Tricyclic compounds

Abstract

The present application relates to compounds of formula (I) as defined herein, and pharmaceutically acceptable salts thereof. The present application also describes pharmaceutical compositions comprising the compounds of formula (I) and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions to treat diseases such as cancer. Also provided herein is a method of inhibiting the proliferation of mammalian cells in vitro or in vivo, comprising contacting the mammalian cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. TIFF2025537304000568.tif2950

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 425,218, filed November 14, 2022, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION This application relates to fused heterocyclic compounds that are useful for treating proliferative disorders such as cancer. [Background technology]

[0003] Wee1 is a highly conserved serine / threonine kinase that inhibits cell cycle progression and cell entry into mitosis through the inhibitory phosphorylation of cyclin-dependent kinases 1 and 2 (CDK1 and 2). It is a key regulator of cell cycle progression through the S phase and at the G2-M checkpoint. See, for example, 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).

[0004] In normal cells, the DNA damage response (DDR) is mediated by various checkpoints that either activate DNA repair systems or induce cell apoptosis / senescence, thus maintaining overall genomic integrity. However, in cancer cells, loss or deficiency of the DDR due to oncogenic activation or tumor suppressor inactivation can cause DNA replication to persist to meet the demands of unlimited proliferation despite the presence of unrepaired DNA lesions, which then leads to replication stress (a hallmark of cancer cells that typically involves perturbations in error-free DNA replication and / or slowing of DNA synthesis). See, e.g., Zhang et al., Genes, 2016, 7, 51; 1-16).

[0005] Overexpression and activation of oncogenes are major contributors to replication stress. For example, the oncogenes KRAS, MYC, and CCNE1, as well as CDC25A, cause replication stress by, for example, creating conflicts between replication and transcription, increasing topological stress, and / or causing nucleotide shortages. Replication stress can slow the cellular replication cycle; therefore, to maintain their proliferation program, cancer cells typically have ways to cope with and resolve replication stress to continue proliferation. One example is by bypassing defects in DNA damage repair mechanisms, such as loss of p53, ATM mutations, and homologous recombination repair pathways (e.g., via mutations in BRCA1, BRCA2, and PALB2). See Forment and O'Connor, Pharmacology & Therapeutics, 188 (2018) 155-167. Together, these compensatory mechanisms can lead to increased genomic instability, which in turn leads to further replication stress. Generally, in tumors where DNA damage response elements are bypassed or impaired, 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 early even when DNA replication is defective or incomplete. The increased CDK activity driven by Wee1 inhibition can also rapidly increase replication initiation, resulting in a shortage of nucleotides necessary for DNA replication. Therefore, Wee1 inhibitors may be effective in enhancing replication stress and driving cancer cells experiencing high levels of this stress into early mitosis and subsequent mitotic cell death. However, there are currently no commercially available therapeutic Wee1 inhibitors. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Hamer,et al.,Clin.Cancer Res.,Vol.17,No.13,pp.4200-4207(2011) [Non-patent document 2] McGowan and Russell,EMBO J.,Vol.14,No.10,pp.2166-2175(1995) [Non-patent document 3] Zhang et al,Genes,2016,7,51;1-16 [Non-patent document 4] Forment and O'Connor,Pharmacology & Therapeutics,188(2018)155-167 Summary of the Invention

[0007] Thus, as used herein, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: (R 1 ) m , R 2 , R 3 , R 4 , R 5 , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I Provided are compounds, or pharmaceutically acceptable salts thereof, wherein , m, and n are as defined herein.

[0008] 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.

[0009] Also provided herein is a method of inhibiting the proliferation of mammalian cells in vitro or in vivo, comprising contacting the mammalian cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0010] Also provided herein is a method for 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) as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein is a method of treating cancer, for example, uterine cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer, 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) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0012] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (a) Identifying cancers as having replication stress; and (b) administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0013] Provided herein is a method of treating cancer in a subject in need thereof, comprising: Also provided is a method comprising administering to a subject identified as having a cancer with replication stress an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0014] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (a) identifying the cancer as having an inactivated tumor suppressor gene; (b) administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0015] Provided herein is a method of treating cancer in a subject in need thereof, comprising: Also provided is a method comprising administering to a subject identified as having a cancer with an inactivated tumor suppressor gene an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0016] Provided herein is a method of treating cancer in a subject in need thereof, 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) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0017] Provided herein is a method of treating cancer in a subject in need thereof, comprising: Also provided is a method comprising administering to a subject identified as having a cancer with an activated oncogene an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0018] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) an effective amount of (a) DNA damaging agents; (b) DNA repair inhibitors; (c) radiation; (d)(a) and (b); (e)(a) and (c); (f)(b) and (c); (g) administering to the subject a therapeutic agent comprising (a), (b), and (c); (ii) after (i), administering to the subject an effective amount of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] Provided herein is a method of treating cancer in a subject in need thereof, comprising: an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, (a) DNA damaging agents; (b) DNA repair inhibitors; (c) radiation; (d)(a) and (b); (e)(a) and (c); (f)(b) and (c); (g) A method is also provided, comprising administering to a subject who has previously been administered one or more doses of a therapeutic agent comprising (a), (b), and (c).

[0020] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, (ii) an effective amount of (a) DNA damaging agents; (b) DNA repair inhibitors; (c) radiation; (d)(a) and (b); (e)(a) and (c); (f)(b) and (c); (g) A method is also provided that includes administering to a subject a therapeutic agent that includes (a), (b), and (c).

[0021] Also provided herein is a method for inducing mitotic disruption in a mammalian cell, comprising contacting the mammalian cell with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0022] Also provided herein is a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer (e.g., a cancer with replication stress).

[0023] Also provided herein is a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0024] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibiting Wee1 kinase activity.

[0025] 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 embodiments, the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung cancer.

[0026] There is also provided herein the use of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of Wee1 kinase activity.

[0027] Also provided herein are processes for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0028] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof obtained by the process for preparing the compounds defined herein.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials are described herein for use in this disclosure, and other suitable methods and materials known in the art can also be used.Materials, methods, and examples are illustrative only and are 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 prevail.

[0030] Other features and advantages of the present disclosure will become apparent from the following detailed description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0031] definition The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. A compound identified herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

[0032] The term "tautomer," as used herein, refers to compounds that differ significantly in structure in the arrangement of atoms, but exist in easy and rapid equilibrium; the compounds provided herein may be represented as different tautomers; it should be understood that, where a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of a compound does not exclude any tautomer. Examples of tautomeric forms include the following: [ka] .

[0033] It will be understood that certain compounds provided herein may contain one or more asymmetric centers and, therefore, may be prepared and isolated in mixtures of isomers, such as racemic mixtures, or in enantiomerically pure form.

[0034] The term "halo" refers to the halogens, one of Group 17 of the periodic table. Specifically, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0035] The term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Similarly, a C1-C3 alkyl group is a straight or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms.

[0036] The term "C1-C6 deuteroalkyl" refers to an alkyl group, as described herein, in which one or more hydrogen atoms are replaced with deuterium, such as -CD3.

[0037] The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group attached to a molecule through an oxygen. It includes moieties where the alkyl part can be straight or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0038] As used herein, the term "cyano" refers to the -CN radical.

[0039] As used herein, the term "hydroxyl" refers to the --OH radical.

[0040] As used herein, the term "amino" refers to the -NH2 radical.

[0041] As used herein, the term "C6-C10 aryl" refers to a 6-10 carbon monocyclic or bicyclic ring system in which at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl. In bicyclic ring systems in which only one ring is aromatic, the non-aromatic ring may be a cycloalkyl group, as defined herein.

[0042] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic group having, for example, 5 to 10 ring atoms, in which the ring system is aromatic and in which one or more carbon atoms in at least one ring in the system are replaced by a heteroatom independently selected from N, O, and S. Non-limiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, pyrazole, imidazole, and indole.

[0043] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated 3-10 monocyclic or bicyclic hydrocarbon group, where 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.

[0044] The term "heterocyclyl" refers to a saturated or partially unsaturated 3- to 12-membered hydrocarbon monocyclic or bicyclic ring system having at least one heteroatom in the ring selected from N, O, and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. Heterocyclyl ring systems can include oxo substitution at one or more C, N, or S ring members. In bicyclic ring systems, if one ring is not aromatic, the other ring can be aromatic. For example, one ring can be phenyl and the other can be pyrrolidine, or one ring can be pyridine and the other can be cyclohexane. Heterocyclyl groups may be referred to, for example, as "5- to 10-membered heterocyclyl groups," which are ring systems containing 5, 6, 7, 8, 9, or 10 atoms, with at least one atom being a heteroatom. For example, there can be 1, 2, or 3 heteroatoms, optionally 1 or 2. Heterocyclyl groups can be attached to the remainder of the molecule through any carbon atom or heteroatom, such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazolidine S,S-dioxide, and decahydronaphthalenyl.

[0045] The term "heterocyclyloxy" refers to a heterocyclyl group attached to a molecule via an oxygen atom.

[0046] As used herein, the term "oxo" refers to an "=O" group attached to a carbon atom.

[0047] As used herein, the symbols [ka] indicates the point of attachment of the atom or moiety to the indicated atom or group in the remainder of the molecule.

[0048] The compound of formula (I) includes its pharmaceutically acceptable salts. In addition, the compound of formula (I) also includes other salts of such compounds that are not necessarily pharmaceutically acceptable salts, but may be useful as intermediates for preparing and / or purifying the compound of formula (I) and / or for separating the enantiomers of the compound of formula (I). Non-limiting examples of pharmaceutically acceptable salts of the compound of formula (I) include trifluoroacetic acid and hydrochloride salts.

[0049] Furthermore, it will be understood that the compounds of formula (I) or their salts may be isolated in the form of a solvate, and therefore, any such solvates are included within the scope of the present disclosure. For example, the compounds of formula (I) and their salts may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0050] In one embodiment, the compounds of Formula (I) include the compounds of Examples 1-832, and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Examples 1-832 are present in the form of a free base. In some embodiments, the compounds of Examples 1-832 are present in the form of a pharmaceutically acceptable salt.

[0051] The term "pharmaceutically acceptable" indicates that a compound, or salt thereof, or composition is chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or the subject being treated therewith.

[0052] The compounds provided herein may also contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute such compounds. That is, when atoms are specifically referred to in relation to compounds according to formula (I), they include all isotopes and isotopic mixtures of the atoms, whether naturally occurring or synthetically produced, with natural abundance or in isotopically enriched form. For example, unless otherwise specified, when hydrogen is referred to, 1 H, 2 H, 3H, or mixtures thereof, and when carbon is mentioned, 11 C. 12 C. 13 C. 14 C, or mixtures thereof, and when nitrogen is mentioned, 13 N, 14 N, 15 N, or mixtures thereof, and when oxygen is mentioned, 14 O. 15 O. 16 O. 17 O. 18 0, or mixtures thereof, and when fluoro is mentioned, 18 F, 19 F, or mixtures thereof. For example, in deuteroalkyl and deuteroalkoxy groups, one or more hydrogen atoms are replaced with deuterium ( 2 Some of the aforementioned isotopes are radioactive, and therefore the compounds provided herein also include compounds with one or more isotopes of one or more atoms, including radioactive compounds, and mixtures thereof, in which one or more non-radioactive atoms are replaced by one of their radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, for example, cancer therapeutic agents, research reagents, for example, assay reagents, and diagnostic agents, for example, in vivo imaging agents. All isotopic variations of all compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0053] Protecting groups may be temporary substituents that protect potentially reactive functional groups from undesired chemical transformations. The selection of the particular protecting group used is well within the skill of one of ordinary skill in the art. Several considerations can determine the selection of a protecting group, including, but not limited to, the functional group to be protected, other functionalities present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, functional group resistance to conditions required to remove the protecting group, and reaction conditions for thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGMP Protective Groups in Organic Synthesis, 2004). nd ed.; Wiley: New York, 1991) (hereby incorporated by reference in its entirety).

[0054] The ability of selected compounds to act as Wee1 inhibitors can be demonstrated by the biological assays described herein. 50 The values ​​are shown in Table A.

[0055] As used herein, the term "treat" or "treatment" refers to curative or palliative measures. Beneficial or desired clinical results include, but are not limited to, the complete or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a decrease in the extent of the disease, stabilization of the disease state (i.e., not worsening), a delay or slowing of disease progression, an improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment.

[0056] 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 is experiencing and / or exhibiting at least one symptom of the disease or disorder being treated and / or prevented.

[0057] Persistent replication stress (sometimes referred to as replicative stress) is a phenomenon observed in cancer cells but rarely observed in non-cancer cells. One hallmark of replication stress is fork stalling. In some embodiments, tumors with "replication stress" are tumors with stalled replication forks. Often, when DNA damage occurs in the replicating strand, the replication machinery is unable to pass through the lesion, resulting in fork stalling. To repair stalled replication forks, single-stranded DNA (ssDNA) on the leading strand is typically exposed, initiating replication protein A (RPA) to bind to the ssDNA and activate the ATR / Chk1 pathway. Activation of this pathway restricts entry into M phase. Mitotic cell death can occur when replication stress is exacerbated by, for example, inactivation of one or more tumor suppressor genes (e.g., p53, RB1, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1, or a combination thereof) (e.g., resulting in early onset of S phase), activation of one or more oncogenes (e.g., cyclin E, CDC25A, Myc, RAS genes (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof), increased DNA damage (e.g., due to reactive oxygen species (ROS)), chemotherapy (e.g., platinum-based chemotherapy, alkylating agents, nucleoside / nucleoside / nucleotide analogs, topoisomerase I and / or topoisomerase II inhibitors, PARP1 and / or PARP2 inhibitors, ATR inhibitors, Chk1 inhibitors), and / or radiation therapy), early entry into M phase (e.g., via inhibition of Wee1), or a combination thereof, resulting in cell death. See, e.g., U.S. Patent 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, 2017 8, 23:36996.Without being bound by any particular theory, it is believed that cells with replicative stress are more dependent on the activity of Wee1 (e.g., preventing aberrant entry into M phase), typically due to dysregulation of one or more other mechanisms that regulate the cell cycle.

[0058] In some embodiments, the subject has been identified or diagnosed with a cancer with replication stress. In some embodiments, the subject has a tumor that is positive for replication stress. The subject may be a subject with tumor(s) that test positive for replication stress. The subject may be a subject whose tumor has replication stress. In some embodiments, the subject is suspected of having a tumor with replication stress. In some embodiments, the subject has clinical records indicating that the subject has a tumor with replication stress. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with replication stress based on histological examination. The presence of replication stress in a subject (e.g., a tumor (e.g., a tumor sample)) can be detected by any suitable method. In some embodiments, 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, for example, to measure γH2AX. In some embodiments, replication stress can be detected by measuring cleaved caspase. In some embodiments, replication stress can be detected using 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 cytoplasmic DNA. See, for example, Ubhi and Brown. Cancer Research 79.8(2019):1730-1739.

[0059] In some embodiments, replication stress can be detected via DNA fiber analysis, for example, by measuring the DNA synthesis rate of individual DNA replication forks. In some embodiments, replication stress can be detected via DNA pull-down to identify proteins directly associated with replication forks in vivo. See, e.g., Ubhi and Brown. Cancer Research 79.8(2019):1730-1739.

[0060] In some embodiments, replication stress can be detected using a replication stress biomarker. In some embodiments, the replication stress biomarker can include Ki-67, cyclin E, POLD3, γH2AX, FANCD2, or a combination thereof. In some embodiments, the replication stress biomarker 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, the replication stress biomarker can be an activated oncogene. In some embodiments, the replication stress biomarker can be an inactivated tumor suppressor gene. In some embodiments, the replication stress biomarker can be one or more genes listed in Table 1A or 1B of WO2019 / 173456 (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 subject's tumor(s), 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.

[0061] In some embodiments, the subject has been identified or diagnosed with cancer with inactivation of one or more tumor suppressor genes (e.g., as determined using a regulatory-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-approved, e.g., FDA-approved, assay or kit). The subject may be a subject with tumor(s) that are positive for inactivation of one or more tumor suppressor genes (e.g., identified as positive using a regulatory-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has inactivation of one or more tumor suppressor genes (e.g., the tumor has been so identified using a regulatory-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having cancer with inactivation of one or more tumor suppressor genes. In some embodiments, the subject has clinical records indicating that the subject has a tumor with inactivation of one or more tumor suppressor genes (optionally, the clinical records indicate 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 is identified or diagnosed as having cancer, and the inactivation of one or more tumor suppressor genes is determined based on histological examination.The inactivation of tumor suppressor genes can be through any suitable mechanism, including but not limited to gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic change, and degradation of gene mRNA and / or protein product.

[0062] The tumor suppressor gene may be any suitable tumor suppressor gene. In some embodiments, the tumor suppressor gene may be p53, RB1, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1, or a combination thereof. See, for example, Forment and O'Connor, Pharmacology & Therapeutics, 188 (2018) 155-167, Reaper et al. Nature Chemical Biology 7.7 (2011): 428-430, and Mendez et al. Clinical Cancer Research 24.12 (2018): 2740-2748. In some embodiments, the inactivated tumor suppressor gene is a mutated p53 gene. In some embodiments, the inactivated tumor suppressor gene is a deleted p53 gene. In some embodiments, the inactivated tumor suppressor gene is a mutated CDKN2A gene. In some embodiments, the inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene is a deleted FBXW7 gene. A non-limiting example of a cancer that may have a deleted FBXW7 gene is uterine serous carcinoma. In some embodiments, the inactivated tumor suppressor gene is a mutated FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene is a mutated RB1 gene. In some embodiments, the inactivated tumor suppressor gene is a deleted BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene is a mutated BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene is a BRCA1 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene is a deleted BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene is a mutated BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene is a mutated BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene is a mutated SETD2 gene.

[0063] In some embodiments, the subject has been identified or diagnosed with cancer with 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 may be a subject with tumor(s) that are 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 may be a subject whose tumor has activation of one or more oncogenes (e.g., the tumor is so identified using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having cancer with activation of one or more oncogenes. In some embodiments, the subject has clinical records indicating that the subject has a tumor with activation of one or more oncogenes (optionally, the clinical records indicate 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 with cancer based on histological examination, in which activation of one or more oncogenes has been determined. Activation of the oncogenes can be through any suitable mechanism, including, but not limited to, gene amplification, activating mutations, activating translocations, transcriptional activation, epigenetic changes, and / or overexpression of the protein product of the oncogene.

[0064] The oncogene can be any suitable oncogene. In some embodiments, the oncogene can be cyclin E (sometimes also referred to as cyclin E1 or CCNE1), CDC25A, Myc, a RAS gene (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof. See, for example, 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, the activated oncogene is an amplified cyclin E gene. Non-limiting examples of cancers that may have amplified cyclin E (e.g., cyclin E1) include rhabdomyosarcoma, urinary bladder adenocarcinoma, malignant fibrous histiocytoma, small intestine adenocarcinoma, medullary breast cancer, gallbladder adenocarcinoma, gastric adenocarcinoma, bladder transitional cell carcinoma, bladder small cell carcinoma, non-serous ovarian cancer, cervical squamous cell carcinoma, and ovarian endometrial (endometrioid) cancer. In some embodiments, the activated oncogene is overexpressed CDC25A. Non-limiting examples of cancers that may 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 tumor, non-Hodgkin's lymphoma, and neuroblastoma. In some embodiments, the activated oncogene is an amplified Myc gene. Non-limiting examples of cancers that may have Myc amplification include breast invasive ductal carcinoma, lung adenocarcinoma, prostate adenocarcinoma, colon adenocarcinoma, and high-grade ovarian serous adenocarcinoma. In some embodiments, the activated oncogene is a Myc gene with an activating translocation. In some embodiments, the activated oncogene is a transcriptionally activated Myc gene. In some embodiments, the 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, the mutated RAS gene (e.g., KRAS gene, NRAS gene, HRAS gene, or a combination thereof) comprises a mutation at position G12 of the protein product of the gene. In some embodiments, the mutated RAS gene (e.g., KRAS gene, NRAS gene, HRAS gene, or a combination thereof) comprises a mutation at position G13 of the protein product of the gene. In some embodiments, the mutated RAS gene (e.g., KRAS gene, NRAS gene, HRAS gene, or a combination thereof) comprises a mutation at position Q61 of the protein product of the gene. Non-limiting examples of cancers that may have KRAS mutations include pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC).

[0065] In some embodiments, the subject has been identified or diagnosed with a cancer with increased DNA damage. In some embodiments, the subject has a tumor that tests positive for increased DNA damage. The subject may be a subject with tumor(s) that test positive for increased DNA damage. The subject may be a subject whose tumor has increased DNA damage. In some embodiments, the subject is suspected of having a tumor with increased DNA damage. In some embodiments, the subject has clinical records indicating that the subject has a tumor with increased DNA damage. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer that has been determined to be associated with increased DNA damage based on histological examination.

[0066] Typically, "increased" DNA damage is achieved by administering one or more DNA damaging agents, one or more DNA repair inhibitors, and / or radiation to a subject. In some embodiments, the DNA damaging agent can include platinum-based chemotherapy, alkylating agents, nucleobases, nucleosides, and / or nucleotide analogs, or a combination thereof. In some embodiments, the DNA repair inhibitor 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 chemotherapy agents 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 nucleobases, nucleosides, 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 idarubasin. 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.

[0067] The term "pediatric subject" as used herein refers to a subject who is under 21 years of age at the time of diagnosis or treatment. The term "pediatric subject" can be further divided into various subgroups, including neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years, including but not limited to their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB 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, the pediatric subject is between birth and 28 days old, between 29 days old and under 2 years old, between 2 years old and under 12 years old, or between 12 years old and 21 years old (including but not including the 22nd birthday). In some embodiments, the pediatric subject is between birth and 28 days old, between 29 days old and under 1 year old, between 1 month old and under 4 months old, between 3 months old and under 7 months old, between 6 months old and under 1 year old, between 1 year old and under 2 years old, between 2 years old and under 3 years old, between 2 years old and under 7 years old, between 3 years old and under 5 years old, between 5 years old and under 10 years old, between 6 years old and under 13 years old, between 10 years old and under 15 years old, or between 15 years old and under 22 years old.

[0068] In certain embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for preventing diseases and disorders (e.g., cancer) defined herein. The term "preventing," as used herein, means preventing the onset, recurrence, or spread of a disease or condition described herein, or a symptom thereof, in whole or in part.

[0069] Without being bound by any particular theory, cancers that exhibit replication stress are believed to be more dependent on cell cycle checkpoint regulators such as Wee1. In some embodiments, cancers that exhibit replication stress overexpress Wee1. Non-limiting examples of cancers that may overexpress Wee1 include hepatocellular carcinoma, breast cancer, cervical cancer, lung cancer, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, ovarian cancer, pancreatic cancer, and colorectal cancer. For example, see P Reigan et al., Trends in Pharmacol Sci 2016; Mir, et al., Cancer Cell, Vol.18, No.3, pp.244-257(2010)).

[0070] The term "regulatory agency" refers to a national agency that approves pharmaceutical agents for medical use in a country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0071] compound Thus, as used herein, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently C1-C6 alkyl; m is 0, 1, or 2; R 2 is hydrogen, C1-C6 alkyl, phenyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, and the phenyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl are each independently R A and optionally substituted with 1 to 3 substituents selected from Each R A are independently halogen, cyano, -NR B R C , -C(=O)NR B R C , -N=S(O)Me), hydroxyl or -NR B RC C1-C6 alkyl optionally substituted with -NR B R C C3-C6 cycloalkyl optionally substituted with; and 4- to 6-membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, Each R B and R C are independently hydrogen or C1-C6 alkyl; R 3 is hydrogen or C1-C6 alkyl; R 4 but, (i) each independently, halogen, cyano, —SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, each independently, —NR B R C and —COH; —(C1-C6 alkyl), optionally substituted with one or two substituents selected from n -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G 4- to 12-membered heterocyclyloxy optionally substituted with G phenyl optionally substituted by 1 or 2 substituents selected from the group consisting of 4- to 12-membered heterocyclyl optionally substituted by (ii) a 9- to 12-membered heterocyclyl optionally substituted with 1 to 3 independently selected C1-C6 alkyls; (iii) a 5- to 6-membered heteroaryl optionally substituted with C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C cycloalkyl, or C-C alkyl; one or two independently selected R G4- to 12-membered heterocyclyloxy optionally substituted with 1- to 2-membered alkyl; and 4- to 12-membered heterocyclyl optionally substituted with 1- to 2-membered alkyl or amino. (iv) C3-C6 cycloalkyl, or (v) C(O)-R I and n is 0 or 1, Each R E and R F are independently hydrogen or C1-C6 alkyl, or R E and R F together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclyl optionally substituted with C1-C6 alkyl; Each R G are independently selected from halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, -NR B R C , or =NR H and R H is hydrogen or C1-C6 alkyl; R I is a C3-C6 cycloalkyl optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, phenyl optionally substituted with 1-3 halogens; a 5-6 membered heteroaryl optionally substituted with 1-3 C1-C6 alkyls; halogen, phenyl, and a 5-6 membered heteroaryl optionally substituted with 1-3 C1-C6 alkyls; R 5 is hydrogen, halogen, or C1-C6 alkyl; R 6 is hydrogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0073] In some embodiments, each R 1 is independently C-C alkyl. In some embodiments, each R 1 is independently C-C alkyl. In some embodiments, each R 1 are the same. In some embodiments, each R 1 In some embodiments, each R 1 In some embodiments, m is 2 and each R 1 is methyl. In some embodiments, two independently selected (R 1 ) m In some embodiments, m is 2 and each R 1 In some embodiments, m is 2 and each R 1 is methyl, and the methyl group is geminal. In some embodiments, two independently selected R 1 The groups are geminal in that the carbon atoms to which they are attached are adjacent to the ring oxygen.

[0074] In some embodiments, R 2 is one to three independently selected R A In some embodiments, R 2 is one to three independently selected R A In some embodiments, R 2 is three independently selected R A In some embodiments, R 2 is one or two independently selected R A In some embodiments, R 2 is two independently selected R A In some embodiments, R 2 is one R A is a phenyl substituted with

[0075] In some embodiments, R 2 is one to three independently selected R A and one or two R A The group R 2 In some embodiments, R 2 is one to three independently selected R A and one or two R A The group R 2 In some embodiments, R 2 is one to three independently selected R A phenyl substituted with one R A The group R 2 It is para to the connection point of .

[0076] In some embodiments, R 2 is unsubstituted phenyl.

[0077] In some embodiments, R 2 is one to three independently selected R A In some embodiments, R is a 5- to 10-membered heteroaryl optionally substituted with 2 is one to three independently selected R A In some embodiments, R is a 5- to 10-membered heteroaryl substituted with 2 is three independently selected R A In some embodiments, R is a 5- to 10-membered heteroaryl substituted with 2 is one or two independently selected R A In some embodiments, R is a 5- to 10-membered heteroaryl substituted with 2 is two independently selected R A In some embodiments, R is a 5- to 10-membered heteroaryl substituted with 2 is one R A is a 5- to 10-membered heteroaryl substituted with

[0078] In some embodiments, R 2 is one to three independently selected R A In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 2 is one to three independently selected R A In some embodiments, R 2 is three independently selected R A In some embodiments, R 2 is one or two independently selected R A In some embodiments, R 2 is two independently selected R A In some embodiments, R 2 is one R A is a 5- to 6-membered heteroaryl substituted with

[0079] In some embodiments, R 2 is one to three independently selected R A In some embodiments, R is pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl optionally substituted with 2 is one to three independently selected R A In some embodiments, R is a pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl substituted with 2 is three independently selected R A In some embodiments, R is a pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl substituted with 2 is two independently selected R A In some embodiments, R is a pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl substituted with 2 is one R A and pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl substituted with

[0080] In some embodiments, R 2 is one to three independently selected R A and pyridyl substituted with, for example, 2-pyridyl, 3-pyridyl, or 4-pyridyl.

[0081] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0082] In some embodiments, R 2 teeth, [ka] wherein R A’ are independently A is selected from.

[0083] In some embodiments, R 2 teeth, [ka] wherein R A’ and R A” are each independently R A is selected from.

[0084] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] where R A’ are independently A is selected from.

[0085] In some embodiments, R 2 is unsubstituted 5-10 membered heteroaryl. In some embodiments, R 2 is an unsubstituted 5-6 membered heteroaryl. In some embodiments, R 2 is unsubstituted pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl.

[0086] In some embodiments, R 2 is one to three independently selected R A In some embodiments, R is a 5- to 10-membered heterocyclyl optionally substituted with 2 is one to three independently selected R A In some embodiments, R is a 5- to 10-membered heterocyclyl substituted with 2 is three independently selected R A In some embodiments, R is a 5- to 10-membered heterocyclyl substituted with 2 is one or two independently selected R A In some embodiments, R is a 5- to 10-membered heterocyclyl substituted with 2 is two independently selected R A In some embodiments, R is a 5- to 10-membered heterocyclyl substituted with 2 is one R A is a 5- to 10-membered heterocyclyl substituted with

[0087] In some embodiments, R 2 is one to three independently selected R A optionally replaced with [ka] wherein ring A is C5-C6 cycloalkyl or 5-6 membered heterocyclyl. In some embodiments, R 2 is one to three independently selected R A replaced with [ka] wherein ring A is C5-C6 cycloalkyl or 5-6 membered heterocyclyl. In some embodiments, R 2 is three independently selected R A optionally replaced with [ka] wherein ring A is C5-C6 cycloalkyl or 5-6 membered heterocyclyl. In some embodiments, R 2 is one or two independently selected R A optionally replaced with [ka] wherein ring A is C5-C6 cycloalkyl or 5-6 membered heterocyclyl. In some embodiments, R 2 is two independently selected R A optionally replaced with [ka] wherein ring A is C5-C6 cycloalkyl or 5-6 membered heterocyclyl. In some embodiments, R 2 is one R A optionally replaced with [ka] wherein ring A is C5-C6 cycloalkyl or 5-6 membered heterocyclyl. In some embodiments, ring A is substituted and the pyridinyl ring is unsubstituted. In some embodiments, ring A is unsubstituted and the pyridinyl ring is substituted. In some embodiments, both ring A and the pyridinyl ring are substituted. In some embodiments, both ring A and the pyridinyl ring are unsubstituted.

[0088] In some embodiments, Ring A is C5-C6 cycloalkyl. In some embodiments, Ring A is cyclopentyl. In some embodiments, Ring A is selected from one or two independently selected R A In some embodiments, ring A is cyclopentyl substituted with two geminal R A In some embodiments, ring A is cyclopentyl substituted with two geminal R A In some embodiments, ring A is cyclopentyl substituted with two different geminal R A and cyclopentyl substituted with .

[0089] In some embodiments, ring A is a 5- to 6-membered heterocyclyl. In some embodiments, ring A is a 5- to 6-membered heterocyclyl containing a nitrogen atom. In some embodiments, ring A is a 5- to 6-membered heterocyclyl containing one or two independently selected R A In some embodiments, ring A is piperidinyl substituted with one R A and piperidinyl substituted with

[0090] In some embodiments, R A is halogen. In some embodiments, R A is fluoro or chloro. In some embodiments, R A is cyano. In some embodiments, R A is -N=S(O)(Me)2.

[0091] In some embodiments, R A is -NR B R C is.

[0092] In some embodiments, R A is -C(=O)NR B R C is.

[0093] In some embodiments, R A is hydroxyl or -NRB R C In some embodiments, R A is a C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A is 2-hydroxy-2-propyl. In some embodiments, R A is -NR B R C In some embodiments, R A is 2-amino-2-propyl. In some embodiments, R A is -CH2NR B CH3 or -CH(CH3)NR B CH3, wherein R B is hydrogen or methyl. In some embodiments, R A is methyl.

[0094] In some embodiments, R A is -NR B R C In some embodiments, R A is -NR B R C In some embodiments, R A is -NR B R C In some embodiments, R is cyclopropyl optionally substituted with A is unsubstituted C-C cycloalkyl. In some embodiments, R A is cyclopropyl.

[0095] In some embodiments, R A is a 4-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R A is a 4-6 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl.

[0096] In some embodiments, one R A is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, 2-pyrrolidinone, oxazolidin-2-onyl, morpholinyl, piperazinyl, and piperidinyl, each optionally substituted with halogen or C-C alkyl. A is selected from azetidinyl, oxetanyl, pyrrolidinyl, 2-pyrrolidinone, oxazolidin-2-onyl, morpholinyl, piperazinyl, and piperidinyl, each of which is substituted with halogen or C-C alkyl. A is selected from azetidinyl, oxetanyl, pyrrolidinyl, 2-pyrrolidinone, oxazolidin-2-onyl, morpholinyl, piperazinyl, and piperidinyl, each optionally substituted with fluoro or methyl. A is selected from azetidinyl, oxetanyl, pyrrolidinyl, 2-pyrrolidinone, oxazolidin-2-onyl, morpholinyl, piperazinyl, and piperidinyl, each of which is substituted with fluoro or methyl. A In some embodiments, the azetidinyl, oxetanyl, pyrrolidinyl, 2-pyrrolidinone, oxazolidin-2-onyl, morpholinyl, piperazinyl, or piperidinyl of is substituted on a carbon atom. A In some embodiments, the azetidinyl, pyrrolidinyl, oxazolidin-2-onyl, morpholinyl, piperazinyl, or piperidinyl is substituted on the nitrogen atom. A is an unsubstituted 5-6 membered heterocyclyl. In some embodiments, one R A is selected from unsubstituted azetidinyl, oxetanyl, pyrrolidinyl, 2-pyrrolidinone, oxazolidin-2-onyl, morpholinyl, piperazinyl, and piperidinyl.

[0097] In some embodiments, RA is a 4-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R A is a 4-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from fluoro and methyl. In some embodiments, R A is azetidinyl optionally substituted with 1 to 2 substituents independently selected from fluoro and methyl.

[0098] In some embodiments, R A is a 5-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R A is a 5-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from fluoro and methyl. In some embodiments, R A is pyrrolidinyl optionally substituted with 1-2 substituents independently selected from fluoro and methyl. In some embodiments, R A is oxazolidin-2-onyl optionally substituted with 1 to 2 substituents independently selected from fluoro and methyl. In some embodiments, R A is a 6-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R A is a 6-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from fluoro and methyl. In some embodiments, R A is selected from the group consisting of piperidinyl, piperazinyl, and morpholinyl, and each R A is optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R A is piperidinyl optionally substituted with 1-2 substituents independently selected from fluoro and methyl. In some embodiments, RA is piperazinyl optionally substituted with 1-2 substituents independently selected from fluoro and methyl. In some embodiments, R A is morpholinyl optionally substituted with 1-2 substituents independently selected from fluoro and methyl. In some embodiments, R A is unsubstituted piperidinyl, piperazinyl, or morpholinyl.

[0099] In some embodiments, R B and R C is independently hydrogen or C-C alkyl. In some embodiments, R B and R C are the same. In some embodiments, R B and R C are different. In some embodiments, R B and R C Each is hydrogen. In some embodiments, R B and R C is hydrogen and R B and R C and the other is C1-C6 alkyl. In some embodiments, R B and R C is hydrogen and R B and R C and the other is methyl. In some embodiments, R B and R C are each independently selected C1-C6 alkyl. In some embodiments, R B and R C are each methyl.

[0100] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0101] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0102] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0103] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0104] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0105] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0106] In some embodiments, R 2 is hydrogen.

[0107] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is methyl.

[0108] In some embodiments, R 3 is hydrogen.

[0109] In some embodiments, R 4 teeth, (i) each independently, halogen, cyano, —SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, each independently, —NR B R C and —COH; —(C1-C6 alkyl) n -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and one or two independently selected R G phenyl optionally substituted by 1 or 2 substituents selected from the group consisting of 4- to 12-membered heterocyclyl optionally substituted by (ii) a 9- to 12-membered heterocyclyl optionally substituted with 1 to 3 independently selected C1-C6 alkyls; (iii) C1-C6 alkyl; C1-C6 haloalkyl, C1-C6 deuteroalkyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G 4- to 12-membered heterocyclyloxy optionally substituted with 1- to 2-membered alkyl; and 4- to 12-membered heterocyclyl optionally substituted with 1- to 2-membered alkyl or amino. (iv) C3-C6 cycloalkyl, or (v) C(O)-R I is.

[0110] In some embodiments, R 4are each independently halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R C and —COH; —(C1-C6 alkyl), optionally substituted with 1 or 2 substituents independently selected from n -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and one or two independently selected R G and 4- to 12-membered heterocyclyl optionally substituted by .

[0111] In some embodiments, R 4 is halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R C and —COH; —(C1-C6 alkyl) n -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and one or two independently selected R G and 4- to 12-membered heterocyclyl optionally substituted by

[0112] In some embodiments, R 4is halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R C and —COH; —(C1-C6 alkyl) n -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and one or two independently selected R G and 4- to 12-membered heterocyclyl optionally substituted by

[0113] In some embodiments, R 4 is halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R C and —COH; —(C1-C6 alkyl) n -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and one or two independently selected R G and 4- to 12-membered heterocyclyl optionally substituted by

[0114] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of In the formula, each R 4A and R 4A’ are independently halogen, cyano, -SO2(C1-C6 alkyl), -NR B R C and —COH; —(C1-C6 alkyl) n -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and one or two independently selected R G and 4- to 12-membered heterocyclyl optionally substituted with

[0115] In some embodiments, R 4 is phenyl substituted with two independently selected C1-C6 alkyl. In some embodiments, R 4 is phenyl substituted with one C1-C6 alkyl. In some embodiments, R 4 is phenyl substituted with t-butyl.

[0116] In some embodiments, R 4 is -NR B R C and —COH. In some embodiments, R 4 are -C(CH3)2CO2H and -CH2CH(NCH3R C phenyl substituted with one or two substituents independently selected from the group consisting of: COH, wherein R C is selected from hydrogen and methyl.

[0117] In some embodiments, R 4 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halogen, —SO(C-C alkyl), and C-C alkyl. In some embodiments, R 4 is phenyl substituted with one or two independently selected halogens. In some embodiments, R 4 is phenyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R 4 is phenyl substituted with two substituents independently selected from halogen and —SO (C-C alkyl). In some embodiments, R 4 is phenyl substituted with two substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 4 is phenyl substituted with two substituents independently selected from -SO2(C1-C6 alkyl) and C1-C6 alkyl. In some embodiments, R 4 is phenyl substituted with -SO2CH3.

[0118] In some embodiments, R 4 is halogen and -(C1-C6 alkyl) n -C(=O)NR E R F In some embodiments, R is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of 4 is fluoro and -(C1-C3 alkyl) n -C(=O)NR E R F In some embodiments, R is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of 4 is -(C1-C6 alkyl) n -C(=O)NR E R F wherein the C1-C6 alkyl is a branched alkyl. In some embodiments, R4 is -(C1-C6 alkyl) n -C(=O)NR E R F In some embodiments, R is phenyl substituted with -C(C-C alkyl)-. 4 is -C(=O)NR E R F or -C(CH3)2C(=O)NR E R F In some embodiments, R 4 is phenyl substituted with one or two substituents independently selected from the group consisting of fluoro, —CO 2 NHCH 3 , —CO 2 N(CH 3 ) 2 , and —C(CH 3 ) 2 CO 2 N(CH 3 ) 2 .

[0119] In some embodiments, R 4 teeth, [ka] where R 4A is -(C1-C3 alkyl) n -C(=O)NR E R F In some embodiments, R 4 teeth, [ka] where R 4A is -C(=O)NR E R F or -C(CH3)2C(=O)NR E R F is.

[0120] In some embodiments, R 4 teeth, [ka] where R 4A is -(C1-C3 alkyl) n -C(=O)NR ER F and R 4A’ is halogen. In some embodiments, R 4 teeth, [ka] where R 4A is -C(=O)NR E R F and R 4A’ is fluoro.

[0121] In some embodiments, n is 0. In some embodiments, n is 1.

[0122] In some embodiments, R E and R F are each independently hydrogen or C1-C6 alkyl. In some embodiments, R E and R F are the same. In some embodiments, R E and R F are different. In some embodiments, R E and R F is hydrogen and R E and R F and the other is C1-C6 alkyl. In some embodiments, R E and R F is hydrogen and R E and R F and the other is C1-C3 alkyl. In some embodiments, R E and R F is hydrogen and R E and R F and the other is methyl. In some embodiments, R E and R F is an independently selected C1-C6 alkyl. In some embodiments, R E and R F is an independently selected C1-C3 alkyl. In some embodiments, R E and R Fand R are both methyl. E and R F are both hydrogen.

[0123] In some embodiments, R E and R F taken together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl. E and R F taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. E and R F are taken together with the nitrogen atom to which they are attached to form a ring selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperzidinyl, pyrrolininyl, and azezidinyl, each optionally substituted with C-C alkyl. E and R F taken together with the nitrogen atom to which they are attached form an unsubstituted 4-8 membered heterocyclyl. In some embodiments, R E and R F taken together with the nitrogen atom to which they are attached form morpholinyl, thiomorpholinyl, piperazinyl, piperzidinyl, pyrrolininyl, or azezidinyl. In some embodiments, R E and R F together with the nitrogen atom to which they are attached form morpholinyl.

[0124] In some embodiments, R 4 is phenyl substituted with C-C cycloalkyl optionally substituted with C-C alkyl. In some embodiments, R 4 is phenyl substituted with C-C cycloalkyl substituted with C-C alkyl. In some embodiments, R 4is phenyl substituted with C-C substituted C-C cycloalkyl. In some embodiments, R 4 is phenyl substituted with cyclobutyl optionally substituted with methyl.

[0125] In some embodiments, R 4 is phenyl substituted with unsubstituted C3-C6 cycloalkyl.

[0126] In some embodiments, R 4 teeth, [ka] where R 4A is C-C cycloalkyl optionally substituted with C-C alkyl. In some embodiments, R 4 teeth, [ka] where R 4A is C-C cycloalkyl optionally substituted with C-C alkyl. In some embodiments, R 4 teeth, [ka] where R 4A is cyclobutyl optionally substituted with methyl.

[0127] In some embodiments, R 4 teeth, [ka] where R 4A is a 5-6 membered heteroaryl optionally substituted with C-C alkyl, and R 4A’ are independently 4A is selected from.

[0128] In some embodiments, R 4 teeth, [ka] where R 4A is a 5-6 membered heteroaryl optionally substituted with C-C alkyl, and R 4A’ is independently selected from halo and C1-C6 alkyl.

[0129] In some embodiments, R 4 teeth, [ka] where R 4A is imidazolyl or pyrazolyl optionally substituted with C1-C3 alkyl, and R 4A’ is independently selected from fluoro, chloro, and methyl.

[0130] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0131] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G and R is a 4- to 12-membered heterocyclyloxy optionally substituted with 4A’ are independently 4A is selected from.

[0132] In some embodiments, R 4 teeth, [ka] where R 4Ais selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, 1,4-oxazepan-4-yl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazepanyl, 2-oxopiperazinyl, 3-oxopiperazinyl, and thiomorpholinyl-1-oxide, each of which is selected from the group consisting of one or two independently selected R G optionally substituted with R 4A’ is independently selected from fluoro, chloro, and C1-C3 alkyl.

[0133] In some embodiments, R 4 is selected from halogen, C1-C6 alkyl, and one or two independently selected R G In some embodiments, R is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of 4- to 12-membered heterocyclyl optionally substituted with 4 is selected from halogen, C1-C6 alkyl, and one or two independently selected R G and phenyl substituted by 1 or 2 substituents independently selected from the group consisting of 4- to 12-membered heterocyclyl substituted by

[0134] In some embodiments, the 4- to 12-membered heterocyclyl is a 4- to 7-membered heterocyclyl. In some embodiments, the 4- to 12-membered heterocyclyl is an unsubstituted 4- to 7-membered heterocyclyl.

[0135] In some embodiments, R 4is phenyl substituted with a 4- to 7-membered heterocyclyl selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, 1,4-oxazepan-4-yl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 1,4-diazepanyl, 2-oxopiperazinyl, 3-oxopiperazinyl, thiomorpholinyl, and thiomorpholinyl-1-oxide, wherein each 4- to 7-membered heterocyclyl is selected from the group consisting of one or two independently selected R G is optionally replaced by

[0136] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is a 4- to 12-membered heterocyclyl optionally substituted with 4A is one or two independently selected R G In some embodiments, R is a 4- to 12-membered heterocyclyl substituted with 4A is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, 1,4-oxazepan-4-yl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 1,4-diazepanyl, 2-oxopiperazinyl, 3-oxopiperazinyl, thiomorpholinyl, thiomorpholinyl-1-oxide, octahydropyrrolo[3,4-c]pyrrolyl, and 2,6-diazaspiro[3.3]heptanyl; and each 4- to 12-membered heterocyclyl is selected from the group consisting of one or two independently selected R GIn some embodiments, R 4A’ is independently selected from halogen and C-C alkyl. In some embodiments, R 4A’ is independently selected from fluoro, chloro, and methyl.

[0137] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is piperidinyl optionally substituted with 4A is one or two independently selected R G In some embodiments, R 4A teeth, [ka] is.

[0138] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0139] In some embodiments, R 4 teeth, [ka] is.

[0140] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R GIn some embodiments, R 4A is one or two independently selected R G In some embodiments, R 4A teeth, [ka] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0141] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is morpholinyl optionally substituted with 4A teeth, [ka] In some embodiments, R 4 teeth, [ka] is.

[0142] In some embodiments, R 4 teeth, [ka] is.

[0143] In some embodiments, R 4 teeth, [ka] where R4A is one or two independently selected R G In some embodiments, R is pyrrolidinyl optionally substituted with 4A teeth, [ka] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0144] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R 4A teeth, [ka] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0145] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is tetrahydrofuranyl optionally substituted with 4A teeth, [ka] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0146] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is tetrahydropyranyl optionally substituted with 4 teeth, [ka] is.

[0147] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is oxetanyl optionally substituted with 4 teeth, [ka] is.

[0148] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is azetidinyl optionally substituted with 4 teeth, [ka] In some embodiments, the phenyl ring is fluoro, e.g., [ka] is further replaced by

[0149] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is thiomorpholinyl-1-oxide optionally substituted with 4A is =NR H In some embodiments, R is a thiomorpholinyl-1-oxide substituted with 4 teeth, [ka] is.

[0150] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is 1,4-oxazepan-4-yl optionally substituted with 4 teeth, [ka] is.

[0151] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G In some embodiments, R is 1,4-diazepanyl optionally substituted with 4 teeth, [ka] is.

[0152] In some embodiments, R 4 teeth, [ka] is.

[0153] In some embodiments, R 4 teeth, [ka] where R 4A is selected from the group consisting of 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and 2-oxa-5-azabicyclo[2.2.1]heptanyl. In some embodiments, R 4 teeth, [ka] In some embodiments, the phenyl ring is further substituted with fluoro.

[0154] In some embodiments, R 4 teeth, [ka] is.

[0155] In some embodiments, R 4 teeth, [ka] where R 4A is selected from the group consisting of octahydropyrrolo[3,4-c]pyrrolyl and 2,6-diazaspiro[3.3]heptanyl. In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0156] In some embodiments, R 4 teeth, [ka] where R 4A is 2-oxopiperazinyl or 3-oxopiperazinyl. In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0157] In some embodiments, R 4 teeth, [ka] where R 4A is one or two independently selected R G and R is a 4- to 12-membered heterocyclyloxy optionally substituted with 4A’ are independently 4A is selected from.

[0158] In some embodiments, R 4 teeth, [ka] where R 4A are selected from the group consisting of azetidinyloxy, piperidinyloxy, and pyrrolidinyloxy, each of which is selected from one or two independently selected R Gis optionally replaced by

[0159] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0160] In some embodiments, R 4 is unsubstituted phenyl.

[0161] In some embodiments, each R G are independently selected from halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, -NR B R C , and =NR H In some embodiments, each R G is halogen or C-C alkyl. In some embodiments, each R G is independently selected from fluoro, chloro, and methyl. In some embodiments, each R G is C1-C3 deuteroalkyl. In some embodiments, each R G is -CD3. In some embodiments, each R G is -NR B R C In some embodiments, each R G is -NCH3R C where R C is selected from hydrogen and methyl. In some embodiments, each R G is =NR H In some embodiments, R G is methyl. In some embodiments, two independently selected R G The base is geminal.

[0162] In some embodiments, R H is hydrogen. In some embodiments, R H is C1-C6 alkyl. In some embodiments, RH is methyl.

[0163] In some embodiments, R 4 is a 9-12 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl. In some embodiments, R 4 is a 9-12 membered heterocyclyl substituted with 1-3 independently selected C1-C6 alkyl.

[0164] In some embodiments, R 4 teeth, [ka] and each is optionally substituted with 1-3 independently selected C1-C6 alkyl. In some embodiments, Ring B1 and Ring B2 are 5- or 6-membered heterocyclyl groups. In some embodiments, Ring B1 and Ring B2 are 5-membered heterocyclyl. In some embodiments, Ring B1 and Ring B2 are 5-membered heterocyclyl containing one nitrogen. In some embodiments, Ring B1 and Ring B2 are 6-membered heterocyclyl. In some embodiments, Ring B1 and Ring B2 are 6-membered heterocyclyl containing one nitrogen. In some embodiments, Ring B1 and Ring B2 are 5- or 6-membered heterocyclyl substituted with 1-3 independently selected C1-C3 alkyl. In some embodiments, Ring B1 and Ring B2 are 5- or 6-membered heterocyclyl substituted with two independently selected geminal C1-C3 alkyl groups. In some embodiments, Ring B1 and Ring B2 are 5-6 membered heterocyclyl with spiro C3-C6 cycloalkyl.

[0165] In some embodiments, Ring B1 and Ring B2 are selected from the group consisting of pyrrolidin-2-onyl, piperidin-2-onyl, piperidinyl, and pyrrolidinyl. 4 teeth, [ka] is selected from the group consisting of:

[0166] In some embodiments, R 4 is an unsubstituted 9-12 membered heterocyclyl.

[0167] In some embodiments, R4 is selected from the group consisting of C1-C6 alkyl; C1-C6 haloalkyl, C1-C6 deuteroalkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino.

[0168] In some embodiments, R 4 is C1-C6 alkyl; C1-C6 haloalkyl, C1-C6 deuteroalkyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and 4- to 12-membered heterocyclyl optionally substituted with C1-C6 alkyl or amino.

[0169] In some embodiments, R 4 is C1-C6 alkyl; C1-C6 haloalkyl, C1-C6 deuteroalkyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R Gand 4-12 membered heterocyclyl optionally substituted with C1-C6 alkyl or amino. 4 is C1-C6 alkyl; C1-C6 haloalkyl, C1-C6 deuteroalkyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and a 4- to 12-membered heterocyclyl optionally substituted with C1-C6 alkyl or amino.

[0170] In some embodiments, R 4 is a 5- to 6-membered heteroaryl substituted with C1-C6 alkyl; a 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G or a 4- to 12-membered heterocyclyl optionally substituted with C1-C6 alkyl or amino.

[0171] In some embodiments, R 4 is a 5-6 membered heteroaryl substituted with one or two independently selected C1-C6 alkyls.

[0172] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0173] In some embodiments, R 4is a 5-6 membered heteroaryl substituted with 1 or 2 substituents independently selected from the group consisting of pyrazolyl and imidazolyl, each optionally substituted with C-C alkyl. In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0174] In some embodiments, R 4 is one or two independently selected R G In some embodiments, R is a 5- to 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from 4- to 12-membered heterocyclyloxy optionally substituted with 4 is substituted with one or two substituents independently selected from the group consisting of azetidinyloxy, piperidinyloxy, and pyrrolidinyloxy, each of which is substituted with one or two independently selected R G is a 5-6 membered heteroaryl optionally substituted with

[0175] In some embodiments, R 4 teeth, [ka] and a 5- to 6-membered heteroaryl substituted with a 4- to 12-membered heterocyclyloxy selected from the group consisting of:

[0176] In some embodiments, R 4 is a 5-6 membered heteroaryl substituted with a 4-12 membered heterocyclyl group optionally substituted with C1-C6 alkyl or amino. 4 is a 5-membered heteroaryl substituted with a 5-6 membered heterocyclyl group optionally substituted with C1-C3 alkyl. 4is a 5-membered heteroaryl substituted with a 5-6 membered heterocyclyl group optionally substituted with methyl. In some embodiments, R 4 is a 6-membered heteroaryl substituted with a 5-6 membered heterocyclyl group optionally substituted with C1-C3 alkyl. 4 is a 6-membered heteroaryl substituted with a 5-6 membered heterocyclyl group optionally substituted with methyl.

[0177] In some embodiments, R 4 is substituted with a 4-12 membered heterocyclyl selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, 1,4-oxazepan-4-yl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, thiomorpholinyl, and thiomorpholinyl-1-oxide, wherein each 4-12 membered heterocyclyl is a 5- to 6-membered heteroaryl optionally substituted with C-C alkyl or amino. In some embodiments, R 4 is a 5-6 membered heteroaryl substituted with a 4-12 membered heterocyclyl group selected from the group consisting of piperidinyl, piperazinyl, and tetrahydropyranyl, and optionally substituted with C1-C3 alkyl. 4 is a 5-6 membered heteroaryl substituted with piperidinyl optionally substituted with methyl or amino. 4 is a 5-6 membered heteroaryl substituted with piperazinyl optionally substituted with methyl or amino. 4 is a 5-6 membered heteroaryl substituted with tetrahydropyranyl optionally substituted with methyl or amino. 4 is a 5- to 6-membered heteroaryl substituted with an unsubstituted 4- to 12-membered heterocyclyl group.

[0178] In some embodiments, R 4 teeth, [ka] and a 5- to 6-membered heteroaryl substituted with a 4- to 12-membered heterocyclyl group selected from the group consisting of:

[0179] In some embodiments, R 4 is a 5-6 membered heteroaryl substituted with one or two independently selected C1-C6 alkyls. In some embodiments, R 4 is a 5-6 membered heteroaryl substituted with C1-C4 alkyl. In some embodiments, R 4 is a 5-6 membered heteroaryl substituted with t-butyl.

[0180] In some embodiments, R 4 is an unsubstituted 5-6 membered heteroaryl.

[0181] In some embodiments, R 4 is selected from pyrazolyl, pyridyl, triazolyl, pyridazinly, and pyridonyl. In some embodiments, R 4 is selected from the group consisting of pyrazolyl, pyridyl, triazolyl, and pyridazinyl.

[0182] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0183] In some embodiments, R 4 is selected from pyrazol-4-yl, 1,2,3-triazol-4-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl. In some embodiments, R 4is selected from pyrazol-4-yl, pyrazol-3-yl, imidazolyl, isoxazolyl, thiazolyl, 1,2,3-triazol-4-yl, pyridin-3-yl, pyrazinyl, pyrimidinyl, and pyridazinyl; in some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0184] In some embodiments, R 4 is a 9-10 membered heteroaryl optionally substituted with one or two C1-C6 alkyls. In some embodiments, R 4 is a 9-10 membered heteroaryl optionally substituted with one C1-C6 alkyl. In some embodiments, R 4 is a 9-10 membered heteroaryl optionally substituted with one C1-C3 alkyl. In some embodiments, R 4 is a 9-10 membered heteroaryl optionally substituted with one methyl. In some embodiments, R 4 teeth, [ka] and a 9- to 10-membered heteroaryl selected from the group consisting of:

[0185] In some embodiments, R 4 is C-C cycloalkyl. In some embodiments, R 4 is a bridged C-C cycloalkyl. In some embodiments, R 4 is bicyclo[1.1.1]pentyl.

[0186] In some embodiments, R 4 is C(O)-R I where R Iis C3-C6 cycloalkyl optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, phenyl optionally substituted with halogen; 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; halogen, phenyl, and 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0187] In some embodiments, R 4 is C(O)-R I where R I is C1-C6 alkyl. In other embodiments, R I is C1-C3 alkyl. In other embodiments, R I is methyl.

[0188] In some embodiments, R 4 is C(O)-R I where R I is phenyl optionally substituted with halogen.

[0189] In some embodiments, R 4 is C(O)-R I where R I is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, R I is piperdinyl. In some embodiments, R I is pyrazolyl optionally substituted with C1-C6 alkyl.

[0190] In some embodiments, R 4 is C(O)-R I where R I is C3-C6 cycloalkyl optionally substituted with one substituent selected from the group consisting of halogen, phenyl, and 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, R Iis cyclopropyl optionally substituted with one substituent selected from the group consisting of halogen, phenyl, and 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, R I teeth, [ka] is selected from the group consisting of:

[0191] In some embodiments, R 5 is halogen. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl.

[0192] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is methyl.

[0193] In some embodiments, the compound of Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the compound of formula (I) is a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, m is 0, 1, or 2; p is 0, 1, or 2; Each R A But independently, -NR B R C , -C(=O)NR B R C , hydroxyl or -NR B R C C1-C6 alkyl substituted with --NR B R C C3-C6 cycloalkyl substituted with -N=S(O)Me)2, and 4- to 6-membered heterocyclyl optionally substituted with halogen or C1-C6 alkyl; Each R B and R C are independently hydrogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, p is 0. In some embodiments, p is 1.

[0196] In some embodiments, the compound of formula (IA) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the compound of formula (IA) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the compound of formula (I) is a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, m is 0, 1, or 2; o is 0, 1, or 2; Each R 4A are independently selected from halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R C and —COH; —(C1-C6 alkyl) n1 -C(=O)NR E R F , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G and one or two independently selected R G is a 4- to 12-membered heterocyclyl optionally substituted with n1 is 0 or 1, Each R E and R F are independently hydrogen or C1-C6 alkyl; Each R G are independently selected from halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, -NR B R C , and =NR H and Each R H is selected from hydrogen and C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2.

[0200] In some embodiments, the compound of formula (IB) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the compound of formula (IB) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the compound of formula (I) is a compound of formula (IC): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, m is 0, 1, or 2; o is 0, 1, or 2; p is 0, 1, or 2; Each R A But independently, -NR B R C , -C(=O)NR B R C , hydroxyl or -NR B R C C1-C6 alkyl substituted with -NR B R C C3-C6 cycloalkyl substituted with -N=S(O)Me)2, 4- to 6-membered heterocyclyl optionally substituted with halogen or C1-C6 alkyl; Each R B and R C are independently hydrogen or C1-C6 alkyl. Each R 4A are independently selected from halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R Cand —COH; —(C1-C6 alkyl) n -C(=O)NR E R F C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G1 and one or two independently selected R G1 is a 4- to 12-membered heterocyclyl optionally substituted with n is 0 or 1, Each R E and R F are independently hydrogen or C1-C6 alkyl; Each R G1 is independently halogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2.

[0204] In some embodiments, the compound of formula (IC) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the compound of formula (IC) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the compound of formula (I) is a compound of formula (ID): [ka] or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the compound of formula (ID) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the compound of formula (ID) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the compound of formula (I) is a compound of formula (IE): [ka] or a pharmaceutically acceptable salt thereof, wherein: p is 1 or 2, Each R in formula (IE) A But independently, -NR B R C , -C(=O)NR B R C , hydroxyl or -NR B R C C1-C6 alkyl substituted with -NR B R C C3-C6 cycloalkyl substituted with; -N=S(O)Me), 4-6 membered heterocyclyl optionally substituted with halogen or C-C alkyl; Each R Band R C are independently hydrogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, p is 1. In some embodiments, p is 2.

[0211] In some embodiments, the compound of formula (IE) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the compound of formula (IE) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the compound of formula (I) is a compound of formula (IF): [ka] or a pharmaceutically acceptable salt thereof, wherein o is 1 or 2; Each R 4A are independently selected from halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R C and —COH; —(C1-C6 alkyl) n -C(=O)NR E R F C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G1and one or two independently selected R G1 is a 4- to 12-membered heterocyclyl optionally substituted with n is 0 or 1, Each R E and R F are independently hydrogen or C1-C6 alkyl; Each R G1 is independently halogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, o is 1. In some embodiments, o is 2.

[0215] In some embodiments, the compound of formula (IF) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the compound of formula (IF) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the compound of formula (I) is a compound of formula (IG): [ka] or a pharmaceutically acceptable salt thereof, wherein: p is 0, 1, or 2; o is 1 or 2, Each R A are independently halogen, cyano, -NR B R C , -C(=O)NR B R C , hydroxyl or -NRB R C C1-C6 alkyl optionally substituted with -NR B R C C3-C6 cycloalkyl optionally substituted with -N=S(O)Me), 4- to 6-membered heterocyclyl optionally substituted with halogen or C1-C6 alkyl; Each R 4A are independently selected from halogen, cyano, -SO2(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, -NR B R C and —COH; —(C1-C6 alkyl) n1 -C(=O)NR E R F C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; one or two independently selected R G1 and one or two independently selected R G1 is a 4- to 12-membered heterocyclyl optionally substituted with n1 is 0 or 1, Each R E and R F are independently hydrogen or C1-C6 alkyl; Each R G1 is independently halogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, o is 1. In some embodiments, o is 2.

[0219] In some embodiments, the compound of formula (IG) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the compound of formula (IG) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0221] 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.

[0222] In some embodiments, the compound is selected from the group consisting of the compounds in Table 1, and pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0223] In some embodiments, the compound is selected from the group consisting of the compounds in Table 2, and pharmaceutically acceptable salts thereof. The absolute stereochemistry of the following examples has been arbitrarily assigned. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 Table 2-48 Table 2-49 Table 2-50 Table 2-51 Table 2-52 Table 2-53 Table 2-54 Table 2-55 [Table 2-56] [Table 2-57] [Table 2-58] [Table 2-59] [Table 2-60]

[0224] Treatment methods Also provided herein is the method for treating cancer in subject using the compound of formula (I), its pharmaceutical salt or its pharmaceutical composition.Replication stress exists in many cancers, and as described herein, in some cases, can be exacerbated by one or more factors, for example, the genetic characteristics of cancer and / or the administration of DNA damage agent, DNA repair inhibitor and / or radiation.

[0225] Accordingly, provided herein is a method of treating cancer in a subject in need thereof, comprising identifying the cancer as having replication stress and administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0226] Identifying a cancer as having replication stress can include any suitable identification method, such as those described herein. For example, in some embodiments, identifying a cancer as having replication stress includes staining replication forks in a sample from the subject. In some embodiments, identifying a cancer as having replication stress includes detecting a replication stress biomarker in a sample from the subject. The replication stress biomarker can include any suitable biomarker or set of biomarkers. In some embodiments, the replication stress biomarker includes Ki-67, cyclin E, POLD3, γH2AX, FANCD2, or a combination thereof. In some embodiments, the replication stress biomarker includes pH2AX Ser139, pATR Thr1989, pCHK1 Ser345, pRPA32 Ser33, or a combination thereof. In some embodiments, the replication stress biomarker includes an activated oncogene. In some embodiments, the replication stress biomarker includes an inactivated tumor suppressor gene.

[0227] Also provided herein is a method of treating cancer in a subject in need thereof, 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 with replication stress.

[0228] In some cases, the genetic characteristics of a cancer may indicate that the cancer may be effectively treated with a compound of Formula (I), 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.

[0229] Thus, provided herein is a method of treating cancer in a subject in need thereof, comprising 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to a subject identified as having a cancer with an inactivated tumor suppressor gene an effective amount of a compound of formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0230] Inactivation of tumor suppressor gene can be achieved by any suitable mechanism, such as those described herein.In some embodiments, inactivated tumor suppressor gene comprises inactivation selected from the group consisting of deletion of gene, inactivating mutation in protein product of gene, inactivating translocation in protein product of gene, transcriptional silencing of gene, epigenetic change of gene, degradation of mRNA product of gene, degradation of protein product of gene, and combinations thereof.

[0231] The inactive tumor suppressor gene can be any suitable inactive 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 combinations thereof.

[0232] In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the p53 gene. In some embodiments, the inactivated tumor suppressor gene comprises a deleted p53 gene. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the CDKN2A gene. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene comprises a deleted FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the RB1 gene. In some embodiments, the inactivated tumor suppressor gene comprises a deleted BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene comprises a BRCA1 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene comprises a deleted BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene comprises a BRCA2 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene comprises a mutation in the protein product of the SETD2 gene.

[0233] In some embodiments, the inactivated tumor suppressor gene is selected from the group consisting of a mutation in the protein product of the p53 gene, a deleted p53 gene, a mutation in the protein product of the CDKN2A gene, a mutation in the protein product of the NOTCH1 gene, a deleted FBXW7 gene, a mutation in the protein product of the FBXW7 gene, a mutation in the protein product of the RB1 gene, a deleted BRCA1 gene, a mutation in the protein product of the BRCA1 gene, a BRCA1 gene with a hypermethylated promoter region, a deleted BRCA2 gene, a mutation in the protein product of the BRCA2 gene, a BRCA2 gene with a hypermethylated promoter region, a mutation in the protein product of the NOTCH1 gene, a mutation in the protein product of the SETD2 gene, and combinations thereof.

[0234] Also provided herein is a method of treating cancer in a subject in need thereof, comprising 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 cancer in a subject in need thereof, comprising administering to a subject identified as having a cancer with an activated oncogene an effective amount of a compound of formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0235] Activation of the oncogene can be achieved by any suitable mechanism, such as those described herein. For example, in some embodiments, the activated oncogene has activation selected from the group consisting of amplification of the oncogene, an activating mutation in the protein product of the oncogene, an activating translocation in the protein product of the oncogene, transcriptional activation of the oncogene, epigenetic alterations in the oncogene, overexpression of the protein product of the oncogene, and combinations thereof.

[0236] The activated oncogene can be any suitable oncogene, such as those described herein.In some embodiments, the oncogene is selected from the group consisting of cyclin E, CDC25A, Myc, RAS gene, and combinations thereof.In some embodiments, the RAS gene comprises KRAS gene.In some embodiments, the RAS gene comprises NRAS gene.In some embodiments, the RAS gene comprises HRAS gene.

[0237] In some embodiments, the activated oncogene comprises an amplified cyclin E gene. In some embodiments, the activated oncogene comprises overexpression of the protein product of the CDC25A gene. In some embodiments, the activated oncogene comprises an amplified Myc gene. In some embodiments, the activated oncogene comprises an activating translocation in the protein product of the Myc gene. In some embodiments, the activated oncogene comprises a transcriptionally activated Myc gene. In some embodiments, the activated oncogene comprises a mutation in the protein product of the RAS gene. In some embodiments, the mutated RAS gene comprises a mutation at position G12 of the protein product of the RAS gene. In some embodiments, the mutated RAS gene comprises a mutation at position G13 of the protein product of the RAS gene. In some embodiments, the mutated RAS gene comprises a mutation at position Q61 of the protein product of the RAS gene. In some embodiments, the RAS gene comprises a KRAS gene.

[0238] In some embodiments, the activated oncogene is selected from the group consisting of an amplified cyclin E gene, overexpression of the protein product of the CDC25A gene, an amplified Myc gene, an activating translocation in the protein product of the Myc gene, a transcriptionally activated Myc gene, a mutation in the protein product of the RAS gene, and combinations thereof. In some embodiments, the mutated RAS gene comprises 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 comprises a KRAS gene.

[0239] In some embodiments, compounds of the present disclosure are particularly useful where the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung.

[0240] In the field of medical oncology, it is common practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology, in addition to the compositions provided herein, other components of such conjoint treatment or therapy may be, for example, surgery, radiation therapy, and chemotherapeutic agents such as other kinase inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, surgery may be open surgery or minimally invasive surgery. Thus, the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be useful as adjuvants for cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be used prior to the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof may be administered one or more doses of the compounds of formula (I) or pharmaceutically acceptable salts thereof for a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof may be administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof over a period of time under one or more rounds of radiation therapy. In some embodiments, treatment with one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) prior to one or more rounds of radiation therapy.

[0241] 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 agents (e.g., a chemotherapeutic agent or an immunomodulatory agent).

[0242] Non-limiting examples of additional therapeutic agents include PARP inhibitors, other DNA repair inhibitors (e.g., topoisomerase inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, ATM inhibitors, Aurora kinase inhibitors (such as Aurora A inhibitors 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 apoptosis pathways, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapeutic agents, immune-targeted agents including immunotherapeutic agents, and radiotherapeutic agents. In some embodiments, the additional therapeutic agent is an antibody.

[0243] 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.

[0244] In some embodiments, the cytotoxic chemotherapeutic agent is 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.

[0245] Non-limiting examples of angiogenesis targeted therapeutic agents include aflibercept and bevacizumab.

[0246] In some embodiments, the DNA repair inhibitor 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 inhibitor and / or an Aurora B inhibitor), or a combination thereof.

[0247] Non-limiting examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and veliparib.

[0248] Non-limiting examples of ATR inhibitors include AZD6738, BAY1895344, and M6620.

[0249] Non-limiting examples of Chk1 inhibitors include prexasertib, GDC-0575, SCH900776, and SRA737.

[0250] Non-limiting examples of DNA-PK inhibitors include AZD7648, M3814, LY294002, nezisertib, and samotricisib.

[0251] Non-limiting examples of ATM inhibitors include KU55933, AZD0156, AZD1390, ductosirib, and berzosertib.

[0252] Non-limiting examples of Aurora kinase inhibitors include LY3295668, ZM447439, tozasertib, hesparazine, alisertib, and MLN8054.

[0253] Non-limiting examples of modulators of the apoptotic pathway include Bcl-2 inhibitors such as obataclax, venetoclax, and navitoclax.

[0254] 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).

[0255] Non-limiting examples of Bcr-Abl inhibitors include imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0256] Non-limiting examples of HDAC inhibitors include pavinostat, vorinostat, belinostat, panobinostat, entinostat, tacedinaline, and mocetinostat.

[0257] Non-limiting examples of platinum-based chemotherapy agents include carboplatin, cisplatin, and oxaplatin. Non-limiting examples of alkylating agents include cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozolomide, 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 idarubasin.

[0258] The term "immunotherapy" refers to an agent that modulates the immune system. In some embodiments, immunotherapy can increase the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy can decrease the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy can recruit and / or enhance the activity of immune cells.

[0259] 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 comprises cells expressing 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™).

[0260] In some embodiments, the immunotherapy is an antibody therapy (e.g., monoclonal antibody, conjugated antibody). In some embodiments, the antibody therapy is selected from the group consisting of bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), edrecolomab (Panorex), daratumab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), and the like. )), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™), cirumutuzumab (UC-961), ibuprofen (TNF-α), rifametidine (RIBA), rifampin ... Britumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab, or amatuximab.

[0261] 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.

[0262] In some embodiments, the immunotherapy comprises blinatumomab (AMG103, Blincyto®) or midostaurin (Rydapt).

[0263] In some embodiments, the immunotherapy comprises a toxin, hi some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[0264] In some embodiments, the immunotherapy is cytokine therapy. In some embodiments, the cytokine therapy is interleukin 2 (IL-2) therapy, interferon alpha (IFNα) therapy, granulocyte colony-stimulating factor (G-CSF) therapy, interleukin 12 (IL-12) therapy, interleukin 15 (IL-15) therapy, interleukin 7 (IL-7) therapy, or 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®).

[0265] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy comprises 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™).

[0266] Non-limiting examples of radiation therapy include radioactive iodide therapy, external beam radiation, and radium-223 therapy.

[0267] In some embodiments, the one or more additional therapies or therapeutic agents are selected from cytarabine, fludarabine, cisplatin, carboplatin, docetaxel, gemcitabine, belinostat, radiation therapy, irinotecan, olaparib, pemetrexed, savolitinib, and temozolomide.

[0268] In some cases, cancers that have replication stress and / or contain genetic characteristics that indicate that the cancer can be effectively treated 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 inhibitor, radiation, or a combination thereof.

[0269] Thus, in some embodiments, the methods described herein can further comprise administering to the subject a DNA damaging agent, a DNA repair inhibitor, radiation, or a combination thereof.

[0270] In some cases, the identification of replication stress may not be performed on cancer or may not be performed on cancer. In some cases, genetic analysis may not be performed on cancer or may not be performed on cancer. In some cases, cancers that may be negative for genetic characteristics of cancer may be shown to be effectively treated with the compound of formula (I), or its pharmaceutical salt, or its pharmaceutical composition. However, many first-line treatment regimens for cancer include DNA damaging agents, DNA repair inhibitors, or combinations thereof. In some such cases, because a combination of factors can promote mitotic breakdown, thereby treating cancer, the compound of formula (I), or its pharmaceutical salt, or its pharmaceutical composition may still be shown for treatment with the compound of formula (I), or its pharmaceutical salt, or its pharmaceutical composition.

[0271] Therefore, provided herein is a method for treating cancer in a subject in need of cancer treatment, comprising: (i) administering to the subject an effective amount of a treatment comprising: (a) a DNA damaging agent, (b) a DNA repair inhibitor, (c) radiation, (d) a DNA damaging agent and a DNA repair inhibitor, (e) a DNA damaging agent and radiation, (f) a DNA repair inhibitor and radiation, or (g) a DNA damaging agent, a DNA repair inhibitor, and radiation; and (i) followed by (ii) 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 of cancer treatment, comprising administering an effective amount of a compound of formula (I), a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject who has previously been administered one or more doses of a treatment comprising: (a) a DNA damaging agent, (b) a DNA repair inhibitor, (c) radiation, (d) a DNA damaging agent and a DNA repair inhibitor, (e) a DNA damaging agent and radiation, (f) a DNA repair inhibitor and radiation, or (g) a DNA damaging agent, a DNA repair inhibitor, and radiation. In some embodiments, the therapeutic agent (e.g., (a)-(g)) continues 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 cancer in a subject in need thereof, 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) effective amounts of therapeutic agents including (a) a DNA damaging agent, (b) a DNA repair inhibitor, (c) radiation, (d) a DNA damaging agent and a DNA repair inhibitor, (e) a DNA damaging agent and radiation, (f) a DNA repair inhibitor and radiation, or (g) a DNA damaging agent, a DNA repair inhibitor, and radiation.

[0272] In some embodiments, the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof, and the therapeutic agent (e.g., (a)-(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 therapeutic agent (e.g., (a)-(g)) are administered sequentially in separate dosages in any order.

[0273] The DNA damaging agent may be any suitable DNA damaging agent, such as those described herein. In some embodiments, the DNA damaging agent is selected from the group consisting of platinum-based chemotherapy agents, alkylating agents, nucleobase, nucleoside, or nucleotide analogs, 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 a combination thereof. In some embodiments, the nucleobase, nucleoside, or nucleotide analog comprises fluorouracil, cytarabine, gemcitabine, azacitidine, decitabine, or a combination thereof.

[0274] DNA repair inhibitor can be any suitable DNA repair inhibitor, such as those described herein.In some embodiments, DNA repair inhibitor is selected from the group consisting of topoisomerase I inhibitor, topoisomerase II inhibitor, PARP inhibitor, ATR inhibitor, Chk inhibitor, DNA-dependent protein kinase (DNA-PK) inhibitor, ATM inhibitor, Aurora kinase inhibitor (such as Aurora A inhibitor and / or Aurora B inhibitor), and combinations thereof.

[0275] In some embodiments, the topoisomerase I inhibitor comprises topotecan, irinotecan, belotecan, camptothecin, or a combination thereof. In some embodiments, the topoisomerase II inhibitor comprises etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubasin, or a combination thereof. In some embodiments, the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, veliparib, or a combination 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, SCH900776, SRA737, or a combination thereof. In some embodiments, the DNA-PK inhibitor comprises AZD7648, M3814, LY294002, nejisertib, samotricisib, or a combination thereof. In some embodiments, the ATM inhibitor comprises KU55933, AZD0156, AZD1390, ductosirib, berzosertib, or a combination thereof. In some embodiments, the Aurora kinase inhibitor comprises LY3295668, ZM447439, tozasertib, hesparazine, alisertib, MLN8054, or a combination thereof.

[0276] 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, idarubasin, 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, SCH900776, SRA737, or a combination thereof. In some embodiments, the DNA-PK inhibitor is AZD7648, M3814, LY294002, nejisertib, samotricisib, or a combination thereof. In some embodiments, the ATM inhibitor is KU55933, AZD0156, AZD1390, ductosirib, berzosertib, or a combination thereof. In some embodiments, the Aurora kinase inhibitor is LY3295668, ZM447439, tozasertib, hesparazine, alisertib, MLN8054, or a combination thereof.

[0277] Also provided herein is a method for treating a subject diagnosed or identified as having a cancer associated with replication stress, such as any of the exemplary cancers disclosed herein, comprising administering to the subject an effective amount of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0278] Also provided herein is a method for treating cancer in a subject in need thereof, 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, comprising administering to a subject identified as having a cancer associated with replication stress an effective amount of a compound of formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0279] In some embodiments of any of the methods described herein, the method further comprises administering an additional therapy or therapeutic agent to the subject. The additional therapy or therapeutic agent can be any suitable therapy or therapeutic agent. In some embodiments, the additional therapy or therapeutic agent is selected from radiation therapy, cytotoxic chemotherapy, kinase-targeted therapy, kinase-targeted therapy, apoptosis modulators, signal transduction inhibitors, immune-targeted therapy, angiogenesis-targeted therapy, and combinations thereof. In some embodiments, the additional therapy or therapeutic agent is selected from kinase-targeted therapy, kinase-targeted therapy, apoptosis modulators, signal transduction inhibitors, immune-targeted therapy, angiogenesis-targeted therapy, 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.

[0280] Also provided herein is a method for inhibiting mammalian cell proliferation, comprising contacting a mammalian cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for inducing mitotic disruption in a mammalian cell, comprising contacting a 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. The mammalian cell can be of any suitable species or type. 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 with replication 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 comprises contacting the mammalian cell with a DNA damaging agent, a DNA repair inhibitor, radiation, or a combination thereof.

[0281] Also provided herein is the 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 with replication stress. In some embodiments, the cancer is a cancer with an inactivated tumor suppressor gene. In some embodiments, the cancer is a cancer with an activated oncogene. In some embodiments, the medicament is labeled for use simultaneously with a DNA damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof. In some embodiments, the medicament is labeled for use after a DNA damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof.

[0282] In some embodiments of any of the methods or uses described herein, the cancer is a blood 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 tumor with BRCA mutation, head and neck cancer squamous cell carcinoma, pancreatic adenocarcinoma, acute myeloid leukemia, osteosarcoma, multiple myeloma, epithelial ovarian cancer, 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 cancer, Sarcoma, renal carcinoma, clear cell renal carcinoma, acute lymphoblastic leukemia, childhood glioma, head and neck precancer, Ewing's sarcoma, gastrointestinal stromal tumor, giant cell tumor of bone, clear cell ovarian carcinoma, mucinous ovarian carcinoma, primary peritoneal carcinoma, serous surface papillary carcinoma, teratoma, dyszelminoma, endodermal sinus tumor, choriomas, granulosa cell tumors, granulosa theca tumors, Sertoli-Leydig cell tumors, endometrial adenocarcinoma, adenosquamous carcinoma, papillary serous carcinoma, and uterine sarcoma.

[0283] In some embodiments, the subject is a human.

[0284] In some embodiments of any of the methods described herein, the compound of Formula (I) is selected from Examples 1-832 or a pharmaceutically acceptable salt thereof.

[0285] Also provided is a method for inhibiting Wee1 kinase activity in a mammalian cell, the method 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 and 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 with 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 described herein. In some embodiments, the mammalian cancer cell is a mammalian cancer cell with replication stress.

[0286] Also provided is a method for inhibiting Wee1 kinase activity in a mammalian cell, the method 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 and 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 with 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 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.

[0287] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" Wee1 kinase with a compound provided herein includes administering a compound provided herein to a subject, such as a human, having Wee1 kinase, and introducing a compound provided herein into a sample containing, for example, a mammalian cell or purified preparation containing Wee1 kinase.

[0288] Also provided herein is a method of inhibiting the proliferation of mammalian cells in vitro or in vivo, comprising contacting the mammalian cells with an effective amount of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0289] As defined herein, a "Wee1 kinase inhibitor" includes any compound that exhibits Wee1 inhibitory activity. In some embodiments, the Wee1 kinase inhibitor is selective for Wee1 kinase. Exemplary Wee1 kinase inhibitors have an inhibitory activity (IC) against 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 the assays described herein. 50 In some embodiments, the Wee1 kinase inhibitor can exhibit an inhibitory activity (IC) against 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 the assays provided herein. 50 ) can be shown.

[0290] The phrase "effective amount" means an amount of a compound sufficient, when administered to a subject in need thereof, to (i) treat cancer (such as a cancer associated with replication stress as described herein), (ii) alleviate, relieve, 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 the compound of Formula (I), or a pharmaceutically acceptable salt thereof that would correspond to such an amount, will vary depending on factors such as the particular compound, the disease state and its severity, and the individual characteristics (e.g., body weight) of the subject requiring treatment, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0291] When used as a pharmaceutical, the compound of formula (I), including its pharmaceutically acceptable salts, can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal, by inhalation or insufflation of powder or aerosol, including by nebulizer), oral, or parenteral. Oral administration can include dosage forms 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, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may 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.

[0292] The present invention also provides pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient 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. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, for example, containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In some embodiments, the compositions are formulated for oral administration. In some embodiments, the compositions are solid oral formulations. In some embodiments, the compositions are formulated as tablets or capsules.

[0293] Further provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an 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 variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0294] Suitable pharmaceutically acceptable carriers are well known in the art, and 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 British Pharmaceutical Society.

[0295] Methods for formulating pharmaceutical compositions are 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. and published by Marcel Dekker, Inc.

[0296] When preparing compositions in oral dosage form, any of the usual pharmaceutical media can be used.Therefore, 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, etc.; for solid oral preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. Suitable binders include, but are not limited to, 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, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Solid oral preparations can also be coated with a substance such as sugar to adjust the primary absorption site, or enteric coated. For parenteral administration, the carrier is usually composed of sterile water, and other ingredients may be added to increase solubility or preservation. Injection suspensions or solutions may also be prepared using aqueous carriers with appropriate additives. The pharmaceutical compositions herein will contain the amount of active ingredient necessary to deliver the effective dose described herein per dosage unit, for example, tablet, capsule, powder, injection, teaspoon, etc.

[0297] Compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be formulated in 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 unit dosages for human and other subjects, each unit containing a predetermined quantity of the active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0298] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One of skill in the art will appreciate that this embodies compounds or compositions containing from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg of the active ingredient.

[0299] In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of active ingredient. One of skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of active ingredient.

[0300] In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of the active ingredient. One of skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0301] The daily dosage of a compound of formula (I) or a pharmaceutically acceptable salt thereof can vary over a wide range, from 1.0 to 10,000 mg or more per adult per day, or any range therein. For oral administration, the composition is preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250, and 500 milligrams of active ingredient, for symptomatic adjustment of dosage to the subject being treated. An effective amount of the drug is usually supplied at a dosage level of about 0.1 mg / kg to about 1000 mg / kg of body weight per day, or any range therein. Preferably, the range is about 0.5 to about 500 mg / kg of body weight per day, or any range therein. More preferably, the dose is about 1.0 to about 250 mg / kg of body weight per day, or any range therein. More preferably, the dose is about 0.1 to about 100 mg / kg of body weight per day, or any range therein. In one example, the range may be about 0.1 to about 50.0 mg / kg of body weight per day, or any amount or range therein. In another example, the range may be about 0.1 to about 15.0 mg / kg of body weight per day, or any range therein. In yet another example, the range may be about 0.5 to about 7.5 mg / kg of body weight per day, or any amount or range therein. The pharmaceutical composition containing the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered in a regimen of 1 to 4 times per day, or in a single daily dose.

[0302] Active compound can be effective in a wide dosage range, and is generally administered in a pharmaceutically effective amount.The optimal dosage to be administered can be easily determined by those skilled in the art.Therefore, it will be understood that the amount of compound actually administered will usually be determined by a doctor and will vary according to relevant circumstances, including administration method, the actual compound to be administered, the strength of preparation, the condition to be treated and the progression of disease state.In addition, factors related to the specific subject being treated will need to adjust dosage, including subject's response, age, weight, diet, administration time and the severity of subject's symptoms.

[0303] In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may be administered in an amount ranging from 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.

[0304] Those skilled in the art will recognize that both in vivo and in vitro tests using suitable, known, and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0305] Those skilled in the art will further recognize that human clinical trials, including first-in-human dose ranging and efficacy studies in healthy subjects and / or subjects afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0306] Provided herein is a pharmaceutical kit useful for treating cancer (such as a replication-sensitive cancer), for example, comprising one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. If desired, such a kit can further comprise one or more of various conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as an insert or label, indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0307] Preparation of compounds As disclosed herein, many of the starting materials used are either commercially available or can be prepared using the routes described below using techniques known to those skilled in the art.

[0308] General scheme Compounds of formula (I) may be prepared as described in the following scheme.

[0309] Tricyclic dihydropyrrolopyrimidines of type 1d used as starting materials in Scheme 2 were prepared via the route shown in Scheme 1.

[0310] Scheme 1 [ka] General procedure for Scheme 1 Hydroxyaminopyrimidines of type 1b can be converted to suitable R-hydroxyaminopyrimidines in the presence of a suitable metal catalyst (e.g., CuI, XantPhos-Pd-G2), a suitable ligand (e.g., DMEDA, XantPhos), and a suitable base (e.g., Cs2CO3). 2 They were prepared from functionalized aminopyrimidines of type 1a via metal-catalyzed coupling reactions with substituted heteroaryl halides.

[0311] The intramolecular Mitsunobu reaction of the respective hydroxyaminopyrimidines of type 1b to provide bicyclic dihydropyrrolopyrimidines of type 1c can be achieved in the presence of an appropriate azodicarboxylate (such as DIAD) and a suitable phosphine (such as PBu3, PPh3) in a suitable organic solvent (such as THF).

[0312] Tricyclic dihydropyrrolopyrimidines of type 1d can be reacted with a suitable acid ([H + ] represents an acid such as hydrochloric acid) from bicyclic dihydropyropyrimidines of type 1c.

[0313] Scheme 2 [ka] General Procedure for Scheme 2 Pyrimidine sulfoxides of type 2a were prepared from tricyclic dihydropyrrolopyrimidines of type 1d by reaction with a suitable oxidizing reagent ([Ox] represents m-CPBA, etc.) in a suitable organic solvent (such as toluene).

[0314] The tricyclic compound 2b, which represents a compound of formula (I), can be reacted with an optionally substituted aniline HNR in a suitable organic solvent (such as toluene). 3 R 4 and prepared from the respective pyrimidine sulfoxides of type 2a by reaction with an appropriate base (such as DIPEA).

[0315] Examples representing formula (I) were prepared under appropriate conditions (column, mobile phase, gradient conditions, etc.) for chiral separation.

[0316] Alternatively, compounds of formula (I) may be prepared in an enantiomerically pure manner as described in Scheme 3 below.

[0317] Scheme 3 [ka] General procedure for Scheme 3 Tricyclic dihydropyrrolopyrimidines of type 3b can be reacted with suitable R-catalysts in the presence of a suitable metal catalyst (e.g., Pd2dba3, CuI, XantPhos-Pd-G2), a suitable ligand (e.g., BINAP, DMEDA, XantPhos), and a suitable base (e.g., Cs2CO3). 2 Prepared from functionalized intermediates of type 3a via metal-catalyzed coupling reactions with substituted heteroaryl halides.

[0318] Pyrimidine sulfoxides of type 3c were prepared from tricyclic dihydropyrrolopyrimidines of type 3b by reaction with a suitable oxidizing reagent ([Ox] represents m-CPBA, etc.) in a suitable organic solvent (such as toluene).

[0319] Examples of formula (I) can be prepared by dissolving optionally substituted anilines HNR in a suitable organic solvent (such as toluene). 3 R 4 and were prepared from the respective pyrimidine sulfoxides of type 3c by reaction with an appropriate base (such as DIPEA).

[0320] Compounds of formula (ID) may also be prepared as described in Scheme 4 below.

[0321] Scheme 4 [ka] General procedure for Scheme 4 Aminopyrimidines of type 4b were prepared from the respective pyrimidine sulfoxides of type 4a (representing sulfoxides of type 3c) by reaction with a substituted amine PG-NH2 (PG-NH2 represents, for example, 2,4-dimethoxybenzylamine) and a suitable base (for example, DIPEA) in a suitable organic solvent (for example, toluene).

[0322] Compounds of type 4c were prepared from the respective amino-pyrimidines of type 4b by reaction with a suitable acid (such as TFA). Examples representing formula (ID) are prepared by the reaction of an optionally substituted heteroaryl halide R with a suitable metal catalyst (such as Xphos-Pd-G3, XantPhos-Pd-G3), a suitable ligand (such as Xphos, XantPhos), and a suitable base (such as Cs2CO3). 4 -Hal was prepared from compound 4c via a metal-catalyzed coupling reaction. [Example]

[0323] material and method The compounds provided herein, including the salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0324] The reaction for preparing the compounds provided herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0325] 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 of ordinary skill in the art. Protecting group chemistry is described, for example, in Protecting Group Chemistry, 1 st Ed.,Oxford University Press,2000,March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,5 thEd., Wiley-Interscience Publication, 2001, and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 74(11), 1297 (1997).

[0326] Moisture- or air-sensitive reactions were carried out under nitrogen or argon using anhydrous solvents and reagents. Reaction progress was determined either by analytical thin-layer chromatography (TLC), usually performed using Sanpont pre-coated TLC plates, silica gel GF-254, 0.25 mm layer thickness, or by liquid chromatography-mass spectrometry (LC-MS).

[0327] The analytical LC-MS system typically used consisted of a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode, using a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS 2020 MS detector. The column was typically a HALO a C18 30*5.0 mm, 2.7 μm column. Mobile phase A was water containing 0.05% TFA, and mobile phase B was acetonitrile containing 0.05% TFA. The gradient was from 5% mobile phase B to 95% in 2.0 min, held for 0.7 min, then returned 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 °C. The flow rate was 1.5 mL / min, and the injection volume was 1 μl. The PDA (SPD-M20A) detection range was 190-400 nm. The MS detector was configured with electrospray ionization as the ionization source. Acquisition mode: scan; nebulization gas flow: 1.5 L / min; drying gas flow: 15 L / min; detector voltage: tuning voltage ±0.2 kV; DL temperature: 250 °C; heating block temperature: 250 °C; scan range: 90.00-900.00 m / z. The ELSD (Alltech 3300) detector parameters were: drift tube temperature: 60 ±5 °C; N2 flow rate: 1.8 ±0.2 L / min. The mobile phase gradient was optimized for each compound.

[0328] The GC-MS system was typically performed using a Shimadzu GCMS-QP2010 Ultra with FID and MS detectors. MS detector in acquisition mode: start time: 2.00 min, end time: 9.00 min, ACQ mode: scan, event time: 0.30 s, scan rate: 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.

[0329] Preparative HPLC purification was typically performed using a Waters Auto Purification System (2545-2767) with a 2489 UV detector. Columns included: Waters C18, 19 x 150 mm, 5 μm; XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; XSelect CSH Prep C18 OBD column, 5 μm, 19 x 150 mm; XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; Xselect CSH Fluorophenyl, 30 x 150 mm, 5 μm; and YMC-Actus Triart C18, 30 x 150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5–95%) or 10 mmol / L NH4HCO3 in water containing 0.1% FA. The flow rate was maintained at 25 mL / min, the injection volume was 1200 μL, and the UV detector used two channels: 254 nm and 220 nm. The mobile phase gradient was optimized for each compound.

[0330] Chiral analytical chromatography was performed on one of the following columns: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, and IH columns (Daicel Chemical Industries, Ltd.), (R,R)-Whelk-O1, and (S,S)-Whelk-O1 columns (Regis Technologies, Inc.), and Chiral Cellulose-SB, SC, and SA columns (YMC Co., Ltd.) in different column sizes (50 x 4.6 mm, 100 x 4.6 mm, 150 x 4.6 mm, 250 x 4.6 mm, 50 x 3.0 mm, and 100 x 3.0 mm) using either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as the isocratic solvent system or under supercritical fluid (SFC) conditions. Chiral preparative chromatography was performed on one of the following columns: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, and IH columns (Daicel Chemical Industries, Ltd.), (R,R)-Whelk-O1, and (S,S)-Whelk-O1 columns (Regis Technologies, Inc.). Chiral cellulose SB, SC, and SA columns (YMC Co., Ltd.) were used in different column sizes (250 × 20 mm, 250 × 30 mm, and 250 × 50 mm) to identify the desired isocratic solvent system for chiral analytical chromatography or supercritical fluid chromatography (SFC) conditions.

[0331] Concentration of solutions was performed on a rotary evaporator under reduced pressure. Flash column chromatography was typically performed using a Biotage flash chromatography instrument (Dyax Corp.) on silica gel (40–60 μM, 60 Å pore size) in prepacked cartridges of the stated size. 1H NMR spectra were acquired at 400 MHz spectrometers (or 300 MHz spectrometers) in DMSO-d solutions unless otherwise noted. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in DMSO-d solutions, and the residual CH3OH peak or TMS was used as an internal reference in CD3OD solutions. Coupling constants (J) are reported in hertz (Hz). [Table 3-1] [Table 3-2] [Table 3-3]

[0332] Preparation of intermediates Intermediate 1: rel-(2S,3S)-2-(4-amino-2-(methylthio)pyrimidin-5-yl)-1-((tert-butyldimethylsilyl)oxy)-2,5-dimethylhex-5-en-3-ol [ka] Step 1. Diethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)propanedioate. 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 M in THF, 20.3 mL, 2 equiv.) at −78° C. under a N atmosphere. The mixture was allowed to stir at −78° C. for 1 h. Then, ethyl carbonocyanidate (8.05 g, 81.06 mmol, 2 equiv.) 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 (3×150 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give diethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)propanedioate (12.00 g, 37.64 mmol, 93% yield) as a yellow oil. LCMS (ES, m / z): 319, 321 [M+H] + , Rt 0.769 min.

[0333] Step 2. Diethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl-propanedioate. To a solution of diethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)propanedioate (11.00 g, 34.51 mmol, 1 equiv) in THF (100 mL) was added NaH (2.76 g, 60% suspension in mineral oil, 69.01 mmol, 2 equiv) at 0 °C for 30 min. The mixture was stirred under N2 atmosphere at 0 °C for another 30 min. Then, MeI (9.80 g, 69.01 mmol, 2 equiv) was added dropwise. The mixture was stirred under N2 atmosphere at 60 °C for 12 h. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature and quenched with ice / water (300 mL). The aqueous layer was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give diethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl-propanedioate (10 g, 30.05 mmol, 77% yield) as a yellow oil. LCMS (ES, m / z): 333, 335 [M+H] + , Rt 0.914 min.

[0334] Step 3. 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 (10.30 g, 30.95 mmol, 1 equiv.) in ether (100 mL) was added DIBAL-H (1 M in toluene, 61.90 mL, 2 equiv.) at −78° C. under a N atmosphere. The mixture was stirred at room temperature under a N atmosphere for 2 hours. The reaction was monitored by LC-MS. The mixture was quenched with saturated sodium potassium tartrate (250 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 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.

[0335] Step 4. 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 Imd (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 room temperature for 3 hours. The reaction was monitored by LC-MS. Ice / water (100 mL) was then 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 NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give 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. 1 H NMR(300MHz,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=7.2Hz ,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.

[0336] Step 5. 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 equiv.) in DCM (20 mL) under a N2 atmosphere, DIBAL-H (1 M in DCM, 10 mL, 2 equiv.) was added dropwise at −78° C. for 1 h. The mixture was then stirred at room temperature for another 1 h. The reaction was monitored by LC-MS. The reaction was quenched with saturated sodium potassium tartrate solution (100 mL), and then the mixture was extracted with EA (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 1:2 EA / PE) to give 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 minutes.

[0337] Step 6. 3-[tert-Butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl-propanal. To a solution of 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl-propan-1-ol (3.10 g, 8.54 mmol, 1 equiv.) in DCM (100 mL) was added DMP (7.24 g, 17.08 mmol, 2 equiv.) in portions at 0° C. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS. The mixture was washed with water (2×100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give 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.

[0338] Step 7. rel-(2S,3S)-1-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2,5-dimethylhex-5-en-3-ol (Int1-7b) To a solution of 3-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2-methyl-propanal (2 g, 5.54 mmol, 1 equiv.) in DCM (50 mL) was added (2-methylallyl)magnesium chloride (0.5 M in THF, 13.6 mL, 1.3 equiv.) dropwise at −5° C. The mixture was stirred at 0° C. for 2 h. LCMS and TLC showed two diastereomers. The mixture was quenched with ice / water (50 mL). The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA / PE) to give rel-(2S,3R)-1-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2,5-dimethylhex-5-en-3-ol (Int1-7a) (1.12 g, 2.43 mmol, 48% yield) as a yellow oil (undesired product) and rel-(2S,3S)-1-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2,5-dimethylhex-5-en-3-ol (Int1-7b) (900 mg, 1.95 mmol, 39% yield) as a yellow oil (desired product).

[0339] rel-(2S,3R)-1-[tert-butyl(dimethyl)silyl]oxy-2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-2,5-dimethyl-hex-5-en-3-ol (Int1-7a): 1H NMR(300MHz,DMSO-d6)δ 8.54(s,1H),4.82-4.78(m,1H),4.70-4.66(m,1H),4.63-4.60(m,1H),4.58-4.52(m,1H),4.46-4.40(m,1H),3.70-3.64(m,1H),2.5 1(s,3H),2.03-1.93(m,1H),1.73-1.61(m,4H),1.41(s,3H),0.69(s,9H),-0.04(s,3H),-0.09(s,3H).LCMS(ES,m / z):417, 419[M+H] + , room temperature 2.124 minutes.

[0340] rel-(2S,3S)-1-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2,5-dimethylhex-5-en-3-ol (Int1-7b): 1 H NMR(300MHz,DMSO-d6)δ 8.56(s,1H),4.75-4.67(m,3H),4.43-4.37(m,1H),4.30-4.25(m,1H),3.77-3.71(m,1H),2.52(s,3H),2.05- 1.97(m,2H),1.70(s,3H),1.40(s,3H),0.74(s,9H),0.00(s,3H),-0.01(s,3H).LCMS(ES,m / z):417, 419[M+H] + , Rt 2.156 minutes.

[0341] Step 8. rel-(2S,3S)-2-(4-Azido-2-methylsulfanyl-pyrimidin-5-yl)-1-[tert-butyl(dimethyl)silyl]oxy-2,5-dimethyl-hex-5-en-3-ol. To a stirred solution of Int1-7b (1 g, 2.40 mmol, 1 equiv) in DMF (15 mL) was added NaN3 (450 mg, 5.99 mmol, 2.5 equiv). The mixture was stirred at 60 °C for 18 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. Ice / water (80 mL) was then added. The resulting mixture was extracted with EA (3 × 80 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:4 EA / PE) to give rel-(2S,3S)-2-(4-azido-2-methylsulfanyl-pyrimidin-5-yl)-1-[tert-butyl(dimethyl)silyl]oxy-2,5-dimethyl-hex-5-en-3-ol (800 mg, 1.89 mmol, 79% yield) as a colorless oil. LCMS (ES, m / z): 424.15 [M+H] + , Rt 0.892 min.

[0342] Steps 9 and 10. rel-(2S,3S)-2-(4-amino-2-(methylthio)pyrimidin-5-yl)-1-((tert-butyldimethylsilyl)oxy)-2,5-dimethylhex-5-en-3-ol (Intermediate 1) To a stirred solution of rel-(2S,3S)-2-(4-azido-2-methylsulfanyl-pyrimidin-5-yl)-1-[tert-butyl(dimethyl)silyl]oxy-2,5-dimethyl-hex-5-en-3-ol (900 mg, 2.12 mmol, 1 equiv.) in toluene (10 mL) was added PBu3 (1.57 mL, 6.37 mmol, 3 equiv.). The mixture was stirred at 100 °C under a N2 atmosphere for 1 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the desired tributyl-phosphanylidene intermediate (1.3 g, crude) as a pale yellow oil. LCMS (ES, m / z): 598.55 [M+H] +, Rt 1.257 min. To a stirred mixture of tributyl-phosphanylidene intermediate (1.3 g, 2.17 mmol, 1 equiv.) in THF (30 mL) and HO (5 mL), AcOH (10 mL) was slowly added. The mixture was stirred at 100 °C for 3 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The pH value was adjusted to 8-9 with saturated NaHCO . The resulting mixture was extracted with EA (3 × 50 mL). The organic layers were combined, dried over anhydrous NaSO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give intermediate 1 (700 mg, 1.67 mmol, 77% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.77(s,1H),7.51(br,2H),6.10(d,J=5.2Hz,1H),4.75-4.63(m,2H),4.03-4.01(m,1H),3.84-3.77(m,1H),3.61-3.55(m,1H),2.3 9(s,3H),2.04-1.95(m,1H),1.69-1.60(m,4H),1.30(s,3H),0.76(s,9H),-0.05(s,3H),-0.16(s,3H).LCMS(ES,m / z):398.15[M+H] + , Rt 0.796 min.

[0343] Intermediate 2: 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 equiv.) and methanamine (2 M in THF, 15 mL, 1.1 equiv.) in DCM (50 mL) was added sodium triacetoxyborohydride (6.27 g, 29.6 mmol, 1.1 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 12 h. The reaction was monitored by LC-MS. The resulting mixture was washed with brine (2 × 80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 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.

[0344] Step 2. tert-Butyl ((6-bromopyridin-2-yl)methyl)(methyl)carbamate (Intermediate 2) To a stirred solution of 1-(6-bromo-2-pyridyl)-N-methyl-methanamine (10 g, 49.7 mmol, 1 equiv.) and triethylamine (0.12 mol, 17.3 mL, 2.5 equiv.) in DCM (100 mL) was added di-tert-butyl dicarbonate (49.7 mmol, 11.4 mL, 1 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by LC-MS. The mixture was washed with brine (2 × 80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl ((6-bromopyridin-2-yl)methyl)(methyl)carbamate (8 g, 23.9 mmol, 53% yield) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)7.77-7.73(m,1H),7.53(d,J=7.8Hz,1H),7.25-7.18(m,1 H),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.

[0345] Intermediates described herein are either commercially available or were synthesized according to the methods shown below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0346] Intermediate 7: 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 equiv.) and 1-methylpiperazine (3.87 g, 38.68 mmol, 4.29 mL, 1.20 equiv.) in DMF (20 mL) was added K2CO3 (9.90 g, 64.46 mmol, 2 equiv.). The resulting mixture was stirred at 90 °C for 3 h. The reaction was monitored by LC-MS. The mixture was allowed to cool 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) 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 1:1 EA / PE) to give 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.

[0347] Step 2. 3-Methyl-4-(4-methylpiperazin-1-yl)aniline (Intermediate 7) To a stirred solution of 1-methyl-4-(2-methyl-4-nitrophenyl)piperazine (5.1 g, 21.68 mmol, 1 equiv) in MeOH (50 mL) was added Pd / C (200 mg, 10 wt%) at room temperature under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 5 h. The solid was 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 give 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. [Table 5-1] [Table 5-2]

[0348] Intermediate 16: (S)-1-(4-aminophenyl)-5-methylpyrrolidin-2-one Step 1. (S)-5-Methyl-1-(4-nitrophenyl)pyrrolidin-2-one A solution of (S)-5-methylpyrrolidin-2-one (800 mg, 8.07 mmol, 1 equiv.), 1-bromo-4-nitrobenzene (1.96 g, 9.68 mmol, 1.00 mL, 1.2 equiv.), Pd(dba) (739 mg, 807.02 μmol, 0.1 equiv.), Xantphos (385 mg, 807 μmol, 0.1 equiv.), and CsCO (5.26 g, 16.14 mmol, 2 equiv.) in dioxane (10 mL) was stirred at 100 °C under a N atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The solid was filtered off and washed with EA (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:2 EA / PE) to give (S)-5-methyl-1-(4-nitrophenyl)pyrrolidin-2-one (1.5 g, 84% yield) as a yellow solid. LCMS (ESI+, m / z): 221 [M+H] +, Rt 0.620 min.

[0349] Step 2. (S)-1-(4-aminophenyl)-5-methylpyrrolidin-2-one (Intermediate 16) To a stirred solution of (S)-5-methyl-1-(4-nitrophenyl)pyrrolidin-2-one (1.0 g, 4.54 mmol) and EA (5 mL) in MeOH (15 mL) was added Pd / C (551 mg, 10 wt%) under a N atmosphere. The mixture was stirred at room temperature under a H atmosphere for 24 h. The reaction was monitored by LCMS. The solid was filtered and washed with MeOH (2 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10:1 DCM / MeOH) to give (S)-1-(4-aminophenyl)-5-methyl-pyrrolidin-2-one (700 mg, 81% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 6.99-6.92(m,2H),6.59-6.52(m,2H),5.06(br,2H),4.17-4.04(m,1H),2.49-2. 18(m,3H),1.71-1.53(m,1H),1.05(d,J=6.0Hz,3H).LCMS(ESI+,m / z):191[M+H] + , Rt 0.403 min.

[0350] Intermediate 19: (R)-1-(4-aminophenyl)-5-methylpyrrolidin-2-one Step 1. (R)-5-Methyl-1-(4-nitrophenyl)pyrrolidin-2-one A solution of (R)-5-methylpyrrolidin-2-one (450 mg, 4.54 mmol, 1 equiv.), 1-bromo-4-nitrobenzene (1.10 g, 5.45 mmol, 1.2 equiv.), Pd(dba) (416 mg, 454 μmol, 0.1 equiv.), Xantphos (216 mg, 454 μmol, 0.1 equiv.), and CsCO (2.96 g, 9.08 mmol, 2 equiv.) in dioxane (5 mL) was stirred at 100 °C under a N atmosphere for 2 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The solid was filtered and washed with EA (2 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:2 EA / PE) to give (R)-5-methyl-1-(4-nitrophenyl)pyrrolidin-2-one (950 mg, 95% yield) as a yellow solid. LCMS (ESI+, m / z): 221 [M+H] + , Rt 0.637 min.

[0351] Step 2. (R)-1-(4-aminophenyl)-5-methylpyrrolidin-2-one (Intermediate 19) To a stirred solution of (R)-5-methyl-1-(4-nitrophenyl)pyrrolidin-2-one (0.95 g, 4.31 mmol, 1 equiv) in MeOH (6 mL) and EA (6 mL) was added Pd / C (100 mg, 10 wt%). The mixture was stirred at room temperature under an H atmosphere for 24 h. The reaction was monitored by LC-MS. The solid was filtered and washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10:1 DCM / MeOH) to give (R)-1-(4-aminophenyl)-5-methyl-pyrrolidin-2-one (750 mg, 92% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 6.99-6.91(m,2H),6.59-6.51(m,2H),5.06(br,2H),4.20-3.97(m,1H),2.49-2. 17(m,3H),1.70-1.53(m,1H),1.05(d,J=6.0Hz,3H).LCMS(ESI+,m / z):191[M+H] + , Rt 0.403 min.

[0352] Intermediates 21 and 22: (S)-4-(tetrahydrofuran-3-yl)aniline and (R)-4-(tetrahydrofuran-3-yl)aniline Step 1. 3-(4-nitrophenyl)-2,5-dihydrofuran A mixture of 1-bromo-4-nitrobenzene (800 mg, 3.96 mmol, 1 equiv.), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.16 g, 5.94 mmol, 1.5 equiv.), Pd(dppf)Cl (323 mg, 396 μmol, 0.1 equiv.), and NaCO (839 mg, 7.92 mmol, 2 equiv.) in a mixed solvent of HO (4 mL) and dioxane (16 mL) was irradiated in a microwave oven at 130 °C for 30 min under a N atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with brine (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give 3-(4-nitrophenyl)-2,5-dihydrofuran (450 mg, 59% yield) as a yellow solid. LCMS (ESI+, m / z): 192 [M+H] + , Rt 0.673 min.

[0353] Step 2. 4-(Tetrahydrofuran-3-yl)aniline To a stirred mixture of 3-(4-nitrophenyl)-2,5-dihydrofuran (450 mg, 2.35 mmol, 1 equiv.) in MeOH (10 mL) was added Pd / C (90 mg, 10 wt%) under N2 atmosphere. The resulting mixture was stirred at room temperature under H2 atmosphere for 2 h. The reaction was monitored by LC-MS. The solid was filtered and washed with EA (3 × 20 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:5 EA / PE) to give 4-(tetrahydrofuran-3-yl)aniline (320 mg, 83% yield) as a brown solid.1 H NMR(300MHz,DMSO-d6)δ 6.93(d,J=8.4Hz,2H),6.51(d,J=8.4Hz,2H),4.90(s,2H),4.01-3.84(m,2H),3.80-3.72(m,1H),3.4 5-3.38(m,1H),3.23-3.12(m,1H),2.26-2.14(m,1H),1.89-1.76(m,1H).LCMS(ESI+,m / z):164[M+H] + , Rt 0.132 min.

[0354] Step 3. Separation of enantiomers to obtain (S)-4-(tetrahydrofuran-3-yl)aniline and (R)-4-(tetrahydrofuran-3-yl)aniline (intermediates 21 and 22). Racemic 4-(tetrahydrofuran-3-yl)aniline (320 mg, 1.96 mmol, 1 equiv.) was separated by preparative chiral HPLC using the following conditions: (Column: CHIRALPAK IH, 2 × 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC; Mobile Phase B: IPA-HPLC; Flow Rate: 20 mL / min; Gradient: 80% B to 80% B in 20 min; Wavelength: 220 / 254 nm; RT1 (min): 12.481; RT2 (min): 15.848). The first eluting isomer was isolated to give Intermediate 21 (150 mg, 47% yield) as a yellow solid. The second eluting isomer was isolated to give Intermediate 22 (140 mg, 44% yield) as a yellow solid.

[0355] Intermediates 28 and 29: (S)-5-(4-aminophenyl)-1-methylpyrrolidin-2-one and (R)-5-(4-aminophenyl)-1-methylpyrrolidin-2-one Step 1. 5-(4-Bromophenyl)-1-methylpyrrolidin-2-one To a solution of 5-(4-bromophenyl)pyrrolidin-2-one (1.00 g, 4.16 mmol, 1 equiv) in DMF (15 mL) was added NaH (60% suspension in mineral oil, 144 mg, 6.25 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at room temperature for 15 min. Then, MeI (709 mg, 5.00 mmol, 1.2 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was monitored by LC-MS. The reaction mixture was quenched with water (50 mL) and extracted with EA (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give 5-(4-bromophenyl)-1-methyl-pyrrolidin-2-one (900 mg, 85% yield) as a yellow oil. LCMS (ESI+, m / z): 254[M+H]+, Rt 1.118 min.

[0356] Step 2. 5-(4-((diphenylmethylene)amino)phenyl)-1-methylpyrrolidin-2-one To a solution of 5-(4-bromophenyl)-1-methyl-pyrrolidin-2-one (900 mg, 3.54 mmol, 1 equiv.), diphenylmethanimine (770 mg, 4.25 mmol, 1.2 equiv.), BrettPhos (190 mg, 354 μmol, 0.1 equiv.), and CsCO (3.46 g, 10.62 mmol, 3 equiv.) in 1,4-dioxane (8 mL) was added BrettPhos-Pd-G (321 mg, 354 μmol, 0.1 equiv.) at room temperature under a N atmosphere. The resulting mixture was stirred at 100° C. for 3 hours under a N atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool 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 1:10 MeOH / DCM) to give 5-(4-((diphenylmethylene)amino)phenyl)-1-methylpyrrolidin-2-one (905 mg, 72% yield) as a yellow solid. LCMS (ESI+, m / z): 355 [M+H] + , Rt 0.978 min.

[0357] Step 3. 5-(4-aminophenyl)-1-methylpyrrolidin-2-one To a solution of 5-(4-((diphenylmethylene)amino)phenyl)-1-methylpyrrolidin-2-one (905 mg, 2.55 mmol) in THF (6 mL) was added HO (1 mL) and AcOH (2 mL). The resulting mixture was stirred at 100° C. for 1 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The reaction was quenched with saturated aqueous NaHCO (50 mL). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:10 MeOH / DCM) to give 5-(4-aminophenyl)-1-methylpyrrolidin-2-one (420 mg, 87% yield) as a yellow solid. LCMS(ESI+,m / z):191[M+H] + , Rt 0.320 min. 1 H NMR(300MHz,DMSO-d6)δ 6.92-6.87(m,2H),6.58-6.54(m,2H),5.08(br,2H),4.37-4.32(m,1H),2. 45(s,3H),2.42-2.20(m,3H),1.80-1.69(m,1H).LCMS(ES,m / z):191[M+H] + , Rt 0.320 min.

[0358] Step 4. Separation of enantiomers to obtain (S)-5-(4-aminophenyl)-1-methylpyrrolidin-2-one and (R)-5-(4-aminophenyl)-1-methylpyrrolidin-2-one (intermediates 28 and 29). The racemic product 5-(4-aminophenyl)-1-methyl-pyrrolidin-2-one (850 mg, 4.47 mmol, 1 equiv.) was separated by preparative chiral HPLC with the following conditions (column: EnantioPak A1-5, 2.12 × 25 cm, 5 μm, mobile phase A: CO, mobile phase B: MeOH (0.1% 2M NH-MeOH), flow rate: 50 mL / min, gradient: isocratic 35% B, column temperature (°C): 35°C, back pressure: 100 bar, wavelength: 220 nm, RT1 (min): 3.4, RT2 (min): 4.61, sample solvent: MeOH (0.1% 2M NH-MeOH) to give intermediate 28 (350 mg, 41% yield) and intermediate 29 (330 mg, 39% yield).

[0359] Intermediate 30: 6-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine Step 1. 2-(3,6-Dihydro-2H-pyran-4-yl)-5-nitropyridine A mixture of 2-bromo-5-nitropyridine (2 g, 9.85 mmol, 1 equiv.), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.14 g, 19.71 mmol, 2 equiv.), KOAc (8.34 g, 29.56 mmol, 3 equiv.), and Pd(dppf)Cl (805 mg, 985 μmol, 0.1 equiv.) in 1,4-dioxane (20 mL) and HO (5 mL) was stirred at 100° C. for 2 h under a N atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Water (30 mL) was then added. The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 2-(3,6-dihydro-2H-pyran-4-yl)-5-nitropyridine (900 mg, 44% yield) as a yellow solid. LCMS (ESI+, m / z): 207 [M+H] + , Rt 0.623 min.

[0360] Step 2. 6-(Tetrahydro-2H-pyran-4-yl)pyridin-3-amine (Intermediate 30) To a stirred solution of 2-(3,6-dihydro-2H-pyran-4-yl)-5-nitropyridine (550 mg, 2.67 mmol, 1 equiv) in EtOH (10 mL) and EA (10 mL) was added Pd / C (110 mg, 10 wt%) under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluted with 1:10 MeOH / DCM) to give 6-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine (420 mg, 76% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 7.86(s,1H),6.96-6.82(m,2H),5.10(br,2H),4.02-3.80(m,2H),3.49-3.3 0(m,2H),2.78-2.60(m,1H),1.74-1.54(m,4H).LCMS(ESI+,m / z):179[M+H] + , Rt 0.385 minutes. [Table 6]

[0361] Intermediates 31 and 32: (R)-4-(tetrahydrofuran-2-yl)aniline and (S)-4-(tetrahydrofuran-2-yl)aniline Step 1. 5-(4-nitrophenyl)-2,3-dihydrofuran A mixture of 1-bromo-4-nitro-benzene (1.50 g, 7.43 mmol, 1 equiv.), Pd2(dba)3 (680 mg, 743 μmol, 0.1 equiv.), sodium formate (656 mg, 9.65 mmol, 1.3 equiv.), TBAC (3.10 g, 11.14 mmol, 1.5 equiv.), and 2,3-dihydrofuran (2.86 g, 40.84 mmol, 5.5 equiv.) in DMF (80 mL) was stirred at room temperature for 16 h. The reaction was monitored by TLC. The resulting mixture was filtered through a Celite pad and washed with EA (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give 5-(4-nitrophenyl)-2,3-dihydrofuran (880 mg, 62% yield) as a yellow oil.

[0362] Step 2. 4-(Tetrahydrofuran-2-yl)aniline To a solution of 5-(4-nitrophenyl)-2,3-dihydrofuran (1.20 g, 6.28 mmol) in EtOH (50 mL) was added Pd / C (120 mg, 10 wt%) under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 1 h. The reaction was monitored by LC-MS. The resulting mixture was filtered through a Celite pad and washed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 4-(tetrahydrofuran-2-yl)aniline (700 mg, 69% yield) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 6.98-6.89(m,2H),6.54-6.44(m,2H),4.96(br,2H),4.58(t,J=6.0Hz,1H),3.95-3.88(m,1H),3.75 -3.68(m,1H),2.20-2.09(m,1H),1.99-1.85(m,2H),1.69-1.57(m,1H).LCMS(ESI+,m / z):164[M+H] + , Rt 0.942 min.

[0363] Step 3. Separation of enantiomers to obtain (R)-4-(tetrahydrofuran-2-yl)aniline and (S)-4-(tetrahydrofuran-2-yl)aniline (intermediates 31 and 32). 4-(Tetrahydrofuran-2-yl)aniline (700 mg, 4.29 mmol, 1 equiv.) was separated by preparative chiral HPLC using the following conditions: Column: Exsil Chiral-NR, 3 × 25 cm, 8 μm; Mobile Phase A: CO; Mobile Phase B: IPA (0.5% 2M NH-MeOH); Flow Rate: 80 mL / min; Gradient: Isocratic 40% B; Column Temperature: 35 °C; Back Pressure: 100 bar; Wavelength: 220 nm; RT1 (min): 3.95; RT2 (min): 5.65; Sample Solvent: MeOH (preparative); Injection Volume: 4.8 mL; Run Number: 4). The first eluting isomer was isolated to give Intermediate 31 (157 mg) as a yellow oil. The second eluting isomer was isolated to give Intermediate 32 (150 mg) as a yellow oil.

[0364] Intermediates 33 and 34: tert-butyl (S)-4-(4-aminophenyl)-2-oxo-pyrrolidine-1-carboxylate and tert-butyl (R)-4-(4-aminophenyl)-2-oxo-pyrrolidine-1-carboxylate Step 1. tert-Butyl 2-hydroxy-4-(4-nitrophenyl)pyrrolidine-1-carboxylate A mixture of 4-nitrobenzenediazonium tetrafluoroborate (5 g, 21.10 mmol, 1 equiv.), tert-butyl 2,5-dihydropyrrole-1-carboxylate (3.57 g, 21.10 mmol, 1 equiv.), and palladium(II) acetate (474 ​​mg, 2.11 mmol, 0.1 equiv.) in ACN (30 mL) was stirred at room temperature under a N atmosphere for 3 h. The reaction was monitored by LC-MS. The reaction mixture was diluted with HO (100 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 2-hydroxy-4-(4-nitrophenyl)pyrrolidine-1-carboxylate (5 g, crude), which was used directly in the next step without further purification. LCMS(ESI+,m / z):309[M+H] + , Rt 0.967 min.

[0365] Step 2. tert-Butyl 4-(4-nitrophenyl)-2-oxo-pyrrolidine-1-carboxylate (Intermediate 33 / 34-2) To a stirred solution of tert-butyl 2-hydroxy-4-(4-nitrophenyl)pyrrolidine-1-carboxylate (5 g, 16.22 mmol, 1 equiv.) in DCM (20 mL) was added pyridinium chlorochromate (6.99 g, 32.43 mmol, 2 equiv.) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The solid was filtered off and washed with DCM (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 4-(4-nitrophenyl)-2-oxo-pyrrolidine-1-carboxylate (Intermediate 33 / 34-2) (2.7 g, 54% yield) as a yellow oil. LCMS (ESI+, m / z): 307 [M+H] + , Rt 0.942 min.

[0366] Step 3. tert-Butyl 4-(4-aminophenyl)-2-oxo-pyrrolidine-1-carboxylate To a stirred mixture of tert-butyl 4-(4-nitrophenyl)-2-oxo-pyrrolidine-1-carboxylate (1.2 g, 3.92 mmol, 1 equiv.) in EA (10 mL) and EtOH (10 mL) was added Pd / C (120 mg, 10 wt%) under N2 atmosphere. The resulting mixture was stirred at room temperature under H2 atmosphere for 2 h. The reaction was monitored by LC-MS. The solid was filtered off and washed with EtOH (2 × 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10:1 DCM / MeOH) to afford tert-butyl 4-(4-aminophenyl)-2-oxo-pyrrolidine-1-carboxylate (700 mg, 65% yield) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 6.97(d,J=8.4Hz,2H),6.52(d,J=8.4Hz,2H),4.98(br,2H),4.01-3.90(m,1H),3.51-3.4 2(m,1H),3.40-3.30(m,1H),2.66-2.59(m,2H),1.45(s,9H).LCMS(ESI+,m / z):277[M+H] + , Rt 0.553 min.

[0367] Step 4. Separation of Enantiomers to Obtain tert-butyl (S)-4-(4-aminophenyl)-2-oxo-pyrrolidine-1-carboxylate and tert-butyl (R)-4-(4-aminophenyl)-2-oxo-pyrrolidine-1-carboxylate (Intermediates 33 and 34) Racemic tert-butyl 4-(4-aminophenyl)-2-oxo-pyrrolidine-1-carboxylate (700 mg, 2.52 mmol, 1 equiv.) was separated by preparative chiral HPLC using the following conditions: CHIRALPAK IF column, 3 × 25 cm, 5 μm column; mobile phase A: CO; mobile phase B: MeOH (0.1% 2M NH-MeOH); flow rate: 70 mL / min; gradient: isocratic 35% B; column temperature: 35 °C; back pressure: 100 bar; wavelength: 220 nm; RT1 (min): 6.13; RT2 (min): 8.14; sample solvent: MeOH (preparative); injection volume: 4.8 mL; number of runs: 5. The first eluting isomer was isolated to give intermediate 33 (300 mg) as a yellow solid. The second eluting isomer was isolated to give Intermediate 34 (310 mg) as a yellow solid.

[0368] Intermediates 35 and 36: (R)-4-(4-aminophenyl)-1-methyl-pyrrolidin-2-one and (S)-4-(4-aminophenyl)-1-methyl-pyrrolidin-2-one Step 1. 4-(4-Nitrophenyl)pyrrolidin-2-one To a solution of intermediate 33 / 34-2 (2.9 g, 9.47 mmol, 1 equiv) in DCM (30 mL) was added TFA (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-MS. The mixture was basified to pH = 8 with NaHCO3 (aq). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 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 10:1 DCM / MeOH) to give 4-(4-nitrophenyl)pyrrolidin-2-one (1.4 g, 72% yield) as a yellow solid. LCMS (ESI+, m / z): 207 [M+H] + , Rt 0.667 min.

[0369] Step 2. 1-Methyl-4-(4-nitrophenyl)pyrrolidin-2-one To a solution of 4-(4-nitrophenyl)pyrrolidin-2-one (1.4 g, 6.79 mmol, 1 equiv) in DMF (40 mL) was added sodium hydride (406 mg, 10.18 mmol, 60 wt% in mineral oil) at 0° C. The mixture was stirred for 15 min, followed by the addition of iodomethane (2.89 g, 20.37 mmol, 3 equiv). The mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The reaction mixture was quenched with ice / water (100 mL). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 20:1 DCM / MeOH) to give 1-methyl-4-(4-nitrophenyl)pyrrolidin-2-one (1.07 g, 72% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 8.21(d,J=9.0Hz,2H),7.61(d,J=9.0Hz,2H),3.80-3.71(m,2H),3.40-3.36(m,1H ),2.78(s,3H),2.74-2.67(m,1H),2.42-2.36(m,1H).LCMS(ESI+,m / z):221[M+H] + , Rt 0.725 min.

[0370] Step 3. 4-(4-aminophenyl)-1-methyl-pyrrolidin-2-one To a stirred mixture of 1-methyl-4-(4-nitrophenyl)pyrrolidin-2-one (970 mg, 4.40 mmol, 1 equiv.) in EA (10 mL) and EtOH (10 mL) was added Pd / C (100 mg, 10 wt%) at room temperature under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 3 h. The reaction was monitored by LC-MS. The solid was filtered off and washed with EtOH (3×20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10:1 DCM / MeOH) to give 4-(4-aminophenyl)-1-methyl-pyrrolidin-2-one (700 mg, 84% yield) as a yellow solid. LCMS (ESI+, m / z): 191 [M+H]+ , Rt 0.553 min.

[0371] Step 4. Separation of enantiomers to obtain (R)-4-(4-aminophenyl)-1-methyl-pyrrolidin-2-one and (S)-4-(4-aminophenyl)-1-methyl-pyrrolidin-2-one (intermediates 35 and 36). The racemic compound 4-(4-aminophenyl)-1-methyl-pyrrolidin-2-one (700 mg, 3.66 mmol, 1 equiv.) was separated by preparative chiral HPLC using the following conditions: column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2M NH3-MeOH) - HPLC; mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 20% B in 11.5 min; wavelength: 254 / 220 nm; RT1 (min): 9.02; RT2 (min): 10.82; sample solvent: EtOH - HPLC; injection volume: 0.8 mL; run number: 7. The first eluting isomer was isolated, yielding intermediate 35 (310 mg) as a yellow solid. The second eluting isomer was isolated to give Intermediate 36 (290 mg) as a yellow solid.

[0372] Intermediate 27: tert-butyl (4-(4-aminophenyl)-1-oxide-116-thiomorpholin-1-ylidene)carbamate Step 1. 4-(4-nitrophenyl)thiomorpholine To a solution of thiomorpholine (3.29 g, 31.89 mmol, 1.5 equiv.) and K2CO3 (5.88 g, 42.52 mmol, 2 equiv.) in DMF (30 mL) was added 1-fluoro-4-nitrobenzene (3.00 g, 21.26 mmol, 1 equiv.) at room temperature. The mixture was stirred at 100 °C for 1 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The reaction was then quenched with water (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (150 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 1:1 EA / PE) to give 4-(4-nitrophenyl)thiomorpholine (4.30 g, 90% yield) as a yellow solid. LCMS(ESI+,m / z):225[M+H] + , Rt 1.093 minutes.

[0373] Step 2. 4-(4-Nitrophenyl)thiomorpholine 1-oxide To a solution of 4-(4-nitrophenyl)thiomorpholine (4.30 g, 19.17 mmol, 1 equiv.) in ACN (50 mL) was added HO (19.56 mL, 632.80 mmol, 33 equiv.) at room temperature. The mixture was stirred at room temperature for 4 h. The reaction was monitored by LC-MS. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (eluted with 3:1 EA / PE) to give 4-(4-nitrophenyl)thiomorpholine 1-oxide (3.5 g, 76% yield) as a yellow solid. LCMS (ESI+, m / z): 241 [M+H] + , Rt 0.678 min.

[0374] Step 3. tert-Butyl (4-(4-nitrophenyl)-1-oxide-1l6-thiomorpholin-1-ylidene)carbamate To a stirred suspension of 4-(4-nitrophenyl)thiomorpholine 1-oxide (1.20 g, 4.99 mmol, 1 equiv.), tert-butyl carbamate (878 mg, 7.49 mmol, 1.5 equiv.), Rh(OAc) (112 mg, 499 μmol, 0.1 equiv.), and MgO (805 mg, 19.98 mmol, 4 equiv.) in 1,2-DCE (10 mL) was added PhI(OAc) (2.41 g, 7.49 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at 70 °C under a N atmosphere for 6 h. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL). The solid was filtered through a pad of Celite and washed with EtOAc (10 mL × 3). The filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with 2:1 EA / PE) to give tert-butyl (4-(4-nitrophenyl)-1-oxide-116-thiomorpholin-1-ylidene)carbamate (750 mg, 42% yield) as a yellow solid. LCMS (ESI+, m / z): 356 [M+H] + , Rt 0.890 min.

[0375] Step 4. tert-Butyl (4-(4-aminophenyl)-1-oxide-116-thiomorpholin-1-ylidene)carbamate (Intermediate 27) To a solution of tert-butyl (4-(4-nitrophenyl)-1-oxide-116-thiomorpholin-1-ylidene)carbamate (300 mg, 844 μmol, 1 equiv.) in EtOH (10 mL) was added Pd / C (60 mg, 10 wt.%) under a N atmosphere. The mixture was stirred at room temperature under a H atmosphere for 2 h. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with EtOH (3 × 5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with 2:1 EA / PE) to give tert-butyl (4-(4-aminophenyl)-1-oxide-116-thiomorpholin-1-ylidene)carbamate (210 mg, 76% yield) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ 6.86-6.77(m,2H),6.55-6.51(m,2H),4.71(br,2H),3.67-3.51(m,4H),3.47-3.36(m,4H),1.40(s,9H).LCMS(ESI+,m / z):326[M+H] + , Rt 0.617 min.

[0376] Intermediate 37: 4-(1-methylimino-1-oxo-1,4-thiazinan-4-yl)aniline Step 1. 1-Imino-4-(4-nitrophenyl)-1,4-thiazinane 1-oxide To a stirred mixture of Intermediate 27 / Step 3 (1.0 g, 2.81 mmol, 1 equiv.) in DCM (20 mL) was added TFA (8 mL) dropwise below 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:20 MeOH / DCM) to give 1-imino-4-(4-nitrophenyl)-1,4-thiazinane 1-oxide (650 mg, 91% yield) as a brown solid. LCMS (ESI+, m / z): 255 [M+H] + , Rt 0.474 min.

[0377] Step 2. 1-Methylimino-4-(4-nitrophenyl)-1,4-thiazinane 1-oxide To a stirred mixture of 1-imino-4-(4-nitrophenyl)-1,4-thiazinane 1-oxide (600 mg, 2.35 mmol, 1 equiv.) in MeOH (30 mL) was added HCHO (705 mg, 23.50 mmol, 10 equiv.), AcOH (0.5 mL), and NaBHCN (1.48 g, 23.50 mmol, 10 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 1-methylimino-4-(4-nitrophenyl)-1,4-thiazinane 1-oxide (500 mg, 79% yield) as a brown solid. LCMS (ESI+, m / z): 269 [M+H] + , Rt 0.544 min.

[0378] Step 3. 4-(1-methylimino-1-oxo-1,4-thiazinan-4-yl)aniline (Intermediate 37) A mixture of 1-methylimino-4-(4-nitrophenyl)-1,4-thiazinane 1-oxide (500 mg, 1.86 mmol, 1 equiv.) and Pd / C (100 mg, 10 wt.%) in EtOH (30 mL) was stirred under a H atmosphere at room temperature for 2 h. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with EA (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:5 EA / PE) to give 4-(1-methylimino-1-oxo-1,4-thiazinane-4-yl)aniline (380 mg, 85% yield) as a brown solid. 1 H NMR(300MHz,DMSO-d6)δ 6.77(d,J=9Hz,2H),6.52(d,J=9Hz,2H),4.67(br,2H),3.55-3.42(m,2H),3. 37-3.28(m,2H),3.21-2.98(m,4H),2.66(s,3H).LCMS(ESI+,m / z):239[M+H] + , Rt 0.149 min.

[0379] Intermediate 38: 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 equiv.), 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 equiv.), Pd(dppf)Cl (759 mg, 926 μmol, 0.1 equiv.), and NaCO (370 mg, 18.52 mmol, 2 equiv.) in dioxane (15 mL) and HO (5 mL) was stirred at 100 °C under a N atmosphere for 1 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature, followed by the addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 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 1:1 EA / PE) to give 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.

[0380] Step 2. 3-Methyl-4-(1-methylpiperidin-4-yl)aniline (Intermediate 38) To a stirred solution of 1-methyl-4-(2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine (2.0 g, 8.61 mmol, 1 equiv) in MeOH (10 mL) under a N atmosphere was added Pd / C (200 mg, 10 wt%). The resulting mixture was stirred at room temperature under a H atmosphere for 4 h. The solid was filtered 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 give 3-methyl-4-(1-methyl-4-piperidyl)aniline (0.80 g, 45% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 6.84(d,J=8.7Hz,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.

[0381] Intermediate 40: 2-(4-aminophenyl)-N,N,2-trimethylpropanamide Step 1. N,N,2-trimethyl-2-(4-nitrophenyl)propanamide To a stirred solution of 2-methyl-2-(4-nitrophenyl)propanoic acid (2.0 g, 9.56 mmol, 1 equiv.) and N-methylmethanamine hydrochloride (779 mg, 9.56 mmol, 1 equiv.) in DMF (20 mL) was added HATU (5.45 g, 14.34 mmol, 1.5 equiv.) and DIEA (3.70 g, 28.68 mmol, 3 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The resulting mixture was diluted with EA (100 mL) and washed with brine (3 × 50 ml). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:2 EA / PE) to give N,N,2-trimethyl-2-(4-nitrophenyl)propanamide (2.0 g, 88% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 8.24(d,J=9.0,2H),7.48(d,J=9.0,2H),2.82(s,3H),2.46(s,3H),1.49(s,6H).LCMS(ESI+,m / z):237[M+H] + , Rt 0.642 min.

[0382] Step 2. 2-(4-aminophenyl)-N,N,2-trimethylpropanamide (Intermediate 40) To a stirred solution of N,N,2-trimethyl-2-(4-nitrophenyl)propanamide (2 g, 8.47 mmol, 1 equiv.) in MeOH (10 mL) under a nitrogen atmosphere, Pd / C (200 mg, 10 wt%) was added. The resulting mixture was stirred at room temperature under an H atmosphere for 2 h. The reaction was monitored by LC-MS. The solid was filtered and washed with MeOH (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 2-(4-aminophenyl)-N,N,2-trimethyl-propanamide (1.5 g, 86% yield) as a yellow solid. LCMS (ESI+, m / z): 207 [M+H] + , Rt 0.333 min.

[0383] Intermediates 41 and 42: (S)-3-(4-aminophenyl)-1,3-dimethylpyrrolidin-2-one and (R)-3-(4-aminophenyl)-1,3-dimethylpyrrolidin-2-one Step 1. 1-Methyl-3-(4-nitrophenyl)pyrrolidin-2-one To a stirred solution of 1-methylpyrrolidin-2-one (540 mg, 5.45 mmol, 1.1 equiv) in THF (10 mL) was added s-BuLi (1.3 M in cyclohexane, 4.57 mL, 1.2 equiv) dropwise at −78° C. under a N atmosphere. The resulting mixture was stirred at 0° C. for 1 hour. The mixture was then cooled to −78° C. To the above mixture was added ZnCl (1 M in EtO, 5.94 mL, 1.2 equiv) dropwise. The resulting mixture was stirred at 0° C. for an additional 1 hour. To the above mixture was added 1-bromo-4-nitrobenzene (1.0 g, 4.95 mmol, 1 equiv), Pd(dba) (453 mg, 495 μmol, 0.1 equiv), and DavePhos (195 mg, 495 μmol, 0.1 equiv) in THF (10 mL) dropwise. The resulting mixture was stirred at 65°C under a N2 atmosphere for an additional 20 hours. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10:1 DCM / MeOH). The crude product was purified by reverse-phase chromatography with the following conditions: column: C18, 40-60 nm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN (20%-30% in 10 min), 254 nm to give 1-methyl-3-(4-nitrophenyl)pyrrolidin-2-one (300 mg, 28% yield) as a yellow solid. LCMS (ES, m / z): 221 [M+H] + , Rt 0.619 min.

[0384] Step 2. 1,3-Dimethyl-3-(4-nitrophenyl)pyrrolidin-2-one To a stirred solution of 1-methyl-3-(4-nitrophenyl)pyrrolidin-2-one (1.0 g, 4.54 mmol, 1 equiv) in DMF (10 mL) under a N atmosphere at 0 °C, NaH (363 mg, 9.08 mmol, 60 wt% in mineral oil, 2 equiv) was added portionwise. The resulting mixture was stirred at room temperature for 1 h. To the above solution, MeI (967 mg, 6.81 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LC-MS. The mixture was quenched with water / ice (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 1,3-dimethyl-3-(4-nitrophenyl)pyrrolidin-2-one (750 mg, 71% yield) as a yellow solid. LCMS (ESI+, m / z): 235 [M+H] + , Rt 0.659 min.

[0385] Step 3. 3-(4-aminophenyl)-1,3-dimethylpyrrolidin-2-one A mixture of 1,3-dimethyl-3-(4-nitrophenyl)pyrrolidin-2-one (750 mg, 3.20 mmol) and Pd / C (150 mg, 10 wt%) in MeOH (10 mL) was stirred at room temperature under a H atmosphere for 2 hours. The reaction was monitored by TLC. After filtration, the filtrate was concentrated under reduced pressure to give 3-(4-aminophenyl)-1,3-dimethylpyrrolidin-2-one (550 mg, 85% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 6.99(d,J=9Hz,2H),6.50(d,J=9Hz,2H),4.92(br,2H),3.26-3.15(m,2H),2.77(s, 3H),2.28-2.21(m,1H),2.05-1.96(m,1H),1.31(s,3H).LCMS(ESI+,m / z):205[M+H] + , Rt 0.440 min.

[0386] Step 4. Separation of enantiomers to obtain (S)-3-(4-aminophenyl)-1,3-dimethylpyrrolidin-2-one and (R)-3-(4-aminophenyl)-1,3-dimethylpyrrolidin-2-one (intermediates 41 and 42). The racemic compound 3-(4-aminophenyl)-1,3-dimethylpyrrolidin-2-one (550 mg, 2.71 mmol, 1 equiv.) was separated by preparative chiral HPLC under the following conditions (Column: (R,R)-WHELK-O1-Kromasil, 2.12 × 25 cm, 5 μm, Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC, Flow Rate: 20 mL / min, Gradient: 40% B in 16 min, Wavelength: 220 / 254 nm, RT1 (min): 11.76, RT2 (min): 14.1), to give Intermediate 41 (240 mg) as a yellow solid and Intermediate 42 (220 mg) as a yellow solid.

[0387] Intermediate 43: 6-(tert-butyl)pyridin-3-amine Step 1. N-(6-(tert-butyl)pyridin-3-yl)-1,1-diphenylmethanimine A mixture of 5-bromo-2-tert-butyl-pyridine (600 mg, 2.80 mmol, 1 equiv.), diphenylmethanimine (609 mg, 3.36 mmol, 1.2 equiv.), Cs2CO3 (2.74 g, 8.41 mmol, 3 equiv.), BrettPhos-G3 (254 mg, 280 μmol, 0.1 equiv.), and BrettPhos (150 mg, 280 μmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was stirred at 100 °C under a N2 atmosphere for 1 h. The reaction was monitored by TLC. The mixture was allowed to cool to room temperature. The solid was filtered off. 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 (eluted with 1:1 EA / PE) to give N-(6-tert-butyl-3-pyridyl)-1,1-diphenylmethanimine (700 mg, 80% yield) as a yellow oil. LCMS (ESI+, m / z): 315 [M+H] + , Rt 0.839 min.

[0388] Step 2. 6-(tert-butyl)pyridin-3-amine (Intermediate 43) To a stirred solution of N-(6-tert-butyl-3-pyridyl)-1,1-diphenylmethanimine (690 mg, 2.19 mmol) in THF (9 mL) was added AcOH (3 mL) and HO (1.5 mL). The resulting mixture was stirred at 100 °C for 1 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse-phase chromatography (column: C18, mobile phase: A: water (containing 10 mmol / L NHHCO) and B: ACN (5% to 100% B in 40 min), detector: UV 254 nm) to give 6-tert-butylpyridin-3-amine (220 mg, 67% yield) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 7.87(s,1H),7.07-7.04(m,1H),6.88-6.84(m,1H),5.02(br,2H),1.23(s,9H).LCMS(ESI+,m / z):151[M+H] + , Rt 0.506 min.

[0389] Intermediate 45: 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylaniline Step 1. 8-(2-methyl-4-nitrophenyl)-3-oxa-8-azabicyclo[3.2.1]octane A mixture of 1-bromo-2-methyl-4-nitrobenzene (1.5 g, 6.94 mmol, 1 equiv.), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.56 g, 10.42 mmol, 1.5 equiv.), CsCO (9.05 g, 27.77 mmol, 4 equiv.), RuPhos Pd G (581 mg, 694 μmol, 0.1 equiv.), and RuPhos (648 mg, 1.39 mmol, 0.2 equiv.) in 1,4-dioxane (15 mL) was stirred at 100 °C under a N atmosphere for 2 h. The reaction was monitored by LC-MS. The resulting mixture was allowed to cool to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:9 EA / PE) to give 8-(2-methyl-4-nitrophenyl)-3-oxa-8-azabicyclo[3.2.1]octane (1.5 g, 87% yield) as a white solid. LCMS (ESI+, m / z): 249 [M+H] + , Rt 0.790 min.

[0390] Step 2. 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylaniline (Intermediate 45) A mixture of (8-(2-methyl-4-nitrophenyl)-3-oxa-8-azabicyclo[3.2.1]octane (580 mg, 2.34 mmol, 1 equiv.) and Pd / C (120 mg, 10 wt%) in EA (15 mL) and EtOH (15 mL) was stirred at room temperature under a H atmosphere for 2 h. The reaction was monitored by LC-MS. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give 3-methyl-4-[(1S,5R)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]aniline (450 mg, 88% yield) as a white solid. 1H NMR(300MHz,DMSO-d6)δ 6.54(d,J=9Hz,1H),6.42(s,1H),6.30(d,J=9Hz,1H),4.60(br,2H),3.72(d,J=12Hz,2H),3.5 6-3.52(m,2H),3.36-3.34(m,2H),2.19(s,3H),1.90-1.79(m,4H).LCMS(ESI+,m / z):219[M+H] + , Rt 0.499 min.

[0391] Intermediate 48: 7-Amino-2,4,4-trimethyl-3H-isoquinolin-1-one Step 1. 2-Bromo-N-methyl-5-nitrobenzamide To a stirred solution of 2-bromo-5-nitrobenzoic acid (6.00 g, 24.4 mmol, 1 equiv.) and MeNH₂·HCl (2.47 g, 36.58 mmol, 1.5 equiv.) in DMF (100 mL) was added PyBOP (19.04 g, 36.58 mmol, 1.5 equiv.) and DIPEA (12.61 g, 97.56 mmol, 4 equiv.). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The resulting mixture was quenched with cold water (300 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 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 1:1 EA / PE) to give 2-bromo-N-methyl-5-nitrobenzamide (3.50 g, 55% yield) as a yellow solid. LCMS (ESI+, m / z): 259, 261 [M+H] + , Rt 0.637 min.

[0392] Step 2. 2-Bromo-N-methyl-N-(2-methylallyl)-5-nitrobenzamide To a solution of 2-bromo-N-methyl-5-nitrobenzamide (3.50 g, 13.5 mmol, 1 equiv) in DMF (50 mL) was added NaH (60%, 1.04 g, 27.02 mmol, 2 equiv) at 0 °C. The mixture was stirred at room temperature for 0.5 h. Then, 3-bromo-2-methylprop-1-ene (2.37 g, 17.56 mmol, 1.3 equiv) was added at 0 °C. The mixture was warmed to room temperature and stirred for 1 h. The reaction was monitored by LC-MS. The reaction mixture was quenched with ice / water (150 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 2-bromo-N-methyl-N-(2-methylallyl)-5-nitrobenzamide (2.9 g, 69% yield) as a yellow solid. LCMS (ESI+, m / z): 313, 315 [M+H] + , Rt 0.898 min.

[0393] Step 3. 2,4,4-Trimethyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one A mixture of 2-bromo-N-methyl-N-(2-methylallyl)-5-nitrobenzamide (2.90 g, 9.26 mmol, 1 equiv.), TEACl (1.68 g, 9.26 mmol, 1 equiv.), HCOONa (693 mg, 10.19 mmol, 1.1 equiv.), NaOAc (1.67 g, 20.37 mmol, 2.2 equiv.), and Pd(OAc) (208 mg, 926 μmol, 0.1 equiv.) in DMF (40 mL) was stirred at 70 °C under a N atmosphere for 16 h. The reaction was monitored by LC-MS. The reaction was cooled to room temperature and filtered through a pad of Celite. The filter cake was washed with DCM (3 × 50 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with 1:4 EA / PE) to give 2,4,4-trimethyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (1.6 g, 74% yield) as a yellow solid. LCMS (ESI+, m / z): 235 [M+H] +, Rt 0.780 min.

[0394] Step 4. 7-Amino-2,4,4-trimethyl-3H-isoquinolin-1-one (Intermediate 48) To a stirred solution of 2,4,4-trimethyl-7-nitro-3H-isoquinolin-1-one (500 mg, 2.13 mmol, 1 equiv.) in EtOH (10 mL) under a N atmosphere was added Pd / C (100 mg, 10 wt%). The resulting mixture was stirred at room temperature under a H atmosphere for 16 h. The solid was filtered off and washed with EtOH (2 × 5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 10:1 DCM / MeOH) to give 7-amino-2,4,4-trimethyl-3H-isoquinolin-1-one (380 mg, 1.77 mmol, 83% yield) as a yellow solid. LCMS (ES, m / z): 205 [M+H] + , Rt 0.294 min.

[0395] Intermediates 49 and 50: (S)-5-(5-aminopyridin-2-yl)-1-methylpyrrolidin-2-one and (R)-5-(5-aminopyridin-2-yl)-1-methylpyrrolidin-2-one Step 1. Methyl 4-(5-bromopyridin-2-yl)-4-oxobutanoate A solution of 5-bromopyridine-2-carbaldehyde (10 g, 53.8 mmol, 1 equiv.), 2-(3-ethyl-4-methyl-thiazol-3-ium-5-yl)ethanol bromide (2.71 g, 10.8 mmol, 0.2 equiv.), EtN (10.9 g, 107.6 mmol, 2 equiv.), and methyl prop-2-enoate (5.55 g, 64.5 mmol, 1.2 equiv.) in MeOH (300 mL) was stirred at 70 °C for 16 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EA (300 mL) and washed with brine (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:4 EA / PE) to give methyl 4-(5-bromopyridin-2-yl)-4-oxobutanoate (4.0 g, 31% yield) as a yellow solid. LCMS (ESI+, m / z): 237 [M+H] + , Rt 0.642 min.

[0396] Step 2. 5-(5-Bromopyridin-2-yl)pyrrolidin-2-one A solution of methyl 4-(5-bromopyridin-2-yl)-4-oxobutanoate (4.0 g, 14.70 mmol, 1 equiv.) and NHOAc (11.32 g, 147.0 mmol, 10 equiv.) in MeOH (70 mL) was stirred at room temperature for 1 h. To the above mixture, NaBHCN (1.02 g, 16.17 mmol, 1.1 equiv.) was added in small portions. The resulting mixture was stirred at 70 °C under a N atmosphere for an additional 4 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EA (200 mL) and washed with brine (3 × 30 mL). The combined organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 24:1 DCM / MeOH) to give 5-(5-bromopyridin-2-yl)pyrrolidin-2-one (2.2 g, 62% yield) as a yellow solid. LCMS (ESI+, m / z): 241, 243 [M+H]+ , Rt 0.547 min.

[0397] Step 3. 5-(5-Bromopyridin-2-yl)-1-methylpyrrolidin-2-one To a solution of 5-(5-bromopyridin-2-yl)pyrrolidin-2-one (2.1 g, 8.71 mmol, 1 equiv) in DMF (30 mL) was added NaH (522 mg, 13.07 mmol, 60% suspension in mineral oil, 1.5 equiv) in small portions at 0 °C. The mixture was stirred at room temperature under N atmosphere for 0.5 h, followed by dropwise addition of MeI (1.48 g, 10.45 mmol, 1.2 equiv) at 0 °C. The mixture was stirred at room temperature under N atmosphere for another 1.5 h. The reaction was monitored by TLC. The resulting mixture was quenched with ice / water (100 mL) and extracted with EA (3 × 60 mL). The combined organic phase was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 19:1 DCM / MeOH) to give 5-(5-bromopyridin-2-yl)-1-methylpyrrolidin-2-one (2.0 g, 90% yield) as a yellow oil. LCMS (ESI+, m / z): 255, 257 [M+H] + , Rt 0.542 min.

[0398] Step 4. 5-(5-((diphenylmethylene)amino)pyridin-2-yl)-1-methylpyrrolidin-2-one A mixture of 5-(5-bromopyridin-2-yl)-1-methylpyrrolidin-2-one (1.9 g, 7.45 mmol, 1 equiv.), diphenylmethanimine (1.62 g, 8.94 mmol, 1.2 equiv.), Pd(dba) (694 mg, 745 μmol, 0.1 equiv.), BINAP (463 mg, 745 μmol, 0.1 equiv.), and CsCO (4.86 g, 14.90 mmol, 2 equiv.) in toluene (20 mL) was stirred at 100 °C under a N atmosphere for 2 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with ethyl acetate (80 mL) and washed with brine (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 2:1 EA / PE) to give 5-(5-((diphenylmethylene)amino)pyridin-2-yl)-1-methylpyrrolidin-2-one (2.0 g, 76% yield) as a yellow solid. LCMS (ESI+, m / z): 356 [M+H] + , Rt 0.720 min.

[0399] Step 5. 5-(5-aminopyridin-2-yl)-1-methylpyrrolidin-2-one A solution of 5-(5-((diphenylmethylene)amino)pyridin-2-yl)-1-methylpyrrolidin-2-one (2.0 g, 5.63 mmol, 1 equiv.) in THF (12 mL), HO (2 mL), and AcOH (4 mL) was stirred at 100 °C for 1 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (column: C18, mobile phase, A: water (containing 10 mmol / L NHHCO) and B: ACN (5% to 10% in 15 min), detector: UV 254 nm, 280 nm) to give 5-(5-aminopyridin-2-yl)-1-methylpyrrolidin-2-one (900 mg, 84% yield). 1H NMR(300MHz,MeOD-d4)δ 8.01-8.00(m,1H),7.13-7.07(m,2H),4.64-4.60(m,1H),2.63(s,3H),2.60-2 .54(m,1H),2.51-2.40(m,2H),2.07-1.96(m,1H).LCMS(ESI+,m / z):192[M+H] + , Rt 0.418 min.

[0400] Step 6. Separation of enantiomers to obtain (S)-5-(5-aminopyridin-2-yl)-1-methylpyrrolidin-2-one and (R)-5-(5-aminopyridin-2-yl)-1-methylpyrrolidin-2-one (intermediates 49 and 50). The racemic product 5-(5-aminopyridin-2-yl)-1-methylpyrrolidin-2-one (900 mg, 4.71 mmol) was separated by preparative chiral HPLC with the following conditions: CHIRALPAK IH, 3 × 25 cm, 5 μm column, mobile phase A: CO , mobile phase B: IPA (0.5% 2M NH -MeOH), flow rate: 70 mL / min, gradient: isocratic 50% B, column temperature: 35 °C, back pressure: 100 bar, wavelength: 220 nm, RT1 (min): 4.51, RT2 (min): 6.39 to give intermediate 49 (400 mg, 44% yield) as a yellow solid, and intermediate 50 (400 mg, 44% yield) as a yellow solid. LCMS (ESI+, m / z): 192 [M+H] + , Rt 0.418 min.

[0401] Intermediate 51: tert-butyl 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate Step 1. tert-Butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a stirred mixture of 1-fluoro-4-nitrobenzene (5 g, 35.44 mmol, 1.0 equiv) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (8.43 g, 42.52 mmol, 1.2 equiv) in DMF (30 mL) was added K2CO3 (14.69 g, 106.31 mmol, 3.0 equiv). The resulting mixture was stirred at 80 °C for 5 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with H2O (200 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 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 1:2 EA / PE) to give tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (10.5 g, 31.28 mmol, 92% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 8.05(d,J=9.0Hz,2H),6.44(d,J=9.3Hz,2H),4.17(s,4H),4.06(s,4H),1.39(s,9H).LCMS(ES,m / z):320[M+H] + , Rt 0.675 min.

[0402] Step 2. tert-Butyl 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 51) To a stirred solution of tert-butyl-6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (10.5 g, 31.28 mmol, 1 equiv.) in EtOH (500 mL) was added Pd / C (1 g, 10%) at room temperature under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 1 h. The solid was filtered and washed with EtOH (3 × 50 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (7.5 g, crude) as a red solid. LCMS (ES, m / z): 290 [M+H]+ , Rt 0.477 min.

[0403] Intermediate 52. (5S)-3-(6-Bromo-2-pyridyl)-5-methyl-oxazolidin-2-one A mixture of (5S)-5-methyloxazolidin-2-one (840.00 mg, 8.31 mmol, 1.2 equiv.), 3,4,7,8-tetramethyl-1,10-phenanthroline (490.83 mg, 2.08 mmol, 0.3 equiv.), tripopotassium phosphate (4.41 g, 20.77 mmol, 3.0 equiv.), copper(I) iodide (263.72 mg, 1.38 mmol, 0.2 equiv.), and 2,6-dibromopyridine (1.64 g, 6.92 mmol, 1.0 equiv.) in toluene (15 mL) was irradiated in a microwave oven at 120 °C for 0.5 h under a N atmosphere. The mixture was allowed to cool to room temperature. The desired product could be detected by LC-MS. The solid was 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 give (5S)-3-(6-bromo-2-pyridyl)-5-methyl-oxazolidin-2-one (1.18 g, 4.59 mmol, 66% yield) as a white solid.

[0404] 1 H NMR(300MHz,CDCl3)δ 8.11(d,J=8.1Hz,1H),7.54(d,J=7.8Hz,1H),7.19(d,J=7.8Hz,1H),4.95-4.85(m,1H),4.5 2(d,J=8.4Hz,1H),4.09-4.04(m,1H),1.48(d,J=6.3Hz,3H).LCMS(ES,m / z):257,529[M+H] + .Rt 0.715 minutes. [Table 7]

[0405] Intermediate 53. (6-Bromo-2-pyridyl)imino-dimethyl-oxo-sulfane To a stirred mixture of 2,6-dibromopyridine (1 g, 4.22 mmol, 1 equiv.) in 1,4-dioxane (35 mL), imino-dimethyl-oxo-sulfane (393 mg, 4.22 mmol, 1 equiv.), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (244 mg, 422.13 μmol), XantPhos Pd G2 (365 mg, 422.13 μmol, 0.1 equiv.), and sodium 2-methylpropane-2-olate (811 mg, 8.44 mmol, 2 equiv.) were added. The resulting mixture was stirred at 80 °C under a N2 atmosphere for 2 h. The reaction was monitored by LC-MS. The solid was filtered off and washed with EA (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 3:1 PE / EA) to give (6-bromo-2-pyridyl)imino-dimethyl-oxo-sulfane (550 mg, 2.21 mmol, 52% yield) as a yellow solid. LCMS (ES, m / z): 249, 251 [M+H] + , Rt 0.589 min.

[0406] Intermediate 56. 3-Methyl-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline The title compound was prepared in a similar manner to Intermediate 45, except that (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide was used instead of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. LCMS (ES, m / z): 218 [M+H] +

[0407] Intermediate 57. 3-Methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline The title compound was prepared in a similar manner to Intermediate 45, except that (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide was used instead of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. LCMS (ES, m / z): 218 [M+H]+

[0408] Intermediate 70. tert-Butyl 4-((5-aminopyridin-2-yl)oxy)piperidine-1-carboxylate Step 1. tert-Butyl 4-((5-nitropyridin-2-yl)oxy)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.2 g, 5.96 mmol, 1.0 equiv) in THF (15 mL) was added NaH (60% in oil, 715.6 mg, 17.89 mmol, 3.0 equiv) in portions at 0 °C under a N atmosphere. The reaction mixture was stirred at 0 °C for 0.5 h. Then, a solution of 2-chloro-5-nitro-pyridine (1.89 g, 11.92 mmol, 2.0 equiv) in THF (10 mL) was added dropwise, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. Saturated NH Cl (80 mL) was then added. The mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 4-[(5-nitro-2-pyridyl)oxy]piperidine-1-carboxylate (1.5 g, 4.64 mmol, 78% yield) as a yellow oil. LCMS (ES, m / z): 268 [M+H-56] + , Rt 0.794 min.

[0409] Step 2. tert-Butyl 4-((5-aminopyridin-2-yl)oxy)piperidine-1-carboxylate (Intermediate 70) To a stirred solution of tert-butyl 4-[(5-nitro-2-pyridyl)oxy]piperidine-1-carboxylate (1.5 g, 4.64 mmol, 1.0 equiv) in EtOH (20 mL) and EA (20 mL) was added Pd / C (300 mg, 10 wt%) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 2 h. The reaction was monitored by LCMS. The solid was filtered off and washed with EtOH (3 × 10 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluted with 1:10 MeOH / DCM) to give tert-butyl 4-[(5-amino-2-pyridyl)oxy]piperidine-1-carboxylate (1 g, 3.41 mmol, 73% yield) as a yellow solid. LCMS (ES, m / z): 294 [M+H] + , Rt 0.516 min. [Table 8]

[0410] Intermediate 73. tert-Butyl (R)-3-(4-amino-2-methylphenoxy)pyrrolidine-1-carboxylate Step 1. tert-Butyl (R)-3-(2-methyl-4-nitrophenoxy)pyrrolidine-1-carboxylate (Compound 2) To a stirred solution of 2-methyl-4-nitrophenol (1.2 g, 7.84 mmol, 1.0 equiv.), tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (1.76 g, 9.40 mmol, 1.2 equiv.), and PPh3 (4.11 g, 15.67 mmol, 2.0 equiv.) in THF (15 mL) was added dropwise DIAD (3.17 g, 15.67 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature under a N2 atmosphere for 12 h. The reaction was monitored by LCMS. Saturated NH4Cl (50 mL) was then added. The mixture was extracted with EA (3 × 50 mL), and the combined organic layers were washed with brine (2 × 60 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 1:1 EA / PE) to give tert-butyl (3R)-3-(2-methyl-4-nitro-phenoxy)pyrrolidine-1-carboxylate (2.07 g, 5.78 mmol, 82% yield) as a yellow solid. LCMS (ES, m / z): 267 [M+H-56] + , Rt 0.805 min.

[0411] Step 2. tert-Butyl (R)-3-(4-amino-2-methylphenoxy)pyrrolidine-1-carboxylate To a stirred solution of tert-butyl (3R)-3-(2-methyl-4-nitro-phenoxy)pyrrolidine-1-carboxylate (1.2 g, 3.72 mmol, 1.0 equiv) in EtOH (25 mL) and EA (25 mL) was added Pd / C (250 mg, 10 wt%) in portions under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 2 h. The reaction was monitored by LCMS. The solid was filtered off and washed with EtOH (3 × 10 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluted with 1:10 MeOH / DCM) to give tert-butyl (3R)-3-(4-amino-2-methyl-phenoxy)pyrrolidine-1-carboxylate (585 mg, 1.80 mmol, 54% yield) as a yellow solid. LCMS (ES, m / z): 237 [M+H-56] + , Rt 0.685 min.

[0412] 1 H NMR(300MHz,DMSO-d6)δ 6.66(d,J=8.4Hz,1H),6.43-6.29(m,2H),4.73-4.70(m,1H),4.59(br,2H),3.47-3.34(m,4H),2.08-1.91(m,5H),1.40(d,J=6.3Hz,9H).

[0413] Intermediate 74. tert-Butyl (S)-3-(4-amino-2-methylphenoxy)pyrrolidine-1-carboxylate Prepared in a similar manner to Intermediate 73. LCMS (ES, m / z): 293 [M+H] + , Rt 0.686 min.

[0414] Intermediate 86. 2-Bromo-5-methylpyrrolo[2,3-b]pyrazine To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (200 mg, 1.01 mmol, 1 equiv) in DMF (5 mL) was added NaH (60% in oil, 101 mg, 2.53 mmol, 2.5 equiv) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h under a N atmosphere. Then, MeI (172.03 mg, 1.212 mmol, 1.2 equiv) was added dropwise, and the mixture was warmed to room temperature and stirred for 2 h. The reaction was monitored using LCMS. The mixture was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 2-bromo-5-methylpyrrolo[2,3-b]pyrazine (150 mg, 70% yield) as a yellow solid. LCMS (ES, m / z): 212, 214 [M+H] + .Rt 0.653 minutes.

[0415] Intermediate 95 and Intermediate 96. (S)-4-(1,3-dimethylpyrrolidin-3-yl)aniline and (R)-4-(1,3-dimethylpyrrolidin-3-yl)aniline Step 1. 3-(4-Bromophenyl)-1,3-dimethyl-pyrrolidin-2-one To a stirred solution of 3-(4-bromophenyl)pyrrolidin-2-one (2 g, 8.33 mmol, 1 equiv) in DMF (20 mL) under a nitrogen atmosphere was added NaH (833.00 mg, 20.82 mmol, 60% purity, 2.5 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. To the above mixture, iodomethane (1.56 mL, 24.99 mmol, 3 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LC-MS. The resulting mixture was quenched with water / ice (50 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried over Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 3:1 EA / PE) to give the crude product, which was then purified by reverse-phase chromatography with the following conditions: column: C18 80 g, 40-60 nm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN (40%-60% in 15 min), 254 nm to give 3-(4-bromophenyl)-1,3-dimethyl-pyrrolidin-2-one (1.4 g, 4.96 mmol, 60% yield) as a white solid. LCMS (ES, m / z): 268, 270 [M+H] + , Rt 0.727 min.

[0416] Step 2. 3-(4-Bromophenyl)-1,3-dimethyl-pyrrolidine To a solution of 3-(4-bromophenyl)-1,3-dimethyl-pyrrolidin-2-one (1.2 g, 4.48 mmol, 1 equiv.) and BF3-Et2O (2.86 g, 20.14 mmol, 4.5 equiv.) in THF (10 mL) was added sodium borohydride (507.91 mg, 13.43 mmol, 3 equiv.) at −10° C. The resulting mixture was stirred at 20° C. under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. To the above mixture was added 10 mL of MeOH and HCl (4 M in dioxane, 2 mL). The resulting mixture was heated at reflux for 1 h. The mixture was cooled to room temperature and basified with saturated Na2CO3 to pH = 8. The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (2 x 100 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 10:1 DCM / MeOH) to give 3-(4-bromophenyl)-1,3-dimethyl-pyrrolidine (800 mg, 3.15 mmol, 70% yield) as a yellow oil. LCMS (ES, m / z): 254, 256 [M+H] + , Rt 0.509 min.

[0417] Step 3. N-[4-(1,3-dimethylpyrrolidin-3-yl)phenyl]-1,1-diphenyl-methanimine To a stirred mixture of 3-(4-bromophenyl)-1,3-dimethyl-pyrrolidine (670 mg, 2.64 mmol, 1 equiv.) and diphenylmethanimine (573.29 mg, 3.16 mmol, 530.83 μL, 1.2 equiv.) in dioxane (10 mL), Brettphos Pd-G3 (238.96 mg, 263.61 μmol, 0.1 equiv.), Brettphos (282.99 mg, 527.22 μmol, 0.2 equiv.), and cesium carbonate (1.72 g, 5.27 mmol, 2 equiv.) were added at room temperature. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The solid was filtered off and washed with EA (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give N-[4-(1,3-dimethylpyrrolidin-3-yl)phenyl]-1,1-diphenylmethanimine (700 mg, 1.98 mmol, 75% yield) as a pale yellow oil. LCMS (ES, m / z): 355 [M+H] + , Rt 0.657 min.

[0418] Step 4. N-[4-[(3S)-1,3-dimethylpyrrolidin-3-yl]phenyl]-1,1-diphenyl-methanimine and N-[4-[(3R)-1,3-dimethylpyrrolidin-3-yl]phenyl]-1,1-diphenyl-methanimine A mixture of N-[4-(1,3-dimethylpyrrolidin-3-yl)phenyl]-1,1-diphenylmethanimine (700 mg, 1.97 mmol, 1 equiv.) was purified by preparative chiral HPLC with the following conditions: column: CHIRALPAK IH-3, 3.0 × 50 mm, 3 μm; mobile phase B: IPA (0.1% DEA); flow rate: 2 mL / min; gradient: isocratic Separation by HPLC (10% B, wavelength: 220 nm) gave N-[4-[(3S)-1,3-dimethylpyrrolidin-3-yl]phenyl]-1,1-diphenyl-methanimine (250 mg, 0.71 mmol, 36% yield) as a yellow oil, and N-[4-[(3R)-1,3-dimethylpyrrolidin-3-yl]phenyl]-1,1-diphenyl-methanimine (250 mg, 0.71 mmol, 36% yield) as a yellow oil. LCMS (ES, m / z): 355 [M+H] + , Rt 0.657 min.

[0419] Absolute stereochemistry was arbitrarily assigned after chiral HPLC separation.

[0420] Step 5. Intermediates 95 and 96: (S)-4-(1,3-dimethylpyrrolidin-3-yl)aniline and (R)-4-(1,3-dimethylpyrrolidin-3-yl)aniline. For each individual enantiomer obtained in step 4 above, imine hydrolysis was carried out according to the following general procedure. A solution of each individual separated enantiomer (50 mg, 141.05 μmol, 1 equiv.) in THF (3 mL), AcOH (1 mL), and water (0.5 mL) was stirred at 100° C. for 1 h. The resulting mixture was concentrated under reduced pressure to afford either (S)-4-(1,3-dimethylpyrrolidin-3-yl)aniline or (R)-4-(1,3-dimethylpyrrolidin-3-yl)aniline (35 mg, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0421] LCMS(ES,m / z):191[M+H] + , Rt 0.266 min.

[0422] Intermediate 97 and Intermediate 98. tert-Butyl (R)-2-(4-aminophenyl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-(4-aminophenyl)pyrrolidine-1-carboxylate Step 1. tert-Butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate To a solution of 4-bromoaniline (1.71 g, 9.94 mmol, 1 equiv) in THF (70 mL) was added s-BuLi (1.3 M in hexane, 9.94 mL, 1.3 equiv) dropwise at −30° C. under a nitrogen atmosphere. The mixture was stirred at −30° C. for 5 min. To the above solution was added ZnCl (1 M, 5.96 mL, 0.6 equiv) dropwise at −30° C. The mixture was stirred at −30° C. for an additional 0.5 h, warmed to room temperature, and stirred for an additional 0.5 h. To the above solution were added tert-butyl pyrrolidine-1-carboxylate (1.19 g, 6.96 mmol, 0.7 equiv), Pd(OAc) (109 mg, 497.03 umol, 0.05 equiv), and tBuPHBF (109 mg, 621.28 umol, 0.0625 equiv). The mixture was stirred at room temperature for an additional 16 h. The reaction was monitored by LCMS. 35% NHOH (100 ml) was then added, and the resulting solution was stirred at room temperature for 1 h. The solid was removed by filtration through Celite and washed with EA (100 ml). The filtrate was washed with HCl (100 ml, 1 M) and saturated brine (200 ml), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:2 EA / PE) to give tert-butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate (1.0 g, 3.61 mmol, 38% yield) as a yellow solid. LCMS (ES, m / z): 263 [M+H] + , Rt 0.542 min.

[0423] Step 2. Intermediates 97 and 98: tert-butyl (R)-2-(4-aminophenyl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-(4-aminophenyl)pyrrolidine-1-carboxylate The racemic product tert-butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate (1.0 g, 3.61 mmol, 1 equiv.) was purified under the following conditions: column: OptiChiral-C9-5, 3 × 25 cm, 5 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1% 2M NH3-MEOH); flow rate: 100 mL / min; gradient: isocratic Separation at 30% B, column temperature (°C): 35, back pressure (bar): 100, wavelength: 220 nm, RT1 (min): 3.1, RT2 (min): 4.7, sample solvent: ACN:MeOH = 4:1 gave tert-butyl (R)-2-(4-aminophenyl)pyrrolidine-1-carboxylate (0.44 g, 1.59 mmol, 32% yield) as a yellow solid, and tert-butyl (S)-2-(4-aminophenyl)pyrrolidine-1-carboxylate (0.44 g, 1.59 mmol, 32% yield) as a yellow solid. LCMS (ES, m / z): 263 [M+H] + , Rt 0.542 min.

[0424] Absolute stereochemistry was arbitrarily assigned after chiral HPLC separation.

[0425] Intermediate 99 and Intermediate 100. tert-Butyl (R)-2-(5-aminopyridin-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-(5-aminopyridin-2-yl)pyrrolidine-1-carboxylate Step 1. tert-Butyl 2-(5-bromo-2-pyridyl)pyrrolidine-1-carboxylate 2,5-Dibromopyridine (500 mg, 2.11 mmol, 1 equiv), 1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (681.47 mg, 3.17 mmol, 1.5 equiv), Ir[(dF(Me)(ppy)]2(dtppy)PF6 (21.44 mg, 21.11 μmol, 0.01 equiv), 5,5'-dimethyl-2'-bipyridine (58.25 mg, 316.60 μmol, 0.15 equiv), dibromonickel 1,2-dimethoxamic acid in DMF (36 mL). A mixture of sietan (65.14 mg, 211.07 μmol, 0.1 equiv.) and Cs2CO3 (1.38 g, 4.22 mmol, 2 equiv.) was irradiated with blue light (450 nm) under a N2 atmosphere at 50 °C for 1 h. The reaction was monitored by LC-MS. The resulting mixture was diluted with EA (100 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 (eluted with 1:4 EA / PE) to give tert-butyl 2-(5-bromo-2-pyridyl)pyrrolidine-1-carboxylate (150 mg, 458.41 μmol, 22% yield) as a white solid. LCMS (ES, m / z): 327, 329 [M+H] + , Rt 0.781 min.

[0426] 1 H NMR (300 MHz, chloroform-d) δ 8.59 (d, J = 2.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 4.93-4.81 (m, 1H), 3.65-3.55 (m, 2H), 2.4-2.29 (m, 1H), 1.92-1.86 (m, 3H), 1.24 (d, J = 8.4 Hz, 9H).

[0427] Step 2. tert-Butyl 2-[5-(benzhydrylideneamino)-2-pyridyl]pyrrolidine-1-carboxylate A mixture of tert-butyl 2-(5-bromo-2-pyridyl)pyrrolidine-1-carboxylate (600 mg, 1.83 mmol, 1 equiv.), diphenylmethanimine (664.63 mg, 3.67 mmol, 615.40 μL, 2 equiv.), BrettPhos (196.93 mg, 366.73 μmol, 0.2 equiv.), BrettPhos Pd G3 (166.50 mg, 183.37 μmol, 0.1 equiv.), and Cs2CO3 (1.19 g, 3.67 mmol, 2 equiv.) in dioxane (10 mL) was stirred at 100 °C under a N2 atmosphere for 2 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The solid was filtered and washed with EA (2 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:2 EA / PE) to give tert-butyl 2-[5-(benzhydrylideneamino)-2-pyridyl]pyrrolidine-1-carboxylate (600 mg, 1.40 mmol, 77% yield) as a white solid. LCMS (ES, m / z): 428 [M+H] + , Rt 0.721 min.

[0428] Step 3. tert-Butyl 2-(5-amino-2-pyridyl)pyrrolidine-1-carboxylate A mixture of tert-butyl 2-[5-(benzylideneamino)-2-pyridyl]pyrrolidine-1-carboxylate (600 mg, 1.40 mmol, 1 equiv.), palladium on carbon (120 mg, 10 wt.%), and ammonium formate (442.46 mg, 7.02 mmol, 5 equiv.) in a mixed solvent of MeOH (5 mL) and THF (5 mL) was stirred at 60° C. for 4 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The solid was filtered and washed with EA (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 2-(5-amino-2-pyridyl)pyrrolidine-1-carboxylate (300 mg, 1.14 mmol, 81% yield) as a yellow solid. LCMS(ES,m / z):264[M+H] + , Rt 0.523 min.

[0429] 1 H NMR (300 MHz, chloroform-d) δ 8.04-8.00 (m, 1H), 7.02-6.91 (m, 2H), 4.91-4.78 (m, 1H), 3.63-3.55 (m, 2H), 2.34-2.22 (m, 2H), 1.89-1.83 (m, 2H), 1.24 (d, J = 8.4 Hz, 9H).

[0430] Step 4. tert-Butyl (R)-2-(5-aminopyridin-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-(5-aminopyridin-2-yl)pyrrolidine-1-carboxylate (Intermediate 99 and Intermediate 100) The racemic product tert-butyl 2-(5-aminopyridin-2-yl)pyrrolidine-1-carboxylate (600 mg, 2.28 mmol, 1 equiv.) was separated by preparative chiral HPLC (Column: CHIRALPAK IA-3, 4.6*50 mm, 3 μm, Mobile phase A: MtBE (0.5% IPAmine):IPA = 70:30, Flow rate: 1 mL / min, Gradient: 0% B to 0% B, Injection volume: 5 mL) to give tert-butyl (R)-2-(5-aminopyridin-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.95 mmol, 42% yield) as a yellow solid, and tert-butyl (S)-2-(5-aminopyridin-2-yl)pyrrolidine-1-carboxylate (240 mg, 0.91 mmol, 40% yield) as a yellow solid. LCMS(ES,m / z):264[M+H] + , Rt 0.523 min.

[0431] Absolute stereochemistry was arbitrarily assigned after chiral HPLC separation.

[0432] Intermediate 101 and Intermediate 102. tert-Butyl (3R)-3-(4-amino-2-methyl-phenyl)morpholine-4-carboxylate and tert-butyl (3S)-3-(4-amino-2-methyl-phenyl)morpholine-4-carboxylate Step 1. 2-(Trimethylsilylmethoxy)ethyl 4-methylbenzenesulfonate A mixture of trimethylsilylmethyl trifluoromethanesulfonate (5 g, 21.16 mmol, 1 equiv.) in ethylene glycol (16.65 g, 268.26 mmol, 15 mL, 13.5 equiv.) was stirred at room temperature for 16 h. The reaction was monitored by LC-MS. Ice / water (50 mL) was then added. The mixture was extracted with EA (3 × 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DCM (20 mL). N,N-dimethylpyridin-4-amine (231.53 mg, 1.90 mmol, 0.1 equiv.), N,N-diethylethanamine (2.11 g, 20.85 mmol, 2.91 mL, 1 equiv.), and 4-methylbenzenesulfonyl chloride (3.61 g, 18.95 mmol, 0.9 equiv.) were then added in small portions. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS. Ice / water (50 mL) was then added. The mixture was extracted with DCM (3 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 10:1 PE / EA) to give 2-(trimethylsilylmethoxy)ethyl 4-methylbenzenesulfonate (4.1 g, 13.56 mmol, 64% yield) as a colorless oil. LCMS (ES, m / z): 303 [M+H] + , Rt 0.913 min.

[0433] Step 2. 2-[2-(trimethylsilylmethoxy)ethyl]isoindoline-1,3-dione A mixture of (1,3-dioxoisoindolin-2-yl)potassium (3.03 g, 16.35 mmol, 1.15 equiv) and 2-(trimethylsilylmethoxy)ethyl 4-methylbenzenesulfonate (4.3 g, 14.22 mmol, 1 equiv) in N,N-dimethylformamide (80 mL) was stirred at 100 °C for 2 h. The reaction was monitored by TLC. The mixture was cooled to room temperature. Water (100 mL) was then added. The mixture was extracted with DCM (80 mL × 3). The organic layers were combined, washed with brine (50 mL × 3), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 5:1 PE / EA) to give 2-[2-(trimethylsilylmethoxy)ethyl]isoindoline-1,3-dione (3.73 g, 13.45 mmol, 95% yield) as a colorless oil. LCMS(ES,m / z):278[M+H] + , Rt 0.900 min.

[0434] Step 3. 2-(Trimethylsilylmethoxy)ethanamine To a solution of 2-[2-(trimethylsilylmethoxy)ethyl]isoindoline-1,3-dione (2.7 g, 9.73 mmol, 1 equiv.) in methanol (60 mL) was added hydrazine hydrate solution (35%) (4.73 mL, 97.34 mmol, 4.73 mL, 10 equiv.). The mixture was stirred for 70 min. o The mixture was stirred at rt for 1 h. The reaction was monitored by TLC. After cooling to room temperature, water (100 mL) was added. The mixture was stirred at room temperature until the white solid dissolved. The mixture was extracted with DCM (100 mL x 3). The organic layers were combined, washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to give 2-(trimethylsilylmethoxy)ethanamine (1.35 g, 9.17 mmol, 94% yield) as a pale yellow oil. LCMS (ES, m / z): 148 [M+H] + , Rt 0.515 min.

[0435] Step 4. 3-(2-methyl-4-nitro-phenyl)morpholine To a mixture of 2-(trimethylsilylmethoxy)ethanamine (1.45 g, 9.84 mmol, 1 equiv.) and 2-methyl-4-nitro-benzaldehyde (1.63 g, 9.84 mmol, 1 equiv.) in acetonitrile (40 mL) was added 4A molecular sieves (900 mg). The mixture was stirred at room temperature for 5 hours. The solid was filtered off. The filtrate was concentrated to give 1-(2-methyl-4-nitro-phenyl)-N-[2-(trimethylsilylmethoxy)ethyl]methanimine (2.7 g, crude) as a pale yellow oil.

[0436] A mixture of 1-(2-methyl-4-nitrophenyl)-N-[2-(trimethylsilylmethoxy)ethyl]methanine (1 g, 3.40 mmol, 1 equiv.) in toluene (9.0 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (1.0 mL) was added to 2,4,6-triphenylpyryl tetrafluoroborate (134.56 mg, 339.65 mmol, 0.1 equiv.) and trimethylsilyl trifluoromethanesulfonate (1.51 g, 6.79 mmol, 2 equiv.). The mixture was stirred under blue light at room temperature for 16 hours. The reaction was monitored by LCMS. DCM (100 mL) and NH4OH solution (10%, 25 mL) were then added. The phases were separated, and the aqueous phase was extracted with DCM (3 × 100 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10:1 DCM:MeOH) to give 3-(2-methyl-4-nitro-phenyl)morpholine (340 mg, 1.53 mmol, 45% yield) as a brown oil. LCMS (ES, m / z): 223 [M+H] + , Rt 0.301 min.

[0437] Step 5. tert-Butyl 3-(2-methyl-4-nitro-phenyl)morpholine-4-carboxylate To a stirred solution of 3-(2-methyl-4-nitrophenyl)morpholine (300 mg, 1.35 mmol, 1 equiv.), N,N-dimethylpyridin-4-amine (16.49 mg, 134.99 umol, 0.1 equiv.), and N,N-diethylethanamine (188.15 uL, 1.35 mmol, 1 equiv.) in DCM (20 mL) was added BocO (441.92 mg, 2.02 mmol, 1.5 equiv.) in portions. The resulting mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. The resulting mixture was diluted with water (20 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 2:1 PE:EA) to give tert-butyl 3-(2-methyl-4-nitrophenyl)morpholine-4-carboxylate (300 mg, 837.58 μmol, 62% yield) as a yellow solid. LCMS (ES, m / z): 323 [M+H] + .Rt 1.277 minutes.

[0438] Step 6. tert-Butyl (3R)-3-(2-methyl-4-nitro-phenyl)morpholine-4-carboxylate and tert-butyl (3S)-3-(2-methyl-4-nitro-phenyl)morpholine-4-carboxylate Racemic tert-butyl 3-(2-methyl-4-nitro-phenyl)morpholine-4-carboxylate (800 mg, 2.48 mmol, 1 equiv.) was purified by preparative HPLC with the following conditions: column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M Separation by HPLC (NH3-MeOH) with mobile phase B: EtOH, flow rate: 20 mL / min, gradient: 15% B to 15% B in 20 min, wavelength: 220 / 254 nm, RT1 (min): 11.323, RT2 (min): 16.352, sample solvent: EtOH, injection volume: 1.2 mL, run number: 5 gave tert-butyl (3R)-3-(2-methyl-4-nitrophenyl)morpholine-4-carboxylate (250 mg, 31%) as a colorless oil, and tert-butyl (3S)-3-(2-methyl-4-nitrophenyl)morpholine-4-carboxylate (280 mg, 35%) as a colorless oil. LCMS (ES, m / z): 323 [M+H] + .Rt 1.277 minutes.

[0439] Absolute stereochemistry was arbitrarily assigned after chiral HPLC separation.

[0440] Step 7. tert-Butyl (3R)-3-(4-amino-2-methyl-phenyl)morpholine-4-carboxylate (Intermediate 101) To a solution of tert-butyl (3R)-3-(2-methyl-4-nitro-phenyl)morpholine-4-carboxylate (250 mg, 775.54 umol, 1 equiv.) in EtOH (5 mL) was added Pd / C (50 mg, 10 wt%) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at room temperature under a H atmosphere for 4 hours. The desired product could be detected by LCMS. The solid was filtered off and washed with EtOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (column: C18 silica gel, mobile phase: A, water (containing 0.1 M NH4HCO3) and B, ACN (5% to 60%) for 60 min, detector: UV 254 nm) to give tert-butyl (3R)-3-(4-amino-2-methylphenyl)morpholine-4-carboxylate (62 mg, 212.06 μmol, 27% yield) as a yellow oil. LCMS (ES, m / z): 293 [M+H] + .Rt 0.633 minutes.

[0441] Step 8. tert-Butyl (3S)-3-(4-amino-2-methyl-phenyl)morpholine-4-carboxylate (Intermediate 102) To a stirred solution of tert-butyl (3S)-3-(2-methyl-4-nitro-phenyl)morpholine-4-carboxylate (280 mg, 868.61 umol, 1 equiv.) in EtOH (10 mL) under N2 atmosphere, Pd / C (60 mg, 10 wt%) was added portionwise at room temperature. The resulting mixture was stirred under H2 atmosphere at 25 °C for 4 h. The reaction was monitored by LC-MS. The solid was filtered off and washed with EtOH (3 × 5 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (3S)-3-(4-amino-2-methyl-phenyl)morpholine-4-carboxylate (220 mg, crude) as a yellow oil. LCMS (ES, m / z): 293 [M+H] + .Rt 0.811 minutes.

[0442] Intermediate 103. tert-Butyl 3-(4-aminophenyl)azetidine-1-carboxylate To a stirred mixture of tert-butyl 3-iodoazetidine-1-carboxylate (500 mg, 1.77 mmol, 1 equiv.) in isopropyl alcohol (10 mL), (4-aminophenyl)boronic acid (314.42 mg, 2.30 mmol, 1.3 equiv.), (1R,2S)-2-aminocyclohexanol hydrochloride (16.07 mg, 105.97 μmol, 0.06 equiv.), and nickel diiodide (33.11 mg, 105.97 μmol, 0.06 equiv.) were added portionwise. The resulting mixture was stirred at 0°C under a N atmosphere for 1 minute. To the above mixture, sodium bis(trimethylsilyl)azanilide (1.62 g, 8.83 mmol, 5 equiv.) was added at 0°C under a N atmosphere. The resulting mixture was stirred at 150°C for 2 hours under microwave irradiation under a N atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with brine (40 mL) and extracted with EA (3 × 40 mL). The combined organic layers were dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 3:1 EA / PE) to give tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (88 mg, 354.38 μmol, 20% yield) as a brown solid.

[0443] 1 H NMR(300MHz,DMSO-d6)δ 6.98(d,J=8.4Hz,2H),6.54(d,J=8.1Hz,2H),4.99(br,2H),4.21-4.12(m,2H),3.81-3.54(m,3H),1.40(s,9H).LCMS(ES,m / z):193[M+H-56] + , Rt 0.577 min.

[0444] Intermediate 104. tert-Butyl 3-(4-amino-2-fluorophenyl)azetidine-1-carboxylate Step 1. (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide To a solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.26 g, 4.45 mmol, 1 equiv.) in DMAc (15 mL) was added Zn (436 mg, 6.68 mmol, 1.5 equiv.), TMSCl (726 mg, 6.68 mmol, 1.5 equiv.), and 1,2-dibromoethane (860 mg, 4.45 mmol, 1 equiv.). The mixture was stirred at 65° C. under a nitrogen atmosphere for 0.5 hours. The reaction was then allowed to cool to room temperature. The mixture was used directly in the next step without further purification.

[0445] Step 2. tert-Butyl 3-(2-fluoro-4-nitrophenyl)azetidine-1-carboxylate To a solution of 1-bromo-2-fluoro-4-nitrobenzene (900 mg, 4.11 mmol, 1 equiv.) in DMAc (10 mL) was added Pd(dppf)Cl (298 mg, 0.411 mmol, 0.1 equiv.), CuI (783 mg, 4.11 mmol, 1 equiv.), and the above solution of (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide in DMAc (15 mL) was added dropwise. The mixture was stirred at 85 °C under a N atmosphere for 2 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature and quenched by adding water (100 mL). The resulting mixture was extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 3-(2-fluoro-4-nitrophenyl)azetidine-1-carboxylate (750 mg, 2.53 mmol, 61% yield) as a yellow solid. LCMS (ES, m / z): 297 [M+H] + , Rt 0.689 min.

[0446] 1H NMR(300MHz,DMSO-d6)δ 8.10-8.06(m,1H),7.95-7.91(m,1H),7.61-7.56(m,1H),4.44-4.35(m,2H),4.13-4.01(m,3H),1.47(s,9H).

[0447] Step 3. tert-Butyl 3-(4-amino-2-fluorophenyl)azetidine-1-carboxylate (Intermediate 104) To a solution of tert-butyl 3-(2-fluoro-4-nitrophenyl)azetidine-1-carboxylate (620 mg, 2.09 mmol, 1 equiv.) in HOAc (10 mL) was added Zn (548 mg, 8.36 mmol, 4 equiv.) and NH4Cl (1.12 g, 20.9 mmol, 10 equiv.). The mixture was stirred at 80°C for 3 h. The reaction was monitored by LC-MS. The reaction was allowed to cool to room temperature. The resulting mixture was filtered. The filter cake was washed with AcOH (2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10:1 DCM / MeOH) to afford tert-butyl 3-(4-amino-2-fluorophenyl)azetidine-1-carboxylate (500 mg, 1.88 mmol, 89% yield) as a yellow solid. LCMS(ES,m / z):211[M+H-56] + .Rt 0.200 minutes.

[0448] Intermediate 105. tert-Butyl 3-(5-amino-2-pyridyl)azetidine-1-carboxylate Step 1. tert-Butyl 3-(5-nitro-2-pyridyl)azetidine-1-carboxylate To a stirred mixture of 2-bromo-5-nitropyridine (0.9 g, 4.47 mmol, 1 equiv.) and (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (Intermediate 104, Step 1, 1.86 g, 5.37 mmol, 1.2 equiv.) in DMAc (15 mL) was added Pd(dppf)Cl (327.76 mg, 0.45 mmol, 0.1 equiv.) and CuI (170 mg, 0.89 mmol, 0.2 equiv.). The resulting mixture was stirred at 80 °C under a N atmosphere for 2 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. Water (50 mL) was then added. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 3:1 PE / EA) to give tert-butyl 3-(5-nitropyridin-2-yl)azetidine-1-carboxylate (750 mg, 2.21 mmol, 55% yield) as a yellow solid. LCMS (ES, m / z): 224 [M+H-56] + , Rt 0.889 min.

[0449] 1 H NMR (300 MHz, chloroform-d) δ 9.45 (d, J = 2.7 Hz, 1H), 8.47-8.43 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.38-4.32 (m, 2H), 4.21-4.11 (m, 2H), 4.05-3.95 (m, 1H), 1.47 (s, 9H).

[0450] Step 2. tert-Butyl 3-(5-amino-2-pyridyl)azetidine-1-carboxylate (Intermediate 105) To a solution of tert-butyl 3-(5-nitro-2-pyridyl)azetidine-1-carboxylate (600 mg, 2.15 mmol, 1 equiv.) in EtOH (20 mL) was added palladium on carbon (120 mg, 10 wt.%). The mixture was stirred at room temperature under a hydrogen atmosphere using a hydrogen balloon for 2 hours. The reaction was monitored by LC-MS. The solid was filtered off and washed with EtOH (3×5 mL). The resulting mixture was concentrated under reduced pressure to give tert-butyl 3-(5-amino-2-pyridyl)azetidine-1-carboxylate (550 mg, crude) as a yellow oil. LCMS (ES, m / z): 250 [M+H] + , Rt 0.943 min.

[0451] Intermediate 106. tert-Butyl 3-(4-amino-2-chlorophenyl)azetidine-1-carboxylate Prepared in a similar manner as intermediate 105. LCMS (ES, m / z): 268, 270 [M+H-56+41]+, Rt 0.787 min. 1 H NMR(300MHz,DMSO-d6)δ 7.13(d,J=8.4Hz,1H),6.61(s,1H),6.54(d,J=8.4Hz,1H),4.22-4.09(m,2H),3.93-3.79(m,3H),1.38(s,9H).

[0452] Intermediate 109. 2-Methylspiro[1,3-dihydroisoquinoline-4,1'-cyclopropane]-7-amine Step 1. Methyl 1-(2-cyanophenyl)cyclopropanecarboxylate To a stirred solution of methyl 2-(2-cyanophenyl)acetate (26.8 g, 152.98 mmol, 1 equiv.) and tetrabutylammonium bromide (54.25 g, 168.28 mmol, 1.1 equiv.) in toluene (216 mL) was added sodium hydroxide solution (50%, 107 mL, 9 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-MS. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with brine. The organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 5:1 PE / EA) to give methyl 1-(2-cyanophenyl)cyclopropanecarboxylate (22 g, 98.40 mmol, 64% yield) as a white solid. LCMS (ES, m / z): 202 [M+H] + , Rt 1.308 minutes.

[0453] Step 2. Methyl 1-[2-(aminomethyl)phenyl]cyclopropanecarboxylate To a stirred solution of 1-(2-cyanophenyl)cyclopropanecarboxylate (11 g, 54.67 mmol, 1 equiv.) in EtOH (85 mL) under N2 atmosphere, Pd / C (6.64 g, 5.47 mmol, 10 wt%) was added portionwise at room temperature. The resulting mixture was stirred under H2 atmosphere at room temperature for 3 h. The reaction was monitored by TLC. After filtration, the filtrate was concentrated under reduced pressure. The crude product was washed with diethyl ether to give methyl 1-[2-(aminomethyl)phenyl]cyclopropanecarboxylate, hydrochloride salt (12 g, crude) as a white solid. LCMS (ES, m / z): 206 [M+H] + , Rt 0.373 min.

[0454] Step 3. Spiro[1,2-dihydroisoquinoline-4,1'-cyclopropan]-3-one To a stirred solution of 1-[2-(aminomethyl)phenyl]cyclopropanecarboxylate (12 g, 49.65 mmol, 1 equiv.) in MeOH (180 mL) under N2 atmosphere was added NaOH (5 M, 12.97 mL, 1.31 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. The reaction was monitored by LC-MS. The mixture was neutralized with 1 M aqueous hydrochloric acid. Then, methanol was removed under reduced pressure. The residue was diluted with water and extracted three times with EA. The organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give spiro[1,2-dihydroisoquinoline-4,1'-cyclopropane]-3-one (8.5 g, crude) as a white solid. LCMS (ES, m / z): 174 [M+H] + , Rt 0.565 min.

[0455] Step 4. 7-Nitrospiro[1,2-dihydroisoquinolin-4,1′-cyclopropan]-3-one Potassium nitrate (5.26 g, 52.02 mmol, 1.06 equiv) was added over 5 min to a solution of spiro[1,2-dihydroisoquinolin-4,1'-cyclopropan]-3-one (8.5 g, 49.07 mmol, 1 equiv) in sulfuric acid (80 mL). The reaction was stirred at room temperature for 10 min. The reaction was monitored by LC-MS. The mixture was then poured into cold water. The precipitate was collected by filtration and washed with water to give 7-nitrospiro[1,2-dihydroisoquinolin-4,1'-cyclopropan]-3-one (9 g, crude). LCMS (ES, m / z): 219 [M+H] + , Rt 0.567 min.

[0456] Step 5. 7'-Nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] To a solution of NaBH4 (4.68 g, 123.73 mmol, 3 equiv.) in THF (42 mL) was added BF3-Et2O (20.09 mL, 82.49 mmol, 47% purity, 2 equiv.) dropwise. The mixture was stirred at room temperature for 1 hour. To the above was added 7-nitrospiro[1,2-dihydroisoquinoline-4,1'-cyclopropane]-3-one (9 g, 41.24 mmol, 1 equiv.) in THF (35 mL) and heated to 70 °C for 2 hours. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature and then neutralized with saturated Na2CO3. The solvent was removed. The residue was dissolved in ethanol and HCl (5 M). The mixture was heated under reflux for 1 hour. The reaction was cooled and then the solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous K2CO3. The aqueous layer was extracted with ×DCM (3100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 7-nitrospiro[2,3-dihydro-1H-isoquinoline-4,1'-cyclopropane] (8 g, crude) as a brown solid. LCMS (ES, m / z): 205 [M+H] + , Rt 0.478 min.

[0457] Step 6. 2-Methyl-7-nitro-spiro[1,3-dihydroisoquinoline-4,1'-cyclopropane]cyanosodium borohydride (4.92 g, 78.35 mmol, 2 equiv.) was added to a solution of 7-nitrospiro[2,3-dihydro-1H-isoquinoline-4,1'-cyclopropane] (8 g, 39.17 mmol, 1 equiv.) in MeOH (190 mL). Then, formaldehyde (10.69 g, 117.52 mmol, 33% purity, 3 equiv.) and acetic acid (2.35 g, 39.17 mmol, 1 equiv.) were added. The reaction was stirred at room temperature for 4 h. The reaction was monitored by LC-MS. The reaction was neutralized with saturated aqueous NaHCO3. The solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with MeOH:DCM (3 x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10:1 DCM / MeOH) to give 2-methyl-7-nitro-spiro[1,3-dihydroisoquinoline-4,1'-cyclopropane] (5 g, 20.62 mmol, 53% yield) as a yellow solid. LCMS (ES, m / z): 219 [M+H] + , Rt 0.319 min.

[0458] Step 7. 2-Methylspiro[1,3-dihydroisoquinoline-4,1'-cyclopropane]-7-amine (Intermediate 109) To a mixture of 2-methyl-7-nitro-spiro[1,3-dihydroisoquinoline-4,1'-cyclopropane] (1.8 g, 8.25 mmol, 1 equiv.) and HCOONH4 (5.20 g, 82.47 mmol, 10 equiv.) in MeOH (80 mL) was added Pd / C (360.00 mg, 10 wt%). The reaction was stirred at room temperature for 12 h. The reaction was monitored by LC-MS. After filtration, the filtrate was diluted with saturated aqueous sodium carbonate solution. The solution was extracted with EA (3 x 100 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel, mobile phase: A, water, and B, ACN (5% to 100%) in 30 min, detector, UV 254 nm to give 2-methylspiro[1,3-dihydroisoquinoline-4,1'-cyclopropane]-7-amine (700 mg, 3.53 mmol, 43% yield) as a yellow solid. LCMS (ES, m / z): 189 [M+H] + , Rt 0.304 min.

[0459] Intermediate 110: 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine Step 1. 2,4,4-trimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline To a stirred solution of 2,4,4-trimethyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 48, Step 3, 500 mg, 2.13 mmol, 1 equiv) in THF (10 mL) was added BH3-THF (1 M in THF, 6.4 mL, 6.4 mmol, 3 equiv) under a N2 atmosphere. The mixture was stirred at room temperature for 30 h. The reaction was monitored by LC-MS. The mixture was concentrated under reduced pressure. To the residue was added HCl (6 M, 8 mL) and stirred at 100 °C for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The mixture was quenched with saturated NaHCO3 (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 50 mL) and 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 give 2,4,4-trimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (350 mg, 75% yield) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 8.04-7.95(m,2H),7.68-7.64(m,1H),3.58(s,2H),2.39(s,2H),2.36(s,3H),1.29(s,6H).LCMS(ESI+,m / z):221[M+H] + , Rt 0.575 min.

[0460] Step 2. 2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine (Intermediate 110) To a stirred solution of 2,4,4-trimethyl-7-nitro-1,3-dihydroisoquinoline (350 mg, 1.59 mmol) in ethanol (10 mL) under a N atmosphere was added Pd / C (70 mg, 10 wt%). The resulting mixture was stirred at room temperature under a H atmosphere for 16 h. The reaction was monitored by LC-MS. The solid was filtered and washed with MeOH (2 × 15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with 10:1 DCM / MeOH) to give 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine (260 mg, 86% yield) as a yellow solid. LCMS (ESI+, m / z): 191 [M+H] + , Rt 0.278 min.

[0461] Intermediate 111. tert-Butyl 3-amino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate Step 1. tert-Butyl 3-nitro-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate A mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.40 mmol, 1 equiv.) and 1-methyl-3,5-dinitro-pyridin-2-one (1.29 g, 6.48 mmol, 1.2 equiv.) in ammonia (7 M in MeOH, 10 mL) was stirred at 90° C. for 16 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 3-nitro-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (0.39 g, 1.47 mmol, 27% yield) as a yellow solid. LCMS (ES, m / z): 266 [M+H] + , Rt 0.830 min.

[0462] 1 H NMR (300 MHz, chloroform-d) δ 9.35 (s, 1H), 8.43-8.31 (m, 1H), 4.86-4.75 (m, 4H), 1.54 (s, 9H).

[0463] Step 2. tert-Butyl 3-amino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (Intermediate 111) To a stirred mixture of tert-butyl 3-nitro-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (150 mg, 565.47 μmol, 1 equiv.) in MeOH (20 mL) was added Pd / C (30 mg, 10 wt.%) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. The solid was filtered off and washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 2:1 EA / PE) to give tert-butyl 3-amino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (100 mg, 425.02 μmol, 75% yield) as a yellow solid. LCMS (ES, m / z): 236 [M+H] + , Rt 0.507 min.

[0464] Intermediate 113. tert-Butyl (2S)-3-(4-aminophenyl)-2-[tert-butoxycarbonyl(methyl)amino]propanoate Step 1. tert-Butyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-nitrophenyl)propanoate To a stirred solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-nitrophenyl)propanoic acid (1 g, 3.23 mmol, 1 equiv.) in tert-butanol (8 mL), BocO (822.92 mg, 3.77 mmol, 1.2 equiv.) and N,N-dimethylpyridin-4-amine (1.42 g, 11.60 mmol, 3.6 equiv.) were added portionwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. Water (50 mL) was then added. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give tert-butyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-nitrophenyl)propanoate (900 mg, 2.51 mmol, 76% yield) as a yellow oil. LCMS (ES, m / z): 252 [M+H-100-56+41] + , Rt 1.107 minutes.

[0465] Step 2. tert-Butyl (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-(4-nitrophenyl)propanoate To a stirred solution of tert-butyl (2R)-2-(tert-butoxycarbonylamino)-3-(4-nitrophenyl)propanoate (880 mg, 2.40 mmol, 1 equiv.) in DMF (10 mL) was added NaH (60% in oil, 144 mg, 3.60 mmol, 1.5 equiv.) slowly over 10 min at 0° C. Then, iodomethane (409.07 mg, 2.88 mmol, 1.2 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 2 h. An additional batch of NaH (60% in oil, 96 mg, 2.40 mmol, 1 equiv.) was added slowly. The resulting mixture was stirred at 0° C. for 10 min. Iodomethane (340.89 mg, 1.87 mmol, 1 equiv.) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for an additional 1 h. The reaction was monitored by LC-MS. The reaction was quenched with saturated NH4Cl (50 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with 1:3 EA / PE) to give tert-butyl (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-(4-nitrophenyl)propanoate (700 mg, 1.84 mmol, 75% yield) as a yellow oil. LCMS (ES, m / z): 381 [M+H] + , Rt 1.201 minutes.

[0466] Step 3. tert-Butyl (2S)-3-(4-aminophenyl)-2-[tert-butoxycarbonyl(methyl)amino]propanoate (Intermediate 113) To a solution of tert-butyl (2R)-2-[tert-butoxycarbonyl(methyl)amino]-3-(4-nitrophenyl)propanoate (700 mg, 1.84 mmol, 1 equiv.) in EtOH (10 mL) was added palladium on carbon (140 mg, 10 wt.%). The mixture was hydrogenated at room temperature using a hydrogen balloon for 1 hour. The reaction was monitored by LC-MS. The solid was filtered off and washed with EtOH (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl (2S)-3-(4-aminophenyl)-2-[tert-butoxycarbonyl(methyl)amino]propanoate (400 mg, 1.14 mmol, 62% yield) as a yellow oil. LCMS (ES, m / z): 351[M+H]+, Rt 1.377 min.

[0467] 1 H NMR(300MHz,DMSO-d6)δ 6.85(d,J=7.5Hz,2H),6.49(d,J=7.8Hz,2H),4.88(br,2H),3.04-2.91(m,1 H),2.98-2.92(m,1H),2.82-2.73(m,1H),2.60(s,3H),1.42-1.32(m,18H).

[0468] Intermediate 114 tert-Butyl (2R)-3-(4-aminophenyl)-2-[tert-butoxycarbonyl(methyl)amino]propanoate. Prepared according to the general procedure for Intermediate 113 starting from (2R)-2-(tert-butoxycarbonylamino)-3-(4-nitrophenyl)propanoic acid. LCMS (ES, m / z): 351 [M+H] + , Rt 1.248 minutes.

[0469] Intermediate 118. 6-tert-butylpyridin-3-amine Step 1. N-(6-tert-butyl-3-pyridyl)-1,1-diphenyl-methanimine To a stirred solution of 5-bromo-2-tert-butyl-pyridine (600 mg, 2.80 mmol, 1 equiv) in dioxane (2 mL) was added diphenylmethanimine (609.46 mg, 3.36 mmol, 564.32 uL, 1.2 equiv), Cs2CO3 (2.74 g, 8.41 mmol, 3 equiv), BrettPhos G3 (253.90 mg, 280.24 umol, 0.1 equiv), and BrettPhos (150.21 mg, 280.24 umol, 0.1 equiv). The resulting mixture was stirred at 100 °C under a N2 atmosphere for 1 hour. The reaction was monitored by LC-MS. The mixture was allowed to cool 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 preparative TLC (eluted with 1:1 EA / PE) to give N-(6-tert-butyl-3-pyridyl)-1,1-diphenyl-methanimine (700 mg, 2.22 mmol, 79% yield) as a yellow oil. LCMS (ES, m / z): 315 [M+H] + , Rt 0.839 min.

[0470] Step 2. 6-tert-butylpyridin-3-amine (Intermediate 118) To a stirred solution of N-(6-tert-butyl-3-pyridyl)-1,1-diphenylmethanimine (690 mg, 2.19 mmol, 1 equiv.) in tetrahydrofuran (9 mL), AcOH (3 mL) and HO (1.5 mL) were added dropwise. The resulting mixture was stirred at 100 °C for 1 h and monitored by LC-MS. The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse-phase chromatography (column: C18, mobile phase, A: water (containing 10 mmol / L NHHCO) and B: ACN (5% to 100% in 40 min), detector: UV 254 nm) to give 6-tert-butylpyridin-3-amine (220 mg, 1.45 mmol, 66% yield) as a yellow oil.

[0471] 1H NMR(300MHz,DMSO-d6)δ 7.88(d,J=5.4Hz,1H),7.07-7.03(m,1H),6.88-6.83(m,1H),5.02(br,2H),1.23(s,9H).LCMS(ES,m / z):151[M+H] + , Rt 0.506 min.

[0472] Intermediate 124. 6-Bromotriazolo[1,5-a]pyridine Step 1. N-[(E)-(5-bromo-2-pyridyl)methyleneamino]-4-methyl-benzenesulfonamide A mixture of 5-bromopyridine-2-carbaldehyde (2 g, 10.75 mmol, 1 equiv) and 4-methylbenzenesulfonohydrazide (2.40 g, 12.90 mmol, 1.72 mL, 1.2 equiv) in MeOH (25 mL) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. MeOH was then removed. Water (50 mL) was added to the above. The mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give N-[(E)-(5-bromo-2-pyridyl)methyleneamino]-4-methyl-benzenesulfonamide (3 g, crude) as a yellow solid. LCMS (ES, m / z): 354, 356 [M+H]+. Rt 0.731 min.

[0473] Step 2. 6-Bromotriazolo[1,5-a]pyridine A solution of N-[(E)-(5-bromo-2-pyridyl)methyleneamino]-4-methyl-benzenesulfonamide (3 g, 8.47 mmol) in NMM (20 mL) was stirred at 90° C. for 2 hours. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column (eluted with 1:1 PE / EA) to give 6-bromotriazolo[1,5-a]pyridine (1.5 g, 7.57 mmol, 89.44% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 8.91(s,1H),8.08(s,1H),7.62(d,J=9.2Hz,1H),7.33(d,J=9.2Hz,1H).LCMS(ES,m / z):198, 200[M+H]+.Rt 0.576 min.

[0474] Intermediate 134. 1-(1-methyl-4-piperidyl)pyrazol-3-amine Step 1. 1-Methyl-4-(3-nitropyrazol-1-yl)piperidine To a solution of 3-nitro-1H-pyrazole (900 mg, 7.96 mmol, 1 equiv.), 1-methylpiperidin-4-ol (1.38 g, 11.94 mmol, 1.5 equiv.), and triphenylphosphine (4.18 g, 15.92 mmol, 2.0 equiv.) in THF (15 mL) was added dropwise DIAD (3.22 g, 15.92 mmol, 2 equiv.). The resulting mixture was stirred at room temperature under a N2 atmosphere for 16 hours. The reaction was monitored by LCMS. Water (50 mL) was then added. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 1-methyl-4-(3-nitropyrazol-1-yl)piperidine (700 mg, 3.33 mmol, 42% yield) as a yellow solid. LCMS (ES, m / z): 211 [M+H] + , Rt 0.363 min.

[0475] Step 2. 1-(1-methyl-4-piperidyl)pyrazol-3-amine (Intermediate 134) To a stirred solution of 1-methyl-4-(3-nitropyrazol-1-yl)piperidine (700.00 mg, 3.33 mmol, 1 equiv.) in MeOH (10 mL) under N2 atmosphere was added Pd / C (70 mg, 10 wt%). The resulting mixture was stirred at room temperature under H2 atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to give 1-(1-methyl-4-piperidyl)pyrazol-3-amine (500 mg, crude) as a yellow solid. LCMS (ES, m / z): 181 [M+H] + , Rt 0.432 min.

[0476] 1 H NMR (400 MHz, chloroform-d) δ 7.30-7.26 (m, 1H), 5.55 (d, J = 2.0 Hz, 1H), 3.98-3.88 (m, 1H), 3.47 (s, 3H), 3.04-2.98 (m, 2H), 2.28-2.20 (m, 2H), 2.19-2.08 (m, 2H), 1.97-1.87 (m, 2H). [Table 9]

[0477] Intermediate 135. tert-Butyl 4-(4-aminotriazol-1-yl)piperidine-1-carboxylate Step 1. tert-Butyl 4-(4-nitrotriazol-1-yl)piperidine-1-carboxylate To a 250 mL flask was added 4-nitro-1H-triazole (3 g, 26.30 mmol, 1 equiv), tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (11.02 g, 39.45 mmol, 1.5 equiv), K2CO3 (10.90 g, 78.90 mmol, 3 equiv), and DMF (50 mL). The mixture was stirred at 80 °C for 16 h. The reaction was complete according to LCMS. Water (150 mL) was then added. The mixture was extracted with EA (50 mL × 3). The organic layers were combined, washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 4-(4-nitrotriazol-1-yl)piperidine-1-carboxylate (2.2 g, 10.42 mmol, 40% yield) as a yellow solid. LCMS (ES, m / z): 242 [M+H-56] + , Rt 0.918 min.

[0478] Step 2. tert-Butyl 4-(4-aminotriazol-1-yl)piperidine-1-carboxylate (Intermediate 135) A mixture of tert-butyl 4-(4-nitrotriazol-1-yl)piperidine-1-carboxylate (500 mg, 1.68 mmol, 1 equiv.) and Pd / C (50 mg, 10 wt.%) in MeOH (10 mL) was stirred at room temperature under an H atmosphere for 2 hours. The reaction was monitored by LC-MS. The solid was filtered off and washed with MeOH (5 mL × 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 4-(4-aminotriazol-1-yl)piperidine-1-carboxylate (350 mg, 1.31 mmol, 78% yield) as a white solid. HNMR(300MHz,DMSO-d6)δ 7.18(s,1H),4.69(br,2H),4.58-4.43(m,1H),4.12-3.96(m,2H),3.04-2.79(m, 2H),2.09-1.93(m,2H),1.87-1.71(m,2H),1.43(s,9H).LCMS(ES,m / z):268[M+H]+ , Rt 0.455 min.

[0479] Intermediate 136. tert-Butyl 4-(5-aminoisoxazol-3-yl)piperidine-1-carboxylate Step 1. tert-Butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate To a mixture of acetonitrile (214.67 μL, 4.11 mmol, 1 equiv) in THF (8.0 mL) was added n-BuLi (2.5 M in THF, 1.64 mL, 1 equiv) dropwise at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 0.5 h. To the above was slowly added 1-(tert-butyl) 4-methylpiperidine-1,4-dicarboxylate (1 g, 4.11 mmol, 1 equiv). The mixture was stirred at −78° C. for 0.5 h and then warmed to room temperature for an additional 2 h. The reaction was monitored by LC-MS. To the above was added HO (50 mL). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:2 EA / PE) to give tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate (0.6 g, 2.38 mmol, 58% yield) as a yellow solid. LCMS (ES, m / z): 197 [M+H-56] + , Rt 0.542 min.

[0480] 1 H NMR (300 MHz, chloroform-d) δ 3.52 (s, 2H), 2.89-2.65 (m, 3H), 1.94-1.82 (m, 2H), 1.67-1.48 (m, 3H), 1.46 (s, 9H), 1.30-1.22 (m, 1H).

[0481] Step 2. tert-Butyl 4-(5-aminoisoxazol-3-yl)piperidine-1-carboxylate (Intermediate 136) A mixture of tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate (500 mg, 1.98 mmol, 1.0 equiv.), hydroxylamine hydrochloride (206.57 mg, 2.97 mmol, 1.5 equiv.), and sodium acetate (487.70 mg, 5.95 mmol, 3.0 equiv.) in MeOH (10 mL) was stirred at room temperature for 24 hours. The reaction was monitored by LC-MS. To the above was added HO (50 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 2:1 EA / PE) to give tert-butyl 4-(5-aminoisoxazol-3-yl)piperidine-1-carboxylate (420 mg, 1.57 mmol, 79% yield) as a yellow solid. LCMS (ES, m / z): 212 [M+H-56] + , Rt 0.842 min.

[0482] Intermediate 137. tert-Butyl 4-(4-amino-1H-imidazol-1-yl)piperidine-1-carboxylate Prepared in a similar manner to Intermediate 135.

[0483] 1 H NMR(400MHz,DMSO-d6)δ 7.06(s,1H),6.91(s,1H),4.16-4.08(m,1H),4.01-3.97(m,2H),3.81-3.74(m,2 H),1.93-1.88(m,2H),1.72-1.62(m,2H),1.41(s,9H).LCMS(ES,m / z):267[M+H] + , Rt 0.868 min.

[0484] Intermediate 138. 2-(1-methylpiperidin-4-yl)thiazol-5-amine Step 1. tert-Butyl (2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thiazol-5-yl)carbamate To a solution of tert-butyl N-(2-bromothiazol-5-yl)carbamate (1 g, 3.58 mmol, 1 equiv.) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.66 g, 5.37 mmol, 1.5 equiv.) in 1,4-dioxane (15 mL) and water (3 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (262 mg, 358.23 μmol, 0.1 equiv.) and potassium carbonate (1.5 g, 10.75 mmol, 3 equiv.) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 3:1 PE / EA) to give tert-butyl N-[2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)thiazol-5-yl]carbamate (750 mg, 2.31 mmol, 64% yield) as a yellow solid. LCMS (ES, m / z): 296 [M+H] + , Rt 0.650 min.

[0485] Step 2. tert-Butyl (2-(1-methylpiperidin-4-yl)thiazol-5-yl)carbamate To a solution of tert-butyl N-[2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)thiazol-5-yl]carbamate (730 mg, 2.47 mmol, 1 equiv.) in ethanol (10 mL) was added Pd / C (150 mg, 10 wt%) under N atmosphere. The mixture was hydrogenated at room temperature under H atmosphere using a hydrogen balloon for 5 hours. The reaction was monitored by LCMS. The solid was filtered through a Celite pad and washed with ethanol (2×5 mL). The filtrate was concentrated under reduced pressure to give tert-butyl N-[2-(1-methyl-4-piperidyl)thiazol-5-yl]carbamate (650 mg, crude) as a yellow solid. LCMS (ES, m / z): 298 [M+H] + , Rt 0.642 min.

[0486] Step 3. 2-(1-methylpiperidin-4-yl)thiazol-5-amine (Intermediate 138) To a solution of tert-butyl N-[2-(1-methyl-4-piperidyl)thiazol-5-yl]carbamate (460 mg, 1.54 mmol, 1 equiv.) in ethanol (8 mL) was added HCl (4 M in dioxane, 4 mL). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. 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 40% in 35 min), detector: UV 254 nm) to give tert-butyl N-[2-(1-methyl-4-piperidyl)thiazol-5-yl]carbamate (180 mg, 913 μmol, 59% yield) as a yellow solid. LCMS (ES, m / z): 198 [M+H] + , Rt 0.775 min. 1 H NMR(400MHz,DMSO-d6)δ 6.56(s,1H),5.34(br,2H),2.79-2.74(m,2H),2.67-2.60(m,1H),2.15(s,3H),1.98-1.86(m,4H),1.64-1.54(m,2H).

[0487] Intermediate 142. tert-Butyl 4-(4-bromo-2-oxo-1-pyridyl)piperidine-1-carboxylate To a stirred mixture of 4-bromo-1H-pyridin-2-one (2 g, 11.49 mmol, 1 equiv.) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (6.42 g, 22.99 mmol, 2 equiv.) in DMSO (20 mL) was added K2CO3 (4.77 g, 34.48 mmol, 3 equiv.). The reaction was stirred at 80 °C for 16 h. The mixture was allowed to cool to room temperature and diluted with HO (200 mL). The resulting mixture was extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (2:1) to give tert-butyl 4-(4-bromo-2-oxo-1-pyridyl)piperidine-1-carboxylate (400 mg, 1.12 mmol, 10% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 7.75(d,J=7.5Hz,1H),6.72(d,J=2.1Hz,1H),6.49-6.40(m,1H),4.86-4.69(m,1H),4.14-3. 97(m,2H),2.99-2.73(m,2H),1.77-1.60(m,4H),1.42(s,9H).LCMS(ES,m / z):357, 359[M+H] + , Rt 0.718 min.

[0488] Intermediate 144. 4-Bromo-1-tetrahydropyran-4-yl-pyridin-2-one To a stirred mixture of 4-bromo-1H-pyridin-2-one (500 mg, 2.87 mmol, 1 equiv.) and tetrahydropyran-4-yl methanesulfonate (1.04 g, 5.75 mmol, 2 equiv.) in DMSO (10 mL) was added K2CO3 (1.19 g, 8.62 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The mixture was allowed to cool to room temperature and diluted with HO (200 mL). The resulting mixture was extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column: C18, mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (30% B to 40% B over 10 min), detector: UV 254 nm) to give 4-bromo-1-tetrahydropyran-4-yl-pyridin-2-one (200 mg, 775.19 μmol, 27% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.75(d,J=7.6Hz,1H),6.73(d,J=2.4Hz,1H),6.55-6.44(m,1H),4.90-4.78(m,1H),4.01-3.93 (m,2H),3.51-3.40(m,2H),1.94-1.79(m,2H),1.73-1.64(m,2H).LCMS(ES,m / z):258, 260[M+H] + , Rt 0.559 min. [Table 10]

[0489] Intermediate 147. 4-Bromo-1-(difluoromethyl)pyridin-2(1H)-one To a solution of 4-bromo-2-chloropyridine (1.25 g, 6.51 mmol, 1 equiv.) in CHCN (15 mL) was added NaHCO (1.64 g, 19.5 mmol, 3 equiv.) in portions. The reaction mixture was stirred at 80° C. for 30 min. Then, a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (3.47 g, 19.5 mmol, 3 equiv.) in CHCN (10 mL) was added over 10 min, and the reaction mixture was stirred at 80° C. for 2 h. The mixture was cooled to room temperature, diluted with water (100 mL), neutralized with 10% aqueous NaHCO solution, and extracted with EA (2×100 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give 4-bromo-1-(difluoromethyl)pyridin-2(1H)-one (560 mg, 2.29 mmol, 39% yield) as a yellow oil. LCMS (ES, m / z): 224, 226 [M+H] + , Rt 0.598 min.

[0490] Intermediate 148. 4-Bromo-1-(methyl-d3)pyridin-2(1H)-one To a stirred solution of 4-bromo-1H-pyridin-2-one (200 mg, 1.15 mmol, 1 equiv) in DMF (2 mL) was added NaH (60% purity, 114.8 mg, 2.87 mmol, 2.5 equiv) in portions at 0 °C under a N atmosphere. The resulting mixture was stirred at −5 °C for 25 min, and then trideuterio(iodo)methane (199.95 mg, 1.38 mmol, 1.2 equiv) was added dropwise at −5 °C over 5 min. The resulting mixture was stirred at room temperature for 2 h, and then it was quenched with ice / water (50 mL) at 0 °C and extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (1:10) to give 4-bromo-1-(methyl-d3)pyridin-2(1H)-one (140 mg, 725.50 μmol, 63% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 7.69(d,J=7.2Hz,1H),6.70(s,1H),6.45(d,J=7.2Hz,1H).LCMS(ES,m / z):191, 193[M+H] + , Rt 0.495 min.

[0491] Intermediate 149. 4-Bromo-1-cyclopropylpyridin-2(1H)-one To a stirred mixture of 4-bromo-1H-pyridin-2-one (500 mg, 2.87 mmol, 1 equiv.) and cyclopropylboronic acid (617.09 mg, 7.18 mmol, 2.5 equiv.) in DCE (10 mL), 2,2′-bipyridine (448.82 mg, 2.87 mmol, 1 equiv.), Cu(OAc) (521.95 mg, 2.87 mmol, 1 equiv.), and NaCO (913.73 mg, 8.62 mmol, 3 equiv.) were added at room temperature under a N atmosphere. The resulting mixture was stirred at 70° C. for 18 h under a N atmosphere. The reaction was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EA (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1:1) to give 4-bromo-1-cyclopropylpyridin-2(1H)-one (300 mg, 1.40 mmol, 48% yield) as a pale yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 7.53(d,J=7.2Hz,1H),6.68(d,J=2.1Hz,1H),6.42-6.33(m,1H),3.34-3.21 (m,1H),1.07-0.98(m,2H),0.93-0.77(m,2H).LCMS(ES,m / z):214,216[M+H] + , Rt 0.646 min.

[0492] Intermediate 160. 1-(6-Bromo-2-pyridyl)pyrrolidin-2-one To a solution of 2,6-dibromopyridine (500 mg, 2.11 mmol, 1 equiv.) and pyrrolidin-2-one (179.63 mg, 2.11 mmol, 1 equiv.) in dioxane (10 mL) was added Pd2dba3 (193.13 mg, 211.07 μmol, 0.1 equiv.), BINAP (131.42 mg, 211.07 μmol, 0.1 equiv.), and Cs2CO3 (1.38 g, 4.22 mmol, 2 equiv.). The mixture was stirred at 100 °C under a N2 atmosphere for 1 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The solid was filtered off and washed with EA (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:5 EA / PE) to give 1-(6-bromo-2-pyridyl)pyrrolidin-2-one (100 mg, 414.79 μmol, 19.65% yield) as a yellow solid. LCMS (ES, m / z): 241, 243 [M+H] + , Rt 0.720 min. [Table 11]

[0493] Intermediate 161. (6-Bromopyridin-2-yl)dimethylphosphine oxide To a mixture of 2,6-dibromopyridine (1 g, 4.22 mmol, 1 equiv.) and dimethylphosphine oxide (988.42 mg, 12.66 mmol, 3 equiv.) in ACN (12 mL) was added TEA (1.50 g, 14.77 mmol, 2.06 mL, 3.5 equiv.) and Pd(PPh3)4 (243.90 mg, 211.07 μmol, 0.05 equiv.). The reaction was stirred at 90 °C under a N2 atmosphere for 13 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to afford (6-bromopyridin-2-yl)dimethylphosphine oxide (520 mg, 2.23 mmol, 52% yield) as a white solid. LCMS (ES, m / z): 234, 236 [M+H] + , Rt 0.513 min.

[0494] Intermediate 163. 1-(6-Bromopyridin-2-yl)-5,5-dimethylpyrrolidin-2-one To a stirred mixture of 2,6-dibromopyridine (1 g, 4.22 mmol, 1 equiv.) and 5,5-dimethylpyrrolidin-2-one (382.14 mg, 3.38 mmol, 0.8 equiv.) in 1,4-dioxane (10 mL) was added CuI (803.95 mg, 4.22 mmol, 1 equiv.), DMEDA (372.11 mg, 4.22 mmol, 1 equiv.), and KCO (1.75 g, 12.66 mmol, 3 equiv.). The reaction was stirred at 100 °C under a N atmosphere for 4 h, and the mixture was allowed to cool to room temperature. The solid was filtered off and washed with EA (3 × 5 mL). The filtrate was dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography (eluted with 1:2 EA / PE) to give 1-(6-bromopyridin-2-yl)-5,5-dimethylpyrrolidin-2-one (400 mg, 1.49 mmol, 35% yield) as a pale yellow oil. LCMS (ES, m / z): 269, 271 [M+H] + , Rt 0.726 min.

[0495] Intermediate 167. 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine Step 1. 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine To a solution of 1-(6-bromo-2-pyridyl)ethanone (1 g, 5.00 mmol, 1 equiv.) and triethylamine (1.52 g, 15.00 mmol, 3 equiv.) in DCM (15 mL) was added TBSOTf (1.59 g, 6.00 mmol, 1.2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature under a N atmosphere for 1 h. The resulting mixture was diluted with HO (100 mL). The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1:3) to give 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (1.3 g, 4.06 mmol, 82% yield) as a colorless oil. LCMS (ES, m / z): 314, 316 [M+H] + , Rt 1.383 minutes.

[0496] Step 2. 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine To a solution of diethylzinc (14.75 g, 119.42 mmol, 30 equiv) in DCM (30 mL) under N2 atmosphere was added chloro(iodo)methane (4.49 g, 25.45 mmol, 6.4 equiv) in DCM (6 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 15 min. To the above was added 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (1.25 g, 3.98 mmol, 1 equiv) in DCM (18 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The resulting mixture was diluted with HO (100 mL). The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1:4) to give 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine (340 mg, 602.60 μmol, 15% yield) as a colorless oil. 1H NMR(300MHz,d6-DMSO)δ 7.74(t,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.42(d,J=8.1Hz,1H),1.29-1.18(m,4H),0.91(s,9H),0.08(s,6H).LCMS(ES,m / z):328,330[M+H] + , Rt 1.258 minutes.

[0497] Intermediate 168. 3-(6-Bromo-2-pyridyl)oxetan-3-ol To a stirred solution of 2,6-dibromopyridine (2 g, 8.44 mmol, 1 equiv) in THF (50 mL) under a N2 atmosphere, n-BuLi (1.3 M / n-hexane, 7.14 mL, 9.29 mmol, 1.1 equiv) was added dropwise at −78°C. The resulting mixture was stirred at −78°C for 30 min. To the above solution, oxetan-3-one (730.08 mg, 10.13 mmol, 1.2 equiv) was added dropwise. The resulting mixture was stirred at −78°C for 2 h. The reaction was monitored by LCMS. The reaction mixture was quenched with saturated NH4Cl (aq) at −78°C. The combined organic layers were extracted with EA (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1:4) to give 3-(6-bromo-2-pyridyl)oxetan-3-ol (1.4 g, 6.09 mmol, 72% yield) as a white solid. LCMS (ES, m / z): 230, 232 [M+H] + , Rt 0.612 min.

[0498] Intermediate 169. 2-Chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol To a solution of 2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (6 g, 35.80 mmol, 1 equiv.) in THF (200 mL) was added ethylmagnesium bromide (1 M in THF, 53.70 mL, 1.5 equiv.) dropwise at −5° C. The mixture was stirred at this temperature for 2 h. The reaction was monitored by LCMS. Water (300 mL) was then added. The mixture was extracted with EA (3×100 mL). The organic layers were combined, washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 1:5 PE / EA) to give 2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (4.2 g, 21.25 mmol, 59% yield) as a white solid. LCMS (ES, m / z): 198, 200 [M + H] + , Rt 0.688 min.

[0499] Intermediate 170. ((3-Bromophenyl)imino)dimethyl-16-sulfanone To a stirred mixture of 1-bromo-3-iodo-benzene (1 g, 3.53 mmol, 1 equiv.) and iminodimethyl-16-sulfanone (493.88 mg, 5.30 mmol, 1.5 equiv.) in 1,4-dioxane (5 mL), Pd2dba3 (80.86 mg, 88.37 μmol, 0.025 equiv.), Xantphos (152.70 mg, 265.11 μmol, 0.075 equiv.), and Cs2CO3 (1.73 g, 5.30 mmol, 1.5 equiv.) were added. The mixture was stirred at 100 °C under a N2 atmosphere for 2 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The solid was filtered off and washed with EA (2 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1.5:1 EA / PE) to give ((3-bromophenyl)imino)dimethyl-16-sulfanone (0.5 g, 2.01 mmol, 57% yield) as a yellow oil. LCMS (ES, m / z): 248, 250 [M+H] + , Rt 0.739 min.

[0500] Intermediates 171 and 172. tert-Butyl (R)-(1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate and tert-butyl (S)-(1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate Step 1. 1-(6-bromopyridin-2-yl)ethan-1-amine To a mixture of 1-(6-bromopyridin-2-yl)ethan-1-one (2 g, 10.00 mmol, 1 equiv.), NHOAc (1.54 g, 20.00 mmol, 2 equiv.) in MeOH (30 mL) was added NaBHCN (1.24 g, 20.00 mmol, 2 equiv.) in portions at 0 °C. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water (150 mL). The resulting mixture was washed with EA (3 × 100 mL). The combined organic phases were dried over anhydrous NaSO. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 1-(6-bromopyridin-2-yl)ethan-1-amine (1 g, 4.95 mmol, 50% yield) as a white solid. LCMS (ES, m / z): 201, 203 [M+H] + , Rt 0.430 min.

[0501] Step 2. tert-Butyl (1-(6-bromopyridin-2-yl)ethyl)carbamate A mixture of 1-(6-bromopyridin-2-yl)ethan-1-amine (1.5 g, 7.46 mmol, 1 equiv.), TEA (2.26 g, 22.38 mmol, 3 equiv.), and BocO (1.95 g, 8.95 mmol, 1.2 equiv.) in THF (15 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (150 mL) and extracted with EA (3 × 100 mL). The combined organic phase was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give tert-butyl (1-(6-bromopyridin-2-yl)ethyl)carbamate (1.0 g, 3.32 mmol, 45% yield) as a white solid. LCMS (ES, m / z): 301, 303 [M+H] +, Rt 0.850 min.

[0502] Step 3. tert-Butyl (1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate To a stirred solution of tert-butyl (1-(6-bromopyridin-2-yl)ethyl)carbamate (500 mg, 1.66 mmol, 1 equiv) in DMF (10 mL) was added NaH (199.20 mg, 4.98 mmol, 60% purity, 3 equiv) in portions at 0 °C. The mixture was stirred at 25 °C for 0.5 h. To the above mixture was added MeI (282.77 mg, 1.99 mmol, 1.2 equiv) dropwise at 0 °C. The mixture was stirred at 25 °C for another 2 h. The reaction was monitored using LCMS. The mixture was diluted with water (100 mL) and extracted with EA (3 × 80 mL). The combined organic phase 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 PE / EA (2:1) to give tert-butyl (1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate (300 mg, 0.95 mmol, 57% yield) as a yellow oil. LCMS (ES, m / z): 315, 317 [M+H] + , Rt 0.844 min.

[0503] Step 4. tert-Butyl (R)-(1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate and tert-butyl (S)-(1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate tert-Butyl (1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate (300 mg, 0.95 mmol, 1 equiv.) was purified by chiral HPLC (column: NB_ASA CHIRAL Separation on ART Cellulose-SC (IC), 5*25 cm / 10 μm, mobile phase A: Hex (0.2% DEA), mobile phase B: IPA, flow rate: 20 mL / min, gradient: 1% B in 20 min, 220 / 254 nm, RT1 (min): 14.1, RT2 (min): 15.8 gave tert-butyl (S)-(1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate (150 mg, 0.48 mmol, 50% yield) as a yellow oil, and tert-butyl (R)-(1-(6-bromopyridin-2-yl)ethyl)(methyl)carbamate (130 mg, 0.41 mmol, 43% yield) as a yellow oil. LCMS (ES, m / z): 315, 317 [M+H] + , Rt 0.844 min. The absolute stereochemistry of the title compound was arbitrarily assigned upon chiral separation.

[0504] Intermediate 175. tert-Butyl 4-(6-bromo-2-pyridyl)piperidine-1-carboxylate A mixture of 2,6-dibromopyridine (500 mg, 2.11 mmol, 1 equiv.), potassium (1-(tert-butoxycarbonyl)piperidin-4-yl)trifluoroborate (614.54 mg, 2.11 mmol, 1 equiv.), (Ir[dF(CF)ppy](dtbpy))PF (23.68 mg, 21.11 µmol, 0.01 equiv.), NiCl(DME) (46.43 mg, 211.07 µmol, 0.1 equiv.), dtbbpy (84.85 mg, 316.60 µmol, 0.15 equiv.), and CsCO (1.38 g, 4.22 mmol, 2 equiv.) in dioxane (40 mL) was irradiated with blue light (450 nm) at 20 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was diluted with brine (100 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:4 EA / PE) to give tert-butyl 4-(6-bromo-2-pyridyl)piperidine-1-carboxylate (350 mg, 1.03 mmol, 49% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 7.63(t,J=7.8Hz,1H),7.42(d,J=8.1Hz,1H),7.29(d,J=7.8Hz,1H),4.28-4.15(m,2H),3.00- 2.81(m,3H),1.96-1.81(m,2H),1.76-1.57(m,2H),1.50(s,9H).LCMS(ES,m / z):341,343[M+H] + , Rt 0.807 min.

[0505] Intermediate 176. 1-(6-Bromo-2-pyridyl)-4-methyl-piperazine A solution of 2,6-dibromopyridine (200 mg, 844.27 μmol, 1 equiv.), 1-methylpiperazine (84.56 mg, 844.27 μmol, 1 equiv.), BINAP G2-Pd (78.69 mg, 84.43 μmol, 0.1 equiv.), BINAP (52.57 mg, 84.43 μmol, 0.1 equiv.), and Cs2CO3 (550.46 mg, 1.69 mmol) in dioxane (2 mL) was stirred at 100 °C for 2 h. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with brine (50 mL) and extracted with ethyl acetate (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 20:1 DCM / MeOH) to give 1-(6-bromo-2-pyridyl)-4-methyl-piperazine (140 mg, 546.88 umol, 65% yield) as a yellow oil.

[0506] 1 H NMR(300MHz,DMSO-d6)δ 7.48-7.40(m,1H),7.42(d,J=7.8Hz,2H),3.53-3.42(m,4H),2.43-2.35(m,4H),2.23(s,3H).LCMS(ES,m / z):256, 258[M+H] + , Rt 0.487 min.

[0507] Intermediate 177 and Intermediate 178. tert-Butyl (R)-3-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-3-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate Step 1. tert-Butyl 3-(6-bromo-2-pyridyl)pyrrolidine-1-carboxylate 2,6-Dibromopyridine (500 mg, 2.11 mmol, 1 equiv.), tert-butyl 3-bromopyrrolidine-1-carboxylate (791.92 mg, 3.17 mmol, 1.5 equiv.), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (23.68 mg, 21.11 mmol, 0.01 equiv.), dtbpy (84. A mixture of Cs2CO3 (85 mg, 316.60 mmol, 0.15 equiv.), Cs2CO3 (1.38 g, 4.22 mmol, 2 equiv.), tris(trimethylsilyl)silane (523.45 mg, 2.11 mmol, 1 equiv.), and NiBr2(DME) (65.01 mg, 211.07 mmol, 0.1 equiv.) was irradiated with blue light (450 nm) under a nitrogen atmosphere at 20 °C for 1 h. The reaction was monitored by LC-MS. The resulting mixture was diluted with brine (80 mL) and extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrat...

Claims

1. A compound of formula (I), 【Chemistry 151】 or a pharmaceutically acceptable salt thereof, wherein: Each R １ are independently C1-C6 alkyl; m is 0, 1, or 2; R ２ is a 5-10 membered heteroaryl containing one or more ring atoms selected from hydrogen, C1-C6 alkyl, phenyl, N, O, or S, or N, O, S, C(O), N(O), S(O), or S(O) ２ and each of phenyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl is independently selected from R Ａ optionally substituted with 1 to 3 substituents selected from Each R Ａ are independently halogen; NR Ｂ R Ｃ C1-C6 haloalkyl optionally substituted with; hydroxyl; cyano; NR Ｂ R Ｃ C(=O)NR Ｂ R Ｃ ; N = S(O)(R Ｊ ) ２ wherein each R Ｊ are methyl or form a five-membered ring together with the S atom to which they are attached, N=S(O)(R Ｊ ) ２ ; S (O) ２ C1-C6 alkyl; S(O)(=NR Ｂ ) C1-C6 alkyl; P(O)(C1-C6 alkyl) ２ hydroxyl or NR Ｂ R Ｃ C1-C6 alkyl optionally substituted with; C1-C6 alkoxy; hydroxyl or NR Ｂ R Ｃ C3-C6 cycloalkyl optionally substituted with; and N, O, S, C(O), N(O), S(O), or S(O) ２ and optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, and C1-C6 alkyl; Each R Ｂ and R Ｃ are independently hydrogen or C1-C6 alkyl; R ３ is hydrogen or C1-C6 alkyl; R ４ but, (iii) hydrogen, (iv) each independently: Halogen; Cyano; SO ２ (C1-C6 alkyl); C1-C6 haloalkyl; C1-C6 deuteroalkyl; each independently -NR Ｂ R Ｃ and -CO ２ C1-C6 alkyl optionally substituted with 1 or 2 substituents selected from H; (C1-C6 alkyl) ｎ -C(=O)NR Ｅ R Ｆ C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and containing one or more ring atoms selected from one, two, or three independently selected R Ｇ phenyl optionally substituted by 1 or 2 substituents selected from the group consisting of 4- to 12-membered heterocyclyl optionally substituted by (iii) N, O, S, C(O), N(O), S(O), or S(O) ２ and optionally substituted with 1 to 4 independently selected C1-C6 alkyl, or halogen; (iv) 5-10 membered heteroaryl containing one or more ring atoms selected from N, O, or S, and optionally substituted with C1-C6 alkyl; cyano; halogen; C1-C6 haloalkyl; C1-C6 deuteroalkyl; C1-C6 alkoxy; C3-C6 cycloalkyl; N, O, or S, and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O). ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and optionally substituted with one or two C1-C6 alkyl, C1-C6 alkoxy, amino, or N, O, S, C(O), N(O), S(O), or S(O). ２ 5- to 10-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: 4- to 12-membered heterocyclyl containing one or more ring atoms selected from (v) C3-C6 cycloalkyl, or (vi)C(O)-R Ｉ and n is 0 or 1; Each R Ｅ and R Ｆ are independently hydrogen or C1-C6 alkyl; or R Ｅ and R Ｆ together with the nitrogen atom to which they are attached, N, O, S, C(O), N(O), S(O), or S(O) ２ and forming a 4-8 membered heterocyclyl containing one or more ring atoms selected from Each R Ｇ are independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 deuteroalkyl, NR Ｂ R Ｃ , or =NR Ｈ and R Ｈ is hydrogen or C1-C6 alkyl; R Ｉ is C1-C6 alkyl; phenyl optionally substituted with 1 to 3 halogens; 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with 1 to 3 C1-C6 alkyl; C3-C6 cycloalkyl which is halogen, phenyl, N, O, S, C(O), N(O), S(O), or S(O) ２ and a 5- to 6-membered heteroaryl containing one or more ring atoms selected from N, O, or S, optionally substituted with 1-3 C1-C6 alkyl; and a C3-C6 cycloalkyl optionally substituted with 1 substituent selected from the group consisting of N, O, S, C(O), N(O), S(O), or S(O). ２ and optionally substituted with 1 or 2 C1-C6 alkyl; R ５ is hydrogen, halogen, or C1-C6 alkyl; R ６ is hydrogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I), 【Chemistry 152】 or a pharmaceutically acceptable salt thereof, wherein: Each R １ are independently C1-C6 alkyl; m is 0, 1, or 2; R ２ is a 5-10 membered heteroaryl containing one or more ring atoms selected from hydrogen, C1-C6 alkyl, phenyl, N, O, or S, or N, O, S, C(O), N(O), S(O), or S(O) ２ and wherein said phenyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl each independently represent R Ａ optionally substituted with 1 to 3 substituents selected from Each R Ａ are independently halogen, cyano, -NR Ｂ R Ｃ , —C(═O)NR Ｂ R Ｃ , -N=S(O)Me) ２ , hydroxyl or —NR Ｂ R Ｃ C1-C6 alkyl optionally substituted with -NR Ｂ R Ｃ C3-C6 cycloalkyl optionally substituted with; and N, O, S, C(O), N(O), S(O), or S(O) ２ and optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; Each R Ｂ and R Ｃ are independently hydrogen or C1-C6 alkyl; R ３ is hydrogen or C1-C6 alkyl; R ４ but, (i) each independently represents a halogen, a cyano, or —SO ２ (C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 deuteroalkyl, each independently -NR Ｂ R Ｃ and -CO ２ C1-C6 alkyl optionally substituted with 1 or 2 substituents selected from H; -(C1-C6 alkyl) ｎ -C(=O)NR Ｅ R Ｆ , C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and one or two independently selected R Ｇ phenyl optionally substituted by 1 or 2 substituents selected from the group consisting of 4- to 12-membered heterocyclyl optionally substituted by (ii) N, O, S, C(O), N(O), S(O), or S(O); ２ and optionally substituted with 1 to 3 independently selected C1-C6 alkyl; (iii) 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S, and containing one or more ring atoms selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C3-C6 cycloalkyl, N, O, or S, and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O). ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and 4-12 membered heterocyclyl optionally substituted with 1 or 2 C1-C6 alkyl or amino; (iv) C3-C6 cycloalkyl, or (v) C(O)-R Ｉ and n is 0 or 1; Each R Ｅ and R Ｆ are independently hydrogen or C1-C6 alkyl; or R Ｅ and R Ｆ together with the nitrogen atom to which they are attached, N, O, S, C(O), N(O), S(O), or S(O) ２ and forming a 4-8 membered heterocyclyl containing one or more ring atoms selected from Each R Ｇ are independently halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, —NR Ｂ R Ｃ , or =NR Ｈ and R Ｈ is hydrogen or C1-C6 alkyl; R Ｉ is a C3-C6 cycloalkyl optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, phenyl optionally substituted with 1-3 halogen; a 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with 1-3 C1-C6 alkyl; halogen, phenyl, and a 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with 1-3 C1-C6 alkyl; R ５ is hydrogen, halogen, or C1-C6 alkyl; R ６ is hydrogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

3. 3. The compound of claim 1, wherein m is 2.

4. Each R １ The compound according to any one of claims 1 to 3, wherein is methyl.

5. Two independently selected R １ 5. The compound of any one of claims 1 to 4, wherein the groups are geminal and the carbon atoms to which they are attached are adjacent to the ring oxygen.

6. R ５ The compound according to any one of claims 1 to 5, wherein is hydrogen.

7. R ６ The compound according to any one of claims 1 to 6, wherein is methyl.

8. 8. The compound of any one of claims 1 to 7, having the following structure: 【Chemistry 153】

9. R ２ is 1 to 3 independently selected R Ａ 9. The compound of any one of claims 1 to 8, wherein the phenyl is optionally substituted with

10. R ２ contains one or more ring atoms selected from N, O, or S, and 1 to 3 independently selected R Ａ 10. The compound of any one of claims 1 to 9, wherein the compound is a 5-10 membered heteroaryl optionally substituted with

11. R ２ contains one or more ring atoms selected from N, O, or S, and 1 to 3 independently selected R Ａ 11. The compound of any one of claims 1 to 8 and 10, wherein the heteroaryl is 5 to 10 membered, substituted with:

12. The R ２ The compound according to any one of claims 1 to 8 and 10 to 11, wherein the 5- to 10-membered heteroaryl containing one or more ring atoms selected from N, O, or S is a 5- to 6-membered heteroaryl containing one or more ring atoms selected from N, O, or S.

13. The R ２ The compound according to any one of claims 1 to 8 and 10 to 12, wherein the 5- to 10-membered heteroaryl containing one or more ring atoms selected from N, O, or S is pyridyl, pyrazinyl, or pyrimidinyl.

14. The R ２ The compound according to any one of claims 1 to 8 and 10 to 13, wherein the 5- to 10-membered heteroaryl containing one or more ring atoms selected from N, O, or S is pyridyl.

15. The R ２ The compound according to any one of claims 1 to 8 and 10 to 14, wherein the pyridyl is 2-pyridyl.

16. R ２ but, 【Chemistry 154】 16. The compound of claim 15, wherein:

17. R ２ but, 【Chemistry 155】 17. The compound of claim 16, selected from:

18. R ２ is N, O, S, C(O), N(O), S(O), or S(O) ２ and containing one or more ring atoms selected from 1 to 3 independently selected R Ａ 9. The compound of any one of claims 1 to 8, wherein the compound is a 5- to 10-membered heterocyclyl optionally substituted with

19. R ２ is N, O, S, C(O), N(O), S(O), or S(O) ２ and containing one or more ring atoms selected from 1 to 3 independently selected R Ａ 16. The compound of any one of claims 1 to 8 and 15, wherein the compound is a 5- to 10-membered heterocyclyl substituted with

20. Each R Ａ are independently fluoro; chloro; hydroxyl; cyano; NR Ｂ R Ｃ C(=O)NR Ｂ R Ｃ ; hydroxyl, NR Ｂ R Ｃ 、 or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl; C1-C6 alkoxy; NR Ｂ R Ｃ C1-C6 haloalkyl optionally substituted with NR Ｂ R Ｃ C3-C6 cycloalkyl optionally substituted with N=S(O)(Me)2; N=S(O)(R Ｊ ) 2, where each R Ｊ is combined with the S atom to which it is attached to form a five-membered ring, N=S(O)(R Ｊ ) 2; S (O) ２ C1-C6 alkyl; S(O)(=NR Ｂ ) C1-C6 alkyl; P(O)(C1-C6 alkyl) ２ and N, O, S, C(O), N(O), S(O), or S(O) ２ and 4-6 membered heterocyclyl containing one or more ring atoms selected from the group consisting of: optionally substituted with halogen, hydroxyl, or C1-C6 alkyl.

21. One or more R Ａ are independently selected NR Ｂ R Ｃ The compound according to any one of claims 1 to 16 and 18 to 20,

22. One or more R Ａ are independently selected C(═O)NR Ｂ R Ｃ The compound according to any one of claims 1 to 16 and 18 to 21,

23. R Ｂ and R Ｃ The compound of any one of claims 1 to 16 and 18 to 22, wherein each is hydrogen.

24. R Ｂ is hydrogen, and R Ｃ The compound of any one of claims 1 to 16 and 18 to 22, wherein is C1-C6 alkyl.

25. R Ｂ and R Ｃ is each independently selected C1-C6 alkyl.

26. One or more R Ａ is hydroxyl or NR Ｂ R Ｃ 21. The compound of any one of claims 1-16 and 18-20, wherein R is an independently selected C1-C6 alkyl optionally substituted with R.

27. R ３ The compound of any one of claims 1 to 26, wherein is hydrogen.

28. R ３ The compound of any one of claims 1 to 26, wherein is C1-C6 alkyl.

29. R ３ The compound of any one of claims 1 to 26, wherein is methyl.

30. R ４ each independently represents a halogen; a cyano; or a SO ２ (C1-C6 alkyl); C1-C6 haloalkyl; C1-C6 deuteroalkyl; each independently, NR Ｂ R Ｃ and CO ２ C1-C6 alkyl optionally substituted with 1 or 2 substituents selected from H; (C1-C6 alkyl) ｎ -C(=O)NR Ｅ R Ｆ C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and one or two independently selected R Ｇ 30. The compound of any one of claims 1 to 29, wherein the phenyl is optionally substituted with one or two substituents selected from the group consisting of: 4- to 12-membered heterocyclyl optionally substituted with

31. R ４ each independently represents a halogen; a cyano; or a SO ２ (C1-C6 alkyl); C1-C6 haloalkyl; C1-C6 deuteroalkyl; each independently, NR Ｂ R Ｃ and CO ２ C1-C6 alkyl optionally substituted with 1 or 2 substituents selected from H; (C1-C6 alkyl) ｎ -C(=O)NR Ｅ R Ｆ C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and one or two independently selected R Ｇ 31. The compound of any one of claims 1 to 30, wherein the phenyl is substituted by one or two substituents selected from the group consisting of: 4- to 12-membered heterocyclyl optionally substituted by

32. R ４ is halogen; C1-C6 haloalkyl; 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and one or two independently selected R Ｇ 32. The compound of any one of claims 1 to 31, wherein the aryl group is phenyl substituted with one or two substituents independently selected from the group consisting of: 4- to 12-membered heterocyclyl optionally substituted with

33. R ４ is fluoro; chloro; C1-C3 alkyl; 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and one or two independently selected R Ｇ 33. The compound of claim 32, wherein the phenyl is substituted with one or two substituents independently selected from the group consisting of: 4- to 12-membered heterocyclyl substituted with

34. R ４ each of which is one or two independently selected R Ｇ 34. The compound of claim 33, wherein the phenyl is substituted with imidazolyl or pyrazolyl, optionally substituted with

35. R ４ is phenyl substituted with piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, 1,4-oxazepan-4-yl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 1,4-diazepanyl, 2-oxopiperazinyl, 3-oxopiperazinyl, thiomorpholinyl, thiomorpholinyl-1-oxide, octahydropyrrolo[3,4-c]pyrrolyl, or 2,6-diazaspiro[3.3]heptanyl, each of which is selected from one or two independently selected R Ｇ 33. The compound of claim 32, optionally substituted with:

36. Each R Ｇ are independently selected from halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, and NR Ｂ R Ｃ The compound according to any one of claims 1 to 35, selected from:

37. Each R Ｇ are independently fluoro, chloro, methyl, CD ３ , and NCH ３ R Ｃ and R Ｃ The compound of any one of claims 1 to 36, wherein is selected from hydrogen and methyl.

38. R ４ is N, O, S, C(O), N(O), S(O), or S(O) ２ and optionally substituted with 1 to 3 independently selected C1-C6 alkyl.

39. R ４ is N, O, S, C(O), N(O), S(O), or S(O) ２ and substituted with one or two independently selected C1-C6 alkyl.

40. R ４ is N, O, S, C(O), N(O), S(O), or S(O) ２ 40. The compound of any one of claims 1 to 29 and 38, which is an unsubstituted 9-12 membered heterocyclyl containing one or more ring atoms selected from:

41. R ４ but, 【Chemistry 156】 wherein each of ring B1 and ring B2 is selected from N, O, S, C(O), N(O), S(O), or S(O) ２ 41. The compound of any one of claims 1 to 29 and 38 to 40, wherein the compound is an independently selected 5- or 6-membered heterocyclyl containing one or more ring atoms selected from:

42. R ４ is a 5- to 6-membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with one or two substituents independently selected from the group consisting of C1-C6 alkyl; a 5- to 6-membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and optionally substituted with C1-C6 alkyl or amino.

43. R ４ is a 5- to 6-membered heteroaryl containing one or more ring atoms selected from N, O, or S and substituted with one or two substituents independently selected from the group consisting of C1-C6 alkyl; a 5- to 6-membered heteroaryl containing one or more ring atoms selected from N, O, or S and optionally substituted with C1-C6 alkyl; N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 4- to 12-membered heterocyclyloxy optionally substituted with: ２ and optionally substituted with C1-C6 alkyl or amino.

44. R ４ contains one or more ring atoms selected from N, O, or S, and is selected from N, O, S, C(O), N(O), S(O), or S(O) ２ and wherein each is a 5- to 6-membered heteroaryl substituted with one or two independently selected 4- to 12-membered heterocyclyl groups, optionally substituted with C1-C6 alkyl or amino.

45. R ４ is a 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and substituted with one or two substituents independently selected from the group consisting of piperidinyl, piperazinyl, and tetrahydropyranyl, each optionally substituted with methyl or amino.

46. R ４ is a 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S, and substituted with one or two independently selected C1-C6 alkyl.

47. R ４ contains one or more ring atoms selected from N, O, or S, and is selected from N, O, S, C(O), N(O), S(O), or S(O) ２ and one or two independently selected R Ｇ 44. The compound of any one of claims 1 to 29, 42, and 43, wherein the aryl is a 5- to 6-membered heteroaryl substituted with one or two substituents independently selected from 4- to 12-membered heterocyclyloxy optionally substituted with

48. R ４ contains one or more ring atoms selected from N, O, or S and is substituted with one or two substituents independently selected from the group consisting of azetidinyloxy, piperidinyloxy, and pyrrolidinyloxy, each of which is substituted with one or two independently selected R Ｇ 47. The compound of any one of claims 1 to 29, 42, 43, and 46, wherein R is a 5-6 membered heteroaryl optionally substituted with R.

49. The R ４ is a 5-6 membered heteroaryl containing one or more ring atoms selected from N, O, or S and selected from the group consisting of pyrazol-4-yl, pyrazol-3-yl, imidazolyl, isoxazolyl, thiazolyl, 1,2,3-triazol-4-yl, pyridin-3-yl, pyrazinyl, pyrimidinyl, and pyridazinyl.

50. R ４ The compound of any one of claims 1 to 29, wherein is C3-C6 cycloalkyl.

51. R ４ But C(O)-R Ｉ The compound according to any one of claims 1 to 29,

52. 3. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of the compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.

53. 53. A pharmaceutical composition comprising a compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

54. 54. 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 to 52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 53.

55. 55. The method of claim 54, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung.

56. 54. Use of a compound according to any one of claims 1 to 52 or a composition according to claim 53 in the manufacture of a medicament for treating cancer in a patient in need thereof.

57. 57. The use of claim 56, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung.

58. 54. A compound or composition for use in the treatment of cancer, comprising a compound according to any one of claims 1 to 52, or a composition according to claim 53.

59. 59. The compound or composition of claim 58, wherein the cancer is selected from one or more of uterine, ovarian, breast, gastric, colorectal, and non-small cell lung.

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