How to use ATR inhibitors

Abstract

Disclosed are methods of treating cancer in a subject using an ATR inhibitor, where the cancer has been previously identified as a cancer having loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B. Also disclosed are methods of inducing cell death in abnormal cancer cells having loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B by contacting the cells with an effective amount of an ATR inhibitor.

Description

[Technical field]

[0001] The present invention relates to the use of ataxia telangiectasia and RAD-3-related protein (ATR) kinase inhibitors in the treatment of cancers harboring loss-of-function mutations in stromal antigen 2 (STAG2), SET domain containing 2 (SETD2), cyclin-dependent kinase 12 (CDK12), ATR interacting protein (ATRIP), reversionless 3-like (REV3L), RAD17, chromosome transmission fidelity factor 8 (CHTF8), fizzy and cell division cycle 20-related 1 (FZR1), RAD51B, RAD51C, RAD51D, partner and localizer of BRCA2 (PALB2), ribonuclease H2 subunit A (RNASEH2A), or ribonuclease H2 subunit B (RNASEH2B). [Background technology]

[0002] DNA damage occurs constantly in cells as a result of environmental stimuli including UV radiation, X-rays, and endogenous stressors such as reactive oxygen species and base hydrolysis. Cancer cells suffer from a high rate of DNA damage, which is essentially caused by the high rate of DNA replication in these cells. Several DNA damage response (DDR) pathways have evolved in a highly coordinated manner to assist in the repair of DNA damage and act as cellular checkpoints that halt the replication of cells with damaged DNA, allowing the repair function to take place before the damaged DNA is passed on to daughter cells. Each of the identified DNA repair pathways senses and repairs different, but overlapping, types of DNA damage.

[0003] One of the major DDR proteins acting as a key cell cycle checkpoint is the ataxia telangiectasia mutated and rad3-related (ATR) kinase, which is related to the phosphoinositide 3-kinase-related protein kinase (PIKK) family. ATR is activated by single-stranded (ss) DNA damage caused by stalled replication forks or during nucleotide excision repair, but also by double-strand breaks after DNA end removal during homologous recombination. ATR, together with a cofactor called ATR-interacting protein (ATRIP), is recruited to the site of DNA damage by binding to RPA proteins that coat ssDNA. The ATR / ATRIP complex is then activated by the recruitment of additional factors of the 9-1-1 complex (RAD9, RAD1, and HUS1), followed by the recruitment of the TOPBP1 protein, a key step in the activation of downstream phosphorylation cascades that lead to cell cycle arrest. The primary target of the ATR kinase is CHK1, which upon phosphorylation targets both the cdc25 protein and Wee1, leading to inhibition of cyclin-dependent kinase activity and cell cycle arrest at S phase or G2 / M.

[0004] ATR is recognized as an important cancer target because it is essential for dividing cells. ATR-deficient mice are embryonic lethal, whereas conditional ATR knockout adult mice are viable, affecting rapidly proliferating tissues and stem cell populations. Thus, cancer cells with high levels of replication stress due to oncogenic mutations, dysfunction of G1 / S checkpoint control (e.g., loss of p53 function), defects in other DNA repair pathways (e.g., ATM), or affected by DNA damaging agents, such as radiation therapy or chemotherapeutic agents, are more dependent on ATR for DNA repair and survival.

[0005] Cancer cells harboring certain genetic mutations have unexpectedly proven to be highly sensitive to ATR inhibitors, and patients with such mutations are more likely to achieve beneficial responses when treated with ATR inhibitors at doses that provide a therapeutic window. Summary of the Invention

[0006] Generally, the present invention provides methods of inhibiting ATR in a cell having a loss-of-function mutation in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B. The methods may include contacting the cell with a compound disclosed herein.

[0007] In one aspect, the invention provides a method of treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an ATR inhibitor, wherein the cancer has been previously identified as a cancer having loss of function (e.g., biallelic loss-of-function mutations) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

[0008] In another aspect, the invention provides a method of treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an ATR inhibitor, wherein the cancer has loss of function (e.g., biallelic loss-of-function mutations) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B. In yet another aspect, the invention provides a method of treating cancer in a subject, comprising: (i) identifying that the cancer has a loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B; (ii) administering to a subject in need thereof a therapeutically effective amount of an ATR inhibitor; The present invention provides a method comprising:

[0009] In yet another aspect, the invention provides a method of inducing cell death in an abnormal cancer cell having loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B, comprising contacting the cell with an effective amount of an ATR inhibitor, wherein the effective amount is sufficient to induce cell death in the abnormal cancer cell.

[0010] In another aspect, the present invention also provides an ATR inhibitor for use in a method of treating cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of an ATR inhibitor, wherein the cancer has been previously identified as a cancer having loss of function (e.g., biallelic loss of function) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

[0011] In another aspect, the present invention also provides an ATR inhibitor for use in a method of treating cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of an ATR inhibitor, wherein the cancer has loss of function (e.g., biallelic loss of function) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

[0012] In another aspect, the present invention also provides an ATR inhibitor for use in a method of treating cancer in a subject, the method comprising the steps of (i) identifying that the cancer has loss of function (e.g., biallelic loss of function) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B, and (ii) administering to a subject in need thereof a therapeutically effective amount of an ATR inhibitor.

[0013] In another aspect, the present invention also provides an ATR inhibitor for use in a method of inducing cell death in an abnormal cancer cell having loss of function (e.g., biallelic loss of function) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B, the method comprising contacting the cell with an effective amount of an ATR inhibitor, the effective amount being sufficient to induce cell death in the abnormal cancer cell.

[0014] In some embodiments of any of the above aspects, the loss of function is a loss of function of STAG2. In some embodiments, the loss of function is a loss of function of SETD2. In some embodiments, the loss of function is a loss of function of CDK12. In some embodiments, the loss of function is a loss of function of ATRIP. In some embodiments, the loss of function is a loss of function of REV3L. In some embodiments, the loss of function is a loss of function of RAD17. In some embodiments, the loss of function is a loss of function of CHTF8. In some embodiments, the loss of function is a loss of function of FZR1. In some embodiments, the loss of function is a loss of function of RAD51B. In some embodiments, the loss of function is a loss of function of RAD51C. In some embodiments, the loss of function is a loss of function of RAD51D. In some embodiments, the loss of function is a loss of function of PALB2. In some embodiments, the loss of function is a loss of function of RNASEH2A. In some embodiments, the loss of function is a loss of function of RNASEH2B.

[0015] In some embodiments, the method further comprises identifying, prior to the administering or contacting step, that the cancer has a biallelic loss-of-function mutation in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

[0016] In some embodiments, the identifying step comprises: determining an integer total copy number of a locus segment and / or an integer allele-specific copy number of two locus segments within a STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B gene region of the cancer cell or cancer cells from a subject from a read count of a plurality of SNVs, including homozygous single nucleotide variants (SNVs) and heterozygous SNVs, obtained from sequencing a sample comprising the cancer cells (e.g., obtained from next generation sequencing) and a reference read count; Here, cancer is at least one of the integer total copy numbers and the integer allele-specific copy numbers is zero (provided that the remaining STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B alleles, if present, contain an inactivating mutation); or if none of the integer allele-specific copy numbers are zero and STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B alleles are present and each of the alleles independently has an inactivating mutation; Identified as having biallelic loss-of-function mutations in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

[0017] In some embodiments, the determining step comprises: determining total copy number log ratios, allele copy number log odds ratios, and target coverage values ​​for the SNVs from the read counts and the reference read counts; Segmenting the total copy number log ratios and the allele copy number log odds ratios; estimating sample purity and sample ploidy of the cancer cells from the total copy number log ratio and the target coverage value; generating an integer total copy number of a segment containing a plurality of SNVs and two integer allele-specific copy numbers of the segment in the STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B gene region of the cancer cell from the target coverage value, sample purity, sample ploidy, total copy number log ratio, and allele copy number log odds ratio; Includes.

[0018] In some embodiments, the method further comprises adjusting the misregistration rate. In some embodiments, the plurality of SNVs includes SNVs with uniform coverage (e.g., each of the SNVs with uniform coverage has an average coverage of at least 200x reads across the panel of normal samples). In some embodiments, each of the SNVs with uniform coverage has an average coverage of at least 300x reads across the panel of normal samples. In some embodiments, the plurality of SNVs includes a high frequency SNV, the high frequency SNV having an allele frequency in humans of 33%-66%. In some embodiments, the plurality of SNVs includes an SNV adjacent to a high frequency SNV (e.g., an SNV located within 300 contiguous nucleobases downstream from the high frequency SNV). In some embodiments, the plurality of SNVs includes a plurality of SNVs, each of the plurality of SNVs having a 5'-flanking sequence of at least 20 contiguous nucleobases with a GC content of 25-75%, where the 5'-flanking sequence is unique and does not include other SNVs. In some embodiments, the plurality of SNVs comprises at least 20 heterozygous SNVs. In some embodiments, the reference read count is derived from a panel of normal samples. In some embodiments, the plurality of SNVs comprises scaffold SNVs (e.g., scaffold SNVs may be useful to constrain the solution space of integer total copy numbers and integer allele-specific copy numbers). In some embodiments, the genic regions each comprise up to 10 kilobases of flanking region. In some embodiments, the genic regions each comprise up to 5 kilobases of flanking region. In some embodiments, the genic regions each comprise up to 2 kilobases of flanking region. In some embodiments, the genic regions are exome regions. In some embodiments, the genic regions are transcriptome regions. In some embodiments, the genic regions are genomic regions.In some embodiments, the biallelic loss-of-function mutations in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B comprise at least one somatic mutation. In some embodiments, the biallelic loss-of-function mutations in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B comprise at least one germline mutation. In some embodiments, the biallelic loss-of-function mutations in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B comprise one somatic loss-of-function mutation and one germline loss-of-function mutation.

[0019] In some embodiments, the ATR inhibitor is a compound of formula (I):

[0020] [ka]

[0021] or a pharma- ceutically acceptable salt thereof (In the formula,

[0022] [ka]

[0023] is a double bond, and each Y is independently N or CR 4 or

[0024] [ka]

[0025] is a single bond, and each Y is independently NR Y , carbonyl, or C(R Y ) 2, wherein each R Y are independently H or optionally substituted C 1-6 is alkyl, R 1 is optionally replaced by C 1-6 alkyl or H; R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl, Each R 4 are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl, Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Each R 5A independently represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, or optionally substituted C 6-10 is aryl, R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 Cycloalkyl, or optionally substituted C 1-9 Heteroaryl or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Q is optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C1-9 Heteroarylene or optionally substituted C 6-10 is an arylene, X is hydrogen or a halogen.

[0026] In some embodiments, the ATR inhibitor is a compound of formula (II):

[0027] [ka]

[0028] or a pharma- ceutically acceptable salt thereof (In the formula, Each Y is independently N or CR 4 and R 1 is optionally replaced by C 1-6 alkyl or H; R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl, Each R4 are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl, Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Each R 5A independently represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, or optionally substituted C 6-10 is aryl, R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C3-8 Cycloalkyl, or optionally substituted C 1-9 Heteroaryl or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Q is optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 Heteroarylene or optionally substituted C 6-10 is an arylene, X is hydrogen or a halogen.

[0029] In some embodiments, 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 pharma- ceutically acceptable salts thereof.

[0030] In some embodiments, the ATR inhibitor is compound 43 or a pharma- ceutically acceptable salt thereof. In some embodiments, the ATR inhibitor is compound 121 or a pharma- ceutically acceptable salt thereof. In some embodiments, the ATR inhibitor is compound 122 or a pharma- ceutically acceptable salt thereof.

[0031] In some embodiments, the route of administration is oral. In some embodiments, the method does not include administering or contacting with a PARP inhibitor. In some embodiments, the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, rucaparib, olaparib, AZD5305, veliparib, iniparib, 2X-121, CEP-9722, AZD9574, pamiparib, and pharmaceutically acceptable salts thereof. In some embodiments, the ATR inhibitor is administered as monotherapy.

[0032] In some embodiments, the cancer is renal cell carcinoma, mature B-cell neoplasms, endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, skin cancer, small intestine cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, or esophagogastric cancer.

[0033] In some embodiments, the loss of function is a loss of function of STAG2. In some embodiments, the cancer is renal cell carcinoma, endometrial cancer, acute myeloid leukemia, bladder cancer, uterine cancer, or gastric cancer.

[0034] In some embodiments, the loss of function is a loss of function of SETD2. In some embodiments, the cancer is mesothelioma, renal clear cell carcinoma, papillary renal cell carcinoma, lung adenocarcinoma, cholangiocarcinoma, uveal melanoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, invasive breast cancer, lung squamous cell carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, or ovarian serous cystadenocarcinoma.

[0035] In some embodiments, the loss of function is a loss of function of CDK12. In some embodiments, the cancer is prostate cancer, ovarian serous cystadenocarcinoma, uterine endometrial cancer, cutaneous melanoma, lung adenocarcinoma, or invasive breast cancer.

[0036] In some embodiments, the loss of function is a loss of function of ATRIP. In some embodiments, the cancer is uveal melanoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, or renal clear cell carcinoma.

[0037] In some embodiments, the loss of function is a loss of function of REV3L. In some embodiments, the cancer is uterine endometrial cancer, gastric adenocarcinoma, prostate cancer, lung squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cutaneous melanoma, or lung adenocarcinoma.

[0038] In some embodiments, the loss of function is a loss of function of RAD17. In some embodiments, the cancer is gastric adenocarcinoma, prostate cancer, or invasive breast cancer. In some embodiments, the loss of function is a loss of function of CHTF8. In some embodiments, the cancer is prostate cancer.

[0039] In some embodiments, the loss of function is a loss of function of FZR1.In some embodiments, the cancer is head and neck squamous cell carcinoma, cutaneous melanoma, or papillary renal cell carcinoma.

[0040] In some embodiments, the loss of function is a loss of function of RAD51B. In some embodiments, the cancer is uterine endometrial cancer, papillary renal cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cutaneous melanoma, or invasive breast cancer.

[0041] In some embodiments, the loss of function is a loss of function of RAD51C.In some embodiments, the cancer is cutaneous melanoma, uterine endometrial carcinoma, ovarian serous cystadenocarcinoma, or invasive breast cancer.

[0042] In some embodiments, the loss of function is a loss of function of RAD51D.In some embodiments, the cancer is ovarian serous cystadenocarcinoma, gastric adenocarcinoma, or cutaneous melanoma. In some embodiments, the loss of function is a loss of function of PALB2. In some embodiments, the cancer is prostate cancer, lung adenocarcinoma, hepatocellular carcinoma, invasive breast cancer, uterine endometrial carcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

[0043] In some embodiments, the loss of function is a loss of function of RNASEH2A. In some embodiments, the loss of function is a loss of function of RNASEH2B. In some embodiments, the cancer is a sarcoma, a bladder urothelial carcinoma, or a chronic lymphocytic leukemia.

[0044] definition The term "abnormal" as used herein refers to something that is different from normal. When used to describe enzyme activity, abnormal refers to activity that is greater or less than the average of normal control or normal non-disease control samples. Abnormal activity can refer to the amount of activity that results in disease, and restoring the abnormal activity to a normal amount or an amount that is not associated with disease (e.g., by administering a compound or using a method described herein) results in the alleviation of the disease or one or more disease symptoms. Abnormal activity can be measured by measuring the modification of the substrate of the enzyme in question, and a difference of 2-fold or more in the fold change of activity can be considered abnormal. Abnormal activity can also refer to an increased dependency on a particular signaling pathway as a result of a defect in another complementary pathway.

[0045] The term "acyl," as used herein, refers to the group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl can be optionally substituted as described herein for each R group.

[0046] The term "adenocarcinoma," as used herein, refers to a malignant tumor arising from the glandular cells lining the organs within an organism. Non-limiting examples of adenocarcinomas include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colon cancer.

[0047] The term "alkanoyl," as used herein, represents a hydrogen or alkyl group attached to the parent molecular group through a carbonyl group, and is exemplified by formyl (i.e., a carboxaldehyde group), acetyl, propionyl, butyryl, and iso-butyryl. Unsubstituted alkanoyl groups contain 1 to 7 carbons. Alkanoyl groups may be unsubstituted or substituted as described herein for alkyl groups (e.g., optionally substituted C 1-7 The term "-oyl" can be attached to other groups defined herein, such as aryl, cycloalkyl, and heterocyclyl, to define "aryloyl", "cycloalkanoyl", and "(heterocyclyl)oyl", which represent a carbonyl group substituted with an aryl, cycloalkyl, or heterocyclyl, respectively. Each of "aryloyl", "cycloalkanoyl", and "(heterocyclyl)oyl" can be optionally substituted as defined for "aryl", "cycloalkyl", or "heterocyclyl", respectively.

[0048] The term "alkenyl" as used herein refers to an acyclic monovalent straight or branched chain hydrocarbon group containing one, two, or three carbon-carbon double bonds. Non-limiting examples of 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 can be optionally substituted as defined herein for alkyl.

[0049] The term "alkoxy" as used herein refers to a chemical substituent of formula -OR, where R is C, unless otherwise specified. 1-6is an alkyl group. In some embodiments, the alkyl group may be further substituted as defined herein. The term "alkoxy" may be combined with other terms defined herein, such as aryl, cycloalkyl, or heterocyclyl, to define "arylalkoxy", "cycloalkylalkoxy" and "(heterocyclyl)alkoxy" groups. These groups represent alkoxy substituted with aryl, cycloalkyl, or heterocyclyl, respectively. Each of "arylalkoxy", "cycloalkylalkoxy" and "(heterocyclyl)alkoxy" may be optionally substituted as defined herein for the individual moieties.

[0050] The term "alkoxyalkyl" as used herein refers to a chemical substituent of formula -LOR, where L is C 1-6 alkylene and R is C 1-6 Optionally substituted alkoxyalkyl is optionally substituted alkoxyalkyl as described herein for alkyl.

[0051] The term "alkyl" as used herein refers to an acyclic straight or branched chain saturated hydrocarbon group, which, if unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyls have from 1 to 6 carbons. Examples of alkyl groups include methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted, if valence allows, with one, two, three, or, in the case of an alkyl group of two or more carbons, 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, =O, =S, -SOR (where R is amino or cycloalkyl), =NR' (where R' is H, alkyl, aryl, or heterocyclyl). Each of the substituents may itself be unsubstituted or, if valence allows, may be substituted with an unsubstituted substituent(s) as defined herein for the respective group.

[0052] The term "alkylene" as used herein refers to a divalent alkyl group. Optionally substituted alkylene is optionally substituted as described herein for alkyl.

[0053] The term “alkylamino” as used herein refers to a group of the formula —N(R N1 )2 or -NHR N1 In the formula, R N1is alkyl as defined herein. The alkyl portion of the alkylamino may be optionally substituted as defined for alkyl. Each of the optional substituents on a substituted alkylamino may itself be unsubstituted or, if valence allows, substituted with unsubstituted substituent(s) as defined herein for the respective group.

[0054] The term "alkylsulfenyl" as used herein refers to a group of the formula -S-(alkyl). Alkylsulfenyl can be optionally substituted as defined for alkyl.

[0055] The term "alkylsulfinyl" as used herein represents a group of the formula -S(O)-(alkyl). Alkylsulfinyl can be optionally substituted as defined for alkyl.

[0056] The term "alkylsulfonyl" as used herein represents a group of formula -S(O)-(alkyl). Alkylsulfonyl can be optionally substituted as defined for alkyl.

[0057] The term "alkynyl," as used herein, refers to a monovalent straight or branched chain hydrocarbon group of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, and is exemplified by ethynyl, 1-propynyl, and the like. Alkynyl groups can be unsubstituted or substituted as defined for alkyl (e.g., optionally substituted alkynyl).

[0058] The term “amino” as used herein refers to —N(R N1 )2, where if amino is unsubstituted, then both R N1 is H, or if amino is substituted, each R N1 are independently H, -OH, -NO2, -N(R N2 )2, -SO2OR N2 , -SO2RN2 , -SOR N2 , -COOR N2 , an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one R N1 is not H, but R N2 is independently H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or substituted with the unsubstituted substituent(s) defined herein for the respective group. In some embodiments, amino is unsubstituted amino (i.e., -NH2) or substituted amino (e.g., NHR N1 ) in which R N1 are independently -OH, SO2OR N2 , -SO2R N2 , -SOR N2 , -COOR N2 , optionally substituted alkyl, or optionally substituted aryl, and each R N2 may be an optionally substituted alkyl or an optionally substituted aryl. In some embodiments, the substituted amino may be an alkylamino, where the alkyl group is optionally substituted as described herein for alkyl. In some embodiments, the amino group is -NHR N1 where R N1 is optionally substituted alkyl.

[0059] The term "aryl" as used herein refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system having one or two aromatic rings. An aryl group may contain from 6 to 10 carbon atoms. All atoms in 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, and the like. An 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 can itself be unsubstituted or substituted with unsubstituted substituent(s) as defined herein for the respective group.

[0060] The term "arylalkyl" as used herein refers to an alkyl group substituted with an aryl group. The aryl and alkyl portions may be optionally substituted as with the individual groups described herein.

[0061] The term "arylene" as used herein refers to a divalent aryl group. An optionally substituted arylene is an optionally substituted arylene as described herein for aryl.

[0062] The term "aryloxy" as used herein represents a chemical substituent of formula -OR, where R is an aryl group, unless otherwise specified. In an optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

[0063] The term "ATM," as used herein, refers to ATM serine / threonine kinase. The term "ATR inhibitor," as used herein, refers to an agent that, upon contact with the enzyme ATR kinase, whether in vitro, in cell culture, or in an animal, reduces the IC of ATR kinase measured. 50 is 10 μM or less (e.g., 5 μM or less or 1 μM or less). 50 can be 100 nM or less (e.g., 10 nM or less, or 1 nM or less), and can be as low as 100 pM or 10 pM. 50 is 0.1 nM to 1 μM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0064] The term "ATR kinase" as used herein refers to ataxia-telangiectasia- and RAD-3-related protein kinase. The term "azido" as used herein refers to a -N3 group.

[0065] The term "BRCA2," as used herein, refers to the breast cancer type 2 susceptibility gene or protein. The term "cancer" as used herein refers to any type of cancer, neoplasm, or malignant tumor found in a mammal (e.g., human), including leukemia, carcinoma, and sarcoma. Non-limiting examples of cancers that may be treated with the compounds or methods provided herein include prostate cancer, thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colon cancer, and pancreatic cancer. Additional non-limiting examples can include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, pancreatic endocrine or exocrine tumors, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colon cancer, papillary thyroid cancer, hepatocellular carcinoma, and prostate cancer.

[0066] The term "carbocyclic" as used herein refers to an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure, the rings of which may be aromatic or non-aromatic and are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups.

[0067] The term "carbonyl" as used herein refers to a -C(O)- group. The term "carcinoma" as used herein refers to a malignant new growth composed of epithelial cells that tend to invade surrounding tissues and give rise to metastases. Non-limiting examples of carcinomas that may be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, lobular carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, encephalomyeloma, cholangiocarcinoma, trophoblastic car ... Tumor, colloid carcinoma, comedocarcinoma, uterine cancer, cribriform carcinoma, armor carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, encephalomyeloid carcinoma, epithelioid carcinoma, glandular carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, mucinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Chrompecher carcinoma, Kruczyk cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma carcinoma), melanoma, soft carcinoma, mucinous carcinoma, mucosecreting carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, mucinous carcinoma, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, soft carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, moniliform carcinoma, vascular ectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0068] The term "cyano" as used herein refers to a -CN group. The term "cycloalkenyl," as used herein, unless otherwise specified, refers to a non-aromatic carbocyclic group having at least one double bond and 3 to 10 carbons in the ring (e.g., C 3-10Cycloalkenyl refers to cycloalkyl, 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. Cycloalkenyl groups can be unsubstituted or substituted as described for cycloalkyl (e.g., optionally substituted cycloalkenyl). 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. Cycloalkenyl groups can be unsubstituted or substituted as described for cycloalkyl (e.g., optionally substituted cycloalkenyl).

[0069] The term "cycloalkenylalkyl," as used herein, refers to an alkyl group substituted with a cycloalkenyl group, each of which is as defined herein. The cycloalkenyl and alkyl portions can be substituted as individual groups defined herein.

[0070] The term "cycloalkoxy" as used herein refers to a chemical substituent of formula -OR, where R is a cycloalkyl group, unless otherwise specified. In some embodiments, the cycloalkyl group can be further substituted as defined herein.

[0071] The term "cycloalkyl," as used herein, unless otherwise specified, refers to a cyclic alkyl group having 3 to 10 carbons (e.g., C 3-C10Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of the type bicyclo[pq0]alkyl, where each of p and q is independently 1, 2, 3, 4, 5, 6, or 7, with the proviso 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, such as bicyclo[pqr]alkyl, where r is 1, 2, or 3, and each of p and q is independently 1, 2, 3, 4, 5, or 6, with the proviso that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. A cycloalkyl group can be a spirocyclic group, such as spiro[pq]alkyl, where 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.]heptyl, 2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1.]heptyl, 7-bicyclo[2.2.1.]heptyl, and decalinyl. A cycloalkyl group can be unsubstituted or can be 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, ═O, ═S, —SOR (where R is amino or cycloalkyl), ═NR′ (where R′ is H, alkyl, aryl, or heterocyclyl), or —CON(R A )2(in the formula, each R A are independently H or alkyl, or both R Atogether with the atom to which they are attached form a heterocyclyl) (e.g., an optionally substituted cycloalkyl). Each of the substituents may itself be unsubstituted or substituted with an unsubstituted substituent(s) as defined herein for the respective group.

[0072] The term "cycloalkylalkyl," as used herein, refers to an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl portions can be optionally substituted as the individual groups described herein.

[0073] The term "cycloalkylene" as used herein refers to a divalent cycloalkyl group. Optionally substituted cycloalkylene is cycloalkylene optionally substituted as described herein for cycloalkyl.

[0074] The term "cycloalkynyl," as used herein, unless otherwise specified, refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having 8 to 12 carbons. Cycloalkynyls can include one transannular bond or bridge. Non-limiting examples of cycloalkynyls include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadinyl. Cycloalkynyl groups can be unsubstituted or substituted as defined for cycloalkyl (e.g., optionally substituted cycloalkynyl).

[0075] "Disease" or "Condition" refers to a condition or medical state of a patient or subject that can be treated with the compounds or methods provided herein. The term "halo," as used herein, refers to a halogen selected from bromine, chlorine, iodine, and fluorine.

[0076] The term "heteroalkyl" as used herein refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms, interrupted twice by one or two heteroatoms, each time independently, interrupted three times by one or two heteroatoms, each time independently, or interrupted four times by one or two heteroatoms, each time independently. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. No heteroalkyl group contains two consecutive oxygen or sulfur atoms. Heteroalkyl groups may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When a heteroalkyl is substituted and a substituent is attached to a heteroatom, the substituent is selected according to the nature and valence of the heteroatom. Thus, substituents attached to a heteroatom may be O, -N(R ), if valence permits, or any other group. N2 )2, -SO2OR N3 , -SO2R N2 , -SOR N3 , -COOR N3 , an N-protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, N2 is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each R N3 is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted with the unsubstituted substituent(s) defined herein for the respective group. When a heteroalkyl is substituted and a substituent is attached to a carbon, the substituent is selected from those described for alkyl, except that the substituent on the carbon atom attached to the heteroatom is not Cl, Br, or I. It is understood that the carbon atom is at the terminal end of the heteroalkyl group.

[0077] The term "heteroarylalkyl," as used herein, refers to an alkyl group substituted with a heteroaryl group, each of which is as defined herein. The heteroaryl and alkyl portions can be optionally substituted as with the individual groups described herein.

[0078] The term "heteroarylene" as used herein refers to a divalent heteroaryl. Optionally substituted heteroarylene is optionally substituted as described herein for heteroaryl.

[0079] The term "heteroaryloxy" as used herein refers to the structure -OR, where R is a heteroaryl. The heteroaryloxy can be optionally substituted as defined for heterocyclyl.

[0080] The term "heterocyclyl" as used herein refers to a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridged, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered rings, and unless otherwise specified, containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a "heterocyclyl" is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridged 5-, 6-, 7-, or 8-membered rings, and unless otherwise specified, containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. A heterocyclyl can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyls have zero or one double bond, 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 carbon-carbon triple bond. Heterocyclyl groups contain 1 to 16 carbon atoms, unless otherwise specified. Certain heterocyclyl groups can contain up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. When a 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, quinazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbon and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as, for example, quinuclidine, tropane, or diaza-bicyclo[2.2.2]octane. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles are fused to one, two, or three carbon rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentene ring, or another monocyclic heterocycle. Examples of fused heterocyclyls include 1,2,3,5,8,8a-hexahydroindolizine, 2,3-dihydrobenzofuran, 2,3-dihydroindole, and 2,3-dihydrobenzothiophene. Heterocyclyl groups can 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 can itself be unsubstituted or substituted with the unsubstituted substituent(s) defined herein for the respective group.

[0081] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocyclyl group, each of which is as defined herein. The heterocyclyl and alkyl portions can be optionally substituted as the individual groups described herein.

[0082] The term "heterocyclylene" as used herein refers to a divalent heterocyclyl. Optionally substituted heterocyclylene is optionally substituted as described herein for heterocyclyl.

[0083] 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 the manner described for heterocyclyl.

[0084] The terms "hydroxyl" and "hydroxy", as used interchangeably herein, refer to the -OH group. The term "isotopically enriched" as used herein refers to a pharmaceutical active agent in which one isotope at a given position in a molecule has an isotopic content that is at least 100 times greater than the natural abundance of the isotope. For example, a composition that is isotopically enriched for deuterium includes an active agent that has at least one hydrogen atom position with an abundance of deuterium that is at least 100 times greater than the natural abundance of deuterium. Preferably, the isotopic enrichment of deuterium is at least 100 times greater than the natural abundance of deuterium. More preferably, the isotopic enrichment of deuterium is at least 4000 times greater than the natural abundance of deuterium (e.g., at least 4750 times greater, e.g., up to 5000 times greater).

[0085] The term "leukemia," as used herein, refers broadly to progressive malignant diseases of the blood-forming organs and is generally characterized by distorted proliferation and growth of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease-acute or chronic; (2) the type of cells involved-bone marrow (myeloid), lymph (lymphoid), or monocytic; and (3) increased or non-increased numbers of abnormal cells in the blood-leukemic or non-leukemic (subleukemic). Exemplary leukemias that may be treated with the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, stem cell leukemia, hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic ... leukemia), lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0086] The term "lymphoma" as used herein refers to cancer that occurs in cells of immune origin. Non-limiting examples of T-cell and B-cell lymphoma include non-Hodgkin's lymphoma and Hodgkin's disease, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, small cell lymphocytic lymphoma-chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma-Waldenstrom's macroglobulinemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL) / follicular T-cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), or extranodal NK / T-cell lymphoma nasal type.

[0087] The term "melanoma," as used herein, is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0088] The term "nitro" as used herein refers to a --NO.sub.2 group. The term "oxo," as used herein, represents a divalent oxygen atom (eg, the structure of oxo can be depicted as ═O).

[0089] The term "PARP inhibitor," as used herein, refers to an agent that, upon contact with PARP, either in vitro, in cell culture, or in an animal, reduces the IC of PARP measured. 50 is 10 μM or less (e.g., 5 μM or less or 1 μM or less). 50can be 100 nM or less (e.g., 10 nM or less, or 1 nM or less), and can be as low as 100 pM or 10 pM. 50 is 0.1 nM to 1 μM (e.g., 0.5 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM).

[0090] The term "PARP," as used herein, refers to poly ADP-ribose polymerase (PARP). The term "Ph," as used herein, represents phenyl.

[0091] The term "pharmaceutical composition" as used herein refers to a composition that contains a compound described herein, is formulated with a pharma- ceutical acceptable excipient, and is manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., tablets, capsules, caplets, gelcaps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use without particulate insoluble matter), or any other formulation described herein.

[0092] The term "pharmaceutical acceptable excipient" or "pharmaceutical acceptable carrier" is used interchangeably herein and refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound) that has non-toxic and non-inflammatory properties in patients. Excipients can include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, bulking agents (diluents), film-forming agents or coating agents, flavors, fragrances, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydrating water. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0093] The term "pharmaceutically acceptable salts" as used herein refers to salts that are suitable for use in contact with human and animal tissues, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reactions, etc., and 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 Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or can be prepared separately by reacting a free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include phosphate, 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, and valerate.Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0094] The term "protecting group" as used herein refers to a group intended to protect a hydroxy, amino, or carbonyl from participating in one or more undesired reactions during chemical synthesis. The term "O-protecting group" as used herein refers to a group intended to protect a hydroxy or carbonyl group from participating in one or more undesired reactions during chemical synthesis. The term "N-protecting group" as used herein refers to a group intended to protect a nitrogen-containing (e.g., amino, amido, heterocyclic NH, or hydrazine) group from participating in one or more undesired reactions during chemical synthesis. Commonly used O-protecting groups and N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O-protecting 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, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl.

[0095] 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.

[0096] Other O-protecting groups include 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., methylthiomethyl ... For example, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, and diphenylmethylsilyl), carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, vinyl, allyl, nitrophenyl, benzyl, methoxybenzyl, 3,4-dimethoxybenzyl, and nitrobenzyl).

[0097] Other N-protecting groups include 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 dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl Examples of the aryl groups include, but are not limited to, aryl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 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; silylalkyl acetal 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).

[0098] The term "RNAse H2A," as used herein, refers to ribonuclease H2 subunit A. The term "RNAse H2B," as used herein, refers to ribonuclease H2 subunit B.

[0099] The term "sarcoma" generally refers to a tumor composed of a substance like embryonic connective tissue, and generally consists of closely packed cells embedded in a fibrous or homogeneous substance. Non-limiting examples of sarcomas that may be treated with the compounds or methods provided herein include, for example, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy sarcoma, liposarcoma (adipose tissue), and sarcoma (sarcoma). sarcoma, liposarcoma), alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chlorosarcoma, 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 multifocal pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cell, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0100] The term "scaffold SNVs" as used herein refers to frequent, well-covered single-nucleotide variants that lie outside of the target gene region and are spaced throughout the chromosome that bears the target gene region.

[0101] The term "STAG2," as used herein, refers to stromal antigen 2. The term "tautomer" refers to structural isomers that are readily interconverted, often by rearrangement of a proton. Tautomers are distinct chemical species that can be distinguished by different spectroscopic characteristics, but generally cannot be individually isolated. Non-limiting examples of tautomers include ketone-enol, enamine-imine, amide-imidic acid, nitroso-oxime, ketene-ynol, and amino acid-ammonium carboxylate.

[0102] The term "subject" as used herein refers to a human or non-human animal (e.g., a mammal) suffering from or at risk of a disease or condition as determined by a qualified professional (e.g., a physician or clinical nurse) with or without clinical test(s) known in the art of a sample(s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases with symptoms of cellular hyperproliferation, such as cancer.

[0103] The term "total copy number log ratio" as used herein refers to the signal ratio of cancer cells to control cells. Deviation of the total copy number log ratio of a given region from the average of 0 indicates that the signal intensity is higher (if greater than 0) or lower (if less than 0) than expected for two chromosome copies. Total copy number log ratio, also known as LogR, can be estimated using Illumina's GenomeStudio™ software.

[0104] "Treatment" and "treating" as used herein refer to the medical management of a subject with the goal of improving, ameliorating, stabilizing, preventing or curing a disease or condition. The term includes active treatment (treatment aimed at improving the disease or condition), causal treatment (treatment aimed at the cause of the associated disease or condition), palliative treatment (treatment designed to relieve the symptoms of the disease or condition), preventive treatment (treatment aimed at minimizing or partially or completely suppressing the occurrence of the associated disease or condition), and supportive treatment (treatment employed to complement another treatment). The disease or condition may be cancer. Non-limiting examples of cancer include, for example, renal cell carcinoma, mature B-cell tumors, endometrial cancer, ovarian cancer, colon cancer, skin cancer (non-melanoma), small intestine cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, and esophagogastric cancer. [Brief description of the drawings]

[0105] [Figure 1A] Growth inhibition of STAG2-KO cells by compound 121. CRISPR-Cas9 was used to knock out the STAG2 gene in RPE1-hTERT-ΔTP53 cells (clones 1 and 2). Cells were then seeded in a 96-well plate format and treated with the indicated concentrations of compound 121 for 7 days. Treatments were refreshed every 4 days. Confluency was then measured using a microscope and normalized to untreated conditions. [Figure 1B] Compound 121 preferentially induces cell death in STAG2-KO cells. RPE1-hTERT-ΔTP53-STAG2 KO cells were seeded in a 6-well plate format and treated with the indicated doses of compound 121 for 10 days. Cells were then fixed and stained using crystal violet in methanol. Colonies were counted and survival percentages were determined by normalizing the number of colonies after treatment to the number of colonies in the untreated condition. [Diagram 2] Compound 121 preferentially induces cell death in bladder cancer cells lacking STAG2. CRISPR-Cas9 was used to knock out the STAG2 gene in T24 cells (clone 1 and 2). Cells were seeded in a 6-well plate format and treated with the indicated doses of compound 121 for 9 days. Cells were then fixed and stained using crystal violet methanol solution. Colonies were counted and survival percentages were determined by normalizing the number of colonies after treatment to the number of colonies in the untreated condition. [Figure 3A] Representative dose-response curves of MCF10A cells transfected with either non-targeting siRNA (siCTRL) or siRNA targeting SETD2 (siSETD2) and then treated with compound 121. Cell viability was determined by CellTiter Glo (CTG) assay. Data (open symbols) were fitted to a four-parameter dose-response model (solid line). Knockdown of ATM (siATM; ATM is a known determinant of compound 121 sensitivity) was used as a positive control. [Figure 3B]IC50 values ​​of compound 121 by CTG cell viability assay in MCF10A and RPE1 TP53- / - cell lines transfected with the indicated siRNAs. Data are from two or more independent experiments (circles) and include the mean (bars) ± SD (error bars). [Figure 3C] HeLa cells are not sensitive to compound 121 when SETD2 is knocked down. Note that the positive control (siATM) also does not sensitize this cell line to compound 121. Data are from three or more independent experiments (circles) and include means (bars) ± SD (error bars). [Figure 4A] Representative immunoblots showing SETD2 expression in whole cell extracts of six SETD2 wild-type (WT) renal and colon cancer cell lines and loss of SETD2 in three SETD2 mutant (LOF) cell lines. Vinculin was used as a loading control. [Figure 4B] Compound 121 IC50 values ​​from CellTiter Glo viability assay of SETD2 WT and LOF cell lines treated with compound 121 from 4 to 8 population doublings. Circles represent average IC50 values ​​from 3 or more independent experiments. Bars are the mean for each cohort (WT or LOF); error bars are ±SD. [Figure 5A] Dose-response curves of isogenic CDK12 wild-type (+ / +) and knockout (- / -) RPE1 TP53- / - cells treated with compound 121. Cell viability was measured by CellTiter Glo assay. Open symbols represent the mean ± SD of three independent experiments. Solid lines indicate nonlinear least-squares fitting to a four-parameter dose-response model. An approximately 2-fold shift in IC50 was observed. [Figure 5B] Dose-response curves of isogenic CDK12 wild-type (+ / +) and knockout (- / -) DLD1 cells treated with compound 121. Cell viability was measured by CellTiter Glo assay. Open symbols represent the mean ± SD of three independent experiments. Solid lines indicate nonlinear least-squares fitting to a four-parameter dose-response model. An approximately 3-fold shift in IC50 was observed. [Figure 6A] Dose-response curves of isogenic RNASEH2B wild-type (+ / +) and knockout (- / -) RPE1 TP53- / - cells treated with compound 121. Cell viability was measured by CellTiter Glo assay. Open symbols represent the mean ± SD of three independent experiments. Solid lines indicate nonlinear least-squares fitting to a four-parameter dose-response model. Immunoblots showing RNASEH2B protein status in whole cell extracts of the indicated cell lines are also shown. α-actinin was used as a loading control. An approximately 4-fold shift in IC50 was observed. [Figure 6B] Dose-response curves of isogenic RNASEH2B wild-type (+ / +) and knockout (- / -) 5637 cells treated with compound 121. Cell viability was measured by CellTiter Glo assay. Open symbols represent the mean ± SD of three independent experiments. Solid lines indicate nonlinear least-squares fitting to a four-parameter dose-response model. Immunoblots showing RNASEH2B protein status in whole cell extracts of the indicated cell lines are also shown. α-actinin was used as a loading control. An approximately 4-fold shift in IC50 was observed. [Figure 7A] Growth of 5637 RNASEH2B+ / + bladder cancer cell line tumors implanted subcutaneously in immunodeficient mice. Mice were treated with either vehicle or the indicated doses of Compound 121 by oral gavage once daily on a 2-day on / 4-day off weekly schedule. Data are presented as mean ± SEM. N=8 mice / group. [Figure 7B] Growth of 5637 RNASEH2B- / - bladder cancer cell line tumors implanted subcutaneously in immunodeficient mice. Mice were treated with either vehicle or the indicated doses of Compound 121 by oral gavage once daily on a 2-day on / 4-day off weekly schedule. Data are presented as mean ± SEM. N=8 mice / group. [Figure 8A]Growth of subcutaneously implanted triple-negative breast cancer (TNBC) PDX tumors with RNASEH2B IHC deletion in immunodeficient mice. Mice were treated with either vehicle or the indicated doses of Compound 121 by oral gavage once daily on an intermittent weekly schedule of 3 days on / 4 days off. Data are presented as mean ± SEM. N=9 mice / group. [Figure 8B] Immunohistochemistry (IHC) staining with RNase H2-specific antibody of the PDX model in Figure 8A (top) and control RNase H2-bearing PDX (bottom). [Figure 9A] Dose-response curve for compound 121 in RPE1 Cas9 TP53- / - cells transduced with a control sgRNA (sgAAVS1) or one of two sgRNAs targeting RAD51B. Cell viability was determined by CellTiter Glo assay. Open symbols represent the mean viability ± SD of three independent experiments. Solid lines represent nonlinear least-squares fits to a four-parameter dose-response model. [Figure 9B] Dose-response curve for compound 121 in RPE1 Cas9 TP53- / - cells transduced with a control sgRNA (sgAAVS1) or one of two sgRNAs targeting RAD51C. Cell viability was determined by CellTiter Glo assay. Open symbols represent the mean viability ± SD of three independent experiments. Solid lines represent nonlinear least-squares fits to a four-parameter dose-response model. [Figure 9C] Dose-response curve for compound 121 in RPE1 Cas9 TP53- / - cells transduced with a control sgRNA (sgAAVS1) or one of two sgRNAs targeting RAD51D. Cell viability was determined by CellTiter Glo assay. Open symbols represent the mean viability ± SD of three independent experiments. Solid lines represent nonlinear least-squares fits to a four-parameter dose-response model. [Figure 10A]Fold shift in IC50 values ​​for compound 121 by CellTiter Glo cell viability assay in MCF10A cells transfected with non-targeting siRNA (siCTRL), positive control siRNA targeting ATM (siATM) or siRNA targeting the indicated STEP2 gene. Circles represent values ​​from two or more independent experiments and include mean (bars) ± SD (error bars). Data were normalized to siCTRL. Values ​​greater than 1 represent increased sensitivity compared to siCTRL. [Figure 10B] Fold shift in IC50 values ​​for compound 121 by CellTiter Glo cell viability assay in RPE1 TP53- / - cells transfected with non-targeting siRNA (siCTRL), positive control siRNA targeting ATM (siATM) or siRNA targeting the indicated STEP2 gene. Circles represent values ​​from two or more independent experiments and include mean (bars) ± SD (error bars). Data were normalized to siCTRL. Values ​​greater than 1 represent increased sensitivity compared to siCTRL. [Figure 10C] Fold shift in IC50 values ​​for compound 121 by CellTiter Glo cell viability assay in HeLa cells transfected with non-targeting siRNA (siCTRL), positive control siRNA targeting ATM (siATM) or siRNA targeting the indicated STEP2 gene. Circles represent values ​​from two or more independent experiments and include mean (bar graph) ± SD (error bars). Data were normalized to siCTRL. Values ​​greater than 1 represent increased sensitivity compared to siCTRL. [Figure 11A] Dose-response curves for isogenic ARID1A wild-type (WT) and knockout (ARID1A- / -) HCT116 cells treated with AZD-6738. Cell growth (confluency) was measured with an IncuCyte automated microscope. Data (circles) were fitted to a four-parameter dose-response model (solid line). [Figure 11B]Dose-response curves for isogenic ARID1A wild-type (WT) and knockout (ARID1A- / -) MCF1A cells treated with AZD-6738. Cell growth (confluency) was measured with an IncuCyte automated microscope. Data (circles) were fitted to a four-parameter dose-response model (solid line). [Figure 11C] Dose-response curves of isogenic ARID1A wild-type (WT) and knockout (ARID1A- / -) BEAS2B cells treated with AZD-6738. Cell growth (confluency) was measured with an IncuCyte automated microscope. Data (circles) were fitted to a four-parameter dose-response model (solid line). [Figure 12] EC50 values ​​of ATRi AZD-6738 in an IncuCyte growth assay in a panel of cancer cell lines that are ARID1A wild type (WT) or harbor deleterious ARID1A alterations (LOF). Data are from two independent experiments (circles) and include means (bars) ± SD (error bars). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0106] Generally, the present invention relates to the use of ATR inhibitor or its pharmaceutically acceptable salt for treating cancer or inducing cell death in cancer cells.The cancers included herein can be, for example, the cancers with loss of function (e.g., biallelic loss of function) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A or RNASEH2B.

[0107] Advantageously, cancers with loss of function (e.g., biallelic loss of function) of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A or RNASEH2B can be particularly sensitive to ATR inhibitor therapy (e.g., ATR inhibitor monotherapy).For example, cancers with loss of function of CDK12, RNASEH2A or RNASEH2B can be treated using ATR inhibitor therapy, e.g., ATR inhibitor monotherapy.

[0108] STAG2 is a gene that encodes the SA-2 protein, a key member of the cohesin complex. This complex forms a ring-like structure that holds the two DNA chromatids together. This physical proximity of DNA molecules is essential for various processes, such as DNA replication, DNA repair, and chromosome segregation during mitosis. Some cancer patients have alterations in the STAG2 gene, which may contribute to the genetic instability observed in tumors. Given this high level of genetic instability, STAG2-deficient tumors are likely dependent on DDR signaling for survival.

[0109] SETD2 is a gene that encodes a histone methyltransferase that specifically methylates lysine 36 of histone H3. The function of the SETD2 protein is important for many cellular processes, including transcription, DNA replication and DNA repair. Some tumors have deleterious changes in the SETD2 gene, and these tumors may have elevated levels of replication stress and genomic instability.

[0110] The CDK12 gene encodes a cyclin-dependent kinase required for DNA transcription. Detrimental changes in CDK12, as seen in some cancers, reduce the expression of genes involved in DNA repair and DNA replication, thereby reducing the ability of these tumors to repair damaged DNA and recover from replication stress.

[0111] The ATRIP and RAD17 genes encode proteins required for the proper functioning of the ATR pathway. Alterations in these genes in tumors can lead to increased levels of replication stress.

[0112] The REV3L gene encodes the catalytic subunit of DNA polymerase ζ, a protein complex required for DNA repair by translesion synthesis. Deleterious alterations of REV3L in cancer are predicted to compromise the ability of tumors to repair DNA damage and recover from replication stress.

[0113] The CHTF8 gene encodes a subunit of the alternative replication factor C (RFC) complex, which is composed of DSCC1, CHTF8, and CHTF18. This protein complex is required for proper DNA replication, sister chromatid cohesion, and DNA repair. Some tumors harbor deleterious alterations in CHTF8, which can lead to DNA repair and replication defects.

[0114] FZR1 (also known as CDH1) is a gene that encodes a regulatory subunit of the anaphase-promoting complex (APC / C). This protein complex is required for proper cell division. Deleterious alterations in the FZR1 gene are predicted to impair the ability of tumor cells to recover from replicative stress and increase genomic instability.

[0115] RAD51B, RAD51C, RAD51D and PALB2 are genes encoding proteins required for DNA repair by homologous recombination (HR). The protein products of these genes together support the proper loading of RAD51 recombinase onto DNA by the BRCA2 protein and are therefore essential for the completion of HR DNA repair. Deleterious alterations in RAD51B, RAD51C, RAD51D or PALB2 can be found in some cancers, leading to defective HR and, as a consequence, increased genomic instability.

[0116] The RNASEH2A and RNASEH2B genes code for subunits of the ribonuclease H2 (RNase H2) complex, which is responsible for removing ribonucleotides (also known as "genomic ribonucleotides") that are mistakenly incorporated into DNA by DNA polymerase during DNA replication and DNA repair. Some tumors harbor deleterious alterations in the RNASEH2A or RNASEH2B genes, causing aberrant processing of genomic ribonucleotides, resulting in increased levels of replication stress and genomic instability.

[0117] Cancers with STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B mutations due to underlying DNA repair deficiencies and genomic instability may respond to treatment with ATR inhibitors at doses capable of establishing a therapeutic window against healthy proliferating cells.

[0118] ATR inhibitors When ATR inhibitors come into contact with the enzyme ATR kinase, whether in vitro, in cell culture, or in animals, they increase the measured IC 50 The compound may be a compound that reduces the activity of ATR kinase such that the IC 50 can be 100 nM or less (e.g., 10 nM or less, or 1 nM or less), and can be as low as 100 pM or 10 pM. 50 is 0.1 nM to 1 μM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0119] Non-limiting examples of ATR inhibitors include, for example:

[0120] [ka]

[0121] and pharma-ceutically acceptable salts thereof. Non-limiting examples of ATR inhibitors include those described in, e.g., International Application Publication Nos. WO2020087170, WO2018218197, WO2020259601, WO2019036641, WO2020049017, WO2019154365, WO2020103897, WO2021233376, WO2022028598, WO2022012484, WO2022002245, WO2022002243 (each of which is incorporated by reference herein), U.S. Pat. Nos. 11,028,076, 10,745,420, 10,301,324, 10,196,405, 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 Nos. 2019 / 0055240 and 2019 / 0300547 (each of which is incorporated by reference herein).

[0122] In one embodiment, the ATR inhibitor is a compound of formula (I):

[0123] [ka]

[0124] or a pharma- ceutically acceptable salt thereof (In the formula,

[0125] [ka]

[0126] is a double bond, and each Y is independently N or CR 4 or

[0127] [ka]

[0128] is a single bond, and each Y is independently NR Y , carbonyl, or C(R Y ) 2, wherein each R Y are independently H or optionally substituted C 1-6 is alkyl, R 1 is optionally replaced by C 1-6 alkyl or H, R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl, Each R 4 are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl, Each R 5 are independently hydrogen, optionally substituted C 1-6Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Each R 5A independently represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, or optionally substituted C 6-10 is aryl, R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 Cycloalkyl, or optionally substituted C 1-9 Heteroaryl or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Q is optionally substituted C 2-9Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 Heteroarylene or optionally substituted C 6-10 is an arylene, X is hydrogen or a halogen.

[0129] ATR inhibitors include, for example, compounds of formula (II):

[0130] [ka]

[0131] or a pharma- ceutically acceptable salt thereof (In the formula, Each Y is independently N or CR 4 and R 1 is optionally replaced by C 1-6 alkyl or H, R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C1-9 Heteroaryl C 1-6 is alkyl, Each R 4 are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl, Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Each R 5A independently represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, or optionally substituted C 6-10 is aryl, R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 Cycloalkyl, or optionally substituted C 1-9 Heteroaryl or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Q is optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 Heteroarylene or optionally substituted C 6-10 is an arylene, X can be hydrogen or a halogen.

[0132] In some embodiments, in a compound of Formula (II), (I), or (Ib), Each Y is independently N or CR 4 and R 1 is H or optionally substituted C 1-6 is alkyl, R 2 is optionally replaced by C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, or -SO2R 5A and R 3 is optionally replaced by C 1-9 is heteroaryl, Each R4 are independently H or optionally substituted C 1-6 is alkyl, Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A where each R 5A independently represents an optionally substituted C 1-6 Alkyl or optionally substituted C 3-8 cycloalkyl or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl, Each R 5A independently represents an optionally substituted C 1-6 Alkyl or optionally substituted C 3-8 is cycloalkyl, Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, or optionally substituted C 1-9 Heteroaryl or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 Forming a heterocyclyl.

[0133] Methods for making compounds of formula (I) are described, for example, in International Application No. PCT / US2019 / 051539, which is incorporated herein by reference. ATR inhibitors include, for example, compounds of formula (Ia):

[0134] [ka]

[0135] or a pharma- ceutically acceptable salt thereof (wherein Y, R 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (Ib):

[0136] [ka]

[0137] or a pharma- ceutically acceptable salt thereof (wherein Y, R 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (IA):

[0138] [ka]

[0139] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (IA-a):

[0140] [ka]

[0141] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4is as described in formula (I). ATR inhibitors include, for example, compounds of formula (IB):

[0142] [ka]

[0143] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (IB-a):

[0144] [ka]

[0145] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (IC):

[0146] [ka]

[0147] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (IC-a):

[0148] [ka]

[0149] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (ID):

[0150] [ka]

[0151] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4 is as described in formula (I). ATR inhibitors include, for example, compounds of formula (ID-a):

[0152] [ka]

[0153] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , and R 4 is as described in formula (I). Preferably, R 1 is methyl.

[0154] In some embodiments, R 2 can be, for example, optionally substituted C 3-8 For example, R 2 is a group of formula (A):

[0155] [ka]

[0156] (In the formula, n is 0, 1, 2, or 3; R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, where each R A are independently H or alkyl, or both R A together with the atoms to which they are attached, C 2-9 forming a heterocyclyl).

[0157] In some embodiments, R 2 can be, for example, optionally substituted C 1-6 Alkyl (e.g., optionally substituted tertiary C 3-6 For example, R 2 is a group of formula (B):

[0158] [ka]

[0159] (In the formula, R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, where each R A are independently H or alkyl, or both R A , together with the atoms to which they are attached, C 2-9 forming a heterocyclyl).

[0160] In some embodiments, R 2 is, for example, an optionally substituted non-aromatic C 2-9 It may be a heterocyclyl. In some embodiments, R 2 For example,

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] It could be. In some embodiments, R 3 is, for example, a monocyclic C ring containing at least one optionally substituted nitrogen atom (e.g., two nitrogen atoms). 1-9 For example, R 3 is a group of formula (C):

[0165] [ka]

[0166] wherein A is an optionally substituted monocyclic C 1-9 heteroaryl ring). In some embodiments, A is, for example, a group of formula (C1):

[0167] [ka]

[0168] (In the formula, R 8 is hydrogen, halogen, or optionally substituted C 1-6 It can be alkyl. In some embodiments, R 3 For example,

[0169] [ka]

[0170] It could be. In some embodiments, R 3 For example,

[0171] [ka]

[0172] It could be. In some embodiments, R 4 can be, for example, hydrogen. The ATR inhibitor can be, for example, a compound listed in Table 1 below, or a pharma- ceutically acceptable salt thereof.

[0173] [Table 1-1]

[0174] [Table 1-2]

[0175] [Table 1-3]

[0176] [Table 1-4]

[0177] [Table 1-5]

[0178] [Table 1-6]

[0179] [Table 1-7]

[0180] [Table 1-8]

[0181] [Table 1-9]

[0182] [Table 1-10]

[0183] [Table 1-11]

[0184] The ATR inhibitor may be isotopically enriched (eg, enriched with deuterium). Isomers and compositions thereof The present invention includes the individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein, as well as mixtures of the diastereomers and / or enantiomers, including racemic mixtures, where possible. The specific stereochemistry disclosed herein is preferred, but other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures thereof, may also be useful in treating disease. Inactive or less active diastereoisomers and enantiomers may also be useful, for example, in scientific studies of receptors and mechanisms of activation.

[0185] It is understood that a particular molecule can exist in more than one tautomeric form, and although only one tautomer may be shown in the examples, the invention includes all tautomers.

[0186] The invention also includes pharma- ceutically acceptable salts of the compounds, and pharmaceutical compositions comprising the compounds and a pharma- ceutically acceptable carrier. The compounds are particularly useful, for example, in certain types of cancer, and for slowing the progression of cancer once it has developed in a patient.

[0187] The compounds disclosed herein may be used in pharmaceutical compositions that include (a) the compound(s) or a pharma- ceutically acceptable salt thereof, and (b) a pharma- ceutically 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 compounds disclosed herein or a pharma- ceutically acceptable salt thereof is the only active ingredient.

[0188] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers The compounds disclosed herein may, for example, contain one or more stereocenters and may exist as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The present invention includes all such isomeric forms of the compounds disclosed herein. All possible stereoisomers (e.g., enantiomers and / or diastereomers) as mixtures and pure or partially purified compounds are intended to be included within the scope of the present invention (i.e., all possible combinations of stereocenters as pure compounds or mixtures).

[0189] Some of the compounds described herein may contain bonds that are hindered in rotation, such that two distinct rotamers, or atropisomers, can be separated and found to have different biological activities that may be advantageous. It is intended that all possible atropisomers are included within the scope of the present invention.

[0190] Some of the compounds described herein may contain olefinic double bonds, and unless otherwise specified, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist as different points of attachment of hydrogen, called tautomers. One example is a ketone and its enol form, known as keto-enol tautomers. Individual tautomers and mixtures thereof are encompassed by the present invention.

[0191] Compounds disclosed herein that possess one or more asymmetric centers can be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.

[0192] Alternatively, enantiomers and other compounds containing chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0193] Metabolites-Prodrugs The present invention includes therapeutically active metabolites, and the metabolites themselves are within the scope of the claims. The present invention also includes prodrugs, which are compounds that are converted to the claimed compounds when or after administration to a patient. The claimed chemical structures of the present application may in some cases themselves be prodrugs.

[0194] Isotopically enriched derivatives The present invention includes molecules that are isotopically enriched at one or more positions within the molecule, and therefore compounds enriched with deuterium are also within the scope of the claims.

[0195] Methods for preparing ATR inhibitors ATR inhibitors can be prepared using reactions and techniques known in the art.For example, certain ATR inhibitors can be prepared using techniques and methods disclosed in, for example, International Application Nos. PCT / US2019 / 051539 and PCT / US2018 / 034729 (each of which is incorporated herein by reference), U.S. Patent Nos. 9,663,535, 9,549,932, 8,552,004, and 8,841,308 (each of which is incorporated herein by reference), and U.S. Patent Application Publication No. 2019 / 0055240 (each of which is incorporated herein by reference).

[0196] How to use ATR inhibitors can be used for the treatment of diseases or conditions with symptoms of cell hyperproliferation.For example, the invention described herein can be applicable to the treatment of various tumor conditions that carry sensitizing gene mutations, such as tumors with any deleterious changes (loss of function) in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.Mutations in this gene can be frequently found in the following tumor types: renal cell carcinoma, mature B-cell tumors, endometrial cancer, ovarian cancer, acute myeloid leukemia, colon cancer, skin cancer (non-melanoma), small intestine cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, uterine cancer, breast cancer, gastric cancer, and esophagogastric cancer.Therefore, the method of the present invention is preferably used to treat these cancers.

[0197] In some embodiments, the loss of function is a loss of function of ATRIP and the cancer is uveal melanoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, or renal clear cell carcinoma.

[0198] In some embodiments, the loss of function is a loss of function of RNASEH2A or RNASEH2B and the cancer is sarcoma, bladder urothelial carcinoma, chronic lymphocytic leukemia. In some embodiments, the loss of function is loss of function of CHTF8 and the cancer is prostate cancer.

[0199] In some embodiments, the loss of function is a loss of function of FZR1 and the cancer is head and neck squamous cell carcinoma, cutaneous melanoma, or papillary renal cell carcinoma. In some embodiments, the loss of function is loss of function of RAD17 and the cancer is gastric adenocarcinoma, prostate cancer, or invasive breast cancer.

[0200] In some embodiments, the loss of function is a loss of function of RAD51B and the cancer is uterine endometrial cancer, papillary renal cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cutaneous melanoma, or invasive breast cancer.

[0201] In some embodiments, the loss of function is a loss of function of RAD51C and the cancer is cutaneous melanoma, uterine endometrial carcinoma, ovarian serous cystadenocarcinoma, or invasive breast cancer. In some embodiments, the loss of function is a loss of function of RAD51D and the cancer is ovarian serous cystadenocarcinoma, gastric adenocarcinoma, or cutaneous melanoma.

[0202] In some embodiments, the loss of function is a loss of function of REV3L and the cancer is uterine endometrial cancer, gastric adenocarcinoma, prostate cancer, lung squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cutaneous melanoma, or lung adenocarcinoma.

[0203] In some embodiments, the loss of function is a loss of function of SETD2 and the cancer is mesothelioma, renal clear cell carcinoma, papillary renal cell carcinoma, lung adenocarcinoma, cholangiocarcinoma, uveal melanoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, invasive breast cancer, lung squamous cell carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, or ovarian serous cystadenocarcinoma.

[0204] In some embodiments, the loss of function is a loss of function of CDK12 and the cancer is prostate cancer, ovarian serous cystadenocarcinoma, uterine endometrial carcinoma, cutaneous melanoma, lung adenocarcinoma, or invasive breast cancer.

[0205] In some embodiments, the loss of function is loss of function of PALB2 and the cancer is prostate cancer, lung adenocarcinoma, hepatocellular carcinoma, invasive breast cancer, uterine endometrial carcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

[0206] The treatment methods of the present invention comprise the step of administering a therapeutically effective amount of an ATR inhibitor to a subject in need thereof. The disease or condition treated by the method of the present invention may have symptoms of cell hyperproliferation.For example, the disease or condition may be cancer.Cancer may be, for example, carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, or melanoma.Cancer may be, for example, solid tumor.

[0207] Non-limiting examples of cancer include prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain cancer, glioma, lung cancer, salivary cancer, gastric cancer, thymic epithelial cancer, thyroid cancer, leukemia, melanoma, lymphoma, stomach cancer, pancreatic cancer, kidney cancer, bladder cancer, uterine cancer, colon cancer, and liver cancer.

[0208] Preferably, the methods of the invention are used to treat renal cell carcinoma, mature B cell neoplasms, endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, skin cancer (non-melanoma), small intestine cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, or esophagogastric cancer.

[0209] Non-limiting examples of carcinomas include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, encephalomyeloma, cholangiocarcinoma, trophoblastic tumor, colloid carcinoma, comedocarcinoma, foetal carcinoma, foetal carcinoma, foetal cell ... Parietal carcinoma, cribriform carcinoma, armor carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, encephalomyeloid carcinoma, epithelioid carcinoma, glandular carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, mucinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Chrompecher carcinoma, Kruczyk cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma carcinoma), melanoma, soft carcinoma, mucinous carcinoma, mucosecreting carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, mucinous carcinoma, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, soft carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, moniliform carcinoma, vascular ectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0210] Non-limiting examples of sarcomas include, for example, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy sarcoma, liposarcoma, and the like. sarcoma, liposarcoma), alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chlorosarcoma, 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 multifocal pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cell, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0211] 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, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, stem cell leukemia, hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia (lymphocytic leukemia, lymphogenous leukemia, lymphoid ... leukemia), lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0212] Non-limiting examples of melanoma include acral lentigo melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0213] Pharmaceutical Compositions The compound used in the method described herein is preferably formulated into a pharmaceutical composition for administration to human subjects in a biologically compatible form suitable for in vivo administration.The pharmaceutical composition typically comprises the compound described herein and a pharmaceutically acceptable excipient.Certain pharmaceutical compositions may comprise one or more additional pharmacoactive agents described herein.

[0214] The compounds described herein may also be used in the form of free base, salts, zwitterions, solvates, or as prodrugs or pharmaceutical compositions thereof. All forms are within the scope of the present invention. The compounds, their salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions may be administered to patients in various 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, oral mucosal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and pharmaceutical compositions may be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0215] For use in humans, the compounds of the present invention can be administered alone or in admixture with a pharmaceutical carrier selected with respect to the intended route of administration and standard pharmaceutical practice. Thus, pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, that facilitate the processing of the compounds of the present invention into pharma- ceutical preparations that can be used.

[0216] The present invention also includes pharmaceutical compositions that may contain one or more pharma- ceutically acceptable carriers. In making pharmaceutical compositions of the present invention, active ingredients are typically mixed with or diluted by excipients, or enclosed within such carriers, for example in the form of capsules, sachets, paper, or other containers. When excipients function as diluents, they can be solid, semi-solid, or liquid materials (e.g., normal saline), and act as vehicles, carriers, or media for the active ingredients. 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 known in the art, the type of diluent can vary depending on the intended route of administration. The resulting compositions can include additional agents, for example, preservatives.

[0217] Excipient or carrier is selected based on the formulation and route of administration. Suitable pharmaceutical carriers and pharmaceutical requirements for use in pharmaceutical formulations are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), well-known references in the field, and USP / NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0218] These pharmaceutical compositions can be manufactured in a conventional manner, for example, by conventional mixing, dissolving, granulating, sugar-coating, levigating, emulsifying, encapsulating, encapsulating or lyophilizing processes. Methods for preparing formulations well known in the art can be 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 JC Boylan, 1988-1999, Marcel Dekker, New York. Appropriate formulations depend on the route of administration selected. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulations. When preparing formulations, the active compound can be milled and then mixed with other ingredients to obtain a suitable particle size. 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, eg, 40 mesh.

[0219] Dosage The dosage of the compound used in the methods described herein, or its pharma- ceutically acceptable salt or prodrug, or its pharmaceutical composition, may vary depending on many factors, such as, for example, the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of symptoms; the frequency of treatment, and the type of concomitant treatment (if any); and the clearance rate of the compound in the treated animal. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound used in the methods described herein can be administered at a suitable dosage initially, which may be adjusted according to clinical response, if necessary. In general, the suitable daily dose of the compound of the present invention is the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose generally depends on the above factors.

[0220] The compounds of the invention may be administered to a patient in a single dose or multiple doses. When multiple doses are administered, the doses may be separated from each other by, for example, 1 to 24 hours, 1 to 7 days, 1 to 4 weeks, or 1 to 12 months. The compounds may be administered according to a schedule, or the compounds may be administered without a set schedule. The active compounds 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 understood that for any particular subject, specific dosage regimens 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.

[0221] Although the attending physician will ultimately determine the appropriate amount and dosing regimen, an effective amount of the compound of the present invention can be, for example, 0.05 mg to 3000 mg of any of the compounds described herein in a total daily dose. Alternatively, the dose can be calculated using the patient's body weight. Such dose ranges include, for example, 0.05 to 1000 mg (e.g., 0.25 to 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.

[0222] In the methods of the invention, the period during which multiple doses of the compound of the invention are administered to the patient can vary. For example, in some embodiments, doses of the compound of the invention are administered to the patient for 1-7 days, 1-12 weeks, or 1-3 months. In other embodiments, the compound is administered to the patient for a period of, for example, 4-11 months or 1-30 years. In other embodiments, the compound is administered to the patient at the onset of symptoms. In any of these embodiments, the amount of compound administered can vary during the administration period. If the compound is administered daily, administration can be, for example, 1, 2, or 3 times per day.

[0223] formulation Compounds identified as capable of treating any of the conditions described herein using any of the methods described herein may be administered to a patient or animal in unit dosage form together with a pharma- ceutically acceptable diluent, carrier, or excipient. Chemical compounds used in such treatments may be produced and isolated by any standard technique known in the art of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions for administering the identified compounds to a subject in need thereof. Administration may begin before the patient becomes symptomatic.

[0224] Exemplary routes of administration of the compounds used in the present invention (e.g., compounds of the present invention), or pharmaceutical compositions thereof, include oral, sublingual, oral mucosal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intravenous, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. Compounds are desirably administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein that are formulated for the treatment of the disorders described herein are also part of the present invention. Oral administration is the preferred route of administration in the method of the present invention.

[0225] Oral Formulations Pharmaceutical compositions contemplated by the present invention include those formulated for oral administration ("oral dosage forms"). Oral dosage forms may be in the form of, for example, tablets, capsules, liquid solutions or suspensions, powders, or liquid or solid crystals, and contain the active ingredient(s) in admixture 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, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and antiadherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc). Other pharma- ceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0226] Formulations for oral administration may also be provided as chewable tablets, hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, e.g., peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared in a conventional manner using the ingredients of the above-mentioned tablets and capsules, for example, using a mixer, fluid bed equipment, or spray drying equipment.

[0227] Controlled release compositions for oral use can be configured to release the active drug by controlling the dissolution and / or diffusion of the active drug substance. Any of a number of strategies can be implemented to obtain controlled release and a target plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In certain embodiments, the composition includes a biodegradable, pH-sensitive, and / or temperature-sensitive polymer coating.

[0228] Controlled release by dissolution or diffusion can be achieved by suitable coating of the compound's tablet, capsule, pellet or granule formulation, or by incorporating the compound into a suitable matrix. Controlled release coatings can include one or more of the above coating materials and / or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0229] Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils, such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0230] Parenteral Formulations The compounds described herein for use in the methods of the present invention can be administered in pharma- ceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations described herein. Pharmaceutical formulations can also be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventional non-toxic pharma- ceutically acceptable carriers and adjuvants. In particular, suitable formulations for parenteral administration include aqueous and nonaqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions that may contain suspending agents and thickening agents. For example, to prepare such compositions, the compounds of the present invention can be dissolved or suspended in parenterally acceptable liquid vehicles. Acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by the addition of an appropriate amount of hydrochloric acid, sodium hydroxide, or suitable buffers, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, such as methyl benzoate, ethyl benzoate, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), incorporated herein by reference.

[0231] Parenteral formulations can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration. (1) "Drug injection": a liquid preparation that is a drug substance (e.g., a compound of the present invention) or a solution thereof; (2) "Drug for injection": a drug substance (e.g., a compound of the invention) that is a dry solid that is combined with a sterile vehicle suitable for parenteral administration as a drug injection; (3) "Drug Injectable Emulsion": a liquid preparation of a drug substance (e.g., a compound of the invention) dissolved or dispersed in a suitable emulsion medium; (4) "Drug Injectable Suspension": A liquid preparation of a drug substance (e.g., a compound of the invention) suspended in a suitable liquid medium; and (5) "Drug for injectable suspension": A drug substance (eg, a compound of the invention) that is a dry solid that is combined with a sterile vehicle suitable for parenteral administration as a drug for injectable suspension.

[0232] Formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof, with or without alcohol, and in oils. These preparations may contain preservatives to prevent the growth of microorganisms under normal storage and use conditions. 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 The United States Pharmacopeia: The National Formulary (USP 36 NF31) (published in 2013).

[0233] Formulations for parenteral administration may contain, for example, excipients, sterilized water or saline, polyalkylene glycols, such as polyethylene glycol, oils derived from plants, or hydrogenated naphthalene. Biocompatible biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems for the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions or gels for administration in the form of nasal drops.

[0234] Parenteral formulations can be formulated for immediate release or sustained / sustained release of the compound. Exemplary formulations for parenteral release of the compound include aqueous solutions, powders for reconstitution, co-solvent solutions, oil / water emulsions, suspensions, oily solutions, liposomes, microspheres, and polymer gels.

[0235] The following examples are intended to illustrate the invention without, however, limiting it in any way. EXAMPLES

[0236] Example 1. ATR inhibition in STAG2-deficient cells To evaluate the impact of STAG2 deficiency on the response to ATRi, we generated RPE1-hTERT-ΔTP53 lacking STAG2 by knocking out the gene using CRISPR-Cas9. To avoid potential off-target effects, two different sgRNAs were used to generate each KO clone. Treatment with compound 121 induced a significantly stronger growth inhibition of STAG2-KO cells compared to their wild-type (WT) counterparts (Figure 1A). This phenotype was also observed in a second assay measuring viability by the colony-forming ability of surviving cells (Figure 1B).

[0237] Bladder cancer is a cancer in which STAG2-deficient tumors are observed, so we attempted to replicate this observation in a bladder cancer-derived cell model. Using a similar approach, we generated T24 cells deficient in STAG2. Interestingly, colony formation of T24-STAG2 KO cells was impaired after treatment with compound 121 (Figure 2). Overall, this indicates that STAG2 loss of function is a determinant of ATRi sensitivity. These results suggest that STAG2 may be a biomarker for patient treatment with ATRi.

[0238] Example 2. ATR inhibition in SETD2-deficient tumor cells To determine whether inactivation of SETD2 results in ATRi sensitivity, we used specific siRNA to deplete SETD2 from two human cell lines, MCF10A and RPE1-hTERT-ΔTP53. We observed that depletion of SETD2 sensitized these cells to treatment with compound 121 to the same extent as depletion of ATM, a known determinant of sensitivity to ATRi (Figures 3A and 3B). Of note, depletion of SETD2 from a third cell line, HeLa, did not result in ATRi sensitivity. However, depletion of ATM did not result in sensitivity to compound 121 in this cell line, suggesting that the HeLa cell line may not be an appropriate model to study ATRi sensitivity by siRNA depletion (Figure 3C).

[0239] To examine whether SETD2 deficiency confers ATRi sensitivity in a more clinically relevant setting, a panel of six SETD2-retaining and three SETD2-deficient renal clear cell carcinoma and colon cancer cell lines was assembled (Figure 4A) and treated with compound 121. On average, SETD2-deficient cell lines were observed to be more sensitive to compound 121 than SETD2-retaining cell lines (Figure 4B).

[0240] Additionally, the monotherapy dose-escalation phase of the study (Module 1) enrolled patients with advanced solid tumors harboring eligible loss-of-function mutations in a predefined subset of genes associated with ATRi sensitivity (STEP2 gene). Multiple tumor and genomic alterations were demonstrated, including five patients with SETD2 mutations. Three of these patients remain on study, with treatment durations ranging from approximately 23 to 45 weeks. In addition, one of these patients had a confirmed partial response (RECIST v1.1). At the time of the latest report, the clinical benefit rate (CBR) for SETD2 patients evaluable for response was 80%, meaning that four out of five patients responded or were treated for 16 weeks or more without progression. Recruitment of patients with tumors harboring SETD2 alterations is ongoing.

[0241] In conclusion, these data support SETD2 status as a biomarker of ATRi sensitivity in tumors. Example 3. ATR inhibition in CDK12-deficient tumor cells To assess the impact of CDK12 inactivation on ATRi sensitivity, we used an isogenic cell line pair in RPE1-hTERT-ΔTP53 and DLD1 human cell line backgrounds to compare clones with CRISPR / Cas9-generated CDK12 gene knockouts (CDK12- / -) to parental CDK12 wild-type controls (CDK12+ / +). In both cell line backgrounds, we confirmed that CDK12 deficiency increased sensitivity to compound 121 treatment (Figures 5A and 5B).

[0242] In the ongoing study, seven CDK12 patients enrolled in M1 of the study were evaluable for response, but none remain on study. One of these patients had a confirmed partial response (RECIST v1.1) and continued on study nearly 27 weeks. The clinical benefit rate (CBR) for CDK12 patients enrolled in module 1 of the study was 29%, meaning that two of seven patients responded or were treated for 16 weeks or more without progression. Recruitment of patients with tumors that have CDK12 alterations is ongoing. Taken together, these data suggest that CDK12 status in tumors is a determinant of ATRi sensitivity.

[0243] Example 4. ATR inhibition in RNASEH2A and RNASEH2B deficient tumor cells The RNase H2 protein complex is composed of three subunits, encoded by the RNASEH2A, RNASEH2B, and RNASEH2C genes, and all three subunits are required for the stability and activity of the complex. To determine whether RNase H2 deficiency increases cellular sensitivity to ATRi, the RNASEH2B gene was inactivated using CRISPR / Cas9 in two human cell lines, RPE1-hTERT-ΔTP53 and 5637 (note that this results in a complete deletion of the RNase H2 complex). In both cell backgrounds, RNase H2-deficient cells (RNASEH2B- / -) were more sensitive to compound 121 compared to the isogenic wild-type (RNASEH2B+ / +) cell line (Figures 6A and 6B).

[0244] To confirm that RNase H2 deficiency also sensitizes to ATRi treatment in vivo, isogenic 5637 RNASEH2B+ / + and RNASEH2B- / - bladder cancer cell lines were developed as subcutaneous xenografts in immunodeficient mice and treated with compound 121 or vehicle control. Compound 121 showed no efficacy in RNASEH2B+ / + tumors, whereas RNASEH2B- / - tumors showed significant dose-dependent tumor growth inhibition upon treatment with compound 121 (Figures 7A and 7B). Furthermore, RNase H2 deficiency was confirmed by immunohistochemistry using an RNase H2-specific antibody to identify triple-negative breast cancer patient-derived xenografts (PDXs). This model also responded to treatment with compound 121 and showed tumor regression at the maximally tolerated dose (Figures 8A and 8B).

[0245] Taken together, these data support the use of alterations in RNase H2 (RNASEH2B or RNASEH2A) as a biomarker for ATRi susceptibility.

[0246] Example 5. ATR inhibition in RAD51B, RAD51C or RAD51D deficient tumor cells To determine the effect of loss of RAD51B, RAD51C or RAD51D on ATRi sensitivity, we inactivated these genes individually in Cas9-expressing RPE1-hTERT-ΔTP53 cells using two independent sgRNAs per gene. We observed that inactivating any of the three genes (RAD51B, RAD51C or RAD51D) sensitized cells to compound 121 treatment to the same extent (Figures 9A, 9B, 9C).

[0247] Additionally, three patients with RAD51C alterations enrolled in M1 of the study are evaluable for response and all remain on study. One of these patients had a confirmed complete response (RECIST v1.1) and remains on study for 41 weeks. In addition, one patient had a CA-125 tumor marker response and remains on study for 43 weeks. The clinical benefit rate (CBR) for RAD51C patients enrolled in Module 1 of the study was 100%, meaning that three out of three patients responded or remained on treatment for 16 weeks or more without progression. Recruitment of patients with tumors harboring RAD51C alterations is ongoing.

[0248] Overall, these data support the conclusion that alterations in RAD51B, RAD51C, or RAD51D are biomarkers of ATRi sensitivity. Example 6. ATR inhibition in cells deficient in ATRIP, RAD17, REV3L, FZR1 or CHTF8 To investigate whether the loss of any of the ATRIP, RAD17, REV3L, FZR1 or CHTF8 genes results in ATRIi sensitivity, their expression in two or three human cell lines, RPE1-hTERT-ΔTP53, MCF10A or HeLa, was downregulated using specific siRNA. siRNA targeting SETD2 or ATM was used as a positive control. It was confirmed that siRNA-mediated knockdown of ATRIP, RAD17, REV3L, FZR1 or CHTF8 sensitized at least one cell line to treatment with compound 121 at a similar or higher level compared to knockdown of ATM or SETD2 (Figures 10A, 10B, and 10C). These data suggest that tumors with inactive alterations in ATRIP, RAD17, REV3L, FZR1 or CHTF8 may be sensitive to ATRIi treatment.

[0249] Example 7. Lack of ATRi sensitivity due to ARID1A In addition to the genes disclosed herein, we investigated ATRi sensitivity to deletion of ARID1A. ARID1A has previously been described as a bona fide biomarker of ATRi sensitivity in Williamson et al., Nat. Comms., 7:13837, 2016. Three isogenic ARID1A wild type (WT) and ARID1A deficient (ARID1A- / -) human cell line pairs were employed: HCT116, MCF10A and BEAS2B. In all cases, ARID1A deficient did not result in sensitivity to ATR inhibition by AZD-6738, contrary to published data (Figures 11A, 11B, and 11C). To reinforce this observation, we assembled a panel of histocompatible cancer cell lines that were either ARID1A WT or had deleterious ARID1A alterations (LOF) and measured their sensitivity to AZD-6738. Consistent with the isogenic cell line data, there was no significant trend towards greater ATRi sensitivity in ARID1A LOF cell lines compared to ARID1A WT (Figure 12). Collectively, the genes named in this application appear to represent a list of bona fide determinants of ATRi sensitivity, as opposed to specific biomarkers described in the scientific literature.

[0250] Other embodiments Various modifications and variations of the invention described herein 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 unnecessarily 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.

[0251] Other embodiments are found in the claims.

Claims

1. A method of treating cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of an ATR inhibitor, wherein the cancer has been previously identified as a cancer having loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

2. A method of treating cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of an ATR inhibitor, wherein the cancer has loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

3. 1. A method of treating cancer in a subject, comprising: (i) identifying the cancer as having a loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B; (ii) administering to said subject in need thereof a therapeutically effective amount of an ATR inhibitor; The method comprising:

4. The method according to any one of claims 1 to 3, wherein the route of administration is oral administration.

5. 1. A method of inducing cell death in an abnormal cancer cell having loss of function of STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B, comprising contacting the cell with an effective amount of an ATR inhibitor, wherein the effective amount is sufficient to induce cell death in the abnormal cancer cell.

6. 1. A method of treating a cancer having a biallelic loss-of-function mutation in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B in a subject, comprising administering to the subject in need thereof an effective amount of an ATR inhibitor.

7. 1. A method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of an ATR inhibitor, wherein the cancer has been previously identified as having biallelic loss-of-function mutations in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

8. 1. A method of inducing cell death in a cancer cell having a STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B loss-of-function mutation, comprising contacting the cell with an ATR inhibitor.

9. The method of claim 8 , wherein the cell is in a subject.

10. 10. The method of any one of claims 6-9, further comprising identifying the cancer as having a biallelic loss-of-function mutation in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B prior to the administering or contacting step.

11. The step of identifying includes: determining an integer total copy number of a locus segment and / or two integer allele-specific copy numbers of the locus segment within a STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B gene region of the cancer cell from the subject or the cancer cell from a read count of a plurality of SNVs, including homozygous single nucleotide variants (SNVs) and heterozygous SNVs, obtained from sequencing the sample comprising the cancer cell, and a reference read count; wherein the cancer is at least one of said integer total copy number and said integer allele-specific copy number is zero (provided that the remaining STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B alleles, if present, contain an inactivating mutation); or if none of said integer allele-specific copy numbers are zero, and a STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B allele is present, and each of said alleles independently contains an inactivating mutation; 11. The method of claim 10, wherein the patient is identified as having a biallelic loss-of-function mutation in STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B.

12. The determining step further comprises: determining a total copy number log ratio, an allele copy number log odds ratio, and a target coverage value for the SNV from the read counts and the reference read counts; Segmenting the total copy number log ratio and the allele copy number log odds ratio; estimating a sample purity and a sample ploidy of the cancer cells from the total copy number log ratio and the target coverage value; generating an integer total copy number and two integer allele-specific copy numbers of a segment containing a plurality of SNVs within a STAG2, SETD2, CDK12, ATRIP, REV3L, RAD17, CHTF8, FZR1, RAD51B, RAD51C, RAD51D, PALB2, RNASEH2A, or RNASEH2B gene region of the cancer cell from the target coverage value, the sample purity, the sample ploidy, the total copy number log ratio, and the allele copy number log odds ratio; The method of claim 11 , comprising:

13. The method of claim 12 , further comprising adjusting the misregistration rate.

14. The method of any one of claims 11 to 13, wherein the plurality of SNVs comprises SNVs with uniform coverage.

15. 15. The method of claim 14, wherein each of the uniform coverage SNVs has an average coverage of at least 200x reads across a panel of normal samples.

16. The method of any one of claims 11 to 15, wherein the plurality of SNVs comprises high frequency SNVs, the high frequency SNVs having an allele frequency in humans of between 33% and 66%.

17. The method of claim 16 , wherein the plurality of SNVs comprises SNVs adjacent to the frequent SNV.

18. 17. The method of any one of claims 11 to 16, wherein the plurality of SNVs comprises a plurality of SNVs, each of the plurality of SNVs having a 5'-flanking sequence of at least 20 contiguous nucleobases with a GC content of 25-75%, wherein the 5'-flanking sequence is unique and does not contain other SNVs.

19. The method of any one of claims 11 to 18, wherein the plurality of SNVs comprises at least 20 heterozygous SNVs.

20. The method of any one of claims 11 to 19, wherein the reference read counts are derived from a panel of normal samples.

21. The method of any one of claims 11 to 19, wherein the gene regions each comprise flanking regions of up to 10 kilobases.

22. The method of any one of claims 11 to 19, wherein the gene regions each comprise flanking regions of up to 5 kilobases.

23. The method of any one of claims 11 to 19, wherein the gene regions each comprise up to 2 kilobases of flanking region.

24. The method according to any one of claims 11 to 23, wherein the gene region is an exome region.

25. The method according to any one of claims 11 to 23, wherein the gene region is a transcriptome region.

26. The method according to any one of claims 11 to 23, wherein the gene region is a genomic region.

27. The method of any one of claims 6 to 26, wherein the biallelic loss-of-function mutations comprise at least one somatic mutation.

28. The method of any one of claims 6 to 27, wherein the biallelic loss-of-function mutations comprise at least one germline mutation.

29. The ATR inhibitor is a compound of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, 【Chemistry 2】 is a double bond, and each Y is independently N or CR ４ or 【Chemistry 3】 is a single bond, and each Y is independently NR Ｙ , carbonyl, or C(R Ｙ ) ２ wherein each R Ｙ is independently H or optionally substituted C １－６ is alkyl, R １ is optionally substituted C １－６ alkyl or H; R ２ is optionally substituted C ２－９ Heterocyclyl, optionally substituted C １－６ Alkyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ２－９ Heterocyclyl C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C １－９ Heteroaryl, optionally substituted C １－９ Heteroaryl C １－６ Alkyl, halogen, -N(R ５ ) ２ , -OR ５ , -CON(R ６ ) ２ , -SO ２ N (R ６ ) ２ , -SO ２ R ５Ａ , or -Q-R ５Ｂ and R ３ is optionally substituted C １－９ Heteroaryl or optionally substituted C １－９ Heteroaryl C １－６ is alkyl, Each R ４ are independently hydrogen, halogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ alkenyl, or optionally substituted C ２－６ is alkynyl, Each R ５ are independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ６－１０ Aryl C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C １－９ Heteroaryl, or -SO ２ R ５Ａ or both R ５ together with the atoms to which they are attached, optionally substituted C ２－９ forming a heterocyclyl, Each R ５Ａ is independently an optionally substituted C １－６ Alkyl, optionally substituted C ３－８ Cycloalkyl, or optionally substituted C ６－１０ is aryl, R ５Ｂ is hydroxyl, optionally substituted C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C １－９ Heteroaryl, -N(R ５ ) ２ , -CON(R ６ ) ２ , -SO ２ N (R ６ ) ２ , -SO ２ R ５Ａ or optionally substituted alkoxy; Each R ６ are independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkoxyalkyl, optionally substituted C ６－１０ Aryl C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C ３－８ Cycloalkyl, or optionally substituted C １－９ heteroaryl, or both R ６ together with the atoms to which they are attached, optionally substituted C ２－９ forming a heterocyclyl, Q is an optionally substituted C ２－９ Heterocyclylene, optionally substituted C ３－８ Cycloalkylene, optionally substituted C １－９ Heteroarylene, or optionally substituted C ６－１０ is an arylene, X is hydrogen or halogen. The method according to any one of claims 1 to 28, wherein

30. The ATR inhibitor is a compound of formula (II): 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof (In the formula, Each Y is independently N or CR ４ and R １ is optionally substituted C １－６ alkyl or H; R ２ is optionally substituted C ２－９ Heterocyclyl, optionally substituted C １－６ Alkyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ２－９ Heterocyclyl C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C １－９ Heteroaryl, optionally substituted C １－９ Heteroaryl C １－６ Alkyl, halogen, -N(R ５ ) ２ , -OR ５ , -CON(R ６ ) ２ , -SO ２ N (R ６ ) ２ , -SO ２ R ５Ａ , or -Q-R ５Ｂ and R ３ is optionally substituted C １－９ Heteroaryl or optionally substituted C １－９ Heteroaryl C １－６ is alkyl, Each R ４ are independently hydrogen, halogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ alkenyl, or optionally substituted C ２－６ is alkynyl, Each R ５ are independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ６－１０ Aryl C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C １－９ Heteroaryl, or -SO ２ R ５Ａ or both R ５ together with the atoms to which they are attached, optionally substituted C ２－９ forming a heterocyclyl, Each R ５Ａ is independently an optionally substituted C １－６ Alkyl, optionally substituted C ３－８ Cycloalkyl, or optionally substituted C ６－１０ is aryl, R ５Ｂ is hydroxyl, optionally substituted C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C １－９ Heteroaryl, -N(R ５ ) ２ , -CON(R ６ ) ２ , -SO ２ N (R ６ ) ２ , -SO ２ R ５Ａ or optionally substituted alkoxy; Each R ６ are independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkoxyalkyl, optionally substituted C ６－１０ Aryl C １－６ Alkyl, optionally substituted C ６－１０ Aryl, optionally substituted C ３－８ Cycloalkyl, or optionally substituted C １－９ heteroaryl, or both R ６ together with the atoms to which they are attached, optionally substituted C ２－９ forming a heterocyclyl, Q is an optionally substituted C ２－９ Heterocyclylene, optionally substituted C ３－８ Cycloalkylene, optionally substituted C １－９ Heteroarylene, or optionally substituted C ６－１０ is an arylene, X is hydrogen or halogen.

30. The method of claim 29, wherein:

31. 30. The method of claim 29, 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 pharma- ceutically acceptable salts thereof.

32. 32. The method of claim 31 , wherein the ATR inhibitor is compound 43 or a pharma- ceutically acceptable salt thereof.

33. 30. The method of claim 29, wherein the ATR inhibitor is compound 121 or a pharma- ceutically acceptable salt thereof.

34. 30. The method of claim 29, wherein the ATR inhibitor is compound 122 or a pharma- ceutically acceptable salt thereof.

35. The ATR inhibitor is 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

36. The ATR inhibitor is 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

37. 37. The method of any one of claims 1 to 36, wherein the method does not include a step of administering or contacting with a PARP inhibitor.

38. The method of any one of claims 1 to 37, wherein the ATR inhibitor is administered as monotherapy.

39. The method of any one of claims 1 to 36, wherein the cancer is renal cell carcinoma, mature B cell tumor, endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, skin cancer, small intestine cancer, non-small cell lung cancer, melanoma, bladder cancer, pancreatic cancer, head and neck cancer, mesothelioma, glioma, prostate cancer, breast cancer, or esophagogastric cancer.

40. The method of any one of claims 1 to 36, wherein the loss of function is a loss of function of STAG2.

41. 38. The method of claim 37, wherein the cancer is renal cell carcinoma, endometrial cancer, acute myeloid leukemia, bladder cancer, uterine cancer, or gastric cancer.

42. The method according to any one of claims 1 to 36, wherein the loss of function is a loss of function of SETD2.

43. 43. The method of claim 42, wherein the cancer is mesothelioma, renal clear cell carcinoma, papillary renal cell carcinoma, lung adenocarcinoma, cholangiocarcinoma, uveal melanoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, invasive breast carcinoma, lung squamous cell carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, or ovarian serous cystadenocarcinoma.

44. The method according to any one of claims 1 to 36, wherein the loss of function is loss of function of CDK12.

45. 45. The method of claim 44, wherein the cancer is prostate cancer, ovarian serous cystadenocarcinoma, uterine endometrial carcinoma, cutaneous melanoma, lung adenocarcinoma, or invasive breast cancer.

46. The method according to any one of claims 1 to 36, wherein the loss of function is a loss of function of ATRIP.

47. 47. The method of claim 46, wherein the cancer is uveal melanoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, or renal clear cell carcinoma.

48. The method according to any one of claims 1 to 36, wherein the loss of function is a loss of function of REV3L.

49. 49. The method of claim 48, wherein the cancer is uterine endometrial cancer, gastric adenocarcinoma, prostate cancer, lung squamous cell carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, cutaneous melanoma, or lung adenocarcinoma.

50. The method of any one of claims 1 to 36, wherein the loss of function is loss of function of RAD17.

51. 51. The method of claim 50, wherein the cancer is gastric adenocarcinoma, prostate cancer, or invasive breast cancer.

52. The method according to any one of claims 1 to 36, wherein the loss of function is loss of function of CHTF8.

53. 53. The method of claim 52, wherein the cancer is prostate cancer.

54. The method according to any one of claims 1 to 36, wherein the loss of function is a loss of function of FZR1.

55. 55. The method of claim 54, wherein the cancer is head and neck squamous cell carcinoma, cutaneous melanoma, or papillary renal cell carcinoma.

56. The method of any one of claims 1 to 55, wherein the loss of function is a loss of function of RAD51B.

57. 57. The method of claim 56, wherein the cancer is uterine endometrial cancer, papillary renal cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cutaneous melanoma, or invasive breast cancer.

58. The method according to any one of claims 1 to 36, wherein the loss of function is a loss of function of RAD51C.

59. 59. The method of claim 58, wherein the cancer is cutaneous melanoma, uterine endometrial carcinoma, ovarian serous cystadenocarcinoma, or invasive breast carcinoma.

60. The method of any one of claims 1 to 36, wherein the loss of function is a loss of function of RAD51D.

61. 61. The method of claim 60, wherein the cancer is ovarian serous cystadenocarcinoma, gastric adenocarcinoma, or cutaneous melanoma.

62. The method of any one of claims 1 to 36, wherein the loss of function is a loss of function of PALB2.

63. 63. The method of claim 62, wherein the cancer is prostate cancer, lung adenocarcinoma, hepatocellular carcinoma, invasive breast cancer, uterine endometrial carcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

64. The method according to any one of claims 1 to 36, wherein the loss of function is a loss of function of RNASEH2A.

65. The method according to any one of claims 1 to 36, wherein the loss of function is a loss of function of RNASEH2B.

66. 66. The method of claim 64 or 65, wherein the cancer is sarcoma, bladder urothelial carcinoma, chronic lymphocytic leukemia.

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