENGOT-OV61 with the combination of PI3Ki and PARP in platinum-resistant or refractory high-grade serous ovarian cancer without germline BRCA mutations, using apelecilis plus olaparib in conjunction with cytotoxic chemotherapy (phase III study).

[0295] The inhibitory and synergistic effects of the combination of enoxacillin and carmenxetine were investigated using a 72-hour CellTiter-Glo survival assay and wild-type and p110α mutant breast cancer cell lines (MCF7 and HCC1954) derived from Cell Central. The parental MCF7 and HCC1954 cell lines were intrinsically PIK3CA mutants. These cell lines were engineered to express WT p110α. Increasing the dose of enoxacillin + carmenxetine decreased cell survival in both wild-type and mutant MCF7 cells, with higher sensitivity observed in mutant PIK3CA cells. A similar pattern was observed in both BRCA1 mutant / p110α wild-type and BRCA1 mutant / p110α mutant breast cancer cells (HCC1954).

[0296] Figure 1 shows ATP-based percentage of cell viability (y-axis) versus different dose levels of carmenereol and enoxacillin in p110α wild-type and mutant MCF7 cells. Each line represents a different dose level of enoxacillin. The y-axis shows the proportion of increased carmenereol dose. The results in Figure 1 indicate that the combination of carmenereol and enoxacillin reduces cell viability in both wild-type and mutant MCF7 cells, with higher sensitivity observed in mutant cells.

[0297] Figure 2 shows a contour plot of the synergistic effect score (y-axis) of icoplanin doses versus the dose levels of carmenereol and icoplanin in combination in p110α wild-type and mutant MCF7 cells. Areas marked with "+" indicate the combined doses with the maximum synergistic effect. The results in Figure 2 show a similar pattern of drug synergism observed in the combination of carmenereol and icoplanin in both wild-type and mutant MCF7 cells.

[0298] Figure 3 shows ATP-based percentage of cell viability (y-axis) versus different dose levels of carmenereol and enoxaparin in p110α wild-type and mutant HCC1954 cells. Each colored line represents a different dose level of enoxaparin. The y-axis shows the proportion of increased carmenereol dose. The results in Figure 3 indicate that the combination of carmenereol and enoxaparin reduces cell viability in both BRCA1 mutant / p110α wild-type and BRCA1 mutant / p110α mutant cells.

[0299] Figure 4 shows a contour plot of the synergistic effect score (y-axis) of inalipate doses versus the dose levels of carmenereol and inalipate in combination in p110α wild-type and mutant HCC1954 cells. Areas marked with "+" indicate the combined doses with the maximum synergistic effect. The results in Figure 4 show that the combination of carmenereol and inalipate exhibits a similar pattern of synergistic drug action in both BRCA1 mutant / p110α wild-type and BRCA1 mutant / p110α mutant cells.

[0300] Figure 5 shows Western blot images of the expression of relevant DNA damage repair proteins in untreated and treated (carmenxetine and inalipse) MCF7 and HCC1954 cells. Iinalipse + carmenxetine treatment induced DNA damage in both p110α mutant and wild-type cells. However, compared to wild-type cells, it particularly induced an increase in γH2AX in the PIK3CAm cell line. The results in Figure 5 indicate that inalipse treatment resulted in a greater increase in pATR and γH2AX in the PIK3CAm cell line compared to wild-type cells.

[0301] Example 3: Phase Ib study of the combination of carmenseloti and enalise Patient selection The eligibility criteria for selecting key research areas are as follows: • Age ≥ 18 years old • Metastatic / unresectable solid tumors for which standard treatment is not available • ≥ 1 previous treatment line.

[0302] • Available tumor tissue samples • Measurable diseases according to RECIST v1.1 • Allow previous PARPi • No previous ATRi • No untreated CNS tumors Original EP ● Safety / Tolerability Level 2 EP ● ORR, DoR, PFS, 6-month PFS, OS Due to unmet needs and promising data from previous apelelis trials, various cancer types (such as, but not limited to, prostate cancer, breast cancer, and ovarian cancer) could be selected as key indications for the combination of inaliprine and carmenxetine.

[0303] The purpose of this Phase Ib multicenter, open-label study is to evaluate the safety, tolerability, antitumor activity, pharmacokinetics, and biomarkers of the combination of carmenxetine and inalipate, and to determine the recommended dose for further development in patients with one or more mutations in the PIK3CA gene (e.g., but not limited to patients with advanced solid tumors) who have received prior systemic therapy.

[0304] The dose-escalation portion (Phase I) of the sub-study will assess safety, tolerability, and pharmacokinetics, and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and schedule for the carmenxetine / inalilex combination. At each dose level, participants will receive carmenxetine and inalilex at the planned doses, as shown in Table 2.

[0305] Table 2. Planned Dosage Elevation Phase Regimen The dose extension portion (Phase II) of the sub-study will further evaluate the safety, tolerability, antitumor activity, pharmacokinetics, and biomarkers of the combination at one or more dose levels equal to or below the MTD or MAD of the combination determined in the dose escalation phase.

[0306] The participants will be 18 years of age or older. The number of participants will be approximately 27 in Phase I and approximately 20-30 in each cohort in Phase II.

[0307] Figure 6 illustrates the study protocol for the combined administration of carmenxetine and enoxaphene. This study protocol includes both dose escalation and dose extension.

[0308] Figure 7 illustrates the individual participant regimen for Phase I dose escalation. Abbreviations: ATRi = ataxia-telangiectasia-mutant and rad-3-related inhibitor; DNA-PKi = DNA-dependent protein kinase inhibitor; PO = oral, via oral cavity; Q90D = every 90 days; RECIST = criteria for evaluating response in solid tumors. Note: Dosage and / or schedule for each agent may vary depending on the open cohort at the time of participant allocation. a The starting dose is carmenxetine 120 mg PO, administered for 3 days and stopped for 4 days, followed by 2 weeks of treatment and 1 week of treatment, combined with enoxacillin 6 mg PO QD.

[0309] Dosage escalation Dose escalation (for carmenxetine) will follow a Bayesian optimal interval (BOIN) design. The Bayesian optimal interval (BOIN) design is a class of model-assisted dose-finding designs used in oncology trials to determine the maximum tolerated dose (MTD) of an investigational drug based on safety or the optimal biological dose (OBD) based on safety and efficacy. BOIN designs provide a complete suite for dose discovery in early-stage trials, offering a consistent approach to exploring different scenarios such as toxicity, efficacy, sustained outcomes, delayed toxicity or efficacy, and drug combinations, and are easy to implement with software. Although based on a Bayesian probabilistic model, BOIN designs are generally simple to operate and exhibit good statistical operability compared to other dose-finding designs. A schematic diagram of the dose escalation rule is outlined in Figure 8.

[0310] The planned starting doses for the Phase I study were carmenxetine 120 mg PO for 3 days / 4 days / 2 weeks / 1 week in a 21-day cycle, and enoxacillin 6 mg PO daily. The selection of the starting doses and schedules was based on an integration of several factors, including the pharmacologically active dose range of each agent as a monotherapy, and the potential overlapping toxicities between carmenxetine and enoxacillin (e.g., gastrointestinal toxicities and some possible hematological toxicities), which were expected to be clinically monitorable and manageable in patients.

[0311] Based on the differentiated mechanisms of action of carmenxetine and inalipse, in order to study the potential additive or synergistic effects of the combination, it is considered optimal for the starting dose of each drug to have sufficient inhibitory effect on their respective ATR and PI3K pathways.

[0312] Carmenxetine PK has been evaluated in patients with advanced cancer at doses ranging from 5 mg to 200 mg, and preliminary results indicate that doses of ≥120 mg QD are pharmacologically active.

[0313] Based on the mechanism of action, elimination pattern, and individual safety profiles of carmenxetine and enoxacillin, these combination drugs are not expected to produce serious unintended toxicities. Therefore, the maximum planned dose of the combination will consist of a single-therapy dose of carmenxetine 160 mg PO for 3 days / 4 days / 2 weeks / 1 week on, and enoxacillin 9 mg PO daily over a 21-day cycle.

[0314] Additional inclusion criteria Potential participants are eligible for inclusion in the carmenxetine + inalice study only if they meet all of the following criteria.

[0315] ● Histologically confirmed unresectable or metastatic solid tumors that are refractory to standard therapy or for which no standard therapy option exists.

[0316] ● The presence of PIK3CA mutations was confirmed by central testing of the submitted tumor tissue or local testing of the blood or tumor tissue.

[0317] ○ The definition of a PIK3CA mutation that meets the criteria is as follows: ■ R88Q ■ G106A / D / R / S / V ■ K111N / R / E ■ G118D ■ N345D / H / I / K / S / T / Y ■ C420R ■ E453A / D / G / K / Q / V ■ E542A / D / G / K / Q / R / V ■ E545A / D / G / K / L / Q / R / V ■ Q546E / H / K / L / P / R ■ M1043I / T / V ■ H1047D / I / L / N / P / Q / R / T / Y ■ G1049A / C / D / R / S Carmenseti The treatment cycle consists of 3 weeks, and carmenxetine will be administered on specific dates as required for each dose level or extended cohort. The initial carmenxetine dose and schedule are as follows: 120 mg orally (PO) administered over a 21-day cycle, starting on day 1 of each week, with 3 days of treatment / 4 days off, followed by 2 weeks of treatment / 1 week off (i.e., participants will receive carmenxetine on days 1–3 [week 1] and days 8–10 [week 2]). Alternative carmenxetine doses and schedules may be explored based on emerging data.

[0318] Carmenxetine is formulated in 40-mg strength capsules, and participants will self-medicate with approximately 240 mL (about 8 oz) of water at home (except on research center visit days). Participants should swallow the entire carmenxetine capsule and should not manipulate or chew the study drug before swallowing.

[0319] Participants will be instructed to take their carmenxetine dose at approximately the same time each morning. Participants will be instructed to postpone self-administration on the scheduled field visit day and take their study drug at the field. If a weekend visit cannot be accommodated at the field, the dosing schedule should be coordinated with the PK and biomarker sampling schedule. The planned dose should be taken on the same consecutive days of the week.

[0320] If a participant forgets to take a dose at the scheduled time, they should take the missed dose as soon as possible on the same day; however, there must be at least 8 hours between the missed dose and the next scheduled dose. If a dose is missed and there are less than 8 hours between the missed dose and the next scheduled dose, it should not be administered again, and the participant should record the missed dose in their medication diary. If a participant vomits during or after taking carmenxetine, a repeat dose is not permitted, and the participant should take the regular dose at the next scheduled dose.

[0321] Inarise Enalix will be administered orally at home by participants (except on research center visit days). Enalix will be administered orally once daily (QD) on days 1-21 of each 21-day cycle, starting with a dose of 6 mg.

[0322] Enallix should be taken at approximately the same time each day, regardless of mealtime. Because enallix is ​​a BCRP substrate and carmenxetine is a BCRP inhibitor, participants are advised to use a staggered dosing regimen on days when both are administered: take enallix first, followed by carmenxetine approximately 2 hours later. If a dose is missed (not taken within 9 hours of the scheduled dosing time), the participant should re-dose the next scheduled dose and record the missed dose in their medication diary. Missed or vomited doses will not be made up.

[0323] The total duration of individual participation in the study is expected to range from 1 day to more than 6 months.

[0324] Other embodiments Various modifications and variations of the invention will be apparent to those skilled in the art without departing from its scope and spirit. Although the invention has been described in conjunction with specific embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications to the described modes of implementation that will be apparent to those skilled in the art are intended to be within the scope of the invention.

[0325] Other embodiments are described in the claims.

Claims

1. A method of treating a subject with cancer, the method comprising administering to the subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the cancer is identified as having PIK3CA One or more mutations in.

2. The method according to claim 1, wherein the PI3Kα inhibitor is a compound of formula (III): ， (III) and its stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, wherein: R 1 Selected from -CH3, -CH2CH3, cyclopropyl, and cyclobutyl; R 2 Selected from —CH3, —CHF2, —CH2F and —CF3.

3. The method of claim 2, wherein R 1 It is -CH3 or cyclopropyl.

4. The method of claim 2, wherein R 2 It is -CHF2.

5. The method according to claim 1, wherein the PI3Kα inhibitor is a compound with the following structure: 。 6. The method according to claim 1, wherein the PI3Kα inhibitor is a compound with the following structure: 。 7. The method according to claim 1, wherein the PI3Kα inhibitor is a compound with the following structure: 。 8. The method according to claim 1, wherein the PI3Kα inhibitor is a compound with the following structure: 。 9. The method according to claim 1, wherein the PI3Kα inhibitor is a compound with the following structure: 。 10. The method of claim 1, wherein the PI3Kα inhibitor is a compound with the following structure: 。 11. The method according to claim 1, wherein the PI3Kα inhibitor is a compound with the following structure: 。 12. A method for treating a subject's cancer according to claim 1, the method comprising: (i) Identifying the cancer as having PIK3CA One or more mutations in; as well as (ii) Administer a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor to the subject in need.

13. The method according to any one of claims 1 to 12, wherein the ATR inhibitor is administered prior to the PI3Kα inhibitor.

14. The method according to any one of claims 1 to 12, wherein the ATR inhibitor is administered after the PI3Kα inhibitor.

15. The method according to any one of claims 1 to 12, wherein the ATR inhibitor is administered in combination with the PI3Kα inhibitor.

16. The method according to any one of claims 1 to 15, wherein the therapeutically effective amount is a subtherapeutic dose regimen of the ATR inhibitor.

17. The method according to any one of claims 1 to 16, wherein the therapeutically effective amount is a subtherapeutic dose regimen of the PI3Kα inhibitor.

18. The method of claim 16 or 17, wherein the subtherapy dosing regimen includes a starting dose that is at least 50% less than the minimum standard starting dose for monotherapy.

19. The method of any one of claims 16 to 18, wherein the sub-therapeutic dosing regimen includes a maintenance dose that is at least 50% less than the minimum standard maintenance dose for monotherapy.

20. The method of claim 19, wherein the maintenance dose comprises a first reduction dose.

21. The method of claim 19 or 20, wherein the maintenance dose comprises a second reduction dose.

22. The method according to any one of claims 19 to 21, wherein the maintenance dose comprises a third reduction dose.

23. The method according to any one of claims 1 to 22, wherein the route of administration is oral.

24. The method according to any one of claims 1 to 23, wherein the ATR inhibitor is administered at 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

25. The method according to any one of claims 1 to 24, wherein the PI3Kα inhibitor is administered at 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

26. An induction having PIK3CA A method for inducing cell death in one or more mutated abnormal cancer cells, the method comprising contacting the cells with an effective amount of an ATR inhibitor and an effective amount of an PI3Kα inhibitor, the effective amounts being sufficient to induce cell death in the abnormal cancer cells.

27. The method according to claim 26, wherein the PI3Kα inhibitor is a compound of formula (III): ， (III) and its stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, wherein: R 1 Selected from -CH3, -CH2CH3, cyclopropyl, and cyclobutyl; R 2 Selected from —CH3, —CHF2, —CH2F and —CF3.

28. The method according to any one of claims 1 to 27, wherein the cancer is a carrier. PIK3CA Any type of cancer with mutations.

29. The method according to any one of claims 1 to 27, wherein the patient is a person with PIK3CA Any patient with the mutation.

30. The method according to any one of claims 1 to 27, wherein the cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or advanced solid tumor.

31. The method according to any one of claims 1 to 27, wherein having PIK3CA The cancer is a solid tumor if one or more mutations are present in it.

32. The method according to any one of claims 1 to 27, wherein having PIK3CA The cancer is an advanced solid tumor if one or more mutations are present in it.

33. The method according to any one of claims 1 to 32, wherein the ATR inhibitor is a compound of formula (I): ， (I) Or its pharmaceutically acceptable salt. in It is a double bond, and each Y is independently either N or CR. 4 ;or It is a single bond, and each Y is independently NR. Y carbonyl or C(R) Y )2; where each R Y H independently or optionally substituted C 1-6 alkyl; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B The C is hydroxyl, optionally substituted. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

34. The method of claim 33, wherein the ATR inhibitor is a compound of formula (II): ， (II) Or its pharmaceutically acceptable salt. in Each Y is independently N or CR 4 ; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B The C is hydroxyl, optionally substituted. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two R 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

35. The method of claim 34, wherein R 2 It is a 5- to 10-membered bicyclic [pqr] heterocyclic group.

36. The method of claim 34, wherein R 2 for , , or .

37. The method of claim 34, wherein R 2 for 。 38. The method of claim 33, wherein the ATR inhibitor is selected from the group consisting of compounds 43, 57, 62, 87, 93, 94, 95, 99, 100, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 135, 147, 148 and pharmaceutically acceptable salts thereof.

39. The method of claim 38, wherein the ATR inhibitor is compound 43 or a pharmaceutically acceptable salt thereof.

40. The method of claim 38, wherein the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof.

41. The method according to claim 40, wherein compound 121 is a hydrogen sulfate.

42. The method of claim 40, wherein compound 121 is carmenthate.

43. The method of claim 38, wherein the ATR inhibitor is compound 122 or a pharmaceutically acceptable salt thereof.

44. The method according to any one of claims 38 to 43, wherein the pharmaceutically acceptable salt is a hydrogen sulfate.

45. The method according to any one of claims 1 to 44, wherein the cancer is renal cell carcinoma, mature B-cell tumor, endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, colorectal cancer, skin cancer, small bowel cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, esophageal and gastric cancer, solid tumor, single tumor type, or triple-negative breast cancer.

46. ​​The method according to any one of claims 1 to 45, wherein the PI3Kα inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

47. The method according to any one of claims 1 to 46, wherein the PI3Kα inhibitor is: (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide, (S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazo-2-yl)pyrrolidine-1,2-dicarboxamide), Or its pharmaceutically acceptable salt.

48. The method according to any one of claims 1 to 46, wherein the PI3Kα inhibitor is (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide or a pharmaceutically acceptable salt thereof.

49. The method according to any one of claims 1 to 48, wherein the PI3Kα inhibitor is inalipase, apelelis, threlisase, HH-CYH33, BAY1082439, ON 146040, AMG 511, buppanic acid, datolis, pitilis, tacelilis, a pharmaceutically acceptable salt thereof, or any combination thereof.

50. A method of treating a subject with cancer, the method comprising administering to the subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the cancer has been previously identified as having PIK3CA One or more mutated cancers, and wherein the PI3Kα inhibitor is inalipase, apelelis, threlisase, HH-CYH33, BAY1082439, ON 146040, AMG 511, bupanisic, datolisic, pitilis, and teselisic, a pharmaceutically acceptable salt thereof, or a combination thereof.

51. A method of treating a subject with cancer, the method comprising administering to the subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the cancer has PIK3CA One or more mutations in, and wherein the PI3Kα inhibitor is inalipase, apelelis, threlisase, HH-CYH33, BAY1082439, ON 146040, AMG 511, bupanisic, datolisic, pitilis, and teselisi, a pharmaceutically acceptable salt thereof, or a combination thereof.

52. A method for treating cancer in a subject, the method comprising: (i) Identifying the cancer as having PIK3CA One or more mutations in; as well as (ii) Administer to a subject in need a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kα inhibitor, wherein the PI3Kα inhibitor is analolisen, apelelix, threlisen, HH-CYH33, BAY1082439, ON 146040, AMG 511, bupanisic, datolix, pitilis, and teselixic, a pharmaceutically acceptable salt thereof, or a combination thereof.

53. The method according to any one of claims 50 to 52, wherein the ATR inhibitor is administered prior to the PI3Kα inhibitor.

54. The method according to any one of claims 50 to 52, wherein the ATR inhibitor is administered after the PI3Kα inhibitor.

55. The method according to any one of claims 50 to 52, wherein the ATR inhibitor is administered in combination with the PI3Kα inhibitor.

56. The method according to any one of claims 50 to 52, wherein the therapeutically effective amount comprises a subtherapeutic dose regimen of the ATR inhibitor.

57. The method according to any one of claims 50 to 56, wherein the therapeutically effective amount comprises a subtherapeutic dose regimen of the PI3Kα inhibitor.

58. The method of claim 56 or 57, wherein the subtherapy dosing regimen includes a starting dose that is at least 50% less than the minimum standard starting dose for monotherapy.

59. The method of any one of claims 56 to 58, wherein the sub-therapeutic dosing regimen includes a maintenance dose that is at least 50% less than the minimum standard maintenance dose for monotherapy.

60. The method of claim 59, wherein the maintenance dose comprises a first reduction dose.

61. The method of claim 59 or 60, wherein the maintenance dose comprises a second reduction dose.

62. The method according to any one of claims 59 to 61, wherein the maintenance dose comprises a third reduction dose.

63. The method according to any one of claims 50 to 62, wherein the route of administration is oral.

64. The method according to any one of claims 50 to 63, wherein the ATR inhibitor is administered at 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

65. The method according to any one of claims 50 to 64, wherein the PI3Kα inhibitor is administered at 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

66. An induction having PIK3CA A method for inducing cell death in one or more mutated abnormal cancer cells, the method comprising contacting the cells with an effective amount of an ATR inhibitor and an effective amount of a PI3Kα inhibitor, the effective amounts being sufficient to induce cell death in the abnormal cancer cells; wherein the PI3Kα inhibitor is enoxacillin, apelelis, threliscillin, HH-CYH33, BAY1082439, ON 146040, AMG 511, buppanisil, datolisil, pitilis, and teseliximab, a pharmaceutically acceptable salt thereof, or a combination thereof.

67. The method according to any one of claims 50 to 66, wherein the ATR inhibitor is a compound of formula (I): ， (I) Or its pharmaceutically acceptable salt. in It is a double bond, and each Y is independently either N or CR. 4 ;or It is a single bond, and each Y is independently NR. Y carbonyl or C(R) Y )2; where each R Y H independently or optionally substituted C 1-6 alkyl; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B The C is hydroxyl, optionally substituted. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two R 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

68. The method of claim 67, wherein the ATR inhibitor is a compound of formula (II): ， (II) Or its pharmaceutically acceptable salt. in Each Y is independently N or CR 4 ; R 1 C is an optional replacement 1-6 Alkyl or H; R 2 C is an optional replacement 2-9 Heterocyclic groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, –N(R) 5 2. –OR 5 –CON(R) 6 )2、–SO2N(R 6 )2、–SO2R 5A Or –Q–R 5B ; R 3 C is an optional replacement 1-9 heteroaryl or optionally substituted C 1-9 heteroaryl C 1-6 alkyl; Each R 4 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; Each R 5 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or –SO2R 5A Or two Rs 5 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 5A C can be substituted independently. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; R 5B The C is hydroxyl, optionally substituted. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, –N(R) 5 )2、–CON(R 6 )2、–SO2N(R 6 )2、–SO2R 5A Or optionally substituted alkoxy groups; Each R 6 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 6 They combine with the atoms they are attached to to form optionally substituted C atoms. 2-9 Heterocyclic groups; Q is an optional substitution for C 2-9 Heterocyclic groups, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroaryl or optionally substituted C 6-10 Alpha-aryl; and X is hydrogen or halogen.

69. The method of claim 68, wherein R 2 It is a 5- to 10-membered bicyclic [pqr] heterocyclic group.

70. The method of claim 69, wherein R 2 for , , or .

71. The method of claim 70, wherein R 2 for 。 72. The method of claim 67, wherein the ATR inhibitor is selected from the group consisting of compounds 43, 57, 62, 87, 93, 94, 95, 99, 100, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 135, 147, 148, and pharmaceutically acceptable salts thereof.

73. The method of claim 72, wherein the ATR inhibitor is compound 43 or a pharmaceutically acceptable salt thereof.

74. The method of claim 72, wherein the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof.

75. The method according to claim 74, wherein compound 121 is a hydrogen sulfate.

76. The method of claim 72, wherein the ATR inhibitor is carmenxetine or a pharmaceutically acceptable salt thereof.

77. The method of claim 72, wherein the ATR inhibitor is compound 122 or a pharmaceutically acceptable salt thereof.

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