Methods of treating cancer

Abstract

The present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof. The present application also describes pharmaceutical composition comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for treating diseases such as cancer.

Description

[0001] METHODS OF TREATING CANCER TECHNICAL FIELD This present application relates to fused heterocyclic compounds that are useful for treating proliferative disorders such as cancer. BACKGROUND Wee1 is a highly conserved serine / threonine kinase that inhibits cell cycle progress and cell entry into mitosis through inhibitory phosphorylation of cyclin-dependent kinase 1 and 2 (CDK1 and 2). It is a key regulator of cell cycle progression through S-phase and at the G2-M checkpoint. See, e.g., Hamer, et al., Clin. Cancer Res., Vol.17, No.13, pp.4200-4207 (2011) and McGowan and Russell, EMBO J., Vol.14, No.10, pp.2166-2175 (1995). In normal cells, DNA damage response (DDR) is mediated by various checkpoints which either activate the DNA repair system or induce cellular apoptosis / senescence, therefore maintaining overall genomic integrity. In cancer cells, however, with a loss of or defect in DDR due to oncogenic activation or tumor suppressor inactivation, DNA replication may persist to meet the demands of unrestrained proliferation despite the presence of unrepaired DNA lesions, which then leads to replication stress—a hallmark of cancer cells that typically includes the perturbation of error-free DNA replication and / or slow-down of DNA synthesis. See, e.g., Zhang et al, Genes, 2016, 7, 51; 1-16. Overexpression and activation of oncogenes are a major driver of replication stress. For example, oncogenes KRAS, MYC, and CCNE1, and CDC25A result in replication stress, for example, through the creation of conflicts between replication and transcription, increasing topological stress, and / or producing a nucleotide shortage. Replication stress can cause cells to slow down replication cycles; therefore, in order to maintain its proliferative program, a cancer cell typically has ways of dealing with and resolving replication stress in order to continue growing. One example is by bypassing mechanisms of DNA damage repair, for example the loss of p53, the mutation of ATM, and defects in the homologous recombination repair pathway (such as via mutation to BRCA1, BRCA2, and PALB2). See Forment and O’Connor, Pharmacology & Therapeutics, 188 (2018) 155–167. Together, these compensatory mechanisms can result in increased genomic instability, which in turn lead to further replication stress. In general, in tumors where DNA damage response elements are bypassed or impaired, the cancer cells may become more dependent on the remaining active components of the DNA damage response and cell cycle checkpoints such as Wee1. Inhibition of Wee1 kinase activity enhances CDK activity, and cells in S phase can be induced to enter mitosis prematurely even if DNA replication is defective or incomplete. The increased CDK activity driven by Wee1 inhibition can also rapidly increase replication initiation, leading to a shortage of nucleotides that are required for DNA replication. Wee1 inhibitors can thus be effective to enhance replicative stress and drive cancer cells undergoing a high level of this stress into premature mitosis and subsequent death from mitotic catastrophe. However, currently there are no marketed therapeutic Wee1 inhibitors. SUMMARY Some embodiments provide compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R1A, R1B, R2, R3, R4, R5, R6A, R6B, RA, RB, RC, RD, RE, RF, RG, RH, RI, RJ, RK, and n, are as defined herein. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of inhibiting Wee1 kinase activity in a mammalian cell, in vitro or in vivo, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of treating cancer, for example, uterine, ovarian, breast, gastric, colorectal, and non-small cell lung cancer, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of a cancer in a subject in need thereof, the method comprising: (a) identifying the cancer as having replication stress; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having replication stress. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: (a) identifying the cancer as having an inactivated tumor suppressor gene; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having an inactivated tumor suppressor gene. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: (a) identifying the cancer as having an activated oncogene; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having an activated oncogene. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: (i) administering to the subject an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) (a) and (b); (e) (a) and (c); (f) (b) and (c); (g) (a), (b), and (c); and (ii) after (i), administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject previously administered one or more doses of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) (a) and (b); (e) (a) and (c); (f) (b) and (c); (g) (a), (b), and (c). Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject: (i) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein; and (ii) an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) (a) and (b); (e) (a) and (c); (f) (b) and (c); (g) (a), (b), and (c). Also provided herein is a method for inducing mitotic collapse in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of cancer (e.g., a cancer with replication stress). Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer. Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the inhibition of Wee1 kinase activity. Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer (e.g., a cancer with replication stress). In some emboidments, the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung. Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, defined herein in the manufacture of a medicament for the inhibition of Wee1 kinase activity. Also provided herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION Definitions The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer. An example of a tautomeric forms includes the following example: . It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form. The term “halogen” refers to one of the halogens, group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine. The term “C1-C6 alkyl” refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Similarly, a C1-C3 alkyl group is a linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms. The term “C1-C6 deuteroalkyl” refers to an alkyl group, as described herein, where one or more hydrogen atoms are replaced with deuterium, such as –CD3. The term “C1-C6 alkoxy” refers to a C1-C6 alkyl group which is attached to a molecule via an oxygen atom. This includes moieties where the alkyl part may be linear or branched, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. As used herein, the term “cyano” refers to a –CN radical. As used herein, the term “hydroxyl” refers to an –OH radical. As used herein, the term “amino” refers to a –NH2radical. As used herein, the term “C6–C10 aryl” refers to a 6 to 10 carbon mono- or bicyclic ring system wherein at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl. In bicyclic ring systems where only one ring is aromatic, the non-aromatic ring can be a cycloalkyl group, as defined herein. As used herein, the term “heteroaryl” refers to a mono- or bicyclic ring system with, for example, 5 to 10 ring atoms, wherein the ring system is aromatic; wherein one or more carbon atoms in at least one ring in the system is / are replaced with an heteroatom independently selected from N, O, and S. Non-limiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, pyrazole, imidazole, and indole. As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated 3–10 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro (optionally referred to as “spirocycloalkyl” groups), and bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl. The term “heterocyclyl” refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, having at least one heteroatom within the ring selected from N, O and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. The heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members. In bicyclic ring systems, one ring can be aromatic, if the other ring is not aromatic. For example, one ring could be phenyl and the other ring could be pyrrolidine, or, one ring could be pyridine and the other ring could be cyclohexane. The heterocyclyl group may be denoted as, for example, a “5-10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidine, piperazine, piperazine-2-one, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidine, pyrrolidin-2-one, oxazolidinone, sulfolane, isoindolin-1-one, 1,2,3,4-tetrahydroisoquinoline, 1,7-diazaspiro[3.5]nonane, and isothiazoline S,S-dioxide. The term “heterocyclyloxy” refers to a heterocyclyl group which is attached to a molecule via an oxygen atom. As used herein, the term “oxo” refers to an “=O” group attached to a carbon atom. As used herein, the symbol depicts the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule. The compounds of Formula (I) include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula (I) also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying compounds of Formula (I) and / or for separating enantiomers of compounds of Formula (I). Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) include trifluoroacetic acid and hydrochloride salts. It will further be appreciated that the compounds of Formula (I) or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure. For example, compounds of Formula (I) and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In one embodiment, the compounds of Formula (I) include the compounds of Examples 1-92 and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Examples 1-92 are present in the form of a free base. In some embodiments, the compounds of Examples 1-92 are present in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable” indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith. Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to1H,2H,3H or mixtures thereof; when carbon is mentioned, it is understood to refer to11C,12C,13C,14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to13N,14N,15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to14O,15O,16O,17O,18O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to18F,19F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium (2H). As some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Protecting groups can be a temporary substituent which protects a potentially reactive functional group from undesired chemical transformations. The choice of the particular protecting group employed is well within the skill of one of ordinary skill in the art. A number of considerations can determine the choice of protecting group including, but not limited to, the functional group being protected, other functionality present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, functional group tolerance to conditions required to remove the protecting group, and reaction conditions for the thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nded.; Wiley: New York, 1991, which is incorporated by reference herein in its entirety. The ability of selected compounds to act as Wee1 inhibitors may be demonstrated by the biological assays described herein. IC50values are shown in Table A. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. As used herein, the term “subject” refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. Persistent replication stress (sometimes also called replicative stress) is a phenomenon that is observed in cancer cells and is rarely observed in non-cancerous cells. One hallmark of replication stress is fork stalling. In some embodiments, a tumor that has “replication stress” is one that has stalled replication forks. In many cases, when DNA damage occurs to a strand being replicated, the replication machinery cannot pass the lesion, resulting in fork stalling. To repair the stalled replication fork, single-stranded DNA (ssDNA) on the leading strand is typically exposed, initiating the Replication protein A (RPA) to bind to the ssDNA and activate the ATR / Chk1 pathway. By activating this pathway, entry into M phase is limited. If replication stress is exacerbated, for example, by inactivation of one or more tumor suppressor genes (e.g., p53, RB1, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1 or a combination thereof) (for instance, resulting in the premature onset of S phase), activation of one or more oncogenes (e.g., Cyclin E, CDC25A, Myc, a RAS gene (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof), increased DNA damage (e.g., through reactive oxygen species (ROS), chemotherapy (e.g., platinum-based chemotherapy, alkylating agents, nucleobase / nucleoside / nucleotide analogs, topoisomerase I and / or II inhibitors, PARP1 and / or PARP2 inhibitors, ATR inhibitors, Chk1 inhibitors), and / or radiation therapy), premature entry into M phase (e.g., via inhibition of Wee1), or a combination thereof, mitotic catastrophe can occur, leading to cell death. See, e.g., U.S. Publication No.2020 / 0157638, Zhang et al, Genes, 2016, 7, 51; 1-16, Berti and Vindigni Nature Structural & Molecular Biology, 2016, 23, 2: 103- 109, and Ren et al. Oncotarget, 20178, 23: 36996. Without being bound by any particular theory, it is believed that cells that have replication stress are more dependent on the activity of Wee1 (e.g., to prevent aberrant entry into M phase) due to the dysregulation of one or more other mechanisms that typically regulate the cell cycle. In some embodiments, the subject has been identified or diagnosed as having a cancer with replication stress. In some embodiments, the subject has a tumor that is positive for replication stress. The subject can be a subject with a tumor(s) that tests positive for replication stress. The subject can be a subject whose tumors have replication stress. In some embodiments, the subject is suspected of having a tumor with replication stress. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has replication stress. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with replication stress. The presence of replication stress in a subject (e.g., in a tumor of a subject (e.g., a sample of the tumor)) can be detected in any appropriate way. In some embodiments, detection of replication stress can be detected directly. In some embodiments, replication stress can be detected indirectly. In some embodiments, replication stress can be detected using H2AX immunohistological staining to measure, for example, γH2AX. In some embodiments, replication stress can be detected by measuring cleaved caspase. In some embodiments, replication stress can be detected using a terminal deoxynucleotidyl transferase– mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. In some embodiments, replication stress can be detected by measuring the immune response to cytosolic DNA. See, e.g., Ubhi and Brown. Cancer Research 79.8 (2019): 1730-1739. In some embodiments, replication stress can be detected via DNA fiber analyses, for example, by measuring DNA synthesis rates of individual DNA replication forks. In some embodiments, replication stress can be detected via DNA pull-downs to identify proteins bound directly at replication forks in vivo. See, e.g., Ubhi and Brown. Cancer Research 79.8 (2019): 1730-1739. In some embodiments, replication stress can be detected using a biomarker of replication stress. In some embodiments, a biomarker of replication stress can include Ki-67, Cyclin E, POLD3, γH2AX, FANCD2, or a combination thereof. In some embodiments, a biomarker of replication stress can include pH2AX Ser139 (γH2AX), pATR Thr1989, pCHK1 Ser345, pRPA32 Ser33, or a combination thereof. See, e.g., Forment and O’Connor, Pharmacology & Therapeutics, 188 (2018) 155–16. In some embodiments, a biomarker of replication stress can be an activated oncogene. In some embodiments, a biomarker of replication stress can be an inactivated tumor suppressor gene. In some embodiments, a biomarker of replication stress can be one or more genes listed in Tables 1A or 1B in WO2019173456(A1). In some embodiments, two or more of these methods can be combined. For example, in some embodiments, replication stress can be detected using the p53 status of the tumor(s) of the subject, optionally combined with the proliferation index of the tumor(s) (e.g., as measured by Ki67). See, e.g., Reaper et al. Nature Chemical Biology 7.7 (2011): 428-430. In some embodiments, replication stress can be detected using chromosomal instability (e.g., by karyotype or by measuring chromosomal instability genes). See, e.g., Burrell et al. Nature 494.7438 (2013): 492-496. In some embodiments, the subject has been identified or diagnosed as having a cancer with an inactivation of one or more tumor suppressor genes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for inactivation of one or more tumor suppressor genes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for inactivation of one or more tumor suppressor genes (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have inactivation of one or more tumor suppressor genes (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA- approved, kit or assay). In some embodiments, the subject is suspected of having a cancer with inactivation of one or more tumor suppressor genes. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has inactivation of one or more tumor suppressor genes (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to inactivation of one or more tumor suppressor genes. Inactivation of a tumor suppressor gene can be through any appropriate mechanism, including, but not limited to, gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic alteration, and degradation of mRNA and / or protein products of the gene. A tumor suppressor gene can be any appropriate tumor suppressor gene. In some embodiments, a tumor suppressor gene can be p53, RB1, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1, or a combination thereof. See, e.g., Forment and O’Connor, Pharmacology & Therapeutics, 188 (2018) 155–167, Reaper et al. Nature Chemical Biology 7.7 (2011): 428-430, and Méndez et al. Clinical Cancer Research 24.12 (2018): 2740-2748. In some embodiments, an inactivated tumor suppressor gene is a mutated p53 gene. In some embodiments, an inactivated tumor suppressor gene is a deleted p53 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated CDKN2A gene. In some embodiments, an inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, an inactivated tumor suppressor gene is a deleted FBXW7 gene. A non-limiting example of a cancer that can have a deleted FBXW7 gene is uterine serous carcinoma. In some embodiments, an inactivated tumor suppressor gene is a mutated FBXW7 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated RB1 gene. In some embodiments, an inactivated tumor suppressor gene is a deleted BRCA1 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated BRCA1 gene. In some embodiments, an inactivated tumor suppressor gene is a BRCA1 gene with a hypermethylated promoter region. In some embodiments, an inactivated tumor suppressor gene is a deleted BRCA2 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated BRCA2 gene. In some embodiments, an inactivated tumor suppressor gene is a BRCA2 gene with a hypermethylated promoter region. In some embodiments, an inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated SETD2 gene. In some embodiments, the subject has been identified or diagnosed as having a cancer with an activation of one or more oncogenes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for activation of one or more oncogenes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for activation of one or more oncogenes (e.g., identified as positive using a regulatory agency- approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have activation of one or more oncogenes (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a cancer with activation of one or more oncogenes. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has activation of one or more oncogenes (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to activation of one or more oncogenes. Activation of an oncogene can be through any appropriate mechanism, including, but not limited to, gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic alteration, and / or overexpression of the protein product of the oncogene. An oncogene can be any appropriate oncogene. In some embodiments, an oncogene can be cyclin E (sometimes also called cyclin E1 or CCNE1), CDC25A, Myc, a RAS gene (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof. See, e.g., Haigis, Trends in Cancer 3.10 (2017): 686-697, Kalkat, et al. Genes (2017) 8, 151, Feng et al. Molecular and Cellular Biology 31.16 (2011): 3457-3471, Kok et al. Oncogenesis (2020) 9:88, Dang, Cell 149.1 (2012): 22-35. In some embodiments, an activated oncogene is an amplified cyclin E gene. Non-limiting examples of cancers that can have amplified cyclin E (e.g., cyclin E1) include rhabdomyosarcoma, urinary bladder adenocarcinoma, malignant fibrous histiocytoma, small intestine adenocarcinoma, medullary breast cancer, gallbladder adenocarcinoma, stomach adenocarcinoma, urinary bladder transitional cell carcinoma, urinary bladder small cell carcinoma, non-serous ovarian carcinoma, uterine cervix squamous cell carcinoma, and ovarian endometrial (endometrioid) carcinoma. In some embodiments, an activated oncogene is an overexpressed CDC25A. Non-limiting examples of cancer that can have overexpressed CDC25A include breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, prostate cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma), pancreatic ductal adenocarcinoma, thyroid neoplasms, non-Hodgkin's lymphoma, and neuroblastoma. In some embodiments, an activated oncogene is an amplified Myc gene. Non- limiting examples of cancers that can have Myc amplification include breast invasive ductal carcinoma, lung adenocarcinoma, prostate adenocarcinoma, colon adenocarcinoma, and high grade ovarian serous adenocarcinoma. In some embodiments, an activated oncogene is a Myc gene with an activating translocation. In some embodiments, an activated oncogene is a transcriptionally activated Myc gene. In some embodiments, an activated oncogene is a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof). In some embodiments, a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position G12 of the protein product of the gene. In some embodiments, a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position G13 of the protein product of the gene. In some embodiments, a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position Q61 of the protein product of the gene. Non-limiting examples of cancers that can have KRAS mutations include pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). In some embodiments, the subject has been identified or diagnosed as having a cancer with increased DNA damage. In some embodiments, the subject has a tumor that is positive for increased DNA damage. The subject can be a subject with a tumor(s) that tests positive for increased DNA damage. The subject can be a subject whose tumors have increased DNA damage. In some embodiments, the subject is suspected of having a tumor with increased DNA damage. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has increased DNA damage. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with increased DNA damage. Typically, “increased” DNA damage is achieved by administration of one or more DNA- damaging agents, one or more DNA repair inhibiting agents, and / or radiation to the subject. In some embodiments, a DNA-damaging agent can include a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, and / or nucleotide analog, or a combination thereof. In some embodiments, a DNA repair inhibiting agent can include a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, or a combination thereof. Non-limiting examples of platinum-based chemotherapeutics include carboplatin, cisplatin, and oxaplatin. Non-limiting examples of alkylating agents include cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, and mitomycin C. Non-limiting examples of nucleobase, nucleoside, and / or nucleotide analogs include fluorouracil, cytarabine, gemcitabine, azacitidine, and decitabine. Non-limiting examples of topoisomerase I inhibitors include topotecan, irinotecan, belotecan, and camptothecin. Non-limiting examples of topoisomerase II inhibitors include etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, and idarubacin. Non-limiting examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and veliparib. Non-limiting examples of ATR inhibitors include AZD6738, BAY1895344, and M6620. Non-limiting examples of Chk1 inhibitors include prexasertib, GDC- 0575, SCH 900776, and SRA737. The term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age. In certain embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are useful for preventing diseases and disorders as defined herein (for example, cancer). The term "preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof. Without being bound by any particular theory, it is believed that cancers that exhibit replication stress are more reliant on the cell cycle checkpoint regulators such as Wee1. In some embodiments, cancers that exhibit replication stress overexpress Wee1. Non-limiting examples of cancers that can overexpress Wee1 include hepatocellular carcinoma, breast cancers, cervical cancers, lung cancers, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, ovarian cancers, pancreatic cancers, and colorectal cancers. See, e.g., P Reigan et al Trends in Pharmacol Sci 2016; Mir, et al., Cancer Cell, Vol.18, No.3, pp.244-257 (2010)). The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA). Compounds Accordingly, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1Aand R1Bare each independently hydrogen or C1-C6 alkyl; R2is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, each optionally substituted with 1-3 independently selected RA; each RAis independently halogen, cyano, –NRDRE, C1-C6 alkyl optionally substituted with hydroxyl, –NRBRC, –C(=O)NRBRC, or –NH(C=O)NH2; –C(=O)NRBRC, –N=S(O)Me2, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxyl, or C1-C6 alkyl optionally substituted with –NRBRC; or C3-C6 cycloalkyl optionally substituted with –NRBRC; each RBis independently hydrogen or C1-C6 alkyl; each RCis independently hydrogen or C1-C6 alkyl; each RDis independently hydrogen or C1-C6 alkyl; each REis independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl optionally substituted with hydroxyl; R3is hydrogen or C1-C6 alkyl; R4is (i) phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 alkyl optionally substituted with 1 or 2 substituents independently selected from –NRBRC, –CO2H, -(C1-C6 alkyl)n-C(=O)NRFRK, C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 4-12 membered heterocyclyloxy optionally substituted with 1 or 2 independently selected RG, and 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; (ii) 9-12 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl; (iii) 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: C1-C6 alkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 4-12 membered heterocyclyloxy optionally substituted with 1 or 2 independently selected RG, and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino; each RFand RKare independently hydrogen or C1-C6 alkyl; or one RFand one RK, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; RGis independently halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, –NRBRC, C3-C6 cycloalkyl, or =NRH; RHis hydrogen or C1-C6 alkyl; n is 0 or 1; R5is hydrogen, halogen, or C1-C6 alkyl; and R6Aand R6Bare independently C1-C6 alkyl optionally substituted with one hydroxyl or one C1-C6 alkoxy. In some embodiments, R1Aand R1Bare both hydrogen. In some embodiments, one of R1Aand R1Bis hydrogen and the other of R1Aand R1Bis C1-C6 alkyl. In some embodiments, one of R1Aand R1Bis hydrogen and the other of R1Aand R1Bis methyl. In some embodiments, R1Aand R1Bboth independently selected C1-C6 alkyl. In some embodiments, R2is phenyl optionally substituted with 1-3 independently selected RA. In some embodiments, R2is phenyl substituted with 1-3 independently selected RA. In some embodiments, R2is phenyl substituted with 3 independently selected RA. In some embodiments, R2is phenyl substituted with 1 independently selected RA. In some embodiments, R2is phenyl substituted with 1 RA. In some embodiments, R2is . In some embodiments, R2is unsubstituted phenyl. In some embodiments, R2is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA. In some embodiments, R2is 5-10 membered heteroaryl substituted with 1-3 independently selected RA. In some embodiments, R2is 5-10 membered heteroaryl substituted with 3 independently selected RA. In some embodiments, R2is 5-10 membered heteroaryl substituted with 2 independently selected RA. In some embodiments, R2is 5-10 membered heteroaryl substituted with 1 RA. In some embodiments, R2is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R2is 5-6 membered heteroaryl optionally substituted with 1-3 independently selected RA. In some embodiments, R2is 5-6 membered heteroaryl substituted with 1-3 independently selected RA. In some embodiments, R2is 5-6 membered heteroaryl substituted with 3 independently selected RA. In some embodiments, R2is 5-6 membered heteroaryl substituted with 2 independently selected RA. In some embodiments, R2is 5-6 membered heteroaryl substituted with 1 RA. In some embodiments, R2is an unsubstituted 5-6 membered heteroaryl. In some embodiments, R2is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each optionally substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each substituted with 3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each substituted with 2 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each substituted with 1 RA. In some embodiments, R2is selected from the group consisting of unsubstituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R2is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl; each optionally substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl; each substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl; each substituted with 3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl; each substituted with 2 independently selected RA. In some embodiments, R2is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl; each substituted with 1 RA. In some embodiments, R2is selected from the group consisting of an unsubstituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. In some embodiments, R2is selected from the group consisting of pyridyl, pyrazolyl, and thiazolyl; each optionally substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridyl, pyrazolyl, and thiazolyl; each substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridyl, pyrazolyl, and thiazolyl; each substituted with 3 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridyl, pyrazolyl, and thiazolyl; each substituted with 2 independently selected RA. In some embodiments, R2is selected from the group consisting of pyridyl, pyrazolyl, and thiazolyl; each substituted with 1 RA. In some embodiments, R2is selected from the group consisting of unsubstituted pyridyl, pyrazolyl, and thiazolyl. In some embodiments, R2is selected from the group consisting of 2-pyridyl, 2-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl; each optionally substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of 2-pyridyl, 2-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl; each substituted with 1-3 independently selected RA. In some embodiments, R2is selected from the group consisting of 2-pyridyl, 2-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl; each substituted with 3 independently selected RA. In some embodiments, R2is selected from the group consisting of 2-pyridyl, 2-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl; each substituted with 2 independently selected RA. In some embodiments, R2is selected from the group consisting of 2-pyridyl, 2-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl; each substituted with 1 RA. In some embodiments, R2is selected from the group consisting of unsubstituted 2-pyridyl, 2-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl. In some embodiments, R2is 2-pyridyl optionally substituted with 1-3 independently selected RA. In some embodiments, R2is 2-pyridyl substituted with 1-3 independently selected RA. In some embodiments, R2is 2-pyridyl substituted with 3 independently selected RA. In some embodiments, R2is 2-pyridyl substituted with 2 independently selected RA. In some embodiments, R2is selected from the group consisting of, , , , wherein RA’is independently selected fA rom R . In some embodiments, R2is 2-pyridyl substituted with 2 RA. In some embodiments, R2is selected from the group consisting of , , , In some embodiments, R2is . In some embodiments, R2is 2-thiazolyl optionally substituted with 1-2 independently selected RA. In some embodiments, R2is 2-thiazolyl substituted with 1-2 independently selected RA. In some embodiments, R2is 2-thiazolyl substituted with 2 independently selected RA. In some embodiments, R2is 2-thiazolyl substituted with 1 RA. In some embodiments, R2is or . In some embodiments, R2is unsubstituted 2-thiazolyl. In some embodiments, R2is 3-pyrazolyl optionally substituted with 1-3 independently selected RA. In some embodiments, R2is 3-pyrazolyl substituted with 1-3 independently selected RA. In some embodiments, R2is 3-pyrazolyl substituted with 3 independently selected RA. In some embodiments, R2is 3-pyrazolyl substituted with 2 independently selected RA. In some embodiments, R2is selected from the group consisting of wherein RA’is independently selected from RA. In some embodiments, R2is 3-pyrazolyl substituted with 1 RA. In some embodiments, R2is selected from the group consisting of , , , and In some embodiments, R2is In some embodiments, R2is 4-pyrazolyl optionally substituted with 1-3 independently selected RA. In some embodiments, R2is 4-pyrazolyl substituted with 1-3 independently selected RA. In some embodiments, R2is 4-pyrazolyl substituted with 3 independently selected RA. In some embodiments, R2is 4-pyrazolyl substituted with 2 independently selected RA. In some embodiments, R2is selected from the group consisting of , and , wherein RA’is independently selected from RA. In some embodiments, R2is 4-pyrazolyl substituted with 1 RA. In some embodiments, R2is or In some embodiments, R2is In some embodiments, R2is 5-10 membered heterocyclyl optionally substituted with 1-3 independently selected RA. In some embodiments, R2is 5-10 membered heterocyclyl substituted with 1-3 independently selected RA. In some embodiments, R2is 5-10 membered heterocyclyl substituted with 3 independently selected RA. In some embodiments, R2is 5-10 membered heterocyclyl substituted with 2 independently selected RA. In some embodiments, R2is 5-10 membered heterocyclyl substituted with 1 RA. In some embodiments, R2is an unsubstituted 5-10 membered heterocyclyl. In some embodiments, one RAis halogen or cyano. In some embodiments, one RAis halogen. In some embodiments, one RAis cyano. In some embodiments, one RAis –NRDRE. In some embodiments, one RAis C1-C6 alkyl optionally substituted with hydroxyl, –NRBRC, –C(=O)NRBRC, or –NH(C=O)NH2. In some embodiments, one RAis unsubstituted C1-C6 alkyl. In some embodiments, one RAis C1-C6 alkyl substituted with hydroxyl. In some embodiments, one RAis C1-C6 alkyl substituted with –NRBRC. In some embodiments, one RAis CH2NRBCH3; wherein RBis hydrogen or methyl. In some embodiments, one RAis CH2N(CH3)2. In some embodiments, one RAis CH2NHCH3. In some embodiments, one RAis C1-C6 alkyl substituted with –C(=O)NRARB. In some embodiments, one RAis C1-C6 alkyl substituted with ––NH(C=O)NH2. In some embodiments, one RAis –CH3. In some embodiments, one RAis –C(=O)NRBRC. In some embodiments, one RAis –C(=O)NRBCH3; wherein RBis hydrogen or methyl. In some embodiments, one RAis -C(=O)N(CH3)2. In some embodiments, one RAis methyl. In some embodiments, one RAis –N=S(O)Me2. In some embodiments, one RAis 4-6 membered heterocyclyl optionally substituted with halogen, hydroxyl, or C1-C6 alkyl optionally substituted with –NRBRC. In some embodiments, one RAis 4-6 membered heterocyclyl substituted with halogen, hydroxyl, or C1-C6 alkyl optionally substituted with –NRBRC. In some embodiments, one RAis 4-6 membered heterocyclyl substituted with halogen. In some embodiments, one RAis 4-6 membered heterocyclyl substituted with hydroxyl. In some embodiments, one RAis 4-6 membered heterocyclyl substituted with C1-C6 alkyl optionally substituted with –NRBRC. In some embodiments, one RAis 4-6 membered heterocyclyl substituted with unsubstituted C1-C6 alkyl. In some embodiments, one RAis 4-6 membered heterocyclyl substituted with C1-C6 alkyl substituted with –NRBRC. In some embodiments, one RAis selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, sulfolanyl, isothiazoline S,S-dioxidyl, pyrrolidinyl, pyrrolidinonyl, and oxazolidinonyl; each optionally substituted with C1-C6 alkyl. In some embodiments, one RAis selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, and oxazolidinonyl; each optionally substituted with C1-C6 alkyl. In some embodiments, one RAis selected from the group consisting of In some embodiments, one RAis . In some embodiments, one RAis . In some embodiments, one RAis . In some embodiments, one RAis . In some embodiments, one RAisA In some embodiments, one R is . In some embodiments, one RAis . In some embodiments, oA ne R is . In some embodiments, one RAis In some embodiments, one RAis C3-C6 cycloalkyl optionally substituted with –NRBRC. In some embodiments, one RAis C3-C6 cycloalkyl substituted with –NRBRC. In some embodiments, one RAis unsubstituted C3-C6 cycloalkyl. In some embodiments, R2is selected from the group consisting of and In some embodiments, R2is In2 some embodiments, R is In some embodiments,2 2 R is . In some embodiments, R is In some embodiments, R2is2 . In some embodiments, R is . In some embodiments, R2is . In some embodiments, R2is . In some embodiments, R2is . In some embodiments, R2is . In some embodiments, R2is . In some embodiments, R2is In some embodiments, R2is unsubstituted 2-pyridyl, 1-thiazolyl, 3-pyrazolyl, or 4-pyrazolyl. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is methyl. In some embodiments, R4is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 alkyl, -(C1-C6 alkyl)n-C(=O)NRFRK, C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, and 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, when R4is substituted with two substituents, those two substituents are not the same. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is halogen. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is cyano. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is -SO2(C1-C6 alkyl). In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is -SO2(methyl). In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is C1-C6 alkyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is methyl. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is methyl; and the other substituent is not a C1-C6 alkyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is -(C1-C6 alkyl)n-C(=O)NRFRK. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, RFand RKare the same. In some embodiments, RFand RKare different. In some embodiments, RFand RKare both hydrogen. In some embodiments, RFand RKare both C1-C6 alkyl. In some embodiments, RFand RKare both methyl. In some embodiments, one of RFand RKis hydrogen and the other of RFand RKis C1-C6 alkyl. In some embodiments, one of RFand RKis hydrogen and the other of RFand RKis methyl. In some embodiments, one RFand one RK, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, one RFand one RK, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, one RFand one RK, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclyl substituted with methyl. In some embodiments, one RFand one RK, together with the nitrogen atom to which they are attached, form an unsubstituted 4-8 membered heterocyclyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is C3-C6 cycloalkyl substituted with methyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is unsubstituted C3-C6 cycloalkyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-12 membered heterocyclyl substituted with 1 or 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-12 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-12 membered heterocyclyl substituted with 1 RG. In some embodiments, R4is phenyl substituted with 4-12 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, R4is phenyl substituted with 4-12 membered heterocyclyl substituted with 1 RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is an unsubstituted 4-12 membered heterocyclyl. In some embodiments, R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is 4-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-6 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is 4-6 membered heterocyclyl substituted with 1 RG. In some embodiments, R4is phenyl substituted with 4-6 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, R4is phenyl substituted with 4-6 membered heterocyclyl substituted with 1 RG. In some embodiments, R4is phenyl substituted with 2 substituents; wherein one substituent is an unsubstituted 4-6 membered heterocyclyl. In some embodiments, one RGis halogen, e.g., chloro or fluoro. In some embodiments, one RGis C1-C6 alkyl. In some embodiments, one RGis methyl. In some embodiments, one RGis C1-C6 deuteroalkyl. In some embodiments, one RGis –CH2D, –CHD2, or –CD3. In some embodiments, one RGis –NRBRC, where RBand RCare as defined herein. In some embodiments, one RGis C3-C6 cycloalkyl. In some embodiments, one RGis C3-C4 cycloalkyl. In some embodiments, one RGis =NRH. In some embodiments, RHis hydrogen. In some embodiments, RHis C1-C6 alkyl. In some embodiments, RHis methyl. In some embodiments, R4is phenyl substituted with 4-6 membered heterocyclyl optionally substituted with amino, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R4is phenyl substituted with 4-6 membered heterocyclyl substituted with amino, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R4is phenyl substituted with 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R4is phenyl substituted with 5-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R4is phenyl substituted with 5-6 membered heterocyclyl substituted with methyl. In some embodiments, R4is phenyl substituted with 5-6 membered heterocyclyl substituted with 2 independently selected C1-C6 alkyl. In some embodiments, R4is phenyl substituted with 5-6 membered heterocyclyl substituted with 2 methyls. In some embodiments of this paragraph, the R4phenyl is further substituted with methyl. In some embodiments, R4is phenyl substituted with C1-C6 alkyl and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R4is phenyl substituted with C1-C6 alkyl and 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R4is phenyl substituted with methyl and 4-6 membered heterocyclyl optionally substituted with methyl. In some embodiments where R4is substituted with two independently selected RG, the RGare the same. In some embodiments where R4is substituted with two independently selected RG, the RGare different. In some embodiments, R4is phenyl substituted with one of . In some embodiments, the R4phenyl is also substituted with methyl. In some embodiments, R4is selected from the group consisting of . In some embodiments, R4is 9-12 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl. In some embodiments, R4is 9-12 membered heterocyclyl substituted with 3 independently selected C1-C6 alkyl. In some embodiments, R4is 9-12 membered heterocyclyl substituted with 1 or 2 independently selected C1-C6 alkyl. In some embodiments, R4is 9-12 membered heterocyclyl substituted with 2 independently selected C1-C6 alkyl. In some embodiments, R4is 9-12 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, the 9-12 membered heterocyclyl of R4is a fused 9-10 membered heterocyclyl. In some embodiments, the 9-12 membered heterocyclyl of R4is a spiro 9-10 membered heterocyclyl. In some embodiments, R4is ; wherein Ring B is 5-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl. In some embodiments, Ring B is 5-6 membered heterocyclyl substituted with 1-3 independently selected C1-C6 alkyl. In some embodiments, Ring B is 5-6 membered heterocyclyl substituted with 3 independently selected C1-C6 alkyl. In some embodiments, Ring B is 5-6 membered heterocyclyl substituted with 2 independently selected C1-C6 alkyl. In some embodiments, Ring B is 5-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, Ring B is 5-6 membered heterocyclyl substituted with one or two methyls. In some embodiments, Ring B is selected from the group consisting of piperidinyl and pyrrolidinonyl, each optionally substituted with C1-C6 alkyl. In some embodiments, R4is or . In some embodiments, R4is 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino. In some embodiments, R4is 5-10 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R4is 5-10 membered heteroaryl substituted with methyl. In some embodiments, R4is 5-10 membered heteroaryl substituted with 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino. In some embodiments, R4is 5-10 membered heteroaryl substituted with 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R4is 5-10 membered heteroaryl substituted with 4-12 membered heterocyclyl optionally substituted with methyl. In some embodiments, R4is 5-10 membered heteroaryl substituted with 4-12 membered heterocyclyl optionally substituted with amino. In some embodiments, R4is 5-10 membered heteroaryl substituted with C1-C6 alkyl and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino. In some embodiments, R4is 5-10 membered heteroaryl substituted with an unsubstituted 4-12 membered heterocyclyl. In some embodiments, R4is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each optionally substituted with methyl. In some embodiments, R4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each optionally substituted with 4-12 membered heterocyclyl optionally substituted with methyl. In some embodiments, R4is pyrazolyl. In some embodiments, R4is selected from the group consisting of In some embodiments, R5is hydrogen. In some embodiments, R5is halogen, such as fluoro or chloro. In some embodiments, R5is C1-C6 alkyl. In some embodiments, R5is methyl. In some embodiments, R6Aand R6Bare independently selected C1-C6 alkyl optionally substituted with one hydroxyl. In some embodiments, R6Aand R6Bare both independently selected C1-C3 alkyl substituted with one hydroxyl. In some embodiments, R6Aand R6Bare both –CH2OH. In some embodiments, one of R6Aand R6Bis methyl and the other of R6Aand R6Bis –CH2OH. In some embodiments, R6Aand R6Bare independently C1-C6 alkyl substituted with one C1-C6 alkoxy. In some embodiments, R6Aand R6Bare independently C1-C3 alkyl substituted with one C1-C3 alkoxy. In some embodiments, R6Aand R6Bare both –CH2OCH3. In some embodiments, one of R6Aand R6Bis methyl and the other of R6Aand R6Bis –CH2OCH3. In some embodiments, R6Aand R6Bare the same. In some embodiments, R6Aand R6Bare different. In some embodiments, one of R6Aand R6Bis unsubstituted C1-C3 alkyl, and the other of R6Aand R6Bis C1-C3 alkyl substituted with hydroxyl or methoxy. In some embodiments, RBis hydrogen. In some embodiments, RBis C1-C6 alkyl. In some embodiments, RBis C1-C3 alkyl. In some embodiments, RBis methyl. In some embodiments, RCis hydrogen. In some embodiments, RCis C1-C6 alkyl. In some embodiments, RCis C1-C3 alkyl. In some embodiments, RCis methyl. In some embodiments, RBand RCare the same. In some embodiments RBand RCare different. In some embodiments, RDis hydrogen. In some embodiments, RDis C1-C6 alkyl. In some embodiments, RDis C1-C3 alkyl. In some embodiments, RDis methyl. In some embodiments, REis hydrogen. In some embodiments, REis C1-C6 alkyl. In some embodiments, REis C1-C3 alkyl. In some embodiments, REis methyl. In some embodiments, REis C3-C6 cycloalkyl optionally substituted with hydroxyl. In some embodiments, REis C3-C6 cycloalkyl substituted with hydroxyl. In some embodiments, REis unsubstituted C3-C6 cycloalkyl. In some embodiments, RDand REare the same. In some embodiments RDand REare different. In some embodiments, R1Ais hydrogen; R1Bis hydrogen; R3is hydrogen; and R5is hydrogen, fluoro, or methyl. In some embodiments, R1Ais hydrogen; R1Bis hydrogen; R3is hydrogen; and R5is hydrogen, fluoro, or methyl; and R2is phenyl substituted with one RAor 5-6 membered heteroaryl substituted with 1 RA. In some embodiments, R1Ais hydrogen; R1Bis hydrogen; R3is hydrogen; and R5is hydrogen, fluoro, or methyl; and R6Ais unsubstituted C1-C6 alkyl; and R6Bis C1-C3 alkyl substituted with hydroxyl, C1-C3 alkoxy, or C1-C3 haloalkoxy. In some embodiments, the compound of Formula (I) has the structure: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has the structure: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has the structure: or or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has the structure: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2. In some embodiments of Formula (I-A), p is 0. In some embodiments of Formula (I-A), p is 1. In some embodiments of Formula (I-A), p is 2. In some embodiments, the compound of Formula (I) is a compound of Formula (I-B): or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (I-B), R4is phenyl, wherein the phenyl is substituted with a 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, and the phenyl of R4is also optionally substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is phenyl, wherein the phenyl is substituted with a 4-10 membered heterocyclyl substituted with C1-C6 alkyl, and the phenyl of R4is also optionally substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is phenyl, wherein the phenyl is substituted with an unsubstituted 4-10 membered heterocyclyl, and the phenyl of R4is also optionally substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is substituted with a 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, and the 5-6 membered heteroaryl of R4is also optionally substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is substituted with a 4-10 membered heterocyclyl substituted with C1-C6 alkyl, and the 5-6 membered heteroaryl of R4is also optionally substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is substituted with an unsubstituted 4-10 membered heterocyclyl, and the 5-6 membered heteroaryl of R4is also optionally substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is 6-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is 6-10 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments of Formula (I-B), R4is 6-10 membered heterocyclyl substituted with methyl. In some embodiments of Formula (I-B), R4is an unsubstituted 6-10 membered heterocyclyl. In some embodiments, the compound of Formula (I) is present in the form of a pharmaceutically acceptable salt. In some embodiments, the compound of Formula (I) is present in the form of a free base. In some embodiments, the compound is selected from the group consisting of the compounds in Table 1, and pharmaceutically acceptable salts thereof. Table 1. Exemplary Compounds of Formula (I)

[0002] In some embodiments, the compound is selected from the group consisting of the compounds in Table 2, and pharmaceutically acceptable salts thereof. Table 2. Exemplary Compounds of Formula (I)

[0003]

[0004]

[0005]

[0006] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the compounds in Table 1 or Table 2, or a pharmaceutically acceptable salt of either of the foregoing. Methods of Treatment Also provided herein are methods of treating cancer in a subject with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Replication stress is present in many cancers, and as noted herein, it can in some cases be exacerbated by one or more factors, such as genetic features of the cancer and / or administration of DNA-damaging agents, DNA repair inhibiting agents, and / or radiation. Accordingly, provided herein is a method of treating a cancer in a subject in need thereof, the method including identifying the cancer as having replication stress; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Identifying the cancer as having replication stress can include any appropriate method of identification, such as the methods described herein. For example, in some embodiments, identifying the cancer as having replication stress includes staining for replication forks in a sample from the subject. In some embodiments, identifying the cancer as having replication stress includes detecting a biomarker of replication stress in a sample from the subject. A biomarker of replication stress can include any appropriate biomarker or set of biomarkers. In some embodiments, a biomarker of replication stress includes Ki-67, Cyclin E, POLD3, γH2AX, FANCD2, or a combination thereof. In some embodiments, a biomarker of replication stress includes pH2AX Ser139, pATR Thr1989, pCHK1 Ser345, pRPA32 Ser33, or a combination thereof. In some embodiments, a biomarker of replication stress includes an activated oncogene. In some embodiments, a biomarker of replication stress includes an inactivated tumor suppressor gene. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having replication stress. In some cases, a genetic characteristic of a cancer can be indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Some such genetic characteristics include one or more inactivated tumor suppressor genes and / or one or more activated oncogenes. Accordingly, also provided herein is a method of treating a cancer in a subject in need thereof, the method including: identifying the cancer as having an inactivated tumor suppressor gene; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method including administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having an inactivated tumor suppressor gene. An inactivation of a tumor suppressor gene can be achieved by any appropriate mechanism, such as those described herein. In some embodiments, an inactivated tumor suppressor gene includes an inactivation selected from the group consisting of a deletion of the gene, an inactivating mutation in the protein product of the gene, an inactivating translocation in the protein product of the gene, a transcriptional silencing of the gene, an epigenetic alteration of the gene, degradation of mRNA products of the gene, degradation of protein products of the gene, and combinations thereof. An inactive tumor suppressor gene can be any appropriate inactivated tumor suppressor gene, such as any of those described herein. In some embodiments, the tumor suppressor gene is selected from the group consisting of p53, RB1, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1, and a combination thereof. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a p53 gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted p53 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a CDKN2A gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a RB1 gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene includes a BRCA1 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene includes a deleted BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene includes a BRCA2 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a SETD2 gene. In some embodiments, the inactivated tumor suppressor gene is selected from the group consisting of a mutation in the protein product of a p53 gene, a deleted p53 gene, a mutation in the protein product of a CDKN2A gene, a mutation in the protein product of a NOTCH1 gene, a deleted FBXW7 gene, a mutation in the protein product of a FBXW7 gene, a mutation in the protein product of a RB1 gene, a deleted BRCA1 gene, a mutation in the protein product of a BRCA1 gene, a BRCA1 gene with a hypermethylated promoter region, a deleted BRCA2 gene, a mutation in the protein product of a BRCA2 gene, a BRCA2 gene with a hypermethylated promoter region, a mutation in the protein product of a NOTCH1 gene, a mutation in the protein product of a SETD2 gene, and a combination thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method including: identifying the cancer as having an activated oncogene; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method including administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having an activated oncogene. An activation of an oncogene can be achieved by any appropriate mechanism, such as those described herein For example, in some embodiments, the activated oncogene has an activation selected from the group consisting of an amplification of the oncogene, an activating mutation of the protein product of the oncogene, an activating translocation of the protein product of the oncogene, transcriptional activation of the oncogene, epigenetic alteration of the oncogene, overexpression of the protein product of the oncogene, and combinations thereof. An activated oncogene can be any appropriate oncogene, such as those described herein. In some embodiments, the oncogene is selected from the group consisting of cyclin E, CDC25A, Myc, a RAS gene, and combinations thereof. In some embodiments, RAS gene includes a KRAS gene. In some embodiments, the RAS gene includes an NRAS gene. In some embodiments, the RAS gene includes an HRAS gene. In some embodiments, the activated oncogene includes an amplified cyclin E gene. In some embodiments, the activated oncogene includes an overexpression of the protein product of the CDC25A gene. In some embodiments, the activated oncogene includes an amplified Myc gene. In some embodiments, the activated oncogene includes an activating translocation in the protein product of a Myc gene. In some embodiments, the activated oncogene includes a transcriptionally activated Myc gene. In some embodiments, the activated oncogene includes a mutation in the protein product of a RAS gene. In some embodiments, the mutated RAS gene includes a mutation at position G12 of the protein product of the RAS gene. In some embodiments, the mutated RAS gene includes a mutation at position G13 of the protein product of the RAS gene. In some embodiments, wherein the mutated RAS gene includes a mutation at position Q61 of the protein product of the RAS gene. In some embodiments, the RAS gene includes a KRAS gene. In some embodiments, the activated oncogene is selected from the group consisting of an amplified cyclin E gene, an overexpression of the protein product of the CDC25A gene, an amplified Myc gene, an activating translocation in the protein product of a Myc gene, a transcriptionally activated Myc gene, a mutation in the protein product of a RAS gene, and a combination thereof. In some embodiments, the mutated RAS gene includes a mutation at position G12, G13, Q61, or a combination thereof, of the protein product of the RAS gene. In some embodiments, the RAS gene includes a KRAS gene. In some embodiments, the compounds of the present disclosure are particularly useful wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung. In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or a pharmaceutically acceptable salt thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy. In some embodiments of any of the methods described herein, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with an effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic or immunomodulatory) agents. Non-limiting examples of additional therapeutic agents include: PARP inhibitors, other DNA repair inhibiting agents (e.g. topoisomerase inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, ATM inhibitors, Aurora kinase inhibitors (such as Aurora A and / or Aurora B inhibitors), ATR inhibitors, and CHK1 inhibitors), signal transduction pathway inhibitors, Bcr- Abl inhibitors, histone deacetylase (HDAC) inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune- targeted agents, including immunotherapy, and radiotherapy. In some embodiments, the additional therapeutic agent is an immunotherapy. Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab. In some embodiments, cytotoxic chemotherapeutics are selected from bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, paclitaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine. Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab. In some embodiments, a DNA repair inhibiting agent can include a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA-dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitor, an Aurora kinase inhibitor (such as an Aurora A and / or B inhibitor), or a combination thereof. Non-limiting examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and veliparib. Non-limiting examples of ATR inhibitors include AZD6738, BAY1895344, and M6620. Non-limiting examples of Chk1 inhibitors include prexasertib, GDC-0575, SCH 900776, and SRA737. Non-limiting examples of DNA-PK inhibitors include AZD7648, M3814, LY294002, nedisertib, and samotolisib. Non-limiting examples of ATM inhibitors include KU55933, AZD0156, AZD1390, dactosilib, and berzosertib. Non-limiting examples of Aurora kinase inhibitors include LY3295668, ZM447439, tozasertib, hesparadin, alisertib, and MLN8054. Non-limiting examples of modulators of the apoptosis pathway include Bcl-2 inhibitors such as obataclax, venetoclax, and navitoclax. In some embodiments, signal transduction pathway inhibitors include Ras-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib) or PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., sirolimus, everolimus, rapamycin, perifosine, temsirolimus). Non-limiting examples of Bcr-Abl inhibitors include imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib. Non-limiting examples of HDAC inhibitors include pabinostat, vorinostat, belinostat, panobinostat, entinostat, tacedinaline, and mocetinostat. Non-limiting examples of platinum-based chemotherapeutics include carboplatin, cisplatin, and oxaplatin. Non-limiting examples of alkylating agents include cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, and mitomycin C. Non-limiting examples of nucleobase, nucleoside, and / or nucleotide analogs include fluorouracil, cytarabine, gemcitabine, azacitidine, and decitabine. Non-limiting examples of topoisomerase I inhibitors include topotecan, irinotecan, belotecan, and camptothecin. Non-limiting examples of topoisomerase II inhibitors include etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, and idarubacin. The term “immunotherapy” refers to an agent that modulates the immune system. In some embodiments, an immunotherapy can increase the expression and / or activity of a regulator of the immune system. In some embodiments, an immunotherapy can decrease the expression and / or activity of a regulator of the immune system. In some embodiments, an immunotherapy can recruit and / or enhance the activity of an immune cell. In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101- 108). In some embodiments, the cellular immunotherapy includes cells that express a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is a CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah™). In some embodiments, the immunotherapy is an antibody therapy (e.g., a monoclonal antibody, a conjugated antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™), cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab or amatuximab. In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-1; Kadcyla®), mirvetuximab soravtansine (IMGN853) or anetumab ravtansine In some embodiments, the immunotherapy includes blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt). In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®). In some embodiments, the immunotherapy is a cytokine therapy. In some embodiments, the cytokine therapy is an interleukin 2 (IL-2) therapy, an interferon alpha (IFNα) therapy, a granulocyte colony stimulating factor (G-CSF) therapy, an interleukin 12 (IL-12) therapy, an interleukin 15 (IL-15) therapy, an interleukin 7 (IL-7) therapy or an erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNα therapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®). In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy includes one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (Imfinzi™). Non-limiting examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy. In some embodiments, the one or more additional therapies or therapeutic agents are selected from cytarabine, fludarabine, cisplatin, carboplatin, docetaxel, gemcitabine, belinostat, radiotherapy, irinotecan, olaparib, pemetrexed, savolitinib, and temozolomide. In some cases, a cancer having replication stress and / or including a genetic characteristic indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof can be treated with a combination of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and another agent that promotes genomic instability, such as a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof. Accordingly, in some embodiments, the methods described herein can further include administering to the subject a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof. In some cases, identification of replication stress might not be carried out on the cancer or might not be able to be carried out on a cancer. In some cases, genetic analysis might not be carried out on the cancer or might not be able to be carried out on a cancer. In some cases, a cancer might be negative for a genetic characteristic of a cancer can be indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. However, many first-line treatment regimens for cancer include a DNA-damaging agent, a DNA repair inhibiting agent, or a combination thereof. In some such cases, a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof can still be indicated for treatment with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof, as the combination of factors can promote mitotic collapse, thereby treating the cancer. Accordingly, provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: (i) administering to the subject an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation; and (ii) after (i), administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject previously administered one or more doses of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation. In some embodiments, the therapy (e.g., of (a) to (g)) is continued to be administered to the subject as combination therapy with the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject: (i) an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof; and (ii) an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation. In some embodiments, the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and the therapy (e.g., of (a) to (g)) are administered simultaneously as separate dosages. In some embodiments, the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and the therapy (e.g., of (a) to (g)) are administered separate dosages sequentially in any order. A DNA-damaging agent can be any appropriate DNA-damaging agent, such as those described herein. In some embodiments, the DNA-damaging agent is selected from the group consisting of a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, or nucleotide analog, and combinations thereof. In some embodiments, the platinum-based chemotherapy comprises carboplatin, cisplatin, oxaplatin, or a combination thereof. In some embodiments, the alkylating agent comprises cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, mitomycin C, or combinations thereof. In some embodiments, the nucleobase, nucleoside, or nucleotide analog comprises fluorouracil, cytarabine, gemcitabine, azacitidine, decitabine, or combinations thereof. A DNA repair inhibiting agent can be any appropriate DNA repair inhibiting agent, such as those described herein. In some embodiments, the DNA repair inhibiting agent is selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA-dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitors, an Aurora kinase inhibitor (such as Aurora A and / or Aurora B inhibitors), and a combination thereof. In some embodiments, the topoisomerase I inhibitor comprises topotecan, irinotecan, belotecan, camptothecin, or combinations thereof. In some embodiments, the topoisomerase II inhibitor comprises etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or combinations thereof. In some embodiments, the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, veliparib, or combinations thereof. In some embodiments, the ATR inhibitor comprises AZD6738, BAY1895344, M6620, or a combination thereof. In some embodiments, the Chk1 inhibitor comprises prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof. In some embodiments, the DNA-PK inhibitor comprises AZD7648, M3814, LY294002, nedisertib, samotolisib, or combinations thereof. In some embodiments, the ATM inhibitor comprises KU55933, AZD0156, AZD1390, dactosilib, berzosertib, or combinations thereof. In some embodiments, the Aurora kinase inhibitor comprises LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, or combinations thereof. In some embodiments, the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, camptothecin, or a combination thereof. In some embodiments, the topoisomerase II inhibitor is etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or a combination thereof. In some embodiments, the PARP inhibitor is olaparib, niraparib, rucaparib, talazoparib, veliparib, or a combination thereof. In some embodiments, the ATR inhibitor is AZD6738, BAY1895344, M6620, or a combination thereof. In some embodiments, the Chk1 inhibitor is prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof. In some embodiments, the DNA-PK inhibitor is AZD7648, M3814, LY294002, nedisertib, samotolisib, or a combination thereof. In some embodiments, the ATM inhibitor is KU55933, AZD0156, AZD1390, dactosilib, berzosertib, or a combination thereof. In some embodiments, the Aurora kinase inhibitor is LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, or a combination thereof. Also provided herein is a method for treating a subject diagnosed with or identified as having a cancer associated with replication stress, e.g., any of the exemplary cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising: determining that the cancer is associated with replication stress; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer associated with replication stress. In some embodiments of any of the methods described herein, the method further includes administering an additional therapy or therapeutic agent to the subject. An additional therapy or therapeutic agent can be any appropriate therapy or therapeutic agent. In some embodiments, the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, angiogenesis-targeted therapies, and combinations thereof. In some embodiments, the additional therapy or therapeutic agent is selected from kinase-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, angiogenesis-targeted therapies, and combinations thereof. In some embodiments, the additional therapy or therapeutic agent is an immune-targeted therapy. In some embodiments, the immune-targeted therapy is an immunotherapy. Also provided herein is a method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutical salt thereof. Also provided herein is a method for inducing mitotic collapse in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutical salt thereof. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. A mammalian cell can be any appropriate species or type of cell. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian cancer cell having replicative stress. In some embodiments, the mammalian cancer cell has an inactivated tumor suppressor gene. In some embodiments, the mammalian cancer cell has an activated oncogene. In some embodiments, the method further includes contacting the mammalian cell with a DNA-damaging agent, a DNA repair inhibitor, radiation, or a combination thereof. Also provided herein is use of a compound of Formula (I), or a pharmaceutical salt thereof in the manufacture of a medicament for the treatment of cancer. In some embodiments, the cancer is a cancer having replication stress. In some embodiments, the cancer is a cancer having an inactivated tumor suppressor gene. In some embodiments, the cancer is a cancer having an activated oncogene. In some embodiments, the medicament is labeled for concurrent use with a DNA-damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof. In some embodiments, the medicament is labeled for use subsequent to a DNA-damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof. In some embodiments of any of the methods or uses described herein, the cancer is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer is small cell lung cancer, ovarian cancer, solid tumors with BRCA mutations, head and neck cancer squamous cell carcinoma, adenocarcinoma of the pancreas, acute myeloid leukemia, osteosarcoma, multiple myeloma, epithelial ovarian cancers, triple negative breast cancer, cervical cancer, mantle cell lymphoma and diffuse large B-cell lymphoma, laryngeal squamous cell carcinoma, basal-like breast cancer, medulloblastoma, oropharyngeal cancers, sarcoma, kidney cancer, clear cell renal cell carcinoma, acute lymphoblastic leukemia, pediatric gliomas, head and neck precancer, Ewing sarcoma, gastrointestinal stromal tumors, giant cell tumor of bone, clear cell ovarian cancer, mucinous ovarian cancer, primary peritoneal carcinoma, serous surface papillary carcinoma, teratoma, dysgerminoma, endodermal sinus tumors, choriocarcinomas, granulosa cell tumors, granulosa-theca tumors, sertoli-leydig cell tumors, endometrial adenocarcinoma, adenosquamous carcinoma, papillary serous carcinoma, and uterine sarcoma. In some embodiments, the subject is a human. In some embodiments of any of the methods described herein, a compound of Formula (I) is selected from Examples 1-92, or a pharmaceutically acceptable salt thereof. Also provided is a method for inhibiting Wee1 kinase activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell having Wee1 kinase activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a mammalian cancer cell having replication stress. Also provided is a method for inhibiting Wee1 kinase activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a mammal having a mammalian cell having Wee1 kinase activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a mammalian cancer cell with replication stress. In some embodiments, the mammalian cell is a gastrointestinal mammalian cell. In some embodiments, the mammalian cell is a hematological mammalian cell. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a Wee1 kinase with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a Wee1 kinase, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the Wee1 kinase. Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, the method comprising contacting a mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. A “Wee1 kinase inhibitor” as defined herein includes any compound exhibiting Wee1 inhibition activity. In some embodiments, a Wee1 kinase inhibitor is selective for a Wee1 kinase. Exemplary Wee1 kinase inhibitors can exhibit inhibition activity (IC50) against a Wee1 kinase of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a Wee1 kinase inhibitor can exhibit inhibition activity (IC50) against a Wee1 kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein. The phrase “effective amount” means an amount of compound that, when administered to a subject in need thereof, is sufficient to (i) treat a cancer (such as cancer associated with replication stress as described herein), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer, or (iii) delay the onset of one or more symptoms of the particular cancer described herein. The amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art. When employed as pharmaceuticals, compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Also provided herein are pharmaceutical compositions which contain, as the active ingredient, a compound of Formula (I) or pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule. Further provided herein are pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient can be prepared by intimately mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition. Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Solid oral preparations can also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients can be added to increase solubility or preservation. Injectable suspensions or solutions can also be prepared utilizing aqueous carriers along with appropriate additives. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described herein. The compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein. The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will be understood, therefore, that the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages. In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. One skilled in the art will recognize that both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder. One skilled in the art will further recognize that human clinical trials including first-in- human, dose ranging and efficacy trials, in healthy subjects and / or those suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts. f Provided herein are pharmaceutical kits useful, for example, in the treatment of cancer (such as replication sensitive cancers), which include one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0007] Preparation of Compounds

[0008] As disclosed herein, many of the starting materials used are commercially available or can be prepared using the routes described below using techniques known to those skilled in the art.

[0009] General Schemes

[0010] Compounds of Formula (I) can be prepared as described in the Schemes below.

[0011] Starting material dihydro-pyrrolo pyrimidines of type 1b used in Scheme 2 were prepared via the route depicted in Scheme 1:

[0012] General Procedure for Scheme 1

[0013] Hydroxy amino-pyrimidines of type la wweerree prepared from 2-(4-amino-2- (methylthio)pyrimidin-5-yl)-3-methoxy-2-methylpropan-1-ol (Intermediate 1) via metal- catalyzed coupling reaction with a suitable R2-substituted heteroaryl halide in the presence of an appropriate metal catalyst (such as Cui, XantPhos-Pd-G2and the like), an appropriate ligand (such as DMEDA, XantPhos and the like), and an appropriate base (such as CS2CO3and the like).

[0014] Intramolecular Mitsunobu reaction of the respective hydroxy amino-pyrimidines of type la to provide bicyclic dihydro-pyrrolopyrimidines of type lb could be accomplished in the

[0015] SUBSTITUTE SHEET presence of an appropriate azodicarboxylate (such as DIAD and the like) and a suitable phosphine (such as PPh3and the like) in a suitable organic solvent (such as THF and the like).

[0016] General Procedure for Scheme 2

[0017] Pyrimidine sulfoxides of type 2a were prepared from bicyclic dihydro-pyrrolopyrimidines of type 1b by reaction with suitable oxidative regents (where [Ox] represents m-CPBA and the like) in a suitable organic solvent (such as toluene and the like).

[0018] Compounds of 2b representative of a compounds Formula (I) were prepared from the respective pyrimidine sulfoxides of type 2a through reaction with an optionally substituted anilines HNR3R4and an appropriate base (such as DIPEA and the like) in a suitable organic solvent (such as toluene and the like).

[0019] General Procedure for Scheme 3

[0020] Bicyclic dihydro-pyrrolopyrimidines of type 3b are prepared from the respective pyrimidine esters of type 3a through reduction with a suitable reducing reagent, such as Red-Al

[0021] SUBSTITUTE SHEET and the like followed by protection of the primary alcohol with a suitable silyl protecting group (PG, such as TBS and the like).

[0022] Silyloxy dihydro-pyrrolopyrimidines of type 3c are prepared from bicyclic dihydro- pyrrolopyrimidines of type 3b via metal-catalyzed coupling reaction with a suitable R2-substituted heteroaryl halide in the presence of an appropriate metal catalyst (such as Cui, XantPhos-Pd-G2and the like), an appropriate ligand (such as DMEDA, XantPhos and the like), and an appropriate base (such as CS2CO3and the like).

[0023] Alternatively, hydroxy amino-pyrimidines of type 3e could be prepared from the respective amino-pyrimidines of type 3d via metal-catalyzed coupling reaction with a suitable R2-substituted heteroaryl halide in the presence of an appropriate metal catalyst (such as Cui, XantPhos-Pd-G2and the like), an appropriate ligand (such as DMEDA, XantPhos and the like), and an appropriate base (such as CS2CO3and the like).

[0024] Subsequently, intramolecular Mitsunobu reaction of the respective hydroxy aminopyrimidines of type 3e to provide silyloxy dihydro-pyrrolopyrimidines of type 3c is accomplished in the presence of an appropriate azodi carb oxy late (such as DIAD and the like) and a suitable phosphine (such as PPhs and the like) in a suitable organic solvent (such as THF and the like).

[0025] General Procedure for Scheme 4

[0026] Pyrimidyl silyl ethers of type 4b are prepared by 2-step sequence including oxidation of thioethers of type 3c followed by nucleophilic substitution reaction of intermediates of type 4a with appropriately R3- and R4- substituted anilines. Compounds of type 4c representative of a compounds Formula (I) are prepared from the respective pyrimidyl silyl ethers of type 4b by reaction with a suitable acid (such as HC1 and the like) in a suitable organic solvent (such as MeOH, THF and the like).

[0027] SUBSTITUTE SHEET EXAMPLES Materials and Methods The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1stEd., Oxford University Press, 2000; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thEd., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997). Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with Sanpont precoated TLC plates, silica gel GF-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS). Typically, the analytical LC-MS system used consisted of Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. The column was usually HALO a C1830*5.0 mm, 2.7 µm. The mobile phase A is water containing 0.05% TFA and mobile phase B is acetonitrile containing 0.05% TFA. The gradient is from 5% mobile phase B to 95% in 2.0 min, hold 0.7 min, then reverting to 5% mobile phase B over 0.05 min and maintained for 0.25 min. The Column Oven (CTO-20AC) was operated at a temperature of 40.0 ℃. The flow rate was 1.5 mL / min, and the injection volume was 1 µl. PDA (SPD-M20A) detection was in the range 190-400 nm. The MS detector, which was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow:1.5 L / min; Drying Gas Flow:15 L / min; Detector Voltage: Tuning Voltage ± 0.2 kv; DL Temperature: 250 ℃; Heat Block Temperature: 250 ℃; Scan Range: 90.00 - 900.00 m / z. ELSD (Alltech 3300) detector Parameters: Drift Tube Temperature:60 ± 5 ℃; N2Flow-Rate: 1.8 ± 0.2 L / min. Mobile phase gradients were optimized for the individual compounds. The GC-MS system was usually performed with Shimadzu GCMS-QP2010 Ultra with FID and MS Detector. The MS detector of acquisition mode: Start Time: 2.00 min; End Time: 9.00 min; ACQ Mode: Scan; Event Time: 0.30 sec; Scan Speed: 2000; Start m / z: 50.00; End m / z: 550.00; Ion Source temperature: 200.00 °C; Interface temperature: 250.00 °C; Solvent Cut Time: 2.00 min. Preparative HPLC purifications were usually performed with Waters Auto purification system (2545-2767) with a 2489 UV detector. The column was Waters C18, 19 x150 mm, 5 μm; XBridge Prep OBD C18 Column, 30×150 mm 5 μm; XSelect CSH Prep C18 OBD Column,, 5 μm,19*150 mm; XBridge Shield RP18 OBD Column, 30x150mm, 5 μm; Xselect CSH Fluoro Phenyl, 30 x 150 mm, 5 μm; YMC-Actus Triart C18, 30 x 150 mm, 5 μm. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1% FA or 10 mmol / L NH4HCO3. Flow rates were maintained at 25 mL / min, the injection volume was 1200 μL, and the UV detector used two channels 254 nm and 220 nm. Mobile phase gradients were optimized for the individual compounds. Chiral analytical chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD,OJ Chiralpak IA,IB,IC,ID,IE,IF,IG,IH columns (Daicel Chemical Industries, Ltd.) (R,R)- Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc. ) CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column size (50x4.6 mm, 100x4.6mm, 150x4.6 mm, 250x4.6 mm, 50x3.0 mm, 100x3.0 mm) with noted percentage of either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as isocratic solvent systems, or by supercritical fluid (SFC) conditions. Chiral preparative chromatography was conducted on one of Chiralpak AS, AD, Chiralcel OD, OJ Chiralpak IA,IB,IC,ID,IE,IF,IG,IH columns (Daicel Chemical Industries, Ltd.) (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc.) CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column size (250x20 mm, 250x30 mm, 250x50 mm) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash column chromatography was usually performed using a Biotage Flash Chromatography apparatus (Dyax Corp.) on silica gel (40-60 μM, 60 Å pore size) in pre-packed cartridges of the size noted.1NMR spectra were acquired at 400 MHz spectrometers (or 300 MHz spectrometers) in DMSO-d6solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in DMSO-d6 solutions, and residual CH3OH peak or TMS was used as internal reference in CD3OD solutions. Coupling constants (J) were reported in hertz (Hz). Table 3. Abbreviations. Preparation of Intermediates The intermediates used in synthesizing the examples are commercially available or were synthesized according to the methods described below. Table 4. Commercially available intermediates. Intermediate 1. 2-(4-amino-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2-methyl-propan-l-ol

[0028] Step 1. ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)propanoate

[0029] To a solution of ethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)acetate (18.00 g, 72.96 mmol, leq.) in THF (200 mL) was added LiHMDS (IM in THF, 86 mL, 1.2 eq.) dropwise at -78 °C under N2atmosphere. The reaction mixture was stirred at -78 °C for 1 h, then a solution of iodomethane (8.28 g, 58.37 mmol, 0.8 eq.) in THF (20 mL) was added dropwise. The resulting mixture was stirred for 1.5 h at -20°C. Another batch of iodomethane (5.18 g, 36.48 mmol, 0.5 eq.) in THF (15 mL) was added. The mixture was stirred for another 2 h at -20°C. The reaction was monitored by TLC. The mixture was quenched with saturated NH4CI (400 mL) and extracted with EA (3x400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting with 1 :5 EA / PE) to afford the mixture ethyl 2-(4- chloro-2-(methylthio)pyrimidin-5-yl)propanoate and ethyl 2-(4-chloro-2-(methylthio) pyrimidin- 5-yl)-2-methylpropanoate (18.00 g, 48.32 mmol, 66% yield, 70% purity) as a yellow oil. LCMS (ES, m / z): 261[M+H]+, Rt 1.050 min.

[0030] Step 2. ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2-methyl-propanoate

[0031] To a solution of the mixture obtained in Step 1 above (18.00 g, 48.32 mmol, 70% purity, leq.) in THF (200 mL) was added dropwise NaHMDS (2M in THF, 68 mL, 2 eq.) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1 h. Then a solution of MOMCI (7.78 g, 96.65 mmol, 2 eq.) in THF (10 mL) was added dropwise and the mixture was stirred for another 2 h at -20°C. The reaction was monitored by LC-MS and was quenched with sat. NH4CI (300 mL). The resulting mixture was extracted with EA (3x300 mL). The combined organic

[0032] SUBSTITUTE SHEET extracts were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was directly purified by flash chromatography (eluting with 1:4 EA / PE) to afford ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2- methyl-propanoate (12.00 g, 39.37 mmol, 81% yield) as a yellow oil. LCMS (ES, m / z): 305 [M+H]+, Rt 1.052 min. Step 3. ethyl 2-(4-azido-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2-methylpropanoate To a solution of ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2-methyl- propanoate (1.00 g, 3.28 mmol, 1 eq.) in DMF (10 mL) was added NaN3 (640 mg, 9.84 mmol, 3 eq.). The resulting mixture was stirred at 60°C for 6 h. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with ice / water (60 mL). The resulting mixture was extracted with EA (2×80 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA / PE) to afford ethyl 2-(4-azido-2-(methylthio)pyrimidin-5- yl)-3-methoxy-2-methylpropanoate (850 mg, 2.68 mmol, 82% yield) as a yellow oil. LCMS (ES, m / z): 312 [M+H]+, Rt 0.819 min. Step 4. ethyl 3-methoxy-2-methyl-2-(2-(methylthio)-4-((triphenyl-l5-phosphane ylidene)amino)pyrimidin-5-yl)propanoate To a solution of ethyl 2-(4-azido-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2- methylpropanoate (1 g, 3.21 mmol, 1 eq.) in toluene (10 mL) was added PPh3(1.85 g, 7.07 mmol, 2.2 eq.). The resulting mixture was stirred for 2 h at 100 °C under the nitrogen atmosphere. The reaction was monitored by LC-MS and was cooled down to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA / PE) to afford ethyl 3-methoxy-2-methyl-2-(2-(methylthio)- 4-((triphenyl-l5-phosphane ylidene)amino)pyrimidin-5-yl)propanoate (1.5 g, 2.72 mmol, 85% yield) as a white solid. LCMS (ES, m / z): 546 [M+H]+, Rt 0.831 min. Step 5.3-methoxy-2-methyl-2-(2-(methylthio)-4-((triphenyl-l5-phosphaneylidene) amino)pyrimidin-5-yl)propan-1-ol To a solution of ethyl 3-methoxy-2-methyl-2-[2-methylsulfanyl-4-[(triphenyl-phosphan ylidene)amino]pyrimidin-5-yl]propanoate (3.00 g, 5.50 mmol, 1 eq.) in DCM (60 mL) was added DIBAL-H (1 M in toluene, 16.49 mL, 3 eq.) at -78°C under N2atmosphere. The mixture was allowed to warm up to -30°C and stirred for 1 h at the same temperature. The reaction was monitored by LC-MS and quenched by addition of saturated potassium sodium tartrate solution (300 mL) at 0°C. The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford 3-methoxy-2-methyl-2-(2-(methylthio)-4-((triphenyl-l5-phosphaneylidene) amino)pyrimidin-5-yl)propan-1-ol (2.12 g, 3.92 mmol, 77% yield) as a yellow oil. LCMS (ES, m / z): 504 [M+H]+, Rt 0.646 min. Step 6.2-(4-amino-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2-methylpropan-1-ol (Intermediate 1) To a solution of 3-methoxy-2-methyl-2-(2-(methylthio)-4-((triphenyl-l5- phosphaneylidene) amino)pyrimidin-5-yl)propan-1-ol (2.12 g, 4.21 mmol, 1 eq.) in H2O (2 mL) and THF (12 mL) was added HOAc (4 mL) slowly. The resulting mixture was stirred for 1 h at 100°C. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the above was added water (10 mL). The pH was adjusted to 8~9 by addition of saturated NaHCO3, and the resulting mixture was extracted with EA (3×80 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:10 MeOH / DCM) to afford 2-(4-amino-2-(methylthio)pyrimidin- 5-yl)-3-methoxy-2-methylpropan-1-ol (880 mg, 3.62 mmol, 86% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 6.95 (s, 2H), 5.22 (t, J=4.8 Hz, 1H), 3.62-3.56 (m, 2H), 3.55-3.46 (m, 2H), 3.23 (s, 3H), 2.37 (s, 3H), 1.16 (s, 3H). LCMS (ES, m / z): 244 [M+H]+, Rt 0.526 min. Intermediate 4. (S)-3-(6-bromopyridin-2-yl)-4-methyloxazolidin-2-one A mixture of (S)-4-methyloxazolidin-2-one (840.00 mg, 8.31 mmol, 1.2 eq.), 3,4,7,8- tetramethyl-1,10-phenanthroline (490.83 mg, 2.08 mmol, 0.3 eq.), tripotassium phosphate (4.41 g, 20.77 mmol, 3.0 eq.), Copper(I) Iodide (263.72 mg, 1.38 mmol, 0.2 eq.) and 2,6-dibromopyridine (1.64 g, 6.92 mmol, 1.0 eq.) in toluene (15 mL) was irradiated with microwave for 0.5 h at 120°C under a N2atmosphere. The mixture was allowed to cool down to room temperature. The desired product could be detected by LC-MS. The solids were filtered and washed with EA (3×15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA / PE) to afford (S)-3-(6-bromopyridin-2-yl)-4- methyloxazolidin-2-one (1.18 g, 4.59 mmol, 66% yield) as a white solid.1H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 4.95-4.85 (m, 1H), 4.52 (d, J = 8.4 Hz, 1H), 4.09-4.04 (m, 1H), 1.48 (d, J = 6.3 Hz, 3H). LCMS (ES, m / z): 257, 259 [M+H]+. Rt 0.715 min. Intermediate 5. tert-butyl ((6-bromopyridin-2-yl)methyl)(methyl)carbamate Step 1.1-(6-bromopyridin-2-yl)-N-methylmethanamine To a stirred solution of 6-bromopyridine-2-carbaldehyde (5 g, 26.9 mmol, 1 eq.) and methanamine (2M in THF, 15 mL, 1.1 eq.) in DCM (50 mL) was added sodium triacetoxyborohydride (6.27 g, 29.6 mmol, 1.1 eq.) in portions at 0°C. The resulting mixture was stirred at r.t. for 12 h. The reaction was monitored by LC-MS. The resulting mixture was washed with brine (2×80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-(6-bromopyridin-2-yl)-N-methylmethanamine (10 g, crude) as a yellow solid. LCMS (ESI+, m / z): 201, 203 [M+H]+, Rt 0.289 min. Step 2. tert-butyl ((6-bromopyridin-2-yl)methyl)(methyl)carbamate (Intermediate 5) To a stirred solution of 1-(6-bromo-2-pyridyl)-N-methyl-methanamine (10 g, 49.7 mmol, 1 eq.) and triethylamine (0.12 mol, 17.3 mL, 2.5 eq.) in DCM (100 mL) was added di-tert-butyl dicarbonate (49.7 mmol, 11.4 mL, 1 eq.) dropwise at 0°C. The resulting mixture was stirred at r.t. for 3 h. The reaction was monitored by LC-MS. The mixture was washed with brine (2×80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford tert-butyl ((6-bromopyridin-2-yl)methyl)(methyl)carbamate (8 g, 23.9 mmol, 53% yield) as a yellow oil.1H NMR (300 MHz, DMSO-d6) 7.77-7.73 (m, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.25-7.18 (m, 1H), 4.44 (s, 2H), 2.87 (s, 3H), 1.43-1.30 (m, 9H). LCMS (ESI+, m / z): 301, 303 [M+H]+, Rt 0.649 min. Intermediate 7. ((6-bromopyridin-2-yl)imino)dimethyl-λ6-sulfanone A mixture of 2,6-dibromopyridine (1 g, 4.22 mmol, 1 eq.), iminodimethyl-λ6-sulfanone (393 mg, 4.22 mmol, 1 eq.), Xantphos G2 Pd (386 mg, 422.13 μmol, 0.1 eq.), Xantphos (244 mg, 422.13 μmol, 0.1 eq.) and t-BuONa (811 mg, 8.44 mmol, 2 eq.) in dioxane (15 mL) was stirred for 2 h at 100 °C under N2atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature. Then brine (50 mL) was added. The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:4 EA / PE) to afford to afford ((6- bromopyridin-2-yl)imino)dimethyl-λ6-sulfanone (700 mg, 2.81 mmol, 66% yield) as yellow oil. LCMS (ES, m / z): 249, 251 [M+H]+, Rt 0.611 min. Intermediates 9 and 10. tert-butyl (R)-2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate Step 1. tert-butyl 2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate A mixture of 2,6-dibromopyridine (0.5 g, 2.11 mmol, 1 eq.), 1-tert- butoxycarbonylpyrrolidine-2-carboxylic acid (681 mg, 3.17 mmol, 1.5 eq.), dibromonickel 1,2- dimethoxyethane (65 mg, 211.07 μmol, 0.1 eq.), Cs2CO3(1.03 g, 3.17 mmol, 1.5 eq.), 4,4'- dimethyl-2,2'-bipyridyl (58 mg, 316.60 μmol, 0.15 eq.) and [IrdF(Me)(ppy)2(dtbbpy][PF6] (21 mg, 21.11 μmol, 0.01 eq.) in DMF (20 mL) was irradiated with blue light (450 nm) for 1 h at 50°C under N2atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with brine (20 mL). The resulting mixture was extracted with EA (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:10 EA / PE) to afford tert- butyl 2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate (400 mg, 1.16 mmol, 58% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.50-7.44 (m, 1H), 7.33-7.28 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 5.01-4.73 (m, 1H), 3.68-3.42 (m, 2H), 2.41-2.19 (m, 1H), 2.08-1.94 (m, 1H), 1.90- 1.80 (m, 2H), 1.22 (s, 9H). LCMS (ES, m / z): 327,329 [M+H]+, Rt 0.804 min. Step 2. tert-butyl (R)-2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)- 2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate (Intermediates 9 and 10) The racemic tert-butyl 2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate (1.2 g, 3.68 mmol, 1 eq.) was separated by Prep-Chiral-HPLC (Column: (R, R)-WHELK-O1-Kromasil, 2.11 x 25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.5% 2M NH3-MeOH); Flow rate: 60 mL / min; Gradient: isocratic 20% B; Wave Length: 220 nm; RT1(min): 3.09; RT2(min): 3.31) to afford tert-butyl (R)-2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate (480 mg, 1.47 mmol, 40% yield) as a colorless oil and tert-butyl (S)-2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate (400 mg, 1.27 mmol, 35% yield) as a colorless oil. The absolute stereochemistry of two enantiomers was arbitrarily assigned upon the chiral HPLC separation of the racemic mixture. Intermediate 14. 3-methyl-4-(1-methylpiperidin-4-yl)aniline Step 1.1-methyl-4-(2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine A solution of 1-bromo-2-methyl-4-nitrobenzene (2.0 g, 9.26 mmol, 1 eq.), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (2.48 g, 11.11 mmol, 1.2 eq.), Pd(dppf)Cl2(759 mg, 926 µmol, 0.1 eq.) and Na2CO3(370 mg, 18.52 mmol, 2 eq.) in dioxane (15 mL) and H2O (5 mL) was stirred for 1 h at 100°C under N2atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature followed by addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford 1-methyl-4-(2-methyl-4- nitrophenyl)-1,2,3,6-tetrahydropyridine (2.0 g, 93% yield) as a yellow solid. LCMS (ESI+, m / z): 233 [M+H]+, Rt 0.680 min. Step 2. 3-methyl-4-(1-methylpiperidin-4-yl)aniline (Intermediate 14) To a stirred solution of 1-methyl-4-(2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine (2.0 g, 8.61 mmol, 1 eq.) in MeOH (10 mL) was added Pd / C (200 mg, 10 wt%) under N2atmosphere. The resulting mixture was stirred for 4 h at room temperature under H2 atmosphere. The solids were filter and washed with MeOH (2×15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 5:1 DCM / MeOH) to afford 3-methyl-4-(1-methyl-4-piperidyl)aniline (0.80 g, 45% yield) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 6.84 (d, J = 8.7 Hz, 1H), 6.42-6.32 (m, 2H), 4.73 (br, 2H), 2.92-2.79 (m, 2H), 2.52-2.35 (m, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 2.01-1.88 (m, 2H), 1.67-1.49 (m, 4H). LCMS (ESI+, m / z): 205 [M+H]+, Rt 0.106 min. Intermediate 16.3-methyl-4-(4-methylpiperazin-1-yl)aniline Step 1.1-methyl-4-(2-methyl-4-nitrophenyl)piperazine To a stirred mixture of 1-fluoro-2-methyl-4-nitrobenzene (5.0 g, 32.23 mmol, 1 eq.) and 1- methylpiperazine (3.87 g, 38.68 mmol, 4.29 mL, 1.20 eq.) in DMF (20 mL) was added K2CO3(9.90 g, 64.46 mmol, 2 eq.). The resulting mixture was stirred for 3 h at 90 °C. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature . The resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford 1-methyl-4-(2- methyl-4-nitrophenyl)piperazine (5.1 g, 67% yield) as a yellow solid. LCMS (ESI+, m / z): 236 [M+H]+, Rt 0.553 min. Step 2. 3-methyl-4-(4-methylpiperazin-1-yl)aniline (Intermediate 16) To a stirred solution of 1-methyl-4-(2-methyl-4-nitrophenyl)piperazine (5.1 g, 21.68 mmol, 1 eq) in MeOH (50 mL) was added Pd / C (200 mg, 10 wt%) at room temperature under N2atmosphere. The resulting mixture was stirred for 5 h at room temperature under H2atmosphere. The solids were filtered and washed with MeOH (3×15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10:1 DCM / MeOH) to afford 3-methyl-4-(4-methylpiperazin-1-yl)aniline (2.7 g, 61% yield) as a yellow solid. LCMS (ESI+, m / z): 206 [M+H]+, Rt 0.305 min. Intermediate 18.3-methyl-4-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)aniline Step 1. tert-butyl 1-methyl-1,7-diazaspiro[3.5]nonane-7-carboxylate To a stirred mixture of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate (1 g, 4.42 mmol, 1 eq.) and formaldehyde (4 M in H2O, 1.66 mL, 1.5 eq.) in EtOH (20 mL) were added NaCNBH3(555 mg, 8.84 mmol, 2 eq.) in portions at 0 °C under N2atmosphere. The resulting mixture was stirred for 2 h at 25 °C. The reaction was monitored by LC-MS. The mixture was concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (Column: C18 Column, 80 g, 40-60 μm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), Mobile Phase B: CH3CN (50% to 60% in 10 min); 220 nm) to afford tert-butyl 1- methyl-1,7-diazaspiro[3.5]nonane-7-carboxylate (0.7 g, 2.62 mmol, 66% yield) as a colorless oil. LCMS (ES, m / z): 241 [M+H]+, Rt 0.474 min. Step 2.1-methyl-1,7-diazaspiro[3.5]nonane A solution of tert-butyl 1-methyl-1,7-diazaspiro[3.5]nonane-7-carboxylate (1.8 g, 7.49 mmol, 1 eq.) in mixed solvent of TFA (5 mL) and DCM (15 mL) was stirred for 2 h at 25 °C. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure to afford 1-methyl-1,7-diazaspiro[3.5]nonane (0.8 g, 4.56 mmol, crude) as a yellow oil. LCMS (ES, m / z): 141 [M+H]+, Rt 0.143 min. Step 3.1-methyl-7-(2-methyl-4-nitrophenyl)-1,7-diazaspiro[3.5]nonane A mixture of 1-methyl-1,7-diazaspiro[3.5]nonane (800 mg, 5.71 mmol, 1 eq.) 1-fluoro-2- methyl-4-nitro-benzene (973 mg, 6.28 mmol, 1.1 eq.) and K2CO3 (1.58 g, 11.41 mmol, 2 eq.) in DMSO (5 mL) was stirred for 16 h at 80 °C. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature, and purified by reversed phase flash chromatography (Column: C18 Column, 80 g, 40-60 μm; Mobile Phase A: water (0.1% TFA), Mobile Phase B: CH3CN (30% to 40% in 10 min); 254 nm) to afford 1-methyl-7-(2-methyl-4-nitrophenyl)-1,7- diazaspiro[3.5]nonane (500 mg, 1.63 mmol, 32% yield) as a yellow solid. LCMS (ES, m / z): 276 [M+H]+, Rt 0.555 min. Step 4.3-methyl-4-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)aniline (Intermediate 18) A mixture of 1-methyl-7-(2-methyl-4-nitrophenyl)-1,7-diazaspiro[3.5]nonane (600 mg, 2.18 mmol, 1 eq.) and Pd / C (50 mg) in MeOH (10 mL) was stirred for 2 h at 25 °C under H2atmosphere. The reaction was monitored by LC-MS. The solids were filtered out, and the filtrate was concentrated under vacuum. The residue was purified by reversed phase flash chromatography with the following conditions (Column: C18 Column, 80 g, 40-60 μm; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: CH3CN (15% to 20% in 10 min); 254 nm) to afford 3-methyl- 4-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)aniline (200 mg, 815.12 μmol, 37% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ δ 7.10-6.95 (m, 3H), 4.11-4.01 (m, 1H), 3.85-3.76 (m, 1H), 3.08-2.92 (m, 2H), 2.71 (s, 3H), 2.69-2.56 (m, 2H), 2.39-2.32 (m, 2H), 2.24 (s, 3H), 2.19- 1.96 (m, 4H). LCMS (ES, m / z): 246 [M+H]+, Rt 0.315 min. Intermediate 21.1-(4-amino-2-methyl-phenyl)pyrrolidin-2-one Step 1.1-(2-methyl-4-nitro-phenyl)pyrrolidin-2-one To a stirred mixture of 1-bromo-2-methyl-4-nitro-benzene (1 g, 4.63 mmol, 1 eq) and pyrrolidin-2-one (473 mg, 5.55 mmol, 1.2 eq) in dioxane (10 mL) were added Pd2(dba)3(423 mg, 463.39 μmol, 0.1 eq.), BINAP (576 mg, 925.79 μmol, 0.2 eq), Cs2CO3(4.52 g, 13.89 mmol, 3.0 eq) at room temperature under N2atmosphere. The resulting mixture was stirred for 3 h at 90 °C under the N2atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA / PE) to afford 1-(2-methyl-4- nitro-phenyl)pyrrolidin-2-one (850 mg, 3.84 mmol, 82% yield) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 8.22-8.18 (m, 1H), 8.13-8.08 (m, 1H), 7.54 (d, J = 9 Hz, 1H), 3.81-3.73 (m, 2H), 2.50-2.43 (m, 2H), 2.28 (s, 3H), 2.21-2.10 (m, 2H). LCMS (ES, m / z): 221 [M+H]+, Rt 0.727min. Step 2.1-(4-amino-2-methyl-phenyl)pyrrolidin-2-one (Intermediate 21) To a stirred mixture of 1-(2-methyl-4-nitro-phenyl)pyrrolidin-2-one (1 g, 4.54 mmol, 1 eq) in MeOH (10 mL) was added Pd / C (100 mg, 10%) at room temperature under N2atmosphere. The resulting mixture was stirred for 16 h at room temperature under H2 atmosphere. The reaction was monitored by LC-MS. The solids were filtered and washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10:1 DCM / MeOH) to afford 1-(4-amino-2-methyl- phenyl)pyrrolidin-2-one (700 mg, 3.66 mmol, 97% yield) as a yellow solid. LCMS (ES, m / z): 191[M+H]+, Rt 0.452 min. Intermediate 26.4-(4-amino-2-methylphenyl)-1-methylpiperazin-2-one Step 1.1-methyl-4-(2-methyl-4-nitrophenyl)piperazin-2-one A mixture of 1-bromo-2-methyl-4-nitro-benzene (2 g, 9.26 mmol, 1 eq.), 1- methylpiperazin-2-one (1.59 g, 13.89 mmol, 1.5 eq.), Pd2(dba)3 (848 mg, 925.79 μmol, 0.1 eq.), Cs2CO3(9.05 g, 27.77 mmol, 3 eq.) and BINAP (1.20 g, 1.85 mmol, 0.2 eq.) in dioxane (30 mL) was stirred for 2 h at 100 °C under N2atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Then water (30 mL) was added. The mixture was extracted with EA (3×30 mL), and the combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel column chromatography (eluting with 10:1 DCM / MeOH) to afford 1-methyl-4-(2- methyl-4-nitro-phenyl)piperazin-2-one (2.07 g, 8.31 mmol, 90% yield) as a yellow oil. LCMS (ES, m / z): 250 [M+H]+, Rt 0.788 min. Step 2.4-(4-amino-2-methylphenyl)-1-methylpiperazin-2-one (Intermediate 26) To a stirred solution of 1-methyl-4-(2-methyl-4-nitro-phenyl)piperazin-2-one (2 g, 8.02 mmol, 1 eq.) in EtOH (15 mL) and EA (15 mL) was added Pd / C (400 mg, 10%) under N2atmosphere. The resulting mixture was stirred for 2 h at room temperature under H2atmosphere. The reaction was monitored by LCMS. The solids were filtered and washed with MeOH (3×20 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluting with 10:1 DCM / MeOH) to afford 4-(4-amino-2-methyl-phenyl)-1-methyl-piperazin-2-one (1.3 g, 5.34 mmol, 66% yield) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 6.77 (d, J = 8.1 Hz, 1H), 6.44-6.32 (m, 2H), 4.77 (br, 2H), 3.38- 3.29 (m, 4H), 3.02-2.94 (m, 2H), 2.88 (s, 3H), 2.13 (s, 3H). LCMS (ES, m / z): 220 [M+H]+, Rt 0.376 min. Intermediate 27.6-Bromo-N,N-dimethyl-2-pyridinecarboxamide To a stirred mixture of 6-bromopyridine-2-carboxylic acid (2 g, 9.90 mmol, 1 eq.) in DMF (20 mL) was added N-methylmethanamine;hydrochloride (888.09 mg, 10.89 mmol, 1.1 eq.), HATU (5.65 g, 14.85 mmol, 1.5 eq.) and DIPEA (2.56 g, 19.80 mmol, 3.45 mL, 2 eq.) at 0°C. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. Then brine (60 mL) was added. The resulting mixture was extracted with EA (3 x 60mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 : 1 ethyl acetate / petroleum ether) to afford 6-bromo-N,N-dimethyl- pyridine-2-carboxamide (2 g, 8.73 mmol, 88% yield) as a white solid. LCMS (ES, m / z): 229 [M+H]+, Rt 0.571 min.

[0033] Intermediate 30. diethyl 2-(4-amino-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate

[0034] Step 1. diethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)malonate

[0035] To a solution of ethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)acetate (10.00 g, 40.53 mmol) in THF (100 mL) was added LiHMDS (2 Min THF, 20.3 mL, 2 eq.) at -78°C under N2atmosphere. The mixture was allowed to stir at -78°C for 1 h. Then ethyl cyanoformate (8.05 g, 81.06 mmol, 2 eq.) was added slowly. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was monitored by LC-MS. Ice / water (300 mL) was added to the reaction. The resulting mixture was extracted with EA (3x 150 mL). The combined organic layers were washed with brine (2x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:3 EA / PE) to afford diethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)malonate (12.00 g, 37.64 mmol, 93% yield) as a yellow oil. LCMS (ES, m / z): 319, 321 [M+H]+, Rt 0.769 min.

[0036] Step 2. diethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate

[0037] To a solution of diethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)malonate (11.00 g, 34.51 mmol, 1 eq.) in THF (100 mL) was added NaH (2.76 g, 60%, 69.01 mmol, 2 eq.) at 0°C in 30 mins. The mixture was stirred for another 30 mins at 0°C under the N2atmosphere. Then Mel (9.80 g, 69.01 mmol, 2 eq.) was added dropwise. The mixture was stirred at 60°C for 12 h under the N2atmosphere. The reaction was monitored by LC-MS. The reaction mixture was allowed to cool down to room temperature and quenched by ice / water (300 mL). The aqueous layer was extracted with EA (3x 100 mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 :3 EA / PE) to afford

[0038] SUBSTITUTE SHEET diethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate (10 g, 30.05 mmol, 77% yield) as a yellow oil. LCMS (ES, m / z): 333, 335 [M+H]+, Rt 0.914 min.

[0039] Step 3. diethyl 2-(4-azido-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate

[0040] Into a solution of diethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate (400 mg, 1.20 mmol, 1 eq.) in DMF (10 mL) was added sodium azide (156.27 mg, 2.40 mmol, 2 eq.). The resulting solution was stirred at 60 °C for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with EA (50 mL×3). The organic phase was combined, washed with brine (100 mL× 2), dried with anhydrous Na2SO4and evaporated to give diethyl 2-(4-azido-2-(methylthio)pyrimidin-5-yl)-2- methylmalonate (400 mg, crude) as a white solid. LCMS (ES, m / z): 340 [M+H]+, Rt 0.712 min.

[0041] Step 4. diethyl 2-(4-amino-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate (Intermediate 30)

[0042] Into a solution of diethyl 2-(4-azido-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate (400 mg, LIS mmol, 1 eq.) in EtOH (10 mL) was placed Pd / C (w / t 10% purity, 100 mg, 25%). The resulting solution was stirred at room temperature for 16 h under H2atmosphere. The reaction was monitored by LC-MS. The solids were filtered out and washed by EtOH (5 mL×3). The filtrate was evaporated and dried to give diethyl 2-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl- propanedioate (300 mg, crude) as a colorless oil. LCMS (ES, m / z): 314 [M+H]+, Rt 0.613 min.

[0043] Intermediate 31. 2-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-3-[tert- butyl(dimethyl)silyl]oxy-2-methyl-propan-1-ol

[0044] SUBSTITUTE SHEET Step 1. ethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-3-hydroxy-2-methyl-propanoate To a solution of diethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl-propanedioate (step2 / Intermediate 30, 10.30 g, 30.95 mmol, 1 eq.) in ether (100 mL) was added DIBAL-H (1 M in toluene, 61.90 mL, 2 eq.) at -78°C under N2atmosphere. The mixture was stirred at room temperature for 2 h under the N2atmosphere. The reaction was monitored by LC-MS. The mixture was quenched by saturated potassium sodium tartrate (250 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford ethyl 2-(4-chloro-2-methylsulfanyl- pyrimidin-5-yl)-3-hydroxy-2-methyl-propanoate (4.8 g, 16.51 mmol, 53% yield) as a yellow oil. LCMS (ES, m / z): 291, 293 [M+H]+, Rt 0.655 min. Step 2. ethyl 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)- 2-methyl-propanoate To a mixture of ethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-3-hydroxy-2-methyl- propanoate (5.30 g, 18.22 mmol, 1 eq.) and imidazole (2.48 g, 36.43 mmol, 2 eq.) in DCM (50 mL) was added TBSCl (3.31 g, 21.93 mmol, 1.2 eq.). The mixture was stirred at r.t. for 3 h. The reaction was monitored by LC-MS. Then ice / water (100 mL) was added. The resulting mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:3 EA / PE) to afford ethyl 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2- methyl-propanoate (6.4 g, 15.80 mmol, 96% yield) as a yellow oil.1H NMR (300 MHz, DMSO- d6) δ 8.62 (s, 1H), 4.26-3.90 (m, 4H), 2.53 (s, 3H), 1.56 (s, 3H), 1.14 (t, J=7.2 Hz, 3H), 0.76 (s, 9H), 0.00 (s, 3H), -0.09 (s, 3H). LCMS (ES, m / z): 405, 407 [M+H]+, Rt 0.907 min. Step 3.3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2- methyl-propan-1-ol To a solution of ethyl 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5- yl)-2-methyl-propanoate (2 g, 4.95 mmol, 1 eq.) in DCM (20 mL) was added dropwise DIBAL-H (1M in DCM, 10 mL, 2 eq.) at -78 °C for 1 h under N2atmosphere. Then the mixture was stirred for another 1 h at room temperature. The reaction was monitored by LC-MS. The reaction was quenched wit saturated sodium potassium tartrate solution (100 mL), and then the mixture was extracted with EA (3×80mL). The combined organic layers were washed with brine (100mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 1:2 EA / PE) to afford 3-[tert-butyl(dimethyl)silyl]oxy-2-(4- chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl-propan-1-ol (1.24 g, 3.38 mmol, 69% yield) as a colorless oil. LCMS (ES, m / z): 363, 365 [M+H]+, Rt 1.323 min. Step 4.2-(4-azido-2-(methylthio)pyrimidin-5-yl)-3-((tert-butyldimethylsilyl)oxy)-2- methylpropan-1-ol To a stirred solution of 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl- pyrimidin-5-yl)-2-methyl-propan-1-ol (2.5 g, 6.89 mmol, 1 eq.) in DMF (25 mL) was added NaN3(1.34 g, 20.66 mmol, 3eq.) in portions at 25 °C. The resulting mixture was stirred for 16 h at 60 °C. The reaction was monitored by TLC. The mixture was allowed to cool down to room temperature. The mixture was diluted with brine (150 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:5 ethyl acetate / petroleum ether) to afford 2-(4- azido-2-(methylthio)pyrimidin-5-yl)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol (2.16 g, 5.67 mmol, 82% yield) as colorless oil. LCMS (ES, m / z): 370 [M+H]+, Rt 0.866 min. Step 5.3-((tert-butyldimethylsilyl)oxy)-2-methyl-2-(2-(methylthio)-4-((tributyl-λ5- phosphaneylidene)amino)pyrimidin-5-yl)propan-1-ol To a stirred mixture of 2-(4-azido-2-methylsulfanyl-pyrimidin-5-yl)-3-[tert- butyl(dimethyl)silyl]oxy-2-methyl-propan-1-ol (1 g, 2.71 mmol, 1 eq.) in toluene (10 mL) was added PBu3(1.09 g, 5.41 mmol, 2 eq.) . The resulting mixture was stirred for 1 h at 100 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The solvent was removed to afford 3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-2-[2- methylsulfanyl-4-[(tributyl-phosphanylidene)amino] pyrimidin-5-yl]propan-1-ol (1.3 g, crude) as a yellow oil. LCMS (ES, m / z): 544 [M+H]+, Rt 1.186 min. Step 6.2-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-3-[tert-butyl(dimethyl)silyl]oxy-2- methyl-propan-1-ol (Intermediate 31) To a stirred solution of 3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-2-[2-methylsulfanyl-4- [(tributyl-phosphanylidene)amino]pyrimidin-5-yl]propan-1-ol (1.6 g, 2.94 mmol, 1 eq.) in H2O (2 mL) and THF (12 mL) was added AcOH (4 mL) slowly. The resulting mixture was stirred for 1 h at 100 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with NaHCO3(100 mL). The resulting mixture was extracted with EA (3×80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with [EA / PE] (1:1) to afford 2-(4-amino-2-methylsulfanyl-pyrimidin-5- yl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propan-1-ol (0.91 g, 2.65 mmol, 90% yield) as a white soild. LCMS (ES, m / z): 344 [M+H]+, Rt 0.800 min. Intermediate 32.3-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-(methylthio)pyrimidin-5-yl)- 2-methylpropanal To a solution of 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2- methyl-propan-1-ol (step 3 / Intermediate 31, 3.10 g, 8.54 mmol, 1 eq.) in DCM (100 mL) was added DMP (7.24 g, 17.08 mmol, 2 eq.) at 0 °C in portions. The mixture was stirred at r.t. for 4 h. The reaction was monitored by LC-MS. The mixture was washed with water (2×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:3 EA / PE) to afford 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl- propanal (2.80 g, 7.76 mmol, 91% yield) as a colorless oil. LCMS (ES, m / z): 361, 363 [M+H]+, Rt 0.924 min.

[0045] Preparation of Exemplary Compounds of Formula (I)

[0046] Examples 1 and 2. (S)-5-(methoxymethyl)-5-methyl-7-(1-methyl-lH-pyrazol-3-yl)-N-(4-(4- methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine and (R)-5-

[0047] (methoxymethyl)-5-methyl-7-(1-methyl-lH-pyrazol-3-yl)-N-(4-(4-methylpiperazin-1- yl)phenyl)-6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidin-2-amine

[0048] Step 1. 3-methoxy-2-methyl-2-[4-[(l-methylpyrazol-3-yl)amino]-2-methylsulfanyl- pyrimidin-5-yl]propan-1-ol

[0049] To a stirred solution of 2-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-3-methoxy-2- methyl-propan-1-ol (Intermediate 1, 150 mg, 0.62 mmol, 1 eq.) and 3-bromo-l-methyl-pyrazole (109 mg, 0.68 mmol, 1.1 eq.) in 1,4-dioxane (8 mL) was added Cui (117 mg, 0.62 mmol, 1 eq.), K2CO3(170 mg, 1.23 mmol, 2 eq.) and DMEDA (54 mg, 616.46 pmol, 1 eq.). The resulting mixture was stirred for 16 h at 90 °C under N2atmosphere. The reaction was monitored by LC- MS. The mixture was allowed to cool down to room temperature. The solids were filtered and washed with DCM (2x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 9: 1 EA / PE) to afford 3-methoxy- 2-methyl-2-[4-[(l-methylpyrazol-3-yl)amino]-2-methylsulfanyl-pyrimidin-5-yl]propan-1-ol (100 mg, 0.28 mmol, 50% yield) as a yellow solid. LCMS (ES, m / z): 324 [M+H]+, Rt 0.642 min.

[0050] Step 2. 5-(methoxymethyl)-5-methyl-7-(11methylpyrazol-3-yl)-2-methylsulfanyl-6H- pyrrolo [2, 3-d] pyrimidine

[0051] To a stirred solution of 3-methoxy-2-methyl-2-[4-[(l-methylpyrazol-3-yl)amino]-2- methylsulfanyl-pyrimidin-5-yl]propan-1-ol (100 mg, 0.31 mmol, 1 eq.) and PPh3(162 mg, 0.62

[0052] SUBSTITUTE SHEET mmol, 2 eq.) in THF (5 mL) was added DIAD (125 mg, 0.62 mmol, 2 eq.) dropwise at 0°C. The resulting mixture was stirred for 4 h at room temperature under N2atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford 5- (methoxymethyl)-5-methyl-7-(1-methylpyrazol-3-yl)-2-methylsulfanyl-6H-pyrrolo[2,3- d]pyrimidine (80 mg, 0.26 mmol, 84% yield,) as a yellow oil. LCMS (ES, m / z): 306 [M+H]+, Rt 1.414 min. Step 3.5-(methoxymethyl)-5-methyl-7-(1-methylpyrazol-3-yl)-2-methylsulfinyl-6H- pyrrolo[2,3-d]pyrimidine To a stirred solution of 5-(methoxymethyl)-5-methyl-7-(1-methylpyrazol-3-yl)-2-methyl sulfanyl-6H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.26 mmol, 1 eq.) in toluene (1 mL) was added m- CPBA (54 mg, 0.31 mmol, 1.2 eq.). The resulting mixture was stirred for 0.5 h at room temperature. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure to afford 5-(methoxymethyl)-5-methyl-7-(1-methylpyrazol-3-yl)-2-methylsulfinyl-6H- pyrrolo[2,3-d]pyrimidine (80 mg, crude) as a yellow oil. LCMS (ES, m / z): 322 [M+H]+, Rt 0.710 min. Step 4.5-(methoxymethyl)-5-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-7-(1- methylpyrazol-3-yl)-6H-pyrrolo[2,3-d]pyrimidin-2-amine To a mixture of 5-(methoxymethyl)-5-methyl-7-(1-methylpyrazol-3-yl)-2-methylsulfinyl- 6H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.25 mmol, 1 eq.) and 4-(4-methylpiperazin-1-yl)aniline (Intermediate 11, 143 mg, 0.75 mmol, 3 eq.) in toluene (1 mL) was added DIPEA (1 mL). The resulting solution was stirred at 100 °C for 16 h. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The crude product was purified by reverse phase chromatography (Column: C18; Mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (5% to 50% over 20 min); Detector, UV 254 nm) to afford 5-(methoxymethyl)-5-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-7-(1- methylpyrazol-3-yl)-6H-pyrrolo[2,3-d]pyrimidin-2-amine (70 mg, 0.15 mmol, 62% yield) as a yellow oil. LCMS (ES, m / z): 449 [M+H]+, Rt 0.638 min. Step 5. (S)-5-(methoxymethyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-N-(4-(4- methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine and (R)-5- (methoxymethyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-N-(4-(4-methylpiperazin-1- yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine (Examples 1 and 2) The racemic 5-(methoxymethyl)-5-methyl-N-[4-(4-methylpiperazin-1-yl) phenyl]-7-(1- methylpyrazol-3-yl)-6H-pyrrolo[2,3-d]pyrimidin-2-amine (60 mg, 0.13 mmol, 1 eq.) was separated by Prep-Chiral-HPLC (Column: CHIRAL ART Cellulose-SC, 2×25cm, 5μm; Mobile Phase A: Hex:DCM=5:1 (0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate:20 mL / min; Gradient: 7% B in 18 min; 220 / 254 nm; RT1:13.941; RT2:15.591; This resulted in (S)-5- (methoxymethyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-N-(4-(4-methylpiperazin-1- yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine (19.3 mg, 64% yield) and (R)-5- (methoxymethyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-N-(4-(4-methylpiperazin-1- yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine (22.5 mg, 75% yield) as a white solids. Example 1:1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.55 (d, J=9.2 Hz, 2H), 6.88-6.85 (m, 3H), 3.95-3.91 (m 1H), 3.77 (s, 3H), 3.64-3.60 (m, 1H), 3.39-3.36 (m, 1H), 3.29 (s, 3H), 3.07-3.04 (m, 4H), 2.48-2.44 (m, 4H), 2.28-2.24 (m, 1H), 2.23 (s, 3H), 1.31 (s, 3H). LCMS (ES, m / z): 449 [M+H]+, Rt 0.709 min. Example 2:1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.85 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.56 (d, J=9.2 Hz, 2H), 6.89-6.85 (m, 3H), 3.94-3.91 (m, 1H), 3.77 (s, 3H), 3.64-3.60 (m, 1H), 3.39-3.36 (m, 1H), 3.28 (s, 3H), 3.07-3.04 (m, 4H), 2.48-2.45 (m, 4H), 2.28-2.24 (m, 1H), 2.23 (s, 3H), 1.31 (s, 3H). LCMS (ES, m / z): 449 [M+H]+, Rt 0.706 min.

[0053] Examples 3 and 4. (R)-5-(methoxymethyl)-5-methyl-N-(4-(4-methylpiperazin-l-yl)phenyl)- 7-(thiazol-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine and (S)-5- (methoxymethyl)-5-methyl-N-(4-(4-methylpiperazin-l-yl)phenyl)-7-(thiazol-2-yl)-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine

[0054] Step 1. 3-methoxy-2-methyl-2-(2-(methylthio)-4-(thiazol-2-ylamino)pyrimidin-5-yl)propan- 1-ol

[0055] Into a mixture of 2-(4-amino-2-(methylthio)pyrimidin-5-yl)-3-methoxy-2-methylpropan- 1-ol (Intermediate 1, 0.50 g, 2.05 mmol, 1 eq.) and 2 -bromothiazole (674 mg, 4.11 mmol, 2 eq.) in dioxane (5 mL) was added XantPhos (119 mg, 205.49 pmol, 0.1 eq.), XantPhos Pd G2(174 mg, 205.49 pmol, 0.1 eq.) and CS2CO3(1.67 g, 5.14 mmol, 2.5 eq.). The mixture was stirred for 18 h at 90 °C under N2atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature. The solids were filtrated out and washed with EA (2x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: Cl 8; Mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (17.5% over 5 min); UV 254 nm) to afford 3-methoxy-2-methyl-2-(2-(methylthio)-4- (thiazol-2-ylamino)pyrimidin-5-yl)propan-1-ol (180 mg, 0.41 mmol, 26% yield) as colorless oil. LCMS (ES, m / z): 327 [M+H]+, Rt 0.567 min.

[0056] Step 2. 2-(5-(methoxymethyl)-5-methyl-2-(methylthio)-5,6-dihydro-7H-pyrrolo [2,3- d]pyrimidin-7-yl)thiazole

[0057] To a solution of 3-methoxy-2-methyl-2-(2-(methylthio)-4-(thiazol-2-ylamino)pyrimidin- 5-yl)propan-l-ol (150 mg, 0.46 mmol, 1 eq.) and PPhi (241 mg, 0.92 mmol, 2 eq.) in THF (1.5 mL) was added DIAD (185 mg, 0.92 mmol, 2 eq.) slowly at 0 °C under nitrogen atmosphere. The

[0058] SUBSTITUTE SHEET mixture was stirred for at room temperature for 16 h. The resulting mixture was diluted with EA (50 mL) and washed with brine (3×20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:4 EA / PE) to afford 2-(5-(methoxymethyl)-5- methyl-2-(methylthio)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazole (120 mg, 0.36 mmol, 84% yield,) as a colorless oil. LCMS (ES, m / z): 309 [M+H]+, Rt 0.712 min. Step 3.2-(5-(methoxymethyl)-5-methyl-2-(methylsulfinyl)-5,6-dihydropyrrolo[2,3- d]pyrimidin-7-yl)thiazole Into a solution of 2-(5-(methoxymethyl)-5-methyl-2-(methylthio)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)thiazole (80 mg, 0.26 mmol, 1 eq.) in toluene (1.5 mL) was added m- CPBA (67 mg, 0.39 mmol, 1.5 eq.) in portions. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure to afford 2-(5-(methoxymethyl)-5-methyl-2-(methylsulfinyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-7 -yl)thiazole (100 mg, crude) as a yellow solid. LCMS (ES, m / z): 325 [M+H]+, Rt 0.620 min. Step 4.5-(methoxymethyl)-5-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-7-(thiazol -2-yl)- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine To the mixture of 2-(5-(methoxymethyl)-5-methyl-2-(methylsulfinyl)-5,6-dihydro pyrrolo[2,3-d]pyrimidin-7 -yl)thiazole (100 mg, crude) in toluene (1 mL) was added DIPEA (167 mg, 1.30 mmol, 5 eq.) and 4-(4-methylpiperazin-1-yl)aniline (Intermediate 11, 99 mg, 0.52 mmol, 2 eq.). The mixture was stirred for 16 h at 110 °C. The mixture was allowed to cool down to room temperature. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH OBD Column 30×150mm 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3·H2O), Mobile Phase B: ACN; Flow rate:60 mL / min; Gradient:37% - 57% B in 7 min; 220 nm; RT1:4.55) to afford the racemic product 5-(methoxymethyl)-5-methyl-N-(4- (4-methylpiperazin-1-yl)phenyl)-7-(thiazol-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2- amine (60 mg, 0.13 mmol, 51%) as a light-yellow solid. LCMS (ES, m / z): 452 [M+H]+, Rt 1.650 min. Step 5. (R)-5-(methoxymethyl)-5-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-7-(thiazol-2- yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine and (S)-5-(methoxymethyl)-5-methyl- N-(4-(4-methylpiperazin-1-yl)phenyl)-7-(thiazol-2-yl)-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-2-amine (Examples 3 and 4) The racemic 5-(methoxymethyl)-5-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl) -7- (thiazol-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine (60 mg, 0.13 mmol) was separated by prep-Chiral-HPLC (Column: CHIRAL ART Cellulose-SB, 2×25cm, 5 μm; Mobile Phase A:Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B:EtOH--HPLC; Flow rate:20 mL / min; Gradient: 20% B in 20 min; 220 / 254 nm; RT1:14.85; RT2:16.264;) to afford (R)-5- (methoxymethyl)-5-methyl-N-(4-(4-methyl piperazin-1-yl)phenyl)-7-(thiazol-2-yl)-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-2-amine (26.3 mg, 43% yield) as a white solid and (S)-5- (methoxymethyl)-5-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-7-(thiazol-2-yl)-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-2-amine (26.5 mg, 44 % yield) as a white solid. Example 3:1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.05 (s, 1H), 7.62 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 4.24-4.18 (m, 1H), 3.93-3.87 (m, 1H), 3.40-3.44 (m, 2H), 3.28 (s, 3H), 3.09-3.06 (m, 4H), 2.48-2.44 (m, 4H), 2.23 (s, 3H), 1.37 (s, 3H). LCMS (ES, m / z): 452 [M+H]+, Rt 0.550 min. Example 4:1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.05 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 4.25-4.17 (m, 1H), 3.94-3.87 (m, 1H), 3.42-3.33 (m, 2H), 3.28 (s, 3H), 3.09-3.06 (m, 4H), 2.48-2.45 (m, 4H), 2.23 (s, 3H), 1.37 (s, 3H). LCMS (ES, m / z): 452 [M+H]+, Rt 0.550 min.

[0059] Table 5. The compounds in the following table were synthesized according to the appropriate method and using appropriate intermediates as demonstrated for Examples 1-4.

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] 45, 46, 47, 48

[0077] Examples 55 and 56: (S)-3-(6-((R)-5-(hydroxymethyl)-5-methyl-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)-4- methyloxazolidin-2-one and (S)-3-(6-((S)-5-(hydroxymethyl)-5-methyl-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin- 2-yl)-4-methyloxazolidin-2-one Step 1. ethyl 5-methyl-2-methylsulfanyl-6-oxo-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate A solution of diethyl 2-(4-amino-2-(methylthio)pyrimidin-5-yl)-2-methylmalonate (Intermediate 30, 4.5 g, 14.4 mmol, 1 eq.) in EtOH (20 mL) was stirred for 4 h at 60°C. The reaction was monitored by LCMS. Then the mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA / PE) to afford ethyl 5-methyl-2-methylsulfanyl-6-oxo-7H- pyrrolo[2,3-d]pyrimidine-5-carboxylate (2.8 g, 10.5 mmol, 73% yield) as a white solid. LCMS (ES, m / z): 268 [M+H]+, Rt 1.112 min. Step 2. tert-butyl-dimethyl-[(5-methyl-2-methylsulfanyl-6,7-dihydropyrrolo[2,3- d]pyrimidin-5-yl)methoxy]silane To a solution of ethyl 5-methyl-2-methylsulfanyl-6-oxo-7H-pyrrolo[2,3-d]pyrimidine-5- carboxylate (0.5 g, 1.87 mmol, 1 eq.) in THF (20 mL) was added Red-Al (1.13 g, 5.61 mmol, 1.11 mL, 3 eq.). The mixture was stirred for 2 h at room temperature. To the above mixture was added tert-butyldimethylsilyl chloride (2.82 g, 18.71 mmol, 10 eq.) and imidazole (1.27 g, 18.71 mmol, 10 eq.). The mixture was stirred at room temperature for 48 h. The reaction was monitored by LCMS. Then ice / water (50 mL) was added. The resulting mixture was extracted with EA (2×50 ml). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford tert-butyl-dimethyl-[(5-methyl-2- methylsulfanyl-6,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)methoxy]silane (0.2 g, 0.61 mmol, 33% yield) as a white solid. LCMS (ES, m / z): 326 [M+H]+, Rt 1.187 min. Step 3. (4S)-3-(6-(5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-2-(methylthio)-5,6- dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)-4-methyloxazolidin-2-one To a solution of tert-butyl-dimethyl-[(5-methyl-2-methylsulfanyl-6,7-dihydropyrrolo[2,3- d]pyrimidin-5-yl)methoxy]silane (200 mg, 0.61 mmol, 1 eq.) in dioxane (5 mL) was added (4S)- 3-(6-bromo-2-pyridyl)-4-methyl-oxazolidin-2-one (Intermediate 4, 157.94 mg, 0.61 mmol, 1 eq.), CuI (117.00 mg, 0.61 mmol, 1 eq.), N,N'-dimethylethane-1,2-diamine (54.16 mg, 0.61 mmol, 1 eq.) and potassium carbonate (212.27 mg, 1.54 mmol, 2.5 eq.). The mixture was stirred at 90 °C for 4 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The solid was filtered out. The filtered was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford (4S)-3-[6-[5- [[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-2-methylsulfanyl-6H-pyrrolo[2,3-d]pyrimidin- 7-yl]-2-pyridyl]-4-methyl-oxazolidin-2-one (200 mg, 398.63 umol, 65% yield) as a colorless oil. LCMS (ES, m / z): 502 [M+H]+Step 4. (4S)-3-(6-(5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-2-(methylsulfonyl)-5,6- dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)-4-methyloxazolidin-2-one To the solution of (4S)-3-[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-2- methylsulfanyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-pyridyl]-4-methyl-oxazolidin-2-one (110 mg, 219.25 umol, 1 eq.) in toluene (3 mL) was added m-CPBA (45.40 mg, 263.10 umol) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure. The crude product was used directly in the next step. LCMS (ES, m / z): 534 [M+H]+, Rt 0.945 min. Step 5. (4S)-3-[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-2-[4-(4-methyl piperazin-1-yl)anilino]-6H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-pyridyl]-4-methyl-oxazolidin-2- one To the solution of (4S)-3-[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-2- methylsulfonyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-pyridyl]-4-methyl-oxazolidin-2-one (90 mg, 0.17 mmol, 1 eq.) in toluene (3 mL) was added 4-(4-methylpiperazin-1-yl)aniline (Intermediate 11, 64.51 mg, 0.34 mmol, 2 eq.) and N-ethyl-N-isopropyl-propan-2-amine (217.94 mg, 1.69 mmol, 10 eq.). The mixture was stirred at 90°C for 16 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature and was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 2:1 EA / PE) to afford (4S)- 3-[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]- 6H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-pyridyl]-4-methyl-oxazolidin-2-one (80 mg, 0.16 mmol, 74% yield ) as a white solid. LCMS (ES, m / z): 645 [M+H]+. Step 6. (S)-3-(6-((R)-5-(hydroxymethyl)-5-methyl-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)-4- methyloxazolidin-2-one and (S)-3-(6-((S)-5-(hydroxymethyl)-5-methyl-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin- 2-yl)-4-methyloxazolidin-2-one (Examples 55 and 56) To a solution of (4S)-3-[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-2-[4-(4- methylpiperazin-1-yl)anilino]-6H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-pyridyl]-4-methyl-oxazolidin- 2-one (95 mg, 0.15 mmol, 1 eq.) in MeOH (2 mL) was added HCl (6M, 1 mL) dropwise at 0°C. The mixture was stirred at room temperature for 6 h. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC: Column: XBridge Prep OBD C18 Column, 19×250 mm, 5 um; Mobile Phase A: Water (10 MMOL / L NH4HCO3), Mobile Phase B: MeOH--HPLC; Flow rate: 25 mL / min; Gradient: 53 % - 81% B in 9 min; 254 nm; RT1: 7.03min, RT2: 7.87min) to afford (S)-3-(6-((R)-5- (hydroxymethyl)-5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)-4-methyloxazolidin-2-one (18.8 mg, 35.43 umol, 24.05% yield) as a white solid and (S)-3-(6-((S)-5-(hydroxymethyl)-5-methyl-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)- 4-methyloxazolidin-2-one (20.0 mg, 37.69 umol, 25.59% yield) as a white solid. Example 55:1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.61-7.54 (m, 3H), 6.88 (d, J = 8 Hz, 2H), 4.85-4.81 (m, 1H), 4.52-4.49 (m, 1H), 4.14-4.03 (m, 2H), 3.5-3.82 (m, 1H), 3.48-3.33 (m, 3H), 3.06-2.98 (m, 4H), 2.40-2.33 (m, 4H), 2.25 (s, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.29 (s, 3H). LCMS (ES, m / z): 531 [M+H]+, Rt 0.905 min. Example 56:1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.61-7.54 (m, 3H), 6.88 (d, J = 8.0 Hz, 2H), 5.02 (d, J = 4.0 Hz, 1H), 4.85 (s, 1H), 4.57-4.49 (m, 1H), 4.25-4.21 (m, 1H), 4.11-4.05 (m, 1H), 3.71-3.66 (m, 1H), 3.45-3.33 (m, 2H), 3.08-3.02 (m, 4H), 2.41-2.33 (m, 4H), 2.16 (s, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.31 (s, 3H). LCMS (ES, m / z): 531 [M+H]+, Rt 0.913 min.

[0078] Table 6. The compounds in the following table were synthesized according to the appropriate method and using appropriate intermediates as demonstrated for Examples 55-56

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085] Examples 77 and 78: (R)-(5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(4- methylpiperazin-1-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl)methanol and (S)-(5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(4- methylpiperazin-1-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl)methanol Step 1.3-((tert-butyldimethylsilyl)oxy)-2-methyl-2-(4-((1-methyl-1H-pyrazol-3-yl)amino)-2- (methylthio)pyrimidin-5-yl)propan-1-ol To a stirred mixture of 2-(4-amino-2-(methylthio)pyrimidin-5-yl)-3-((tert-butyldimethyl silyl)oxy)-2-methylpropan-1-ol (Intermediate 31, 300 mg, 0.87 mmol, 1 eq.) in 1,4-dioxane (15 mL) was added 3-bromo-1-methyl-1H-pyrazole (168.70 mg, 1.05 mmol, 1.2 eq.), CuI (166.30 mg, 0.87 mmol, 29.59 uL, 1 eq.) and K2CO3(241.37 mg, 1.75 mmol, 2 eq.). The resulting mixture was stirred at 100 °C for 5 min under N2atmosphere. To above mixture was added DMEDA (76.97 mg, 0.87 mmol, 1 eq.) dropwise. The resulting mixture was stirred at 100 °C for 16 h under the N2atmosphere. The reaction was monitored by LCMS. The resulting mixture was cool down to room temperature. The solids were filtered out. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA / PE) to afford 3-((tert-butyldimethylsilyl)oxy)-2-methyl-2-(4-((1-methyl-1H-pyrazol-3-yl)amino)-2- (methylthio)pyrimidin-5-yl)propan-1-ol (300 mg, 0.67 mmol, 81% yield) as a white solid. LCMS (ES, m / z): 424 [M+H]+ , Rt 0.702 min. Step 2.5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2- (methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine To a stirred mixture of 3-((tert-butyldimethylsilyl)oxy)-2-methyl-2-(4-((1-methyl-1H- pyrazol-3-yl)amino)-2-(methylthio)pyrimidin-5-yl)propan-1-ol (250 mg, 590.11 umol, 1 eq.) in THF (5 mL) was added PPh3 (309.56 mg, 1.18 mmol, 2 eq.) and DIAD (238.65 mg, 1.18 mmol, 2 eq.) dropwise. The resulting mixture was stirred for 3 h at 50 °C under N2atmosphere. The reaction was monitored by LCMS. The resulting mixture was cool down to room temperature and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:4 EA / PE) to afford 5-(((tert-butyldimethylsilyl) oxy)methyl)-5- methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.47 mmol, 83% yield) as a white solid. LCMS (ES, m / z): 406 [M+H]+, Rt 0.756 min. Step 3. 5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2- (methylsulfinyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine To a stirred mixture of 5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl- 1H-pyrazol-3-yl)-2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (250 mg, 0.62 mmol, 1 eq.) in DCM (5 mL) was added m-CPBA (127.63 mg, 0.74 mmol, 1.2 eq.) under 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 5-(((tert- butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfinyl)-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidine (220 mg, crude) as a brown oil. LCMS (ES, m / z): 422 [M+H]+, Rt 0.798 min. Step 4.5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-N- (3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2- amine To a stirred mixture of 5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl- 1H-pyrazol-3-yl)-2-(methylsulfinyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (80 mg, crude) in toluene (0.5 mL) and DIEA (0.5 mL) was added 3-methyl-4-(4-methylpiperazin-1-yl)aniline (Intermediate 16, 116.86 mg, 0.57 mmol, 3 eq.). The resulting mixture was stirred for 16 h at 100°C. The reaction was monitored by LCMS. The resulting mixture was cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:10 MeOH / DCM) to afford 5-(((tert- butyldimethyl silyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-N-(3-methyl-4-(4- methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine (70 mg, 0.12 mmol, 65% yield) as a white solid. LCMS (ES, m / z): 563 [M+H]+, Rt 0.660 min. Step 5. (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)- N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2- amine and (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3- yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-2-amine The racemic 5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1- methyl-1H-pyrazol-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-2-amine (70 mg, 0.12 mmol, 1 eq.) was separated by Prep-CHIRAL- HPLC (Column: CHIRALPAK IA, 2×25cm, 5um; Mobile Phase A:Hex (0.5% 2M NH3-MeOH), Mobile Phase B:EtOH (15% B in 14min); Flow rate: 20 mL / min; 220 / 254 nm; RT1:9.652; RT2:12.947) to afford (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H- pyrazol-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-2-amine (20 mg, 57% yield) as a white solid and (S)-5-(((tert- butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-N-(3-methyl-4-(4- methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine (15 mg, 43% yield) as a white solid. LCMS (ES, m / z): 563 [M+H]+, Rt 0.660 min. The absolute stereochemistry of two enantiomers was arbitrarily assigned upon the chiral HPLC separation of the racemic mixture and they were used directly in Step 6 below. Step 6. (R)-(5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(4-methylpiperazin-1- yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol and (S)-(5- methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(4-methylpiperazin-1- yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (Examples 77 and 78) To a stirred mixture of (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1- methyl-1H-pyrazol-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-2-amine (15 mg, 26.65 umol, 1 eq.) in THF (2.5 mL) were added concentrated HCl (0.5 mL) dropwise. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30×150mm 5um; Mobile Phase A:Water (10MMOL / L NH4HCO3), Mobile Phase B: ACN (24% to 44%B in 7 min); Flow rate:60 mL / min; 254 nm; RT:6.07) to afford (R)-(5- methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (9.6 mg, 79% yield) as a white solid. To a stirred mixture of (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-7-(1- methyl-1H-pyrazol-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-2-amine (15 mg, 26.65 umol, 1 eq.) in THF (2.5 mL) were added concentrated HCl (0.5 mL) dropwise. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30×150mm 5um; Mobile Phase A:Water (10MMOL / L NH4HCO3), Mobile Phase B: ACN (24% to 44%B in 7 min); Flow rate:60 mL / min; 254 nm; RT:5.87) to afford (S)-(5- methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (4.6 mg, 38 % yield) as a white solid. Example 77:1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.85 (s, 1H), 7.68-7.62 (m, 2H), 7.41 (d, J = 8.7 Hz, 1H), 6.96-6.91 (m, 2H), 5.03 (t, J = 5.4 Hz, 1H), 4.01-3.97 (m, 1H), 3.78 (s, 3H), 3.61-3.39 (m, 5H), 2.83-2.74 (m, 6H), 2.25 (s, 3H), 2.24 (s, 3H), 1.31 (s, 3H). LCMS (ES, m / z): 449 [M+H]+, Rt 0.544 min. Example 78:1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.85 (s, 1H), 7.68-7.62 (m, 2H), 7.42-7.39 (m, 1H), 6.96-6.91 (m, 2H), 5.04-5.01 (m, 1H), 4.01-3.95 (m, 1H), 3.78 (s, 3H), 3.59- 3.52 (m, 1H), 3.46-3.39 (m, 4H), 2.85-2.78 (m, 4H), 2.51-2.47 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.31 (s, 3H). LCMS (ES, m / z): 449 [M+H]+, Rt 0.539 min. Examples 79 and 80: (R)-(5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl)methanol and (S)-(5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl)methanol Title compounds are prepared in an analogous manner to Examples 77 and 78, except with Intermediate 14 being used in place of Intermediate 16 in step 4. Chiral separation details: Column: Lux 5um Cellulose-2 , 2.12X25cm,5μm; Mobile Phase A:Hex(0.5% 2M NH3-MeOH)-- HPLC, Mobile Phase B:EtOH—HPLC(10% to 10% in 13 min); Flow rate:20 mL / min; 254 / 220 nm; RT1:9.518; RT2:11.524 to afford (R)-(5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl- 4-(1-methylpiperidin-4-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl)methanol and (S)-(5-methyl-7-(1-methyl-1H-pyrazol-3-yl)-2-((3-methyl-4-(1-methylpiperidin- 4-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol. Example 79:1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.86 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.93 (s, 1H), 5.05- 5.03 (m, 1H), 4.08-3.99 (m, 1H), 3.79 (s, 3H), 3.66-3.60 (m, 1H), 3.47-3.40 (m, 1H), 2.95-2.89 (m, 2H), 2.59-2.51 (m, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 2.02-1.98 (m, 2H), 1.69-1.62 (m, 4H), 1.31 (s, 3H). LCMS (ES, m / z): 448 [M+H]+, Rt 0.558 min. Example 80:1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.86 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.47-7.40 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 5.05-5.03 (m, 1H), 4.05-4.01 (m, 1H), 3.79 (s, 3H), 3.65-3.61 (m, 1H), 3.58-3.39 (m, 1H), 2.88- 2.81 (m, 2H), 2.59-2.51 (m, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 2.03-1.95 (m, 2H), 1.67-1.61 (m, 4H), 1.31 (s, 3H). LCMS (ES, m / z): 448 [M+H]+, Rt 0.550 min. Examples 81, 82, 83 and 84: ((6-((5S,6R)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4- (1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone, ((6-((5R,6S)-5-(hydroxymethyl)-5,6-dimethyl- 2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone, ((6-((5R,6R)-5- (hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6- dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone, ((6- ((5S,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone

[0086] Step 1. rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-2-(methylthio)pyrimidin-5- yl)-3-methylbutan-2-ol and rac-(2R,3R)-4-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-2- (methylthio)pyrimidin-5-yl)-3-methylbutan-2-ol To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-(methylthio) pyrimidin-5-yl)-2-methylpropanal (Intermediate 32, 1.3 g, 3.60 mmol, 1 eq.) in DCM (150 mL) was added chloro(methyl)magnesium (3 M, 2.40 mL, 2 eq.) dropwise at 0 °C. The resulting mixture was stirred for 2 h at 25 °C. The reaction was monitored by TLC. The mixture was quenched with ice / water (50 mL). The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA / PE) to afford rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)- 3-(4-chloro-2-(methylthio)pyrimidin-5-yl)-3-methylbutan-2-ol (540 mg, 1.44 mmol, 79% yield) (1a) as a white oil and rac-(2R,3R)-4-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-2- (methylthio)pyrimidin-5-yl)-3-methylbutan-2-ol (580 mg, 1.56 mmol, 86% yield) (1b) as a white oil. 1a:1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 4.78 (d, J = 5.6 Hz, 1H), 4.49 (p, J = 6.4 Hz, 1H), 4.39 (d, J = 10.0 Hz, 1H), 3.65 (d, J = 10.0 Hz, 1H), 1.36 (s, 3H), 0.84 (d, J = 6.4 Hz, 3H), 0.69 (s, 9H), -0.06 (s, 3H), -0.10 (s, 3H). LCMS (ES, m / z): 377 [M+H]+, Rt 0.984 min. 1b:1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 4.68 (d, J = 5.2 Hz, 1H), 4.40-4.32 (m, 1H), 4.22 (d, J = 10.0 Hz, 1H), 3.62 (d, J = 10.0 Hz, 1H), 1.35 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.69 (s, 9H), -0.04 (s, 6H). LCMS (ES, m / z): 377 [M+H]+, Rt 0.991 min. Step 2. rac-(2R,3S)-3-(4-azido-2-(methylthio)pyrimidin-5-yl)-4-((tert- butyldimethylsilyl)oxy)-3-methylbutan-2-ol A mixture of rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-2- (methylthio)pyrimidin-5-yl)-3-methylbutan-2-ol (1a, 550 mg, 1.46 mmol, 1 eq.) and sodium azide (284.51 mg, 4.38 mmol, 3 eq.) in DMF (100 mL) was stirred for 16 h at 60 °C. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature and then diluted with brine (100 mL). The resulting mixture was extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford rac-(2R,3S)-3-(4-azido-2-(methylthio)pyrimidin-5-yl)-4-((tert- butyldimethylsilyl)oxy)-3-methylbutan-2-ol (350 mg, crude) as a yellow oil. LCMS (ES, m / z): 384 [M+H]+, Rt 0.840 min. Step 3-4. rac-(2R,3S)-3-(4-amino-2-(methylthio)pyrimidin-5-yl)-4-((tert- butyldimethylsilyl)oxy)-3-methylbutan-2-ol A solution of rac-(2R,3S)-3-(4-azido-2-(methylthio)pyrimidin-5-yl)-4-((tert- butyldimethylsilyl)oxy)-3-methylbutan-2-ol (200 mg, 521.40 umol, 1 eq.) and tributylphosphane (316.46 mg, 1.56 mmol, 3 eq.) in toluene (5 mL) was stirred for 2 h at 100 °C under N2atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure to afford the crude product (250 mg, crude) which was dissolved in THF (3 mL), H2O (0.5 mL) and HOAc (1.5 mL). The reaction mixture was stirred for 2 h at 100 °C. The reaction progress was monitored by LC- MS. The mixture was allowed to cool down to room temperature. The resulting mixture was neutralized to pH = 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to afford rac-(2R,3S)-3-(4-amino-2- (methylthio)pyrimidin-5-yl)-4-((tert-butyldimethylsilyl)oxy)-3-methylbutan-2-ol (140 mg, 371.94 umol, 91% yield) as a white solid. LCMS (ES, m / z): 358 [M+H]+, Rt 0.641 min. Step 5. rac-((6-((5-((2R,3S)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylbutan-2-yl)- 2-(methylthio)pyrimidin-4-yl)amino)pyridin-2-yl)imino)dimethyl-λ6-sulfanone A mixture of rac-(2R,3S)-3-(4-amino-2-(methylthio)pyrimidin-5-yl)-4-((tert- butyldimethylsilyl)oxy)-3-methylbutan-2-ol (220 mg, 615.24 umol, 1 eq.), ((6-bromopyridin-2- yl)imino)dimethyl-λ6-sulfanone (Intermediate 7, 183.93 mg, 738.28 umol, 1.2 eq.), BINAP-Pd G2 (2.61 mg, 61.51 umol, 0.1 eq.), cesium carbonate (400.91 mg, 1.23 mmol, 2 eq.) and BINAP (80.07 mg, 123.05 umol, 0.2 eq.) in dioxane (4 mL) was stirred for 2 h at 100 °C under N2atmosphere. The mixture was allowed to cool down to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10:1 DCM / MeOH) to afford rac-((6-((5-((2R,3S)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2- methylbutan-2-yl)-2-(methylthio)pyrimidin-4-yl)amino)pyridin-2-yl)imino)dimethyl-λ6- sulfanone (280 mg, 505.89 umol, 87% yield) as a yellow solid. LCMS (ES, m / z): 526 [M+H]+, Rt 0.709 min. Step 6. rac-((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2- (methylthio)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6- sulfanone A solution of rac-((6-((5-((2R,3S)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2- methylbutan-2-yl)-2-(methylthio)pyrimidin-4-yl)amino)pyridin-2-yl)imino)dimethyl-λ6- sulfanone (280 mg, 532.52 umol, 1 eq.), DIAD (215.36 mg, 1.07 mmol, 2 eq.) and PPh3(279.34 mg, 1.07 mmol, 2 eq.) in THF (5 mL) was stirred for 2 h at 50 °C under N2atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EA) to afford rac-((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2- (methylthio)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6- sulfanone (240 mg, 449.01 umol, 89% yield) as a yellow solid. LCMS (ES, m / z): 508 [M+H]+, Rt 0.707 min. Step 7. rac-((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2- (methylsulfinyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl- λ6-sulfanone To a stirred mixture of rac-((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6- dimethyl-2-(methylthio)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone (150 mg, 295.27 umol, 1 eq.) in DCM (3 mL) was added m-CPBA (61.30 mg, 354.33 umol, 1.2 eq.) under 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford rac-((6- ((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-(methylsulfinyl)-5,6-dihydro- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (150 mg, crude) as a yellow oil. LCMS (ES, m / z): 524 [M+H]+, Rt 0.530 min. Step 8. rac-((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl- 4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone To a stirred mixture of rac-((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6- dimethyl-2-(methylsulfinyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone (150 mg, crude) in toluene (0.5 mL) and DIPEA (0.5 mL) was added 3-methyl- 4-(1-methylpiperidin-4-yl)aniline (Intermediate 14, 175.53 mg, 859.13 umol, 3 eq.) at room temperature. The resulting mixture was stirred for 16 h at 100 °C. The reaction was monitored by LC-MS. The resulting mixture was cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (eluting with 10:1 DCM / MeOH) to afford rac-((6-((5R,6S)-5-(((tert- butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6- sulfanone (150 mg, 225.90 umol, 79% yield) as a white solid. LCMS (ES, m / z): 664 [M+H]+, Rt 0.610 min. Step 9. ((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin- 2-yl)imino)dimethyl-λ6-sulfanone and ((6-((5S,6R)-5-(((tert-butyldimethylsilyl)oxy)methyl)- 5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone rac-((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone (150 mg, 225.90 umol, 1 eq.) was separated by Prep-CHIRAL- HPLC (Column: CHIRALPAK IG, 2×25 cm,5um; Mobile Phase A: Hex:DCM=3:1 (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH(20 % B in 18 min); Flow rate:20 mL / min; 220 / 254 nm; RT1:7.198; RT2:9.423) to afford ((6-((5S,6R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6- dimethyl-2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (50 mg, 67% yield) as a white solid and ((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone (52 mg, 69% yield) as a white solid. LCMS (ES, m / z): 664 [M+H]+, Rt 0.610 min. The absolute stereochemistry of two enantiomers was arbitrarily assigned upon the chiral HPLC separation of the racemic mixture. Step 10. ((6-((5S,6R)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone and ((6-((5R,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((3- methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (Examples 81 and 82) To a stirred mixture of ((6-((5S,6R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3- methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (40 mg, 60.24 umol, 1 eq.) in THF (5 mL) were added HCl (1 mL) dropwise. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30×150mm 5µm; Mobile Phase A: Water(10 MMOL / L NH4HCO3), Mobile Phase B:ACN (21% to 41% B in 7 min); Flow rate:60 mL / min; 254 nm; RT:6.95) to afford ((6-((5S,6R)- 5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6- dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (26.4 mg, 79% yield) as a white solid. To a stirred mixture of ((6-((5R,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl- 2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (40 mg, 60.24 umol, 1 eq.) in THF (5 mL) were added HCl (1 mL) dropwise. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30×150mm 5µm; Mobile Phase A: Water(10MMOL / L NH4HCO3), Mobile Phase B: ACN(23% to 43% B in 7 min); Flow rate: 60 mL / min; 254 nm; RT:6.40) to afford ((6-((5R,6S)-5- (hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6- dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (27.1 mg, 81% yield) as a white solid. Example 81:1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.93 (s, 1H), 7.60-7.50 (m, 2H), 7.44-7.41 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 5.04 (t, J = 5.1 Hz, 1H), 4.75-4.69 (m, 1H), 3.48 (s, 3H), 3.34 (s, 3H), 3.29-3.20 (m, 2H), 2.91- 2.83 (m, 2H), 2.59-2.51 (m, 1H), 2.29 (s, 3H), 2.21 (s, 3H), 2.03-1.95 (m, 2H), 1.73-1.66 (m, 4H), 1.36-1.18 (m, 6H). LCMS (ES, m / z): 550 [M+H]+, Rt 0.686 min. Example 82:1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.93 (s, 1H), 7.60-7.50 (m, 2H), 7.44-7.41 (m, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.75-4.69 (m, 1H), 3.48 (s, 3H), 3.33 (s, 3H), 3.29-3.20 (m, 2H), 2.91-

[0087] 2.85 (m, 2H), 2.63-2.56 (m, 1H), 2.28 (s, 3H), 2.21 (s, 3H), 2.03-1.94 (m, 2H), 1.69-1.62 (m, 4H), 1.30-1.25 (m, 6H). LCMS (ES, m / z): 550 [M+H]+, Rt 0.689 min. Step 11. ((6-((5R,6R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4- (1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone and ((6-((5S,6S)-5-(((tert- butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone rac-((6-((5R,6R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone was prepared following the experimental proceures decribed for Examples 81-82 (steps 2-8) starting from rac-(2R,3R)-4-((tert-butyldimethylsilyl)oxy)-3-(4- chloro-2-(methylthio)pyrimidin-5-yl)-3-methylbutan-2-ol (1b). rac-((6-((5R,6R)-5-(((tert- butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6- sulfanone (85 mg, 128.01 umol) was separated by chiral-HPLC (Column: CHIRALPAK IE, 2×25 cm, 5 μm; Mobile Phase A: Hex: DCM=3:1(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 10% B in 20 min; Wave Length: 220 / 254 nm; RT1(min): 13.881; RT2(min): 17.272) to afford ((6-((5R,6R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl- 2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (32 mg, 75% yield) and ((6-((5S,6S)-5-(((tert- butyldimethylsilyl)oxy)methyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6- sulfanone (33 mg, 78% yield) as a colorless oil. The absolute stereochemistry of two enantiomers was arbitrarily assigned upon the chiral HPLC separation of the racemic mixture. Step 12. ((6-((5R,6R)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone and ((6-((5S,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((3- methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (Examples 83 and 84) To a stirred solution of ((6-((5R,6R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl- 2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (48.49 mg, 73.03 umol, 1 eq) in dioxane (2 mL) and HCl (1 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC (Column: XSelect CSH Fluoro Phenyl, 30 mm×150 mm, 5um; Mobile Phase A: water (50 MMOL / L NH4HCO3), Mobile Phase B:ACN; Flow rate:60 mL / min; Gradient:24% to 44% B in 9 min, 254 nm; RT: 7min) to afford ((6-((5R,6R)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone (20.8 mg, 51% yield) as a white solid. To a stirred solution of ((6-((5S,6S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dimethyl- 2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone (48.49 mg, 73.03 umol) in dioxane (2 mL) and HCl (1 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 µm; Mobile Phase A: water (50 MMOL / L NH4HCO3), Mobile Phase B: ACN; Flow rate:60 mL / min; Gradient:24% to 44% B in 9 min, 254 nm; RT: 7.8min) to afford ((6-((5S,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(1- methylpiperidin-4-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone (18.4 mg, 45 yield) as a white solid. Example 83:1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.04-7.96 (m, 2H), 7.58-7.51 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 5.00 (t, J = 2.4 Hz, 1H), 4.49-4.46 (m, 1H), 3.76-3.58 (m, 2H), 3.43 (s, 3H), 3.32 (s, 3H), 2.88-2.85 (m, 2H), 2.60- 2.54 (m, 1H), 2.27 (s, 3H), 2.19 (s, 3H), 2.00-1.94 (m, 2H), 1.64-1.61 (m, 4H), 1.31 (d, J = 6.4 Hz, 3H), 1.24 (s, 3H). LCMS (ES, m / z): 550 [M+H]+. Rt 0.693 min. Example 84:1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.04-8.02 (m, 1H), 7.96 (s, 1H), 7.58-7.51 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 5.00 (t, J = 2.4 Hz, 1H), 4.48-4.46 (m, 1H), 3.76-3.66 (m, 2H), 3.43 (s, 3H), 3.32 (s, 3H), 2.88-2.85 (m, 2H), 2.58-2.56 (m, 1H), 2.27 (s, 3H), 2.19 (s, 3H), 2.00-1.94 (m, 2H), 1.66-1.61 (m, 4H), 1.31 (d, J = 6.4 Hz, 3H), 1.25 (s, 3H). LCMS (ES, m / z): 550 [M+H]+. Rt 0.692 min. Examples 85, 86, 87, 88 ((6-((5R,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(4- methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin- 2-yl)imino)dimethyl-λ6-sulfanone, ((6-((5S,6R)-5-(hydroxymethyl)-5,6-dimethyl-2-((3- methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone, ((6-((5R,6R)-5-(hydroxymethyl)-5,6- dimethyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ6-sulfanone, ((6-((5S,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((3-methyl-4-(4-methylpiperazin-1- yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2- yl)imino)dimethyl-λ6-sulfanone Examples 85 and 86 were prepared in an analogous manner to Examples 81-82, except with 3- methyl-4-(4-methylpiperazin-1-yl)aniline (Intermediate 16) being used in place of 3-methyl-4-(1-methylpiperidin-4-yl)aniline in step 8. Example 85:1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.43-7.40 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.32 (d, J = 7.8 Hz, 1H), 5.04 (t, J = 5.1 Hz, 1H), 4.75-4.68 (m, 1H), 3.47 (s, 3H), 3.30-3.19 (m, 5H), 2.87-2.82 (m, 4H), 2.75-2.70 (m, 4H), 2.40 (s, 3H), 2.25-2.20 (m, 3H), 1.32-1.22 (m, 6H). LCMS (ES, m / z): 551 [M+H]+, Rt 1.138 min. Example 86:1H NMR (300 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.32 (d, J = 7.8 Hz, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.75-4.68 (m, 1H), 3.48 (s, 3H), 3.34 (s, 3H), 3.30-3.19 (m, 2H), 2.84-2.78 (m, 4H), 2.51-2.42 (m, 4H), 2.32-2.28 (m, 6H), 1.29-1.24 (m, 6H). LCMS (ES, m / z): 551 [M+H]+, Rt 0.688 min. Examples 87 and 88 were prepared in an analogous manner to Examples 83-84, except with 3- methyl-4-(4-methylpiperazin-1-yl)aniline (Intermediate 16) being used in place of 3-methyl-4- (1-methylpiperidin-4-yl)aniline in step 8. Example 87:1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.05 (d, J = 8.1Hz, 1H), 7.97 (s, 1H), 7.66-7.65 (m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 7.5 Hz, 1H), 5.01 (t, J = 4.5 Hz, 1H), 4.52-4.45 (m, 1H), 3.79-3.67 (m, 2H), 3.44 (s, 3H), 3.36 (s, 3H), 3.18-2.85 (m, 8H), 2.64 (s, 3H), 2.26 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.26 (s, 3H). LCMS (ES, m / z): 551 [M+H]+. Rt 0.843 min. Example 88:1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.05 (d, J = 8.1Hz, 1H), 7.97 (s, 1H), 7.63-7.52 (m, 2H), 7.42-7.38 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 5.01 (t, J = 4.5 Hz, 1H), 4.51-4.45 (m, 1H), 3.79-3.67 (m, 2H), 3.44 (s, 3H), 3.36 (s, 3H), 2.83-2.80 (m, 4H), 2.47-2.41 (m, 4H), 2.24 (s, 6H), 1.33 (d, J = 6.3 Hz, 3H), 1.26 (s, 3H). LCMS (ES, m / z): 551 [M+H]+. Rt 0.700 min.

[0088] Examples 89 and 90 (S)-3-(6-((5S,6R)-5-(hydroxymethyl)-5,6-dimethyl-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin- 2-yl)-4-methyloxazolidin-2-one and (S)-3-(6-((5R,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((4- (4-methylpiperazin-1-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyridin-2-yl)-4-methyloxazolidin-2-one Examples 89 and 90 were prepared in an analogous manner to Examples 81-82, except with (S)- 3-(6-bromopyridin-2-yl)-4-methyloxazolidin-2-one (Intermediate 4) being used in place of ((6-bromopyridin-2-yl)imino)dimethyl-λ6-sulfanone in step 5 and with 4-(4-methylpiperazin-1-yl)aniline (Intermediate 11) being used in place of 3- methyl- 4-(1-methylpiperidin-4-yl)aniline in step 8. Chiral purification for 89 and 90: Column: CHIRALPAK IG, 2 x 25 cm,5 μm; Mobile Phase A:MTBE(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B:EtOH—HPLC(50 % to 50 % in 13 min); Flow rate:20 mL / min; 220 / 254 nm; RT1: 5.667 min; RT2: 9.540 min. Compound 89:1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.61-7.54 (m, 3H), 6.90 (d, J = 9.2 Hz, 2H), 5.03 (t, J = 5.2 Hz, 1H), 4.93-4.90 (m, 1H), 4.82-4.78 (m, 1H), 4.54 (t, J = 8.4 Hz, 1H), 4.12-4.09 (m, 1H), 3.25-3.15 (m, 2H), 3.09-3.01 (m, 4H), 2.50-2.39 (m, 4H), 2.25 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.27 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H). LCMS (ES, m / z): 545 [M+H]+, Rt 0.615 min. Compound 90:1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 7.95 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.64-7.55 (m, 3H), 6.93-6.90 (m, 2H), 5.02 (t, J = 5.4 Hz, 1H), 4.82- 4.72 (m, 2H), 4.58 (t, J = 8.1 Hz, 1H), 4.12-4.08 (m, 1H), 3.30-3.23 (m, 2H), 3.13-3.10 (m, 4H), 2.65-2.60 (m, 4H), 2.33 (s, 3H), 1.49 (d, J = 6.0 Hz, 3H), 1.34-1.25 (m, 6H). LCMS (ES, m / z): 545 [M+H]+, Rt 0.581 min. Examples 91 and 92 (S)-3-(6-((5R,6R)-5-(hydroxymethyl)-5,6-dimethyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin- 2-yl)-4-methyloxazolidin-2-one and (S)-3-(6-((5S,6S)-5-(hydroxymethyl)-5,6-dimethyl-2-((4- (4-methylpiperazin-l-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyridin-2-yl)-4-methyloxazolidin-2-one

[0089] Examples 91 and 92 were prepared in an analogous manner to Examples 83-84, except with (S)- 3-(6-bromopyridin-2-yl)-4-methyloxazolidin-2-one (Intermediate 4) being used in place of ((6- bromopyridin-2-yl)imino)dimethyl-X6-sulfanone in step 5 and with 4-(4-methylpiperazin-1- yl)aniline (Intermediate 11) being used in place of 3-methyl-4-(l-methylpiperidin-4-yl)aniline in step 8.

[0090] Chiral purification details for examples 91 and 92: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 pm; Mobile Phase A: Hex(0.1% 2M NH3-MeOH)-HPLC, Mobile Phase B EtOH— HPLC(20 % to 20 % in 12 min); Flow rate:20 mL / min; 220 / 254 nm; RT1 : 9.27 min; RT2: 10.663 mm.

[0091] Example 91: NMR (400 MHz, DMSO-d6) 5 9.09 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 5.03 (t, J = 4.8 Hz, 1H), 4.80-4.76 (m, 1H), 4.56 (t, J = 8.4 Hz, 1H), 4.49-4.44 (m, 1H), 4.09- 4.07 (m, 1H), 3.79-3.67 (m, 2H), 3.07-3.02 (m, 4H), 2.51-2.43 (m, 4H), 2.25 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.22 (s, 3H). LCMS (ES, m / z): 545 [M+HJ+, Rt 0.592 min. Example 92:JH NMR (400 MHz, DMSO-d6) 5 9.09 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.81 (t, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.04 (t, J = 4.8 Hz, 1H), 4.93-4.88 (m, 1H), 4.62-4.51 (m, 2H), 4.01-4.08 (m, 1H), 3.81-3.69 (m, 2H), 3.11-3.02 (m, 4H), 2.51-2.40 (m, 4H), 2.28 (s, 3H), 1.38 (d, J = 6.2 Hz, 3H), 1.26-1.21 (m, 6H). LCMS (ES, m / z): 545 [M+HJ+, Rt 0.589 min.

[0092] SUBSTITUTE SHEET Wee1 Kinase Biochemical Assay Protocol Wee1 kinase domain was purchased from Carna (catalog #05-177). Wee1 kinase activity was determined with Poly(Lys,Tyr 4:1) hydrobromide as a substrate (Sigma-Aldrich) and by measuring ADP production using the ADP-Glo Kinase Assay kit (Promega) following the manufacturer’s instructions. The kinase reaction was performed using the following conditions: Buffer: 40 mM Tris-HCl, 20 mM magnesium chloride, supplemented with 0.1 mg / mL bovine serum albumin and 2 mM DTT. The final reaction mix contained 1 nM Wee1 enzyme, 15 μM ATP, and 2 ng / mL Poly(Lys,Tyr 4:1) hydrobromide substrate. The reaction time was 4 hours at 25 °C. The ADP-Glo signal was measured using the Envision plate reader and the percentage inhibition of kinase activity calculated for each inhibitor tested. Percent inhibition of Wee1 kinase activity was calculated based on the following formula. SSample: the signal of compounds SHigh Ctrl: the signal of high control (DMSO) SLow Ctrl : the signal of low control (positive control Wee1 inhibitor at saturating concentration) Phosphorylated A427 Cdc2 MSD Electrochemiluminescence Assay The effect of Wee1 inhibitors on cellular phosphorylation of the Wee1 substrate Cdc2 was determined using the following protocol: A total of 20,000 A427 cells in 100 μL culture medium (1640 medium + 10% Fetal bovine serum + 1% Penicillin-Streptomycin) were plated in 96-well cell culture plates. 3-fold serial dilutions of test compounds were prepared in completed PBS at 25X final concentration. The compound source plates were then incubated at room temperature with shaking for 30 minutes. After 20 hours, the cell plates were removed and 4 µL of the compounds were added to the wells of the plates. After 4 hours, the plates were centrifuged at 3000 rpm for 5 minutes. and 100 μL of supernatant from each well was removed. Cells were washed with 200 µL PBS and lysed with 50 µL MSD lysis buffer (Meso Scale Diagnostics) supplied with 1X complete ULTRA cocktail inhibitor (Roche), PMSF and Na3VO4, and incubated with shaking for 2 hours. Cell lysates were aliquoted and stored at -80 °C. To detect phosphorylation of Cdc2 Y15, 30 μL of capture antibody solution (CST catalog #9116S 1:200) was added into each well of the MSD plate (MSD catalog # L15XB-6), sealed and incubated at 4°C with shaking (450 rpm) overnight. The antibody solution was removed, wells blocked with BSA solution and plates washed three times with PBST, followed by addition of 30 µl of cell lysate per well. After 2 hours of incubation, plates were washed three times with PBST. 30 μL of 1X detection antibody solution (CST catalog #4539S 1:200) was then added to each well and incubated for 1 hour. Plates were washed three times with PBST and 30 μL of 1X secondary antibody solution (MSD, catalog #:R32AB-1, 1:5000) was added to each well and incubated for 1 hour. Plates were washed three times with PBST and 150 μL of 1X Read Buffer T (MSD, catalog #R92TC-1) was added to each well of the MSD plate. The electrochemiluminescence signal was measured on a MESO SECTOR S600 plate reader. The percentage of remaining phosphorylated Cdc2 signal was calculated following the equation below. HC (high control): Cells treated with DMSO Cpds: Cells treated with test compounds LC (low control): Cells treated with positive control Wee1 inhibitor The Wee1 IC50 ranges in Table A are as follows: A: IC50< 10 nM; B: 10 nM ≤ IC50< 100 nM; C: 100 nM ≤ IC50< 1000 nM; D: IC50≥ 1000 nM. The A427 pCDC2 IC50ranges in Table A are as follows: A: IC50< 100 nM; B: 100 nM ≤ IC50< 1000 nM; C: 1000 nM ≤ IC50< 10000 nM; D: IC50≥ 10000 nM. Table A. Biological data obtained in the biological assays. Numbered Embodiments 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1Aand R1Bare each independently hydrogen or C1-C6 alkyl; R2is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, each optionally substituted with 1-3 independently selected RA; each RAis independently halogen, cyano, –NRDRE, C1-C6 alkyl optionally substituted with hydroxyl, –NRBRC, –C(=O)NRBRC, or –NH(C=O)NH2; –C(=O)NRBRC, –N=S(O)Me2, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxyl, or C1-C6 alkyl optionally substituted with –NRBRC; or C3-C6 cycloalkyl optionally substituted with –NRBRC; each RBis independently hydrogen or C1-C6 alkyl; each RCis independently hydrogen or C1-C6 alkyl; each RDis independently hydrogen or C1-C6 alkyl; each REis independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl optionally substituted with hydroxyl; R3is hydrogen or C1-C6 alkyl; R4is (i) phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 alkyl optionally substituted with 1 or 2 substituents independently selected from –NRBRC, –CO2H, -(C1-C6 alkyl)n-C(=O)NRFRK, C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 4-12 membered heterocyclyloxy optionally substituted with 1 or 2 independently selected RG, and 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; (ii) 9-12 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl; (iii) 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: C1-C6 alkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 4-12 membered heterocyclyloxy optionally substituted with 1 or 2 independently selected RG, and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino; each RFand RKare independently hydrogen or C1-C6 alkyl; or one RFand one RK, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; RGis independently halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, –NRBRC, C3-C6 cycloalkyl, or =NRH; RHis hydrogen or C1-C6 alkyl; n is 0 or 1; R5is hydrogen, halogen, or C1-C6 alkyl; and R6Aand R6Bare independently C1-C6 alkyl optionally substituted with one hydroxyl or one C1-C6 alkoxy. 2. The compound of embodiment 1, wherein R1Aand R1Bare both hydrogen. 3. The compound of embodiment 1 or 2, wherein R2is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA. 4. The compound of embodiment 1 or 2, wherein R2is 5-6 membered heteroaryl optionally substituted with 1-3 independently selected RA. 5. The compound of embodiment 4, wherein R2is selected from the group consisting of pyridyl, pyrazolyl, and thiazolyl, each optionally substituted with 1-3 independently selected RA. 6. The compound of any one of embodiments 1-5, wherein one RAis C1-C6 alkyl optionally substituted with hydroxyl, –NRBRC, –C(=O)NRBRC, or –NH(C=O)NH2. 7. The compound of one of embodiments 1-6, wherein one RAis C1-C6 alkyl substituted with –NRBRC. 8. The compound of any one of embodiments 1-7, wherein one RAis CH2NRBCH3; wherein RBis hydrogen or methyl. 9. The compound of any one of embodiments 1-5, wherein one RAis –N=S(O)Me2. 10. The compound of any one of embodiments 1-5, wherein one RAis 4-6 membered heterocyclyl optionally substituted with halogen, hydroxyl, or C1-C6 alkyl optionally substituted with –NRBRC. 11. The compound of embodiment 10, wherein one RAis selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, and oxazolidinonyl optionally substituted with C1-C6 alkyl. 12. The compound of embodiment 11, wherein one RAis selected from the group consisting of . 13. The compound of any one of embodiments 1-12, wherein R3is hydrogen. 14. The compound of any one of embodiments 1-12, wherein R3is C1-C6 alkyl. 15. The compound of any one of embodiments 1-14, wherein R4is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 alkyl, -(C1-C6 alkyl)n-C(=O)NRFRK, C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, and 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. 16. The compound of embodiment 15, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is methyl. 17. The compound of embodiment 15, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. 18. The compound of embodiment 17, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. 19. The compound of embodiment 18, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is a 5-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected C1-C6 alkyl, and the optional second substituent is methyl. 20. The compound of embodiment 19, wherein the optionally substituted heterocyclyl attached to the R4phenyl is selected from the group consisting of: . 21. The compound of any one of embodiments 1-14, wherein R4is ; wherein B is independently selected 5-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl. 22. The compound of embodiment 21 wherein B is selected from the group consisting of piperidinyl and pyrrolidinonyl, each optionally substituted with C1-C6 alkyl. 23. The compound of any one of embodiments 1-14, wherein R4is 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino. 24. The compound of embodiment 23, wherein the 5-10 membered heteroaryl of R4is 4-pyrazolyl. 25. The compound of embodiment 24, wherein R4is selected from the group consisting of: 26. The compound of any one of embodiments 1-25, wherein R5is hydrogen. 27. The compound of any one of embodiments 1-26, wherein R6Aand R6Bare both independently selected C1-C3 alkyl substituted with hydroxyl. 28. The compound of embodiment 27, wherein one of R6Aand R6Bis methyl and the other of R6Aand R6Bis –CH2OH. 29. The compound of any one of embodiments 1-26, wherein R6Aand R6Bare independently C1-C6 alkyl substituted with C1-C6 alkoxy. 30. The compound of embodiment 29, wherein one of R6Aand R6Bis –CH3and the other of R6Aand R6Bis –CH2OCH3. 31. The compound of Embodiment 1, wherein the compound is selected from the group consisting of the compounds in Table 1 or Table 2, or a pharmaceutically acceptable salt of either of the foregoing. 32. A pharmaceutical composition comprising a compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 33. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 32. 34. The method of embodiment 33, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung. 35. The method of embodiment 33 or 34, wherein the method further comprises administering to the subject a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof. 36. Use of a compound of any one of embodiments 1 – 31 or a composition of embodiment 32 in the manufacture of a medicament for treating cancer in a patient in need thereof. 37. The use of embodiment 36, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung. 38. A compound or composition for use in the treatment of cancer comprising a compound of any one of embodiments 1 – 31, or a composition of embodiment 32. 39. The compound or composition of embodiment 38, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung. A number of embodiments of the present disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1Aand R1Bare each independently hydrogen or C1-C6 alkyl; R2is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, each optionally substituted with 1-3 independently selected RA; each RAis independently halogen, cyano, –NRDRE, C1-C6 alkyl optionally substituted with hydroxyl, –NRBRC, –C(=O)NRBRC, or –NH(C=O)NH2; –C(=O)NRBRC, –N=S(O)Me2, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxyl, or C1-C6 alkyl optionally substituted with –NRBRC; or C3-C6 cycloalkyl optionally substituted with –NRBRC; each RBis independently hydrogen or C1-C6 alkyl; each RCis independently hydrogen or C1-C6 alkyl; each RDis independently hydrogen or C1-C6 alkyl; each REis independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl optionally substituted with hydroxyl; R3is hydrogen or C1-C6 alkyl; R4is (i) phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 alkyl optionally substituted with 1 or 2 substituents independently selected from –NRBRC, –CO2H, -(C1-C6 alkyl)n-C(=O)NRFRK, C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 4-12 membered heterocyclyloxy optionally substituted with 1 or 2 independently selected RG, and 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; (ii) 9-12 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl;(iii) 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: C1-C6 alkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 4-12 membered heterocyclyloxy optionally substituted with 1 or 2 independently selected RG, and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino; each RFand RKare independently hydrogen or C1-C6 alkyl; or one RFand one RK, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; RGis independently halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, –NRBRC, C3-C6 cycloalkyl, or =NRH; RHis hydrogen or C1-C6 alkyl; n is 0 or 1; R5is hydrogen, halogen, or C1-C6 alkyl; and R6Aand R6Bare independently C1-C6 alkyl optionally substituted with one hydroxyl or one C1-C6 alkoxy.

2. The compound of claim 1, wherein R1Aand R1Bare both hydrogen.

3. The compound of claim 1 or 2, wherein R2is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA.

4. The compound of claim 1 or 2, wherein R2is 5-6 membered heteroaryl optionally substituted with 1-3 independently selected RA.

5. The compound of claim 4, wherein R2is selected from the group consisting of pyridyl, pyrazolyl, and thiazolyl, each optionally substituted with 1-3 independently selected RA.

6. The compound of any one of claims 1-5, wherein one RAis C1-C6 alkyl optionally substituted with hydroxyl, –NRBRC, –C(=O)NRBRC, or –NH(C=O)NH2.

7. The compound of one of claims 1-6, wherein one RAis C1-C6 alkyl substituted with –NRBRC.

8. The compound of any one of claims 1-7, wherein one RAis CH2NRBCH3; wherein RBis hydrogen or methyl.

9. The compound of any one of claims 1-5, wherein one RAis –N=S(O)Me2.

10. The compound of any one of claims 1-5, wherein one RAis 4-6 membered heterocyclyl optionally substituted with halogen, hydroxyl, or C1-C6 alkyl optionally substituted with –NRBRC.

11. The compound of claim 10, wherein one RAis selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, and oxazolidinonyl optionally substituted with C1-C6 alkyl.

12. The compound of claim 11, wherein one RAis selected from the group consisting of.

13. The compound of any one of claims 1-12, wherein R3is hydrogen.

14. The compound of any one of claims 1-12, wherein R3is C1-C6 alkyl.

15. The compound of any one of claims 1-14, wherein R4is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 alkyl, -(C1-C6 alkyl)n-C(=O)NRFRK, C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, and 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG.

16. The compound of claim 15, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is methyl.

17. The compound of claim 15, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is 4-12 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG.

18. The compound of claim 17, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.

19. The compound of claim 18, wherein R4is phenyl substituted with 1 or 2 substituents; wherein one substituent is a 5-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected C1-C6 alkyl, and the optional second substituent is methyl.

20. The compound of claim 19, wherein the optionally substituted heterocyclyl attached to the R4phenyl is selected from the group consisting of:

21. The compound of any one of claims 1-14, wherein R4is; wherein B is independently selected 5-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl.

22. The compound of claim 21 wherein B is selected from the group consisting of piperidinyl and pyrrolidinonyl, each optionally substituted with C1-C6 alkyl.

23. The compound of any one of claims 1-14, wherein R4is 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino.

24. The compound of claim 23, wherein the 5-10 membered heteroaryl of R4is 4-pyrazolyl.

25. The compound of claim 24, wherein R4is selected from the group consisting of:.

26. The compound of any one of claims 1-25, wherein R5is hydrogen.

27. The compound of any one of claims 1-26, wherein R6Aand R6Bare both independently selected C1-C3 alkyl substituted with hydroxyl.

28. The compound of claim 27, wherein one of R6Aand R6Bis methyl and the other of R6Aand R6Bis –CH2OH.

29. The compound of any one of claims 1-26, wherein R6Aand R6Bare independently C1-C6 alkyl substituted with C1-C6 alkoxy.

30. The compound of claim 29, wherein one of R6Aand R6Bis –CH3and the other of R6Aand R6Bis –CH2OCH3.

31. The compound of Claim 1, wherein the compound is selected from the group consisting of the compounds in Table 1 or Table 2, or a pharmaceutically acceptable salt of either of the foregoing.

32. A pharmaceutical composition comprising a compound of any one of Claims 1-31, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

33. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Claims 1-31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 32.

34. The method of claim 33, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung.

35. The method of claim 33 or 34, wherein the method further comprises administering to the subject a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof.

36. Use of a compound of any one of claims 1 – 31 or a composition of claim 32 in the manufacture of a medicament for treating cancer in a patient in need thereof.

37. The use of claim 36, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung.

38. A compound or composition for use in the treatment of cancer comprising a compound of any one of claims 1 – 31, or a composition of claim 32.

39. The compound or composition of claim 38, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung.

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