Use of ATR inhibitors in combination with PI3k alpha inhibitors

Abstract

Disclosed are methods of treating a cancer in a subject using an ATR inhibitor and phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor, wherein the cancer has one or more mutations in PIK3CA. Also disclosed are methods of inducing cell death in an aberrant cancer cell having one or more mutations in PIK3CA, by contacting the cell with an effective amount of an ATR inhibitor and PI3Kα inhibitor.

Description

[0001] USE OF ATR INHIBITORS IN COMBINATION WITH PI3K ALPHA INHIBITORS

[0002] FIELD OF THE DISCLOSURE

[0003] The disclosure relates to combinations of at least one Ataxia-Telangiectasia and Rad-3-related protein (ATR) kinase inhibitors, pharmaceutically acceptable salts thereof, or pharmaceutical composition containing the same, and at least one phosphatidylinositol 3-kinase alpha (PI3Kct) inhibitors, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, and their use in the treatment of a disease or condition, such as a cancer.

[0004] BACKGROUND

[0005] DNA damage occurs continually in cells as a result of environmental insults including ultraviolet radiation, X-rays and endogenous stress factors, such as reactive oxygen and hydrolysis of bases. Cancer cells are subject to a higher rate of DNA damage inherently induced by higher rates 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 to act as a cellular checkpoint to stop the replication of cells with damaged DNA, allowing for repair functions to occur before the damaged DNA is passed on to daughter cells. Each of the identified DNA repair pathways sense and repair distinct but overlapping types of DNA damage.

[0006] One major DDR protein that acts as a key cell cycle checkpoint is the Ataxia- Telangiectasia mutated and Rad-3-related (ATR) kinase, related to the family of phosphoinositide 3-kinase-related protein kinases (PIKKs). ATR is activated by single stranded (ss) DNA lesions caused by stalled replication forks or during nucleotide excision repair but is also activated by double strand breaks following DNA end resection during homologous recombination. ATR is recruited to sites of DNA damage by binding to the RPA protein that coats ssDNA along with an accessory factor called ATR-interacting protein (ATRIP). The ATR / ATRIP complex is then activated by recruitment of additional factors in the 9-1-1 complex (RAD 9, RAD1, and HUS1) which subsequently recruits the TOPBP1 protein and represents critical steps for activation of the downstream phosphorylation cascade that results in cell cycle arrest. The primary target for ATR kinase is CHK1, which when phosphorylated, targets both cdc25 proteins and Wee1 resulting in inhibition of cyclin-dependent kinase activity and cell cycle arrest in S-phase or in G2 / M.

[0007] ATR has been identified as an important cancer target since it is essential for dividing cells. ATR deficient mice are embryonic lethal, however, adult mice with conditional ATR knocked out are viable with effects on rapidly proliferating tissues and stem cell populations. Mouse embryonic stem cells lacking ATR will only divide for 1-2 doublings and then die, suggesting that ATR is required for the maintenance of dividing cells. Interestingly, mice harboring hypomorphic ATR mutations that reduce expression of ATR to 10% of normal levels showed reduced H-rasG12D- induced tumor growth with minimal effects on proliferating normal cells, e.g., the bone marrow or intestinal epithelial cells. Cancer cells that have high levels of replication stress due to oncogenic mutations, dysfunctional G1 / S checkpoint control (e.g., loss of p53 function), defects in other DNA repair pathways (e.g., ATM) or that are subject to the effects of DNA damaging agents, e.g., radiation therapy or chemotherapeutic agents, are therefore more dependent on ATR for DNA repair and survival. Together, these results highlight a rationale for the selective sensitivity of proliferating tumor cells to ATR inhibition and the potential for a therapeutic window over healthy proliferating cells.

[0008] PIK3CA is the gene encoding the alpha isoform of the catalytic subunit of phosphatidylinositol 4,5-bisphosphate 3-kinase. The p110ct subunit of PI K3CA is frequently mutated and amplified (-30%) in a variety of cancers. Mishra, R., et al. "PI3K inhibitors in cancer: clinical implications and adverse effects." International Journal of Molecular Sciences 22.7 (2021):3464. A recent study has shown that C2 domain deletions in PIK3CA activate PI3K signaling significantly and also enhance the sensitivity to PI3Kct 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. The deregulation of PI3K signaling leads to several oncogenic activities such as cancer cell proliferation, invasion, migration, glucose transport and angiogenesis that regulate tumor progression. Levine D.A., 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 alpha (PI3Kct inhibitors) target the p110ct catalytic subunit of PI3K. Several PI3Kct inhibitors are undergoing studies for treatment of various cancers (e.g., without limitations, solid tumors, advanced solid tumors, ovarian cancer, breast cancer, and colorectal cancer). Toxicities from small-molecule PI3K inhibitors depend on their PI3K isozyme specificity. For example, the adverse effects associated with PI3Kct inhibitors are mostly rash and hyperglycemia, whereas the side effects associated with 5 subunits are mostly gastrointestinal, transaminitis, and myelosuppression. Mishra, R., et al. "PI3K inhibitors in cancer: clinical implications and adverse effects." International Journal of Molecular Sciences 22.7 (2021 ):3464.

[0009] To date, five PI3K inhibitors (Copanlisib, Idelalisib, Umbralisib, Duvelisib, and Alpelisib) have been approved by the United States 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 is a PI3Ka inhibitor that has been approved by the FDA for adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-re\ated overgrowth spectrum (PROS) who require systemic therapy. Singh, S., et al. "FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum." Clinical Cancer Research (2023):OF1-OF6.

[0010] SUMMARY

[0011] One aspect of the disclosure is a method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor, wherein the cancer is identified as having one or more mutations in PIK3CA.

[0012] In another aspect, the PI3Kct inhibitor of the disclosure is a compound of formula (III): (Ill) and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:

[0013] R1is selected from — CH3, — CH2CH3, cyclopropyl, and cyclobutyl; R2is selected from — CH3, — CHF2, — CH2F, and — CF3.

[0014] In aspect, R1is — CH3 or cyclopropyl.

[0015] In aspect, R2is — CHF2.

[0016] In another aspect, the PI3Kct inhibitor is a compound of the structure: In another aspect, the PI3Kct inhibitor is a compound of the structure:

[0017] In another aspect, the PI3Kct inhibitor is a compound of the structure:

[0018] In another aspect, the PI3Kct inhibitor is a compound of the structure:

[0019] In another aspect, the PI3Kct inhibitor is a compound of the structure:

[0020] In another aspect, the PI3Kct inhibitor is a compound of the structure:

[0021] In another aspect, the PI3Kct inhibitor is a compound of the structure:

[0022] In some aspects, the disclosure provides a method of treating a cancer in a subject of the disclosure, the method comprising: (i) identifying the cancer as having one or more mutations in PIK3CA', and

[0023] (ii) administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor.

[0024] In aspects, the ATR inhibitor is administered before the PI3Kct inhibitor.

[0025] In aspects, the ATR inhibitor is administered after the PI3Kct inhibitor. In aspects, the ATR inhibitor is co-administered with the PI3Kct inhibitor.

[0026] In some aspects, the therapeutically effective amount is a subtherapeutic regimen of the ATR inhibitor.

[0027] In some aspects, the therapeutically effective amount is a subtherapeutic regimen of the PI3Kct inhibitor.

[0028] In yet another aspect, the subtherapeutic regimen comprises a starting dosage that is at least 50% less than the lowest standard starting dosage that is used for a monotherapy.

[0029] In aspects, the subtherapeutic regimen comprises a maintenance dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy.

[0030] In aspects, the maintenance dosage comprises a first reduced dosage.

[0031] In aspects, the maintenance dosage comprises a second reduced dosage.

[0032] In aspects, the maintenance dosage comprises a third reduced dosage.

[0033] In some aspects, the route of administration is an oral administration.

[0034] In some other aspects, the ATR inhibitor is administered 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0035] In some aspects, the PI3Kct inhibitor is administered 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0036] In additional aspect, the disclosure provides a method of inducing cell death in an aberrant cancer cell having one or more mutations in PIK3CA, the method comprising contacting the cell with an effective amount of an ATR inhibitor and an effective amount of a PI3Kct inhibitor, the effective amounts being sufficient to induce cell death in the aberrant cancer cell.

[0037] In aspect, the PI3Kct inhibitor is a compound of formula (III): (Ill) and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:

[0038] R1is selected from — CH3, — CH2CH3, cyclopropyl, and cyclobutyl;

[0039] R2is selected from — CH3, — CHF2, — CH2F, and — CF3.

[0040] In aspects, the cancer is any type of cancer carrying a PIK3CA mutation.

[0041] In aspects, the patient is any patient with a PIK3CA mutation.

[0042] In aspects, the cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or an advanced solid tumor.

[0043] In aspects, the cancer having one or more mutations in PIK3CA is a solid tumor.

[0044] In aspects, the cancer having one or more mutations in PIK3CA is an advanced solid tumor.

[0045] In aspects, the ATR inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0046] - is a double bond, and each Y is independently N or CR4; or - is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; wherein each RYis independently H or optionally substituted C1-6 alkyl;

[0047] R1is optionally substituted C1-6 alkyl or H;

[0048] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B; R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;

[0049] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0050] Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and

[0051] X is hydrogen or halogen.

[0052] In additional aspect, the present disclosure provides a method wherein the ATR inhibitor is a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein each Y is independently N or CR4;

[0053] R1is optionally substituted C1-6 alkyl or H;

[0054] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;

[0055] R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;

[0056] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0057] Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted Ce-io arylene; and

[0058] X is hydrogen or halogen.

[0059] In aspects, R2is a 5-10 membered bicyclic [p.q.r] heterocyclyl.

[0060] In aspects, R2is a

[0061] In aspects, R2is a

[0062] In additional aspect, 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.

[0063] In aspects, the ATR inhibitor is compound 43 or a pharmaceutically acceptable salt thereof. In aspects, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In aspects, compound 121 is a hydrogen sulfate salt. In aspects, compound 121 is Camonsertib.

[0064] In aspects, the ATR inhibitor is compound 122 or a pharmaceutically acceptable salt thereof. In aspects, the pharmaceutically acceptable salt is hydrogen sulfate.

[0065] In additional aspects, the present disclosure provides a method for treating cancer, wherein the cancer is renal cell carcinoma, mature B-cell neoplasms, 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, esophagogastric cancer, solid tumors, single tumor type, or triple-negative breast cancer.

[0066] In aspects, the PI3Kct inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0067] In aspects, the PI3Kct inhibitor is:

[0068] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9-yl)amino)propanamide,

[0069] (S) — N1-(4-methyl-5-(2-(1 ,1 ,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)pyrrolidine-1 ,2-dicarboxamide), or a pharmaceutically acceptable salt thereof.

[0070] In aspects, the PI3Kct inhibitor is (S)-2-((2-((S)-4-(difluoromethyl)-2- oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9- yl)amino)propanamide, or a pharmaceutically acceptable salt thereof.

[0071] In aspects, the PI3Kct inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, Taselisib, a pharmaceutically acceptable salt thereof, or any combination thereof.

[0072] In additional aspects, the disclosure provides a method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor, wherein the cancer has been previously identified as a cancer having one or more mutations in PIK3CA, and wherein the PI3Kct inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0073] In yet another aspect, the disclosure provides a method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor, wherein the cancer has one or more mutations in PIK3CA', and wherein the PI3Ka inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0074] In aspects, the disclosure further provides a method of treating a cancer in a subject, the method comprising:

[0075] (i) identifying the cancer as having one or more mutations in PIK3CA', and

[0076] (ii) administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor that is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof. In aspects, the ATR inhibitor is administered before the PI3Kct inhibitor. In aspects, the ATR inhibitor is administered after the PI3Kct inhibitor. In aspects, the ATR inhibitor is co-administered with the PI3Kct inhibitor.

[0077] In aspects, the therapeutically effective amount comprises a subtherapeutic regimen of the ATR inhibitor. In aspects, the therapeutically effective amount comprises a subtherapeutic regimen of the PI3Kct inhibitor. In aspects, the subtherapeutic regimen comprises a starting dosage that is at least 50% less than the lowest standard starting dosage that is used for a monotherapy. In aspects, the subtherapeutic regimen comprises a maintenance dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy.

[0078] In aspects, the maintenance dosage comprises a first reduced dosage. In aspects, the maintenance dosage comprises a second reduced dosage. In aspects, the maintenance dosage comprises a third reduced dosage.

[0079] In aspects, the route of administration is an oral administration.

[0080] In aspects, the ATR inhibitor is administered 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0081] In aspects, the PI3Kct inhibitor is administered 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

[0082] In aspects, the present disclosure provides a method of inducing cell death in an aberrant cancer cell having one or more mutations in PIK3CA, the method comprising contacting the cell with an effective amount of an ATR inhibitor and an effective amount of a PI3Kct inhibitor, the effective amounts being sufficient to induce cell death in the aberrant cancer cell; wherein the PI3Kct inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0083] In aspects, the present disclosure provides a method wherein the ATR inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0084] - is a double bond, and each Y is independently N or CR4; or - is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; wherein each RYis independently H or optionally substituted C1-6 alkyl;

[0085] R1is optionally substituted C1-6 alkyl or H;

[0086] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;

[0087] R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;

[0088] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0089] Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and

[0090] X is hydrogen or halogen.

[0091] In aspect, the ATR inhibitor is a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein each Y is independently N or CR4;

[0092] R1is optionally substituted C1-6 alkyl or H;

[0093] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;

[0094] R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted Ci-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;

[0095] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0096] Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and

[0097] X is hydrogen or halogen.

[0098] In aspects, R2is a 5-10 membered bicyclic [p.q.r] heterocyclyl.

[0099] In aspects, R2is a

[0100] In aspects, R2is a

[0101] In aspects, 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.

[0102] In aspects, the ATR inhibitor is compound 43 or a pharmaceutically acceptable salt thereof. In aspects, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In aspects, compound 121 is a hydrogen sulfate salt. In aspects, the ATR inhibitor is Camonsertib or a pharmaceutically acceptable salt thereof. In aspects, the ATR inhibitor is compound 122 or a pharmaceutically acceptable salt thereof.

[0103] BRIEF DESCRIPTION OF FIGURES

[0104] Figure 1 shows plots of the percentage of cell viability based on ATP (y-axis) with different dose levels of Camonsertib and Inavolisib combined in p110o wild type and mutant MCF7 cells. Each line represents a distinct dose level of Inavolisib. The y-axis displays the scale of increasing Camonsertib doses.

[0105] Figure 2 shows contour plots of the synergy scores of Inavolisib doses (y-axis) dose levels of Camonsertib and Inavolisib combined in p110o wild type and mutant MCF7 cells. The regions labeled “+” are labeled at the center(s) or maxima of regions having positive synergistic effects; the unlabeled regions indicate negative effects. The results from Figure 2 show similar drug synergy patterns observed in the combination of Camonsertib and Inavolisib in both wildtype and mutant MCF7 cells.

[0106] Figure 3 shows plots of the percentage of cell viability based on ATP (y-axis) with different dose levels of Camonsertib and Inavolisib combined in p110o wild type and mutant HCC1954 cells. Each line with different intensity of darkness represents a distinct dose level of Inavolisib. The y-axis displays the scale of increasing Camonsertib doses.

[0107] Figure 4 shows contour plots of the synergy scores of Inavolisib doses (y-axis) and dose levels of Camonsertib and Inavolisib combined in p110o wild type and mutant HCC1954 cells. The regions labeled “+” are labeled at the center(s) or maxima of regions having positive synergistic effects; the unlabeled regions indicate negative effects. The results from Figure 4 show the combination of Camonsertib and Inavolisib shows similar drug synergy patterns in both BRCA1 mutant / p110a wild type and BRCA1 mutant / p110a mutant cells.

[0108] Figure 5 shows western blot images of the expression of relevant DNA damage repair proteins in untreated and treated (Camonsertib and Inavolisib) MCF7 and HCC1954 cells. Inavolisib + Camonsertib treatment induces DNA damage in p110a mutant and wildtype cells but particularly induces increased yH2AX in the P / K3CA-mutant (PIK3Cam) cell lines compared to wildtype cells. The data in Figure 5 is consistent with the expectations for the combination mechanism of increasing cellular DNA damage (supported by increased yH2AX expression) when both PI3K and ATR signaling are inhibited.

[0109] Figure 6 shows a study schema for the administration of Camonsertib in combination with Inavolisib. This study schema includes both dose escalation and dose expansion. Abbreviations: DL = dose level; SRC = safety review committee.

[0110] Figure 7 shows individual participant schema for Stage I dose escalation. Abbreviations: ATRi = ataxia telangiectasia-mutated- and rad-3 related inhibitor; DNA-PKi = DNA-dependent protein kinase inhibitor; PO = orally, by mouth; Q90D = every 90 days; RECIST = Response Evaluation Criteria in Solid Tumors. Note: Depending on the cohort open at time of participant assignment, the dose and / or schedule of each agent may differ from the schema.aStarting dose is Camonsertib 120 mg PO, 3 days on / 4 days off, 2 weeks on / 1 week off in combination with Inavolisib 6 mg PO QD.

[0111] Figure 8 outlines the schematic of dose escalation rules.

[0112] DETAILED DESCRIPTION

[0113] In general, the disclosure relates to a combination of an ATR inhibitor, or a pharmaceutically acceptable salt thereof, and a phosphatidylinositol 3-kinase alpha (PI3Ka) inhibitor, or a pharmaceutically acceptable salt thereof, and use thereof for the treatment of cancers or for inducing cell death in cancer cells. The cancers included herein may be, e.g., a cancer that bears one or more mutations in PIK3CA. In embodiments, the cancer that bears one or more mutations in PIK3CA is an advanced solid tumor.

[0114] All of the features disclosed in this specification on ATR inhibitors (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any embodiments explicitly disclosed herein on ATR inhibitors Any embodiment described in this application on ATR inhibitors can be combined with any other embodiment. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, and abstract), or to any novel one, or any novel combination, of the any embodiment on ATR inhibitors, or any steps of any method or process so disclosed.

[0115] Advantageously, an ATR inhibitor and a PI3Kct inhibitor may act synergistically to induce cell death in cancer cells having one or more mutations in PIK3CA. Advantageously, combination cancer therapies including an ATR inhibitor and a PI3Kct inhibitor may exhibit reduced morbidities, as ATR inhibitor and PI3Kct inhibitor dosages may be reduced, e.g., relative to those administered in corresponding monotherapies. Thus, ATR and PI3Kct inhibitors may be used in subtherapeutic regimens in the methods of the disclosure. The present disclosure demonstrates a belief that combination cancer therapies, including an ATR inhibitor and a PI3Kct inhibitor, may synergistically induce cell death in cancer cells through a combination of an ATR inhibitor and a PI3Kct inhibitor, optionally, in close proximity to a cancer cell. Thus, the present disclosure examined both the advantages and disadvantages of using either an ATR inhibitor or a PI3Kct inhibitor to treat cancer and determined that a combination of the two therapies will induce cell death in cancer cells while exhibiting reduced morbidities due to the use of subtherapeutic dosages of the agents as relative to the dosages administered in the corresponding monotherapies. It may remain to post-published evidence to confirm the plausibility of these synergistic effects (US Rule 132 Declaration or evidence under EPO Decision G2 / 21).

[0116] Moreover, it is to be understood that based on the present disclosure, the skilled person, having the common general knowledge of the art, would derive the provision of synergistically active combination therapy for prostate cancer as being encompassed by the technical teaching and embodied by the present disclosure. In particular, it is a synergistically active combination therapy for prostate cancer when combining Camonsertib and Inavolisib.

[0117] Ataxia-Telangiectasia-mutated- and Rad-3-related (ATR) inhibitors (ATRi) elicit cell death in rapidly growing tumor cells by exacerbating endogenous replication stress and replication fork collapse, as well as by disabling cell cycle checkpoints. Camonsertib has demonstrated antitumoral-activity in several xenograft models of cancer as a single agent. Pharmacokinetic (PK) and pharmacodynamic (PD) marker analysis from tumor xenografts demonstrates target engagement and a dose-dependent increase in double-strand DNA breaks leading to tumor cell death in vivo.

[0118] Preclinical studies indicate that PI3K pathway inhibition induces replication stress by decreasing the activity of Aurora kinase B, a spindle assembly checkpoint protein, and by depleting nucleotides which are 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 result in synthetic lethality and may offer additional benefit to patients with advanced solid tumors.

[0119] Phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) are major nodes in the PI3K / AKT / mTOR intracellular signaling pathway which mediates critical cellular processes including cell-cycle modulation, growth, metabolism, motility, and survival (Cantrell 2001 ; Hanahan and Weinberg 2011 ; Vanhaesebroeck et al. 2012). The PI3K / AKT / mTOR pathway is generally activated following ligand-receptor tyrosine kinase (RTK) interactions. Under physiologic conditions, PI3K phosphorylates membrane-bound 4,5- phosphatidylinositol bisphosphate (PIP2) to 3,4,5-phosphatidylinositol triphosphate (PIP3), required for intracellular signal transduction.

[0120] There are three classes of PI3K, with Class I being the most responsive to external stimuli. Class I PI3Ks are composed of two subunits: a p110 catalytic subunit and a regulatory adapter subunit, p85. There are four isoforms of the p110 catalytic subunit of PI3K: a, , y, and 5. These four isoforms are the respective 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 multiple tissues, including the pancreas, skeletal muscle, liver, and heart.

[0121] Dysregulation of the PI3K / AKT / mTOR signaling pathway has been described in multiple solid tumor malignancies (e.g., glioblastoma, colorectal, gastric, lung, endometrial, ovarian, prostate, head and neck, breast cancers [Gustin et al. 2008; Marquard and Jucker 2020]). Pathway activation may occur through multiple mechanisms.

[0122] Activating mutations in the PIK3CA gene occur primarily in exons 9 and 20 ("hotspot" regions), which encode the helical and kinase domains of the p110ct 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 aberrant growth and proliferation of cancer cells. These effects can be abrogated by PI3K inhibitors. Therefore, inhibition of PI3K represents an attractive strategy for the treatment of solid tumor malignancies with PI3K / AKT / mTOR pathway dysregulation, and a number of agents targeting this pathway have been tested in clinical trials (Janku et al. 2018). However, because mutated p110a may not be able to induce invasive cancer progression on its own (Hanker et al. 2019) and the PI3K / AKT / mTOR pathway cross-talks with several other signaling pathways, leading to adaptive feedback mechanisms (Carracedo and Pandolfi 2008), it has been suggested to combine PI3K inhibitors with mechanistically rational therapeutic agents to improve their efficacy (Hanker et al. 2019). p110a inhibitors’ metabolic effects are hypothesized to synergize with DNA damage repair inhibitors. The present disclosure is based on synergy between ATR inhibitors and PI3Ka inhibitors. Continuous combination treatment will be well tolerated in preclinical models and there may be potentially overlapping toxicities observed for each drug class in the clinic. Until the present disclosure, specific populations of cancer patients that could benefit from a combination of an ATR inhibitor and a PI3Ka inhibitor were limited, especially those that could benefit from the dose reductions for the ATR inhibitors and / or PI3Ka inhibitors.

[0123] ATR Inhibitors

[0124] An ATR inhibitor is a compound that upon contacting the enzyme ATR kinase, whether in vitro, in cell culture, or in an animal, reduces the activity of ATR kinase, such that the measured ATR kinase IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain ATR inhibitors, the ATR kinase IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the ATR kinase IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0125] Non-limiting examples of ATR inhibitors include, e.g.:

[0126]

[0127] BAY1895344 ceralasertib (AZD6738) berzosertib (VE-822) , and pharmaceutically acceptable salts thereof.

[0128] VX-803

[0129] Non-limiting examples of ATR inhibitors include, e.g., those described in, e.g., International Application Nos. PCT / US2019 / 022727 and PCT / US2018 / 034729, each of which is incorporated by reference herein; U.S. Patent Nos. 9,663,535, 9,549,932, 8,552,004, and 8,841 ,308, each of which is incorporated by reference herein; and U.S. Patent Application Publication No. 2019 / 0055240, which is incorporated by reference herein.

[0130] In one embodiment, an ATR inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0131] - is a double bond, and each Y is independently N or CR4; or - is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; where each RYis independently H or optionally substituted C1-6 alkyl;

[0132] R1is optionally substituted C1-6 alkyl or H;

[0133] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;

[0134] R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;

[0135] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SC>2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0136] Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and

[0137] X is hydrogen or halogen. The ATR inhibitor may be, e.g., a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein each Y is independently N or CR4;

[0138] R1is optionally substituted C1-6 alkyl or H;

[0139] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;

[0140] R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;

[0141] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted Ci-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0142] Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and

[0143] X is hydrogen or halogen.

[0144] In some embodiments, in the compound of formula (II), (I), or (l-b): each Y is independently N or CR4;

[0145] R1is H or optionally substituted C1-6 alkyl;

[0146] R2is optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -N(R5)2, - CON(R6)2, -SO2N(R6)2, or -SO2R5A;

[0147] R3is optionally substituted C1-9 heteroaryl; each R4is independently H or optionally substituted C1-6 alkyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A, wherein each R5Ais independently optionally substituted C1-6 alkyl or optionally substituted C3-8 cycloalkyl; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl or optionally substituted C3-8 cycloalkyl; and each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl.

[0148] Methods of making compounds of formula (I) are described, e.g., in International Application No. PCT / US2019 / 022727, hereby incorporated by reference.

[0149] The ATR inhibitor may be, e.g., a compound of formula (l-a):

[0150] (l-a) or a pharmaceutically acceptable salt thereof, wherein Y, R1, R2, R3, and R4are as described for formula (I). The ATR inhibitor may be, e.g., a compound of formula (l-b):

[0151] (l-b) or a pharmaceutically acceptable salt thereof, wherein Y, R1, R2, R3, and R4are as described for formula (I). The ATR inhibitor may be, e.g., a compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I). The ATR inhibitor may be, e.g., a compound of formula (lA-a): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I). The ATR inhibitor may be, e.g., a compound of Formula (IB): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I). The ATR inhibitor may be, e.g., a compound of formula (IB-a): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I). The ATR inhibitor may be, e.g., a compound of Formula (IC): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I).

[0152] The ATR inhibitor may be, e.g., a compound of formula (IC-a):

[0153] (IC-a) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I).

[0154] The ATR inhibitor may be, e.g., a compound of formula (ID): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I).

[0155] The ATR inhibitor may be, e.g., a compound of formula (ID-a):

[0156] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as described for formula (I).

[0157] R1can be methyl.

[0158] In some embodiments, R2may be, e.g., optionally substituted C3-8 cycloalkyl. For example, R2may be a group of formula (A): wherein n is 0, 1 , 2, or 3; and

[0159] R7is hydrogen, alkylsulfonyl, cyano, -CON(RA)2, -SON(RA)2, optionally substituted C1-9 heteroaryl, hydroxy, or alkoxy, wherein each RAis independently H or alkyl; or both RA, together with the atom to which they are attached, combine to form C2-9 heterocyclyl.

[0160] In some embodiments, R2may be, e.g., optionally substituted C1-6 alkyl (e.g., optionally substituted tertiary C3-6 alkyl. For example, R2may be a group of formula (B): wherein R7is hydrogen, alkylsulfonyl, cyano, -CON(RA)2, -SON(RA)2, optionally substituted C1-9 heteroaryl, hydroxy, or alkoxy, wherein each RAis independently H or alkyl; or both RA, together with the atom to which they are attached, combine to form C2-9 heterocyclyl.

[0161] In some embodiments, R2may be, e.g., optionally substituted non-aromatic C2-9 heterocyclyl. In some embodiments, R2may be, e.g.: In some embodiments, R2may be a 5-10 membered bicyclic [p.q.r] heterocyclyl.

[0162] In some embodiments, R2may be In some embodiments, R2may be

[0163] In some embodiments, R3may be, e.g., optionally substituted, monocyclic

[0164] C1-9 heteroaryl including at least one nitrogen atom (e.g., two nitrogen atoms). For example, R3may be a group of formula (C): J0

[0165] (C) wherein A is optionally substituted, monocyclic C1-9 heteroaryl ring.

[0166] In some embodiments, A may be, e.g., a group of formula (C1 ): wherein R8is hydrogen, halogen, or optionally substituted C1-6 alkyl.

[0167] In some embodiments, R3may be, e.g.:

[0168] In some embodiments, R3may be, e.g.:

[0169] In some embodiments, R4may be, e.g., hydrogen.

[0170] The ATR inhibitor may be, e.g., a compound listed in Table 1 below or a pharmaceutically acceptable salt thereof.

[0171] Table 1

[0172]

[0173] An ATR inhibitor may be isotopically enriched (e.g., enriched for deuterium). In some embodiments, the ATR inhibitor of the present disclosure may be presented as a salt. In some embodiments, the ATR inhibitor may come in the form of a pharmaceutically acceptable salt thereof.

[0174] Camonsertib

[0175] In some embodiments, the ATR inhibitor is Camonsertib. In some embodiments, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In some embodiments, the ATR inhibitor is the hydrogen sulfate salt of compound 121. In some embodiments, Camonsertib is compound 121. In embodiments, Camonsertib is also known as RP-3500 and terms may be used interchangeably herein. In some embodiments, Camonsertib may be presented in the form of a hydrogen sulfate salt.

[0176] Camonsertib is a novel, orally bioavailable clinical-stage ATR kinase inhibitor. Camonsertib is highly potent with IC50 values of 1 .0 and 0.33 nmol / L in biochemical and cell-based assays, respectively. Camonsertib is highly selective for ATR with 30- fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000- fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kct) kinases. In vivo, Camonsertib treatment results in potent single-agent efficacy and / or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg / kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1 ) (ICso = 18.6 nmol / L) and induction of phosphorylated H2A.X variant histone (yH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB- associated protein 1 (pKAP1 ). Camonsertib exposure at MED indicates that circulating free plasma levels above the in vivo tumor ICso for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on / 4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with Camonsertib and demonstrating superior efficacy compared with sequential treatment. 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.

[0177] Camonsertib has been under development for the treatment of solid tumors. In some embodiments, a solid tumor is 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). Camonsertib can be administered through oral routes. In some embodiments, Camonsertib is undergoing development for the treatment of various diseases. In embodiments, the various diseases include but are not limited to cancer. In embodiments, the cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or an advanced solid tumor. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is an ovarian cancer. Camonsertib acts by targeting Ataxia-Telangiectasia and Rad-3-related protein (ATR).

[0178] Camonsertib has demonstrated antitumor activity in several xenograft models of cancer as a single agent. Preclinically, PK and PD marker analysis from tumor xenografts demonstrates target engagement and a dose-dependent increase in double-strand DNA breaks leading to tumor cell death in vivo.

[0179] In embodiments, Camonsertib at doses >120 mg QD are pharmacologically active. In embodiments, the disclosure provides a hydrogen sulfate salt of Camonsertib. In embodiments, the disclosure provides a crystalline form of a hydrogen sulfate salt of Camonsertib. The hydrogen sulfate salt form of Camonsertib is previously described as example 121 in International Application No. PCT / CA2022 / 050892, which is incorporated by reference herein in its entirety.

[0180] PI3Ka Inhibitors

[0181] The PIK3CA gene encodes the p110a catalytic subunit of PI3K, and its mutation occurs at a high rate in endometrial, breast, bladder, cervical and colorectal cancers. The PIK3CA activation mutation is among the most common oncogenic mutations described in breast cancer to date. Arafeh, R., and Samuels, Y. "PIK3CA in cancer: the past 30 years." Seminars in Cancer Biology. Vol. 59. Academic Press, 2019. p110a is a widely expressed PI3K isoform in vivo and a key intermediate in insulin-like growth factor-1 (IGF-1), insulin and leptin signaling, where it plays a key role in growth factor and metabolic signaling through highly selective recruitment and activation of the insulin receptor substrate (IRS) signaling complex. p110a is significantly expressed in endothelial cells and its activity is necessary for vascular development.

[0182] In embodiments, a PIK3CA mutation is selected from:

[0183] ■ R88Q

[0184] ■ G106A / D / R / S / V

[0185] ■ K111N / R / E

[0186] ■ G118D

[0187] ■ N345D / H / I / K / S / T / Y

[0188] ■ C420R

[0189] ■ E453A / D / G / K / Q / V

[0190] ■ E542A / D / G / K / Q / R / V

[0191] ■ E545A / D / G / K / L / Q / RA /

[0192] ■ Q546E / H / K / L / P / R ■ M1043I / T / V

[0193] ■ H1047D / I / L / N / P / Q / R / T / Y

[0194] ■ G1049A / C / D / R / S

[0195] The term “PI3Kct inhibitor,” as used throughout this disclosure, refers to any PI3K inhibitor that targets the p110a catalytic subunit of PI3K. In some embodiments, the PI3Ka inhibitor specifically targets only the p110a. In some embodiments, the PI3Ka inhibitor specifically targets the p110a in addition to one or more other subunits (i.e., p1100 and p1105). In some embodiments, the PI3Ka inhibitor is Alpelisib. Alpelisib is a PI3K inhibitor that is known to target the p110a subunit only. In some embodiments, the PI3Ka inhibitor is Inavolisib. Inavolisib is a PI3K inhibitor that is known to target the p110a subunit only. In some embodiments, the PI3Ka inhibitor is Serabelisib. Serabelisib is a PI3K inhibitor that is known to target the p110a subunit only. In some embodiments, the PI3Ka inhibitor is Taselisib. Taselisib is a PI3K inhibitor that is known to target the p110a, p110 , and p1105 subunits. In some embodiments, the PI3Ka inhibitor is AZD8835. AZD8835 is a PI3K inhibitor that is known to target the p110a and p1105 subunits.

[0196] The importance and high frequency of PIK3CA mutation in solid tumors has attracted attention towards the development of PI3Ka-selective inhibitors.

[0197] In embodiments, the PI3Ka inhibitor of the present disclosure is a compound of formula (III): and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:

[0198] R1is selected from — CH3, — CH2CH3, cyclopropyl, and cyclobutyl;

[0199] R2is selected from — CH3, — CHF2, — CH2F, and — CF3. In embodiments, R1is — CH3 or cyclopropyl.

[0200] In embodiments, R2is — CHF2.

[0201] In embodiments, the compound of formula (III) is selected from:

[0202] , or a pharmaceutically acceptable salt thereof.

[0203] Inavolisib is named as (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)- 5,6-dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9-yl)amino)propanamide and has the structure: In embodiments, the compound of formula (III) is selected from:

[0204] In embodiments, 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]oxazepin-9-yl)amino)propanamide. The PI3Ka inhibitor may be:

[0205] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9-yl)amino)propanamide,

[0206] (S) — N1-(4-methyl-5-(2-(1 ,1 ,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)pyrrolidine-1 ,2-dicarboxamide), or a pharmaceutically acceptable salt thereof.

[0207] The PI3Ka inhibitor may be (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin- 3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9-yl)amino)propanamide, or a pharmaceutically acceptable salt thereof. The PI3Ka inhibitor may be (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin- 3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9-yl)amino)propanamide.

[0208] The PI3Ka inhibitor may be (S) — N1-(4-methyl-5-(2-( 1 ,1 ,1 -trifluoro-2- methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1 ,2-dicarboxamide), or a pharmaceutically acceptable salt thereof.

[0209] The PI3Ka inhibitor may be (S) — N1-(4-methyl-5-(2-( 1 ,1 ,1 -trifluoro-2- methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1 ,2-dicarboxamide).

[0210] The PI3Ka inhibitor may be isotopically enriched (e.g., enriched for deuterium).

[0211] The PI3Ka inhibitors may be prepared as described in, for instance, U.S. Patent Nos. 9,650,393, 8,227,462, 8,476,268, and 9,085,560, the disclosures of which are incorporated herein in their entirety.

[0212] Alternatively, the PI3Kct inhibitor used in the methods of the disclosure may be Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof. In embodiments, the PI3Kct inhibitor used in the methods of the disclosure is a Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof. In embodiments, the PI3Kct inhibitor used in the methods of the disclosure is a Pictilisib, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0213] Alpelisib

[0214] In some embodiments, the PI3Kct inhibitor is Alpelisib.

[0215] The compound known as Alpelisib (BYL719) is an oral, selective inhibitor of the PI3K alpha isoform, and is in clinical trials for the potential treatment of a variety of 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; U.S. Patent Nos 8,227,462, 8,476,268, and 8,710,085). Alpelisib is named as (S) — N1-(4-methyl-5-(2-(1 ,1 ,1- trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1 ,2-dicarboxamide) and has the structure:

[0216]

[0217] PIK3CA activating mutations increase sensitivity to the antiproliferative effect of PI3Ka inhibition in cell lines, as well as in tumor samples from breast cancer patients treated with Alpelisib (Vanhaesebroeck et al. 2021 ). This has been validated clinically in patients with P / K3CA-mutated, HR positive / HER2-negative advanced breast cancer in the SOLAR-1 and BYLieve trials (Andre F et al. 2019; Rugo et al. 2021 ).

[0218] Alpelisib is previously described in U.S. Patent Nos. 8,227,462 and 8,476,268 which are incorporated by reference in their entireties.

[0219] Serabelisib

[0220] In some embodiments, the PI3Kct inhibitor is Serabelisib.

[0221] Serabelisib is also known as INK-1117, MLN-1117, or TAK-117, each of which may be used interchangeably throughout this disclosure. Serabelisib is a potent oral PI3K inhibitor with an IC50 of 21 nmol / L against PI3Kct isoform. The first in human phase I study evaluated the safety and efficacy of Serabelisib 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 Serabelisib with oral mTORC1 / 2 inhibitor Sapanisertib (TAK- 228) in TNBC patients to target the DNA repair pathway. A phase II study evaluated the efficacy and safety of MLN0128 and the combination of MLN0128 plus Serabelisib versus Everolimus in the treatment of metastatic clear-cell renal cell carcinoma (mccRCC) patients who progressed on vascular endothelial growth factor (VEGF)-targeted therapy. A phase I study tested Serabelisib with mTORC1 / 2 inhibitor Sapanisertib (TAK-228) in patients with advanced non-hematological patients to determine the DLTs, MTD and / or RP2D of this drug combination. Mishra, R., et al. "PI3K inhibitors in cancer: clinical implications and adverse effects." International Journal of Molecular Sciences 22.7 (2021 ):3464.

[0222] Serabelisib has the structure:

[0223] Serabelisib is previously described as compound 54 in U.S. Patent No. 9,085,560 which is incorporated by reference in its entirety.

[0224] Inavolisib

[0225] In some embodiments, the PI3Kct inhibitor is Inavolisib.

[0226] Inavolisib, as described herein, refers to a benzoxazepin-oxazolidinone ATP- competitive inhibitor of PI3Kct which also induce the selective degradation of the mutant p110ct protein. Inavolisib is a highly selective inhibitor and degrader of mutant PI3Ka. Inavolisib is a potent selective inhibitor of PI3Kct with an IC50 of 0.038 nM. Inavolisib is >300-fold more selective for PI3K alpha over the other class I PI3K isoforms (beta, delta, and gamma) and >2000-fold more selective over PIK family members. Inavolisib binds to the ATP binding site of PI3K and inhibits the phosphorylation of PIP2 to PIP3.

[0227] The terms “Inavolisib” and “GDC-0077” refer to the same PI3Kct inhibitor and the terms may be used interchangeably throughout the present disclosure.

[0228] Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for the treatment of cancers. The class I isoform PI3Kct is most commonly associated with solid tumors via gene amplification or activating mutations. However, inhibitors demonstrating both PI3K isoform and mutant specificity have remained elusive. Inavolisib is a benzoxazepin- oxazolidinone ATP-competitive inhibitor of PI3Kct. Inavolisib also induces the selective degradation of the mutant p110ct protein, the catalytic subunit of PI3Kct. Inavolisib was generated from structure-based design informed isoform-specific interactions within the binding site, leading to potent inhibitors with greater than 300- fold selectivity over the other Class I PI3K isoforms. Further optimization of pharmacokinetic properties led to excellent in vivo exposure and efficacy and the identification of clinical candidate Inavolisib, which is now under evaluation in a Phase III clinical trial as a treatment for patients with P / K3CA-mutant breast cancer. Hanan, E.J. et al. “Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kct.” Journal of Medicinal Chemistry vol. 65,24 (2022):16589-16621.

[0229] Nonclinical studies demonstrate that Inavolisib promotes the specific degradation of mutated, but not wild-type, p11Oct, a feature that appears dependent on RTK activity (Song et al. 2022). Furthermore, Inavolisib reduces expression of downstream PI3K-pathway markers, including phosphorylation of AKT, proline-rich AKT substrate of 40 kDa, and S6, which results in inhibited proliferation and induced apoptosis of PIK3CA -mutated breast cancer cell lines, and inhibition of tumor growth in breast cancer xenograft models harboring PIK3CA mutations.

[0230] Results from the nonclinical toxicity and safety pharmacology studies completed to date provide a robust characterization of the toxicology profile of Inavolisib and support the administration of Inavolisib to patients with advanced cancer. The nonclinical findings (dose-limiting toxicities [DLTs]) identified in nonclinical toxicology studies were consistent with the anticipated pharmacologic effects of PI3K inhibition, and included hyperglycemia, body weight loss in rats and dogs, and inflammation in dogs. In addition, bone marrow hypocellularity, atrophy of glandular and reproductive tissues, and eye lens degeneration were observed in rats; and lymphoid depletion and swelling of the lens fibers in the eye were observed in dogs. Findings were generally dose-dependent and reversible, considered to be clinically monitorable and / or manageable. In vitro and in vivo safety pharmacology studies of Inavolisib demonstrated a low risk for adverse cardiovascular, neurologic, and respiratory effects at clinically relevant exposures. Inavolisib does not pose a genotoxic risk in humans and is considered to have no phototoxic potential. Inavolisib has been shown to be teratogenic in nonclinical studies. Fetal malformations and variations observed in rats warrant the continued use of highly effective contraception in clinical trials utilizing Inavolisib. Clinical results to date using Inavolisib as a single agent, and in various combinations with approved therapies, have been encouraging. A registrational, global, blinded, randomized Phase III trial of Inavolisib in combination with the full- labeled doses of palbociclib and fulvestrant is currently underway in first-line treatment of metastatic, P / K3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer (NCT04191499). Numerous other cancer types are also being studied in earlier phase trials (e.g., NCT04931342, NCT04486352, and NCT04929223).

[0231] Since Inavolisib is a highly potent and selective inhibitor of the p110a isoform that promotes the degradation of mutated p110a (Song et al. 2022), fewer off-target toxicities and a better therapeutic window compared to other PI3K inhibitors are anticipated. This is further supported by nonclinical and safety data from the Phase l / lb Study GO39374 for Inavolisib alone and combined with targeted therapies (i.e., endocrine therapy, CDK4 / 6 inhibitors) (Juric et al. 2020; Juric et al. 2022).

[0232] Inavolisib is named as (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)- 5,6-dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9-yl)amino)propanamide and has the structure:

[0233] Inavolisib is previously described as Compound 101 in U.S. Patent No. 9,650,393 which is incorporated by reference in its entirety.

[0234] Isomers and Compositions Thereof

[0235] The disclosure includes (where possible) individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein, and mixtures of diastereomers and / or enantiomers thereof including racemic mixtures. Although the specific stereochemistries disclosed herein are preferred, other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures of these may also have utility in treating diseases. Inactive or less active diastereoisomers and enantiomers may be useful, e.g., for scientific studies relating to the receptor and the mechanism of activation.

[0236] It is understood that certain molecules can exist in multiple tautomeric forms. This disclosure includes all tautomers even though only one tautomer may be indicated in the examples.

[0237] The disclosure also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions including the compounds and a pharmaceutically acceptable carrier. The compounds are especially useful, e.g., in certain kinds of cancer and for slowing the progression of cancer once it has developed in a patient.

[0238] The compounds disclosed herein may be used in pharmaceutical compositions including (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients. The compounds may also be used in pharmaceutical compositions in which the compound disclosed herein or a pharmaceutically acceptable salt thereof is the only active ingredient.

[0239] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

[0240] Compounds disclosed herein may contain, e.g., one or more stereogenic centers and can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The disclosure includes all such isomeric forms of the compounds disclosed herein. It is intended that all possible stereoisomers (e.g., enantiomers and / or diastereomers) in mixtures and as pure or partially purified compounds are included within the scope of this disclosure (i.e., all possible combinations of the stereogenic centers as pure compounds or in mixtures).

[0241] Some of the compounds described herein may contain bonds with hindered rotation such that two separate rotomers, or atropisomers, may be separated and found to have different biological activity which may be advantageous. It is intended that all of the possible atropisomers are included within the scope of this disclosure. Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0242] Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the disclosure.

[0243] Compounds disclosed herein having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.

[0244] Alternatively, enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0245] Pharmaceutically Acceptable Salt

[0246] The disclosure also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions including the compounds (e.g., without limitations, Camonsertib) and a pharmaceutically acceptable carrier. The disclosure provides pharmaceutically acceptable salts of various compounds disclosed herein. In embodiments, Camonsertib is presented in the form of a pharmaceutically acceptable salt. In embodiments, Camonsertib is presented in the form of a hydrogen sulfate salt. Although Camonsertib may be effective in various forms (including, without limitations, as a free base), it may in practice be administered in the form of a salt of a pharmaceutically acceptable acid or base. In embodiments, the hydrogen sulfate salt form of Camonsertib is significantly more effective than other known forms. In embodiments, the hydrogen sulfate salt form of Camonsertib is significantly more effective than the free base form. The hydrogen sulfate salt form of Camonsertib is previously described as example 121 in International Application No. PCT / CA2022 / 050892, which is incorporated by reference herein in its entirety. Metabolites - Prodrugs

[0247] The disclosure includes therapeutically active metabolites, where the metabolites themselves fall within the scope of the claims. The disclosure also includes prodrugs, which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient. The claimed chemical structures of this application in some cases may themselves be prodrugs.

[0248] Isotopically Enriched Derivatives

[0249] The disclosure includes molecules which have been isotopically enriched at one or more position within the molecule. Thus, compounds enriched for deuterium fall within the scope of the claims.

[0250] Methods of Preparing ATR Inhibitors and PI3Ka Inhibitors

[0251] ATR inhibitors may be prepared using reactions and techniques known in the art. For example, certain ATR inhibitors may be prepared using techniques and methods disclosed in, e.g., International Application Nos. PCT / US2019 / 022727 and PCT / US2018 / 034729, each of which is incorporated by reference herein; U.S. Patent Nos. 9,663,535, 9,549,932, 8,552,004, and 8,841 ,308, each of which is incorporated by reference herein; and U.S. Patent Application Publication No. 2019 / 0055240, which is incorporated by reference herein in its entirety.

[0252] PI3Ka inhibitors may be prepared using reactions and techniques known in the art. For example, certain PI3Kct inhibitors may be prepared using techniques and methods disclosed in, e.g., 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 herein in its entirety.

[0253] Methods of Use

[0254] ATR inhibitors and PI3Kct inhibitors may be used together for the treatment of a disease or condition having the symptom of cell hyperproliferation. For example, the disclosure described herein may be applicable for treatment of various oncological conditions harboring one or more mutations in PIK3CA. In particular, mutations in PIK3CA gene may be found in the following tumor types: renal cell carcinoma, mature B-cell neoplasms, 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 esophagogastric cancer. Accordingly, methods of the present disclosure can be used in the treatment of these cancers. In any and every aspect of the disclosure herein wherein a method of treatment is described, the equivalent use of the compound(s) in treatment, and use of the compound(s) in manufacture of a medicament for treatment use and treatment are contemplated. Further, a combination of an ATR inhibitor and a PI3Kct inhibitor for use in the treatment of a disease or condition having the symptom of cell hyperproliferation, which, without wishing to be bound to a specific theory, subsequently results in cell death. Additionally, a combination of an ATR inhibitor and a PI3Kct inhibitor for use in the treatment of a disease or condition having the symptom of cell hyperproliferation may be used in the manufacture of a medicament for use in the treatment of a disease or condition having the symptom of cell hyperproliferation and subsequently resulting in cell death.

[0255] Therapeutic methods of the disclosure include the step of administering a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor to a subject in need thereof. The therapeutically effective amount of a PI3Kct inhibitor may be, e.g., a subtherapeutic regimen of a PI3Kct inhibitor. The therapeutically effective amount of an ATR inhibitor may be, e.g., a subtherapeutic regimen of an ATR inhibitor.

[0256] The disease or condition treated using methods of the disclosure may have the symptom of cell hyperproliferation. For example, the disease or condition may be a cancer. The cancer may be, e.g., carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, or melanoma. The cancer may be, e.g., a solid tumor.

[0257] Non-limiting examples of cancers include prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain cancer, glioma, lung cancer, salivary cancer, stomach cancer, thymic epithelial cancer, thyroid cancer, leukemia, melanoma, lymphoma, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, and liver cancer.

[0258] Methods of the disclosure can be used in the treatment of renal cell carcinoma, mature B-cell neoplasms, endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, colorectal cancer, skin cancer (nonmelanoma), small bowel cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, or esophagogastric cancer.

[0259] Non-limiting examples of carcinomas include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum. Non-limiting examples of sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part 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 multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

[0260] Non-limiting examples of leukemias include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0261] Non-limiting examples of melanomas include acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0262] In some embodiments, Camonsertib is undergoing development for the treatment of various diseases. In embodiments, the various diseases include but are not limited to cancer. In embodiments, the cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or an advanced solid tumor. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is an ovarian cancer.

[0263] Pharmaceutical Compositions

[0264] The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include a compound as described herein and a pharmaceutically acceptable excipient. Certain pharmaceutical compositions may include one or more additional pharmaceutically active agents described herein.

[0265] The compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the disclosure. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof, may be administered to a patient in a variety of forms depending on the selected 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, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0266] For human use, a compound of the disclosure can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of a compound of the disclosure into preparations which can be used pharmaceutically. This disclosure also includes pharmaceutical compositions which can contain one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, e.g., preservatives.

[0267] The excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0268] These pharmaceutical compositions can be manufactured in a conventional manner, e.g., without limitations, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen. The formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., 40 mesh.

[0269] Administration of Camonsertib and / or Inavolisib

[0270] The compounds of the present disclosure may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal. It will be appreciated that the preferred route may vary with, for example, the recipient's condition. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc., with a pharmaceutically acceptable carrier or excipient. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for several cycles of therapy.

[0271] In embodiments, Camonsertib is administered orally. In embodiments, Inavolisib is administered orally. In embodiments, the combination of Camonsertib and Inavolisib is administered orally. Oral formulation refers to developing and manufacturing pharmaceuticals designed for oral delivery. In embodiments, Camonsertib and Inavolisib are administered as oral formulations.

[0272] Dosages

[0273] The dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0274] An ATR inhibitor may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compound may be administered according to a schedule or the compound may be administered without a predetermined schedule. An active compound may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per day, every 2nd, 3rd, 4th, 5th, or 6th day, 1 , 2, 3, 4, 5, 6, or 7 times per week, 1 , 2, 3, 4, 5, or 6 times per month, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per year. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0275] While the attending physician ultimately will decide the appropriate amount and dosage regimen of the ATR inhibitor, an effective amount of a compound of the disclosure may be, for example, a total daily dosage of, e.g., between 0.05 mg and 3000 mg of any of the compounds described herein. Alternatively, the dosage amount can be calculated using the body weight of the patient. Such dose ranges may include, for example, between 0.05-1000 mg (e.g., 0.25-800 mg). In some embodiments, 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 of the compound is administered.

[0276] Preferably, the subtherapeutic regimen of an ATR inhibitor is a low dosage (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95% less than the lowest standard recommended dosage of the ATR inhibitor for a given route of administration).

[0277] The ATR inhibitor may be administered once daily, 1 day / week, 2 days / week, 3 days / week, or 4 days / week. Preferably, the ATR inhibitor (e.g., without limitations, Camonsertib) has a starting dose frequency of 3 day on / 4 days off, 2 weeks on / 1 week off in a 21 -day cycle (i.e., participants will take Camonsertib on Days 1-3 [Week 1] and Days 8-10 [Week 2]).

[0278] The dosage of a PI3Kct inhibitor can be a low dosage (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95% less than the lowest standard recommended dosage of the PI3Ka inhibitor for a given route of administration). The PI3Kct inhibitor (e.g., without limitations, Inavolisib) may be administered orally QD (daily), 1 day / week, 2 days / week, 3 days / week, or 4 days / week. Preferably, the PI3Kct inhibitor (e.g., without limitations, Inavolisib) has a dose frequency as daily.

[0279] In the methods of the disclosure, the time period during which multiple doses of a compound of the disclosure are administered to a patient can vary. For example, in some embodiments, doses of the compounds of the disclosure are administered to a patient over a time period that is 1-7 days; 1-12 weeks; or 1-3 months. In other embodiments, the compounds are administered to the patient over a time period that is, for example, 4-11 months or 1-30 years. In other embodiments, the compounds are administered to a patient at the onset of symptoms. In any of these embodiments, the amount of compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1 , 2, or 3 times per day.

[0280] In embodiments, a treatment cycle for Camonsertib consists of 3 weeks and Camonsertib will be taken on specific days as required by each dose level or expansion cohort. In embodiments, the starting dose of Camonsertib and schedule are as follows: 120 mg administered orally (PO) starting on Day 1 of each week, 3 days on / 4 days off, 2 weeks on / 1 week off in a 21 -day cycle (i.e., participants will take Camonsertib on Days 1-3 [Week 1] and Days 8-10 [Week 2]). In embodiments, alternative Camonsertib dose and schedule may be explored based on emerging data.

[0281] In embodiments, Inavolisib is self-administered orally by participants at home (except on site visit days). In embodiments, Inavolisib will be administered orally QD (daily) on Days 1-21 of each 21 -day cycle at a starting dose of 6 mg.

[0282] In embodiments, the maximum planned dose for the combination therapy will consist of doses of Camonsertib 160 mg PO 3 days on / 4 days off, 2 weeks on / 1 week off in a 21 -day cycle, and Inavolisib 9 mg PO daily.

[0283] Formulations A compound identified as capable of treating any of the conditions described herein, using any of the methods described herein, may be administered to patients or animals with a pharmaceutically-acceptable diluent, carrier, or excipient, in unit dosage form. The chemical compounds for use in such therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to subjects in need thereof. Administration may begin before the patient is symptomatic.

[0284] Exemplary routes of administration of the compounds (e.g., a compound of the disclosure), or pharmaceutical compositions thereof, used in the present disclosure include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds desirably are administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein formulated for treatment of the disorders described herein are also part of the present disclosure. Oral administration is a preferred route of administration in the methods of the disclosure.

[0285] Formulations for Oral Administration

[0286] The pharmaceutical compositions contemplated by the disclosure include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) 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, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and anti adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0287] Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, gradules, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

[0288] Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and / or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., 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 certain embodiments, compositions include biodegradable, pH, and / or temperature-sensitive polymer coatings.

[0289] Dissolution- or diffusion- controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and / or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylatemethyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon.

[0290] The liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0291] In embodiments, the maximum planned dose for the combination therapy will consist of doses of Camonsertib 160 mg PO 3 days on / 4 days off, 2 weeks on / 1 week off in a 21 -day cycle, and Inavolisib 9 mg PO daily.

[0292] Formulations for Parenteral Administration

[0293] The compounds described herein for use in the methods of the disclosure can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulation as described herein. The pharmaceutical formulation may also be administered parenterally (intravenous, intramuscular, subcutaneous or the like) in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the disclosure may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP- NF), herein incorporated by reference.

[0294] The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:

[0295] (1) “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound of the present disclosure), or a solution thereof;

[0296] (2) “Drug for Injection:” the drug substance (e.g., a compound of the present disclosure) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection;

[0297] (3) “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound of the present disclosure) that is dissolved or dispersed in a suitable emulsion medium;

[0298] (4) “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound of the present disclosure) suspended in a suitable liquid medium; and

[0299] (5) “Drug for Injectable Suspension:” the drug substance (e.g., a compound of the present disclosure) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

[0300] Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0301] Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[0302] The parenteral formulation can be formulated for prompt release or for sustained / extended release of the compound. Exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymeric gels.

[0303] Definitions

[0304] The term “Camonsertib,” “RP-3500,” or “compound 121 ,” as used herein, refer to a novel, potent, and selective inhibitor of ATR. Camonsertib has been a potential candidate for the treatment of specific cancers. See, for instance, NCT04497116. In some embodiments, the ATR inhibitor is compound 121 or a pharmaceutically acceptable salt thereof. In some embodiments, the ATR inhibitor is the hydrogen sulfate salt of compound 121. In some embodiments, Camonsertib is a hydrogen sulfate salt of the ATR inhibitor.

[0305] The term "co-administration," "administration with," "administration in combination with," or the like, as used herein, encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0306] The term "progression-free survival (PFS)" means time from initiation of therapy to first evidence of disease progression or death due to any cause, whichever occurs first. For the purpose of the clinical trial described in the example, PFS is defined as the time from randomization of a study population to the first documented disease progression or death due to any cause. In some embodiments, administration of an ATR inhibitor and a PI3Kct inhibitor provides an increase in the progression-free survival of a human subject with cancer (e.g., without limitations, cancer bearing one or more mutation in the PIK3CA gene), compared to a human subject who is administered either with an ATR inhibitor alone or without any inhibitor. The increase in the progression-free survival refers to an increase in PFS in cancer patients (e.g., without limitations, patients with advanced solid tumors) treated with an ATR inhibitor and a PI3Kct inhibitor relative to PFS in cancer patients treated either with an ATR inhibitor only or without any inhibitor. In some embodiments, the increase in progression-free survival is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, about 36 months, or greater than 36 months increased over that of a subject administered either with an ATR inhibitor alone or without any inhibitor.

[0307] The term "aberrant," as used herein, refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, where returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms. The aberrant activity can be measured by measuring the modification of a substrate of the enzyme in question; a difference of greater or equal to a 2-fold change in activity could be considered as aberrant. Aberrant activity could also refer to an increased dependence on a particular signaling pathway as a result of a deficiency in a separate complementary pathway.

[0308] The term “acyl,” as used herein, represents a group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group.

[0309] The term “adenocarcinoma,” as used herein, represents a malignancy of the arising from the glandular cells that line organs within an organism. Non-limiting examples of adenocarcinomas include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer. The term “alkanoyl,” as used herein, represents a hydrogen or an alkyl group that is attached to the parent molecular group through a carbonyl group and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, propionyl, butyryl, and iso-butyryl. Unsubstituted alkanoyl groups contain from 1 to 7 carbons. The alkanoyl group may be unsubstituted of substituted (e.g., optionally substituted C1-7 alkanoyl) as described herein for alkyl group. The ending “-oyl” may be added to another group defined herein, e.g., aryl, cycloalkyl, and heterocyclyl, to define “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl.” These groups represent a carbonyl group substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl” may be optionally substituted as defined for “aryl,” “cycloalkyl,” or “heterocyclyl,” respectively.

[0310] The term “alkenyl,” as used herein, represents acyclic monovalent straight or branched chain hydrocarbon groups of containing one, two, or three carbon-carbon double bonds. Non-limiting examples of the alkenyl groups include ethenyl, prop-1 - enyl, prop-2-enyl, 1 -methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop- 1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl. Alkenyl groups may be optionally substituted as defined herein for alkyl.

[0311] The term “alkoxy,” as used herein, represents a chemical substituent of formula -OR, where R is a C1-6 alkyl group, unless otherwise specified. In some embodiments, the alkyl group can be further substituted as defined herein. The term “alkoxy” can be combined with other terms defined herein, e.g., aryl, cycloalkyl, or heterocyclyl, to define an “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” groups. These groups represent an alkoxy that is substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” may optionally substituted as defined herein for each individual portion.

[0312] The term “alkoxyalkyl,” as used herein, represents a chemical substituent of formula -L-O-R, where L is C1-6 alkylene, and R is C1-6 alkyl. An optionally substituted alkoxyalkyl is an alkoxyalkyl that is optionally substituted as described herein for alkyl.

[0313] The term “alkyl,” as used herein, refers to an acyclic straight or branched chain saturated hydrocarbon group, which, when unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyl has from 1 to 6 carbons. Alkyl groups are exemplified by methyl; ethyl; n- and iso-propyl; n-, sec-, iso- and tert-butyl; neopentyl, and the like, and may be optionally substituted, valency permitting, with one, two, three, or, in the case of alkyl groups of two carbons or more, four or more substituents independently selected from the group consisting of: amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfenyl; =0; =S; -SO2R, where R is amino or cycloalkyl; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group.

[0314] The term “alkylene,” as used herein, refers to a divalent alkyl group. An optionally substituted alkylene is an alkylene that is optionally substituted as described herein for alkyl.

[0315] The term “alkylamino,” as used herein, refers to a group having the formula -N(RN1)2 or -NHRN1, in which RN1is alkyl, as defined herein. The alkyl portion of alkylamino can be optionally substituted as defined for alkyl. Each optional substituent on the substituted alkylamino may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group.

[0316] The term “alkylsulfenyl,” as used herein, represents a group of formula -S- (alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl.

[0317] The term “alkylsulfinyl,” as used herein, represents a group of formula -S(0)- (alkyl). Alkylsulfinyl may be optionally substituted as defined for alkyl.

[0318] The term “alkylsulfonyl,” as used herein, represents a group of formula -S(0)2-(alkyl). Alkylsulfonyl may be optionally substituted as defined for alkyl.

[0319] The term “alkynyl,” as used herein, represents monovalent straight or branched chain hydrocarbon groups of from two to six carbon atoms containing at least one carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like. The alkynyl groups may be unsubstituted or substituted (e.g., optionally substituted alkynyl) as defined for alkyl.

[0320] The term “amino,” as used herein, represents -N(RN1)2, where, if amino is unsubstituted, both RN1are H; or, if amino is substituted, each RN1is independently H, -OH, -NO2, -N(RN2)2, -SO2ORN2, -SO2RN2, -SORN2, -C00RN2, an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one RN1is not H, and where each RN2is independently H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. In some embodiments, amino is unsubstituted amino (i.e., -NH2) or substituted amino (e.g., NHRN1), where RN1is independently -OH, -SO2ORN2, -SO2RN2, -SORN2, -COORN2, optionally substituted alkyl, or optionally substituted aryl, and each RN2can be optionally substituted alkyl or optionally substituted aryl. In some embodiments, substituted amino may be alkylamino, in which the alkyl groups are optionally substituted as described herein for alkyl. In some embodiments, an amino group is -NHRN1, in which RN1is optionally substituted alkyl.

[0321] The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings. Aryl group may include from 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, indanyl, indenyl, etc. The aryl group may be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; and cyano. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0322] The term “aryl alkyl,” as used herein, represents an alkyl group substituted with an aryl group. The aryl and alkyl portions may be optionally substituted as the individual groups as described herein.

[0323] The term “arylene,” as used herein, refers to a divalent aryl group. An optionally substituted arylene is an arylene that is optionally substituted as described herein for aryl.

[0324] The term “aryloxy,” as used herein, represents a chemical substituent of formula -OR, where R is an aryl group, unless otherwise specified. In optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

[0325] The term “ATM,” as used herein, represents ATM serine / threonine kinase. The term “ATR inhibitor” or “ATRi,” as used herein, represents a compound that upon contacting the enzyme ATR kinase, whether in vitro, in cell culture, or in an animal, reduces the activity of ATR kinase, such that the measured ATR kinase IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain ATR inhibitors, the ATR kinase IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the ATR kinase IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0326] The term “ATR kinase,” as used herein, refers to Ataxia-Telangiectasia and Rad-3-related protein kinase.

[0327] The term “azido,” as used herein, represents an -N3 group.

[0328] The term “BRCA2,” as used herein, represents a breast cancer type 2 susceptibility gene or protein.

[0329] The term "cancer," as used herein, refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, carcinomas, and sarcomas. Non-limiting examples of cancers that may be treated with a compound or method provided herein include prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, ampullary cancer, colorectal cancer, and pancreatic cancer. Additional non-limiting examples may include, Hodgkin's disease, NonHodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, and prostate cancer.

[0330] The term “carbocyclic,” as used herein, represents an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups. The term “carbonyl,” as used herein, represents a -C(O)- group.

[0331] The term "carcinoma," as used herein, refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Non-limiting examples of carcinomas that may be treated with a compound or method provided herein include, e.g., medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.

[0332] The term “cyano,” as used herein, represents -CN group.

[0333] The term “cycloalkenyl,” as used herein, refers to a non-aromatic carbocyclic group having at least one double bond in the ring and from three to ten carbons (e.g., a C3-10 cycloalkenyl), unless otherwise specified. Non-limiting examples of cycloalkenyl include cycloprop-1 -enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-1- enyl, cyclobut-2-enyl, cyclopent-1 -enyl, cyclopent-2-enyl, cyclopent-3-enyl, norbornen-1-yl, norbornen-2-yl, norbornen-5-yl, and norbornen-7-yl. The cycloalkenyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl) as described for cycloalkyl.

[0334] The term “cycloalkenyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl portions may be substituted as the individual groups defined herein.

[0335] The term “cycloalkoxy,” as used herein, represents a chemical substituent of formula -OR, where R is cycloalkyl group, unless otherwise specified. In some embodiments, the cycloalkyl group can be further substituted as defined herein.

[0336] The term “cycloalkyl,” as used herein, refers to a cyclic alkyl group having from three to ten carbons (e.g., a C3-C10 cycloalkyl), unless otherwise specified. Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of bicyclo[p.q.O]alkyl type, in which 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 may include bridged cycloalkyl structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1 , 2, or 3, 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. The cycloalkyl group may be a spirocyclic group, e.g., spiro[p.q]alkyl, in which 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 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1 .Jheptyl, 2-bicyclo[2.2.1 Jheptyl, 5-bicyclo[2.2.1 Jheptyl, 7- bicyclo[2.2.1 Jheptyl, and decalinyl. The cycloalkyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkyl) with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; =0; =S; -SO2R, where R is amino or cycloalkyl; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl; or -C0N(RA)2, where each RAis independently H or alkyl, or both RA, together with the atom to which they are attached, combine to form heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0337] The term “cycloalkyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0338] The term “cycloalkylene,” as used herein, represents a divalent cycloalkyl group. An optionally substituted cycloalkylene is a cycloalkylene that is optionally substituted as described herein for cycloalkyl.

[0339] The term “cycloalkynyl,” as used herein, refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having from eight to twelve carbons, unless otherwise specified. Cycloalkynyl may include one transannular bond or bridge. Non-limiting examples of cycloalkynyl include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadiynyl. The cycloalkynyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkynyl) as defined for cycloalkyl.

[0340] The term “halo,” as used herein, represents a halogen selected from bromine, chlorine, iodine, and fluorine.

[0341] The term “heteroalkyl,” as used herein refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms; twice, each time, independently, by one or two heteroatoms; three times, each time, independently, by one or two heteroatoms; or four times, each time, independently, by one or two heteroatoms. Each heteroatom is, independently, O, N, or S. In some embodiments, the heteroatom is O or N. None of the heteroalkyl groups includes two contiguous oxygen or sulfur atoms. The heteroalkyl group may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When heteroalkyl is substituted and the substituent is bonded to the heteroatom, the substituent is selected according to the nature and valency of the heteratom. Thus, the substituent bonded to the heteroatom, valency permitting, is selected from the group consisting of =0, -N(RN2)2, -SO2ORN3, -SO2RN2, -SORN3, -COORN3, an N protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, where each RN2is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each RN3is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. When heteroalkyl is substituted and the substituent is bonded to carbon, the substituent is selected from those described for alkyl, provided that the substituent on the carbon atom bonded to the heteroatom is not Cl, Br, or I. It is understood that carbon atoms are found at the termini of a heteroalkyl group.

[0342] The term “heteroaryl alkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein.

[0343] The term “heteroarylene,” as used herein, represents a divalent heteroaryl. An optionally substituted heteroarylene is a heteroarylene that is optionally substituted as described herein for heteroaryl.

[0344] The term “heteroaryloxy,” as used herein, refers to a structure -OR, in which R is heteroaryl. Heteroaryloxy can be optionally substituted as defined for heterocyclyl.

[0345] The term “heterocyclyl,” as used herein, represents a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridging, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, “heterocyclyl” is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridging 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyl has zero or one double bonds, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carboncarbon triple bond. Heterocyclyl groups include from 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may include up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. If the heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, such structure is an aromatic heterocyclyl (i.e., heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1 ,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and / or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropanes, or diaza-bicyclo[2.2.2]octane. The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring. Examples of fused heterocyclyls include 1 ,2,3,5,8,8a-hexahydroindolizine; 2,3- dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. The heterocyclyl group may be unsubstituted or substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; cyano; =0; =S; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0346] The term “heterocyclyl alkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0347] The term “heterocyclylene,” as used herein, represents a divalent heterocyclyl. An optionally substituted heterocyclylene is a heterocyclylene that is optionally substituted as described herein for heterocyclyl. The term “(heterocyclyl)oxy,” as used herein, represents a chemical substituent of formula -OR, where R is a heterocyclyl group, unless otherwise specified. (Heterocyclyl)oxy can be optionally substituted in a manner described for heterocyclyl.

[0348] The terms “hydroxyl” and “hydroxy,” as used interchangeably herein, represent an -OH group.

[0349] The term “isotopically enriched,” as used herein, refers to the pharmaceutically active agent with the isotopic content for one isotope at a predetermined position within a molecule that is at least 100 times greater than the natural abundance of this isotope. For example, a composition that is isotopically enriched for deuterium includes an active agent with at least one hydrogen atom position having at least 100 times greater abundance of deuterium than the natural abundance of deuterium. Preferably, an isotopic enrichment for deuterium is at least 1000 times greater than the natural abundance of deuterium. More preferably, an isotopic enrichment for deuterium is at least 4000 times greater (e.g., at least 4750 times greater, e.g., up to 5000 times greater) than the natural abundance of deuterium.

[0350] The term "leukemia," as used herein, refers broadly to progressive, malignant diseases of the blood-forming organs, and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, e.g., acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0351] The term “lymphoma,” as used herein, refers to a cancer arising from cells of immune origin. Non-limiting examples of T and B cell lymphomas include nonHodgkin lymphoma and Hodgkin disease, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphatic 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 leukaemia / lymphoma (ATLL), or extranodal NK / T-cell lymphoma, nasal type.

[0352] The term "melanoma," as used herein, is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, e.g., acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0353] The term “nitro,” as used herein, represents an -NO2 group.

[0354] The term “oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =0).

[0355] The term “PI3Kct inhibitor,” as used herein, refers to any PI3K inhibitor that targets the p110a catalytic subunit of PI3K. In some embodiments, the PI3Ka inhibitor specifically targets only the p110a. In some embodiments, the PI3Ka inhibitor specifically targets the p110a in addition to one or more other subunits (i.e., p110p and p1105). In some embodiments, PI3Ka inhibitor is selected from a group consisting of Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib. In some embodiments, PI3Kct inhibitor represents a compound of formula (III): and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:

[0356] R1is selected from — CH3, — CH2CH3, cyclopropyl, and cyclobutyl;

[0357] R2is selected from — CH3, — CHF2, — CH2F, and — CF3.

[0358] The term “Inavolisib,” as used herein, refers to a specific PI3K inhibitor that targets the p110a catalytic subunit of PI3K. Inavolisib is named as (S)-2-((2-((S)-4- (difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,2- d][1 ,4]oxazepin-9-yl)amino)propanamide and has the structure:

[0359] Inavolisib is previously described as Compound 101 in U.S. Patent No. 9,650,393 which is incorporated by reference in its entirety.

[0360] The term “Ph,” as used herein, represents phenyl.

[0361] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient. It can be manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); 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.

[0362] The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier,” as used interchangeably herein, refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, 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.

[0363] The term “pharmaceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable 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 in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. In embodiments, Camonsertib is presented in the form of a pharmaceutically acceptable salt as described herein. In embodiments, Camonsertib is presented in the form of a hydrogen sulfate salt. The hydrogen sulfate salt form of Camonsertib is previously described as example 121 in International Application No. PCT / CA2022 / 050892, which is incorporated by reference herein in its entirety.

[0364] The term “protecting group,” as used herein, represents a group intended to protect a hydroxy, an amino, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis. The term “O-protecting group,” as used herein, represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. The term “N-protecting group,” as used herein, represents a group intended to protect a nitrogen containing (e.g., an amino, amido, heterocyclic N-H, or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis. Commonly used O- 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- and N- protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl.

[0365] Exemplary O-protecting groups for protecting carbonyl containing groups include, but are not limited to: acetals, acylals, 1 ,3-dithianes, 1 ,3-dioxanes, 1 ,3- dioxolanes, and 1 ,3-dithiolanes.

[0366] Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2, 2, 2, -trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t- butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p- methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenymethylsilyl); 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).

[0367] 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, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5 dimethoxybenzyl oxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l - methylethoxycarbonyl, a,a-dimethyl-3,5 dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, aryl-alkyl groups such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, and the like, silylalkylacetal groups such as [2-(trimethylsilyl)ethoxy]methyl and silyl groups such as trimethylsilyl, and the like. Useful N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t- butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2- (trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0368] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Non-limiting examples of sarcomas that may be treated with a compound or method provided herein include, e.g., a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part 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 multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

[0369] The term “tautomer” refers to structural isomers that readily interconvert, often by relocation of a proton. Tautomers are distinct chemical species that can be identified by differing spectroscopic characteristics, but generally cannot be isolated individually. Non-limiting examples of tautomers include ketone - enol, enamine - imine, amide - imidic acid, nitroso - oxime, ketene - ynol, and amino acid - ammonium carboxylate.

[0370] The term “therapeutically effective amount,” as used herein, means the amount of a compound or a pharmaceutically acceptable salt thereof that, in a combination of an ATR inhibitor and PI3Kct inhibitor, is sufficient to treat cancer. Typically, a therapeutically effective amount is a subtherapeutic regimen.

[0371] The term “subject,” as used herein, represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, disease or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases having the symptom of cell hyperproliferation, e.g., a cancer.

[0372] The term “subtherapeutic regimen,” as used herein, refers to a dosing regimen that is at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosing regimen of a particular compound formulated for a given route of administration for treatment of cancer. A subtherapeutic regimen of a compound may be therapeutically ineffective for the compound in a monotherapy regimen. In the methods of the present disclosure, a therapeutically effective amount of a PI3Kct inhibitor is preferably a subtherapeutic regimen (e.g., a regimen that is therapeutically ineffective for the PI3Kct inhibitor in a monotherapy regimen). A subtherapeutic regimen of a PI3Kct inhibitor that is formulated for oral administration may differ from a subtherapeutic regimen of the same agent formulated for intratumoral administration. A subtherapeutic regimen may include a “subtherapeutic starting regimen” and a “subtherapeutic maintenance regimen.” A “subtherapeutic starting regimen” of a compound (e.g., a PI3Kct inhibitor) is lower than the lowest standard starting dosage of the same compound (e.g., a PI3Ka inhibitor). Similarly, a “subtherapeutic maintenance regimen” of a compound (e.g., a PI3Kct inhibitor) is lower than the lowest standard maintenance regimen of the same compound (e.g., a PI3Kct inhibitor). Typically, the subtherapeutic regimen is at least 1 % of the lowest standard subtherapeutic regimen.

[0373] “Treatment” and "treating," as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent, or cure a disease or condition. This term includes active treatment (treatment directed to improve the disease or condition); causal treatment (treatment directed to the cause of the associated disease or condition); palliative treatment (treatment designed for the relief of symptoms of the disease or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease or condition); and supportive treatment (treatment employed to supplement another therapy). A disease or condition may be cancer. Non-limiting examples of cancers include, e.g., renal cell carcinoma, mature B-cell neoplasms, 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 esophagogastric cancer. The term “uM” or “pM” are used interchangeably herein throughout the disclosure, including in the figures and / or drawings. The term “uM” or “pM” stands for “micromolar (micromoles / liter)”.

[0374] If any publication incorporated herein by reference contains a definition not consistent with a definition presented herein, the latter definition prevails.

[0375] The following examples are meant to illustrate the present disclosure. They are not meant to limit the present disclosure in any way.

[0376] EXAMPLES

[0377] Example 1 : Synergy between ATR inhibitors and PI3Ka inhibitors in various cancer cell line backgrounds

[0378] An ATR inhibitor (e.g., compound 121 ) may synergize with a PI3Kct inhibitor (e.g., Inavolisib) in cancer cell lines (e.g. MCF7 and HCC1954 p110a wild type and MCF7 p110a E545K and HCC1954 H1074R p110a mutant cell lines). As a result, the apparent IC50 of the PI3Ka inhibitor may shift in the presence of the ATR inhibitor (e.g., compound 121 ). The ATR inhibitor, as referred to herein and throughout the present disclosure, may be a hydrogen sulfate salt of compound 121 .

[0379] In addition to selecting a sensitized genetic background, tolerability of the combination treatment with an ATR inhibitor and PI3Ka inhibitor can be improved by optimizing dosing schedules. To guide the combined dosing of the ATR inhibitor (e.g., compound 121 ) and the PI3Ka inhibitor (e.g., Inavolisib a continuous longer concomitant treatment with both compounds may be compared to a shorter treatment followed by removal of compounds and growth in drug-free media. The presence of the ATR inhibitor (e.g., compound 121 ) may decrease the apparent IC50 value of the PI3Ka inhibitor (e.g., Inavolisib) when dosed continuously for a longer period of time (e.g., 168 h). No significant difference in the apparent IC50 values might be observed when treatment is shortened, suggesting that an intermittent dosing schedule of the ATR inhibitor (e.g., compound 121 ) in combination with the PI3Ka inhibitor (e.g., Inavolisib) followed by a recovery period may be efficacious. If the above results are observed, they would suggest that tumor cells of a specific genetic makeup can be treated with reduced doses of the PI3Ka and ATR inhibitors for reduced amounts of time as compared to standard therapeutic regimens, while maintaining efficacy. Example 2: Inhibitory and synergistic effects of Inavolisib in combination with Camonsertib p110a inhibitors’ metabolic effects are hypothesized to synergize with DNA damage repair inhibitors. p110a inhibition depletes nucleotide pools which increases replication stress hence increases susceptibility to DNA damage repair inhibitors (e.g., ATRi and PARPi). Additionally, promising results for PI3Ki and PARP combination was observed in the EPIK-O / ENGOT-OV61 : Alpelisib plus olaparib vs. cytotoxic chemotherapy in platinum-resistant or -refractory high grade serous ovarian cancer with no germline BRCA mutation (phase III study).

[0380] The inhibitory and synergistic effects of Inavolisib in combination with Camonsertib was investigated using the 72 hour CellTiter-Glo viability assay and wild type and p110a mutant breast cancer cell lines (MCF7 and HCC1954) derived from Cell Central. The MCF7 and HCC1954 parental cell lines are inherently PIK3CA mutated. These cell lines were engineered to express WT p110a. Increasing doses of Inavolisib + Camonsertib reduced cell viability in both wildtype and mutant MCF7 cells, with more sensitivity observed in the mutant PIK3CA cells. A similar pattern was observed in both BRCA1 mutant / p110a wild type and BRCA1 mut / p110a mutant breast cancer cells (HCC1954).

[0381] Figure 1 shows plots of the percentage of cell viability based on ATP (y-axis) with different dose levels of Camonsertib and Inavolisib combined in p110a wild type and mutant MCF7 cells. Each line represents a distinct dose level of Inavolisib. The y-axis displays the scale of increasing Camonsertib doses. The results from Figure 1 suggest that the combination of Camonsertib and Inavolisib reduces cell viability in both wildtype and mutant MCF7 cells with more sensitivity observed in the mutant cells.

[0382] Figure 2 shows contour plots of the synergy scores of Inavolisib doses (y-axis) and dose levels of Camonsertib and Inavolisib combined in p110a wild type and mutant MCF7 cells. The regions labeled “+” represent the combination doses that have the most synergistic effects. The results from Figure 2 show similar drug synergy patterns observed in the combination of Camonsertib and Inavolisib in both wildtype and mutant MCF7 cells. Figure 3 shows plots of the percentage of cell viability based on ATP (y-axis) with different dose levels of Camonsertib and Inavolisib combined in p110o wild type and mutant HCC1954 cells. Each colored line represents a distinct dose level of Inavolisib. The y-axis displays the scale of increasing Camonsertib doses. The results from Figure 3 suggest that the combination of Camonsertib and Inavolisib reduces cell viability in both BRCA1 mutant / p110a wild type and BRCA1 mutant / p110a mutant cells.

[0383] Figure 4 shows contour plots of the synergy scores of Inavolisib doses (y-axis) and dose levels of Camonsertib and Inavolisib combined in p110o wild type and mutant HCC1954 cells. The regions labeled “+” represent the combination doses that have the most synergistic effects. The results from Figure 4 show the combination of Camonsertib and Inavolisib shows similar drug synergy patterns in both BRCA1 mutant / p110a wild type and BRCA1 mutant / p110a mutant cells.

[0384] Figure 5 shows western blot images of the expression of relevant DNA damage repair proteins in untreated and treated (Camonsertib and Inavolisib) MCF7 and HCC1954 cells. Inavolisib + Camonsertib treatment induces DNA damage in p110a mutant and wildtype cells. But particularly induces increased yH2AX in the PIK3CAm cell lines compared to wildtype cells. The results from Figure 5 suggest that Inavolisib treatment leads to a greater increase in pATR and yH2AX in the PIK3CAm cell lines compared to wildtype.

[0385] Example 3: Phase lb study of Camonsertib in combination with Inavolisib

[0386] Patients Selection

[0387] The screening key study wide eligibility criteria were as follows:

[0388] • Age 18 years old

[0389] • Metastatic / unresectable solid tumor with no existing standard therapy

[0390] • > 1 prior line of therapy.

[0391] • Available tumor tissue sample

[0392] • Measurable disease per RECIST v1 .1

[0393] • Prior PARPi allowed

[0394] • No prior ATRi

[0395] • No untreated CNS tumors Primary EP

[0396] • Safety / Tolerability

[0397] Secondary EP • ORR, DoR, PFS, 6-month PFS, OS

[0398] Various cancer types (e.g., without limitations, prostate cancer, breast cancer, and ovarian cancer) could be picked as a focus indication for the Inavolisib and Camonsertib combination due to unmet need and promising data from a prior Alpelisib trial.

[0399] The effects of the Inavolisib and Camonsertib combination was assessed in wild type and pllOa mutant breast cancer cell lines

[0400] *Notes 1. CellCentral is Genentech’s cell line database

[0401] 2. The MCF7 and HCC1954 parental cell lines are inherently PIK3CA mutated; these were engineered to express WT pllOa

[0402] The purpose of this Phase lb multicenter, open-label substudy is to assess the safety, tolerability, antitumor activity, pharmacokinetics, and biomarkers of Camonsertib in combination with Inavolisib and to determine the recommended dose for further development of the combination in patients with one or more mutations in the PIK3CA gene (e.g., without limitations, patients with advanced solid tumors) who have received prior systemic therapy.

[0403] The dose escalation part (Stage I) of the substudy will evaluate the safety, tolerability, and pharmacokinetics and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and schedule of Camonsertib in combination with Inavolisib. At each dose level, participants will be treated at planned doses of Camonsertib and Inavolisib as shown in Table 2. Table 2. Planned dose escalation stage regimens

[0404] The dose expansion part (Stage II) of the substudy will further evaluate the safety, tolerability, antitumor activity, pharmacokinetics, and biomarkers of the combination at one or more dose levels at or below the MTD or MAD of the combination determined in the dose escalation stage.

[0405] The population age will be greater than or equal to 18 years. The number of participants to be enrolled is approximately 27 participants in Stage I and approximately 20-30 participants per cohort in Stage II.

[0406] The study schema for the administration of Camonsertib in combination with Inavolisib is shown in Figure 6. This study schema includes both dose escalation and dose expansion.

[0407] Figure 7 shows individual participant schema for Stage I dose escalation. Abbreviations: ATRi = ataxia telangiectasia-mutated- and rad-3 related inhibitor; DNA-PKi = DNA-dependent protein kinase inhibitor; PO = orally, by mouth; Q90D = every 90 days; RECIST = Response Evaluation Criteria in Solid Tumors. Note: Depending on the cohort open at time of participant assignment, the dose and / or schedule of each agent may differ from the schema.aStarting dose is Camonsertib 120 mg PO, 3 days on / 4 days off, 2 weeks on / 1 week off in combination with Inavolisib 6 mg PO QD.

[0408] Dose Escalation

[0409] Dose escalation (for Camonsertib) will follow a Bayesian Optimal Interval (BOIN) design. Bayesian Optimal Interval (BOIN) designs are a class of model- assisted dose-finding designs that can be used in oncology trials to determine the maximum tolerated dose (MTD) of a study drug based on safety or the optimal biological dose (OBD) based on safety and efficacy. BOIN designs provide a complete suite for dose finding in early phase trials, as well as a consistent way to explore different scenarios such as toxicity, efficacy, continuous outcomes, delayed toxicity or efficacy and drug combinations in a unified manner with easy access to software to implement most of these designs. Although built upon Bayesian probability models, BOIN designs are operationally simple in general and have good statistical operating characteristics compared to other dose-finding designs. The schematic of dose escalation rules is outlined in Figure 8.

[0410] The planned starting dose for the study treatment in Stage I is Camonsertib 120 mg PO 3 days on / 4 days off, 2 weeks on / 1 week off, in a 21 -day cycle and Inavolisib 6 mg PO daily. The starting dose and schedule have been selected based on the integration of several factors, including the pharmacologically active dose range of each agent as monotherapy and the potential for overlapping toxicities between Camonsertib and Inavolisib (e.g., gastro-intestinal toxicities and possibly some hematologic toxicity) that are expected to be clinically monitorable and manageable in patients.

[0411] Based on the differentiated mechanisms of action of Camonsertib and Inavolisib, a starting dose of each agent with adequate inhibition of the respective ATR and PI3K pathways was considered as optimal in order to study the potential additive or synergistic effects of the combination.

[0412] Camonsertib PK has been evaluated in patients with advanced cancer at doses from 5 mg to 200 mg and preliminary results suggest that doses >120 mg QD are pharmacologically active.

[0413] Based on the mechanisms of action, the modes of elimination, and the individual safety profiles of Camonsertib and Inavolisib, these agents are anticipated to combine without severe unexpected toxicities. Therefore, the maximum planned dose for the combination will consist of the monotherapy dose of Camonsertib 160 mg PO 3 days on / 4 days off, 2 weeks on / 1 week off in a 21 -day cycle, and Inavolisib 9 mg PO daily.

[0414] ADDITIONAL INCLUSION CRITERIA

[0415] Potential participants are eligible to be included in the Camonsertib + Inavolisib substudy only if all of the following criteria also apply.

[0416] • Histologically confirmed unresectable or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy options exist

[0417] • Confirmed presence of PIK3CA mutation as determined through either central testing of submitted tumor tissue or local testing of blood or tumor tissue. o Eligible PIK3CA mutations are defined as follows:

[0418] ■ R88Q

[0419] ■ G106A / D / R / S / V

[0420] ■ K111N / R / E

[0421] ■ G118D

[0422] ■ N345D / H / I / K / S / T / Y

[0423] ■ C420R

[0424] ■ E453A / D / G / K / Q / V ■ E542A / D / G / K / Q / R / V

[0425] ■ E545A / D / G / K / L / Q / R / V

[0426] ■ Q546E / H / K / L / P / R

[0427] ■ M1043I / T / V

[0428] ■ H1047D / I / L / N / P / Q / R / T / Y

[0429] ■ G1049A / C / D / R / S

[0430] Camonsertib

[0431] A treatment cycle consists of 3 weeks and Camonsertib will be taken on specific days as required by each dose level or expansion cohort. The starting Camonsertib dose and schedule are as follows: 120 mg administered orally (PO) starting on Day 1 of each week, 3 days on / 4 days off, 2 weeks on / 1 week off in a 21- day cycle (i.e., participants will take Camonsertib on Days 1-3 [Week 1] and Days 8- 10 [Week 2]). Alternative Camonsertib dose and schedule may be explored based on emerging data.

[0432] Camonsertib is formulated in 40-mg strength capsules and will be selfadministered orally with approximately 240 mL (approximately 8 oz) of water by participants at home (except on site visit days). Participants should swallow the Camonsertib capsule whole and should not manipulate or chew the study drug prior to swallowing.

[0433] Participants will be instructed to take their Camonsertib dose in the morning at approximately the same time each day. Participants will be instructed to delay self-administration of their treatment dose on days scheduled for site visits and to take their study drug at the site. The dosing schedule should be coordinated with the PK and biomarker sampling schedule if the site is unable to accommodate weekend visits. Planned doses should be taken on the same consecutive days each week.

[0434] If participants forget to take their dose at their usual time, they should take the missed dose as soon as possible on the same day it was missed; however, there must be at least 8 hours between the missed dose and the next scheduled dose. If a dose is missed and there is less than 8 hours until the next dose, the missed dose should not be administered and the participant should record this missed dose in the medication diary. If a participant vomits during or after taking Camonsertib, re-dosing is not permitted and the participant should take their regular dose at the next scheduled dose. Inavolisib

[0435] Inavolisib will be self-administered orally by participants at home (except on site visit days). Inavolisib will be administered orally QD (daily) on Days 1-21 of each 21 -day cycle at a starting dose of 6 mg.

[0436] Inavolisib should be taken at approximately the same time each day without regards to the timing of administration of food. Because Inavolisib is a BCRP substrate and Camonsertib is a BCRP inhibitor, participants are recommended to take the Inavolisib dose first, and then the Camonsertib dose approximately 2 hours later in a staggered dosing approach for days when they are both administered. If a dose is missed (not taken within 9 hours after the scheduled dosing time), the participant should resume dosing with the next scheduled dose and record this missed dose in the medication diary. Missed or vomited doses will not be made up.

[0437] The total duration of study participation for each individual is expected to range from 1 day to more than 6 months.

[0438] OTHER EMBODIMENTS

[0439] Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

[0440] Other embodiments are in the claims.

Claims

CLAIMS1 . A method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor, wherein the cancer is identified as having one or more mutations in PIK3CA.

2. The method of claim 1 wherein the PI3Kct inhibitor is a compound of formula (HI):and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:R1is selected from — CH3, — CH2CH3, cyclopropyl, and cyclobutyl;R2is selected from — CH3, — CHF2, — CH2F, and — CF3.

3. The method of claim 2 wherein R1is — CH3 or cyclopropyl.

4. The method of claim 2 wherein R2is — CHF2.

5. The method of claim 1 wherein the PI3Kct inhibitor is a compound of the structure:

6. The method of claim 1 wherein the PI3Kct inhibitor is a compound of the structure:

7. The method of claim 1 wherein the PI3Kct inhibitor is a compound of the structure:

8. The method of claim 1 wherein the PI3Kct inhibitor is a compound of the structure:

9. The method of claim 1 wherein the PI3Kct inhibitor is a compound of the structure:

10. The method of claim 1 wherein the PI3Kct inhibitor is a compound of the structure:11 . The method of claim 1 wherein the PI3Kct inhibitor is a compound of the structure:

12. A method of treating a cancer in a subject of claim 1 , the method comprising:(i) identifying the cancer as having one or more mutations in PIK3CA', and (ii) administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor.

13. The method of any one of claims 1 to 12, wherein the ATR inhibitor is administered before the PI3Kct inhibitor.

14. The method of any one of claims 1 to 12, wherein the ATR inhibitor is administered after the PI3Kct inhibitor.

15. The method of any one of claims 1 to 12, wherein the ATR inhibitor is coadministered with the PI3Ka inhibitor.

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

17. The method of any one of claims 1 to 16, wherein the therapeutically effective amount is a subtherapeutic regimen of the PI3Kct inhibitor.

18. The method of claim 16 or 17, wherein the subtherapeutic regimen comprises a starting dosage that is at least 50% less than the lowest standard starting dosage that is used for a monotherapy.

19. The method of any one of claims 16to 18, wherein the subtherapeutic regimen comprises a maintenance dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy.

20. The method of claim 19, wherein the maintenance dosage comprises a first reduced dosage.21 . The method of claim 19 or 20, wherein the maintenance dosage comprises a second reduced dosage.

22. The method of any one of claims 19 to 21 , wherein the maintenance dosage comprises a third reduced dosage.

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

24. The method of any one of claims 1 to 23, wherein the ATR inhibitor is administered 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 of any one of claims 1 to 24, wherein the PI3Kct inhibitor is administered 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

26. A method of inducing cell death in an aberrant cancer cell having one or more mutations in PIK3CA, the method comprising contacting the cell with an effective amount of an ATR inhibitor and an effective amount of a PI3Kct inhibitor, the effective amounts being sufficient to induce cell death in the aberrant cancer cell.

27. The method of claim 26 wherein the PI3Kct inhibitor is a compound of formula (HI):and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:R1is selected from — CH3, — CH2CH3, cyclopropyl, and cyclobutyl;R2is selected from — CH3, — CHF2, — CH2F, and — CF3.

28. The method of any one of claims 1 to 27, wherein the cancer is any type of cancer carrying a PIK3CA mutation.

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

30. The method of any one of claims 1 to 27, wherein the cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or an advanced solid tumor.31 . The method of any one of claims 1 to 27, wherein the cancer having one or more mutations in PIK3CA is a solid tumor.

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

33. The method of any one of claims 1 to 32, wherein the ATR inhibitor is a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein- is a double bond, and each Y is independently N or CR4; or - is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; wherein each RYis independently H or optionally substituted C1-6 alkyl;R1is optionally substituted C1-6 alkyl or H;R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; andX is hydrogen or halogen.

34. The method of claim 33, wherein the ATR inhibitor is a compound of formula (II):or a pharmaceutically acceptable salt thereof, whereineach Y is independently N or CR4;R1is optionally substituted C1-6 alkyl or H;R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted Ce-io arylene; andX is hydrogen or halogen.

35. The method of claim 34 wherein R2is a 5-10 membered bicyclic [p.q.r] heterocyclyl.

36. The method of claim 34 wherein R2is a37. The method of claim 34 wherein R2is a38. 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 of claim 40, wherein compound 121 is a hydrogen sulfate salt.

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

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

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

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

46. The method of any one of claims 1 to 45, wherein the PI3Kct inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 1 to 46, wherein the PI3Kct inhibitor is: (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1 ,2-d][1 ,4]oxazepin-9-yl)amino)propanamide,(S) — N1-(4-methyl-5-(2-(1 ,1 ,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)pyrrolidine-1 ,2-dicarboxamide), or a pharmaceutically acceptable salt thereof.

48. The method of any one of claims 1 to 46, wherein the PI3Kct inhibitor is (S)-2- ((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,2- d][1 ,4]oxazepin-9-yl)amino)propanamide, or a pharmaceutically acceptable salt thereof.

49. The method of any one of claims 1 to 48, wherein the PI3Kct inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, Taselisib, a pharmaceutically acceptable salt thereof, or any combination thereof.

50. A method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor, wherein the cancer has been previously identified as a cancer having one or more mutations in PIK3CA, and wherein the PI3Kct inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof.51 . A method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor, wherein the cancer has one or more mutations in PIK3CA; and wherein the PI3Kct inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof.

52. A method of treating a cancer in a subject, the method comprising:(i) identifying the cancer as having one or more mutations in PIK3CA', and(ii) administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and a PI3Kct inhibitor that is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof.

53. The method of any one of claims 50 to 52, wherein the ATR inhibitor is administered before the PI3Kct inhibitor.

54. The method of any one of claims 50 to 52, wherein the ATR inhibitor is administered after the PI3Kct inhibitor.

55. The method of any one of claims 50 to 52, wherein the ATR inhibitor is co-administered with the PI3Kct inhibitor.

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

57. The method of any one of claims 50 to 56, wherein the therapeutically effective amount comprises a subtherapeutic regimen of the PI3Kct inhibitor.

58. The method of claim 56 or 57, wherein the subtherapeutic regimen comprises a starting dosage that is at least 50% less than the lowest standard starting dosage that is used for a monotherapy.

59. The method of any one of claims 56 to 58, wherein the subtherapeutic regimen comprises a maintenance dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy.

60. The method of claim 59, wherein the maintenance dosage comprises a first reduced dosage.61 . The method of claim 59 or 60, wherein the maintenance dosage comprises a second reduced dosage.

62. The method of any one of claims 59 to 61 , wherein the maintenance dosage comprises a third reduced dosage.

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

64. The method of any one of claims 50 to 63, wherein the ATR inhibitor is administered 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 of any one of claims 50 to 64, wherein the PI3Kct inhibitor is administered 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or 7 days / week.

66. A method of inducing cell death in an aberrant cancer cell having one or more mutations in PIK3CA, the method comprising contacting the cell with an effective amount of an ATR inhibitor and an effective amount of a PI3Kct inhibitor, the effective amounts being sufficient to induce cell death in the aberrant cancer cell; wherein the PI3Ka inhibitor is Inavolisib, Alpelisib, Serabelisib, HH-CYH33, BAY1082439, ON 146040, AMG 511 , Buparlisib, Dactolisib, Pictilisib, and Taselisib, a pharmaceutically acceptable salt thereof, or a combination thereof.

67. The method of any one of claims 50 to 66, wherein the ATR inhibitor is a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein- is a double bond, and each Y is independently N or CR4; or - is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; wherein each RYis independently H or optionally substituted C1-6 alkyl;R1is optionally substituted C1-6 alkyl or H;R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy;each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; andX is hydrogen or halogen.

68. The method of claim 67, wherein the ATR inhibitor is a compound of formula (II):.0.or a pharmaceutically acceptable salt thereof, wherein each Y is independently N or CR4;R1is optionally substituted C1-6 alkyl or H;R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R5)2, -OR5, -CON(R6)2, - SO2N(R6)2, -SO2R5A, or -Q-R5B;R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substitutedC1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, - SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; andX is hydrogen or halogen.

69. The method of claim 68 wherein R2is a 5-10 membered bicyclic [p.q.r] heterocyclyl.

70. The method of claim 69 wherein R2is a71 . The method of claim 70 wherein R2is a72. 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 of claim 74, wherein compound 121 is a hydrogen sulfate salt.

76. The method of claim 72, wherein the ATR inhibitor is Camonsertib 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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