Tricyclic aryl derivatives and compositions and methods thereof

Abstract

The present invention provides novel tricyclic aryl compounds and derivatives thereof, as well as pharmaceutical compositions and methods for treating diseases and disorders, such as various types of cancer.

Description

[Technical Field]

[0001] Priority claims and related applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 393,570, filed July 29, 2022, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] The present invention generally relates to novel compounds and their therapeutic uses. More specifically, the present invention provides novel tricyclic compounds that are shown to be potent and selective phosphoinositide 3-kinase alpha (PI3Kα) inhibitors. The present invention also provides pharmaceutical compositions containing the compounds of the present invention and methods for treating diseases and disorders associated with or related to PI3Kα activity, such as various types of cancer. [Background technology]

[0003] Phosphoinositide 3-kinases (PI3Ks) are a family of related intracellular signal transducer enzymes that can phosphorylate the hydroxyl group at the 3 position of the inositol ring of phosphatidylinositol (PtdIns). PI3Ks are associated with a wide variety of cellular functions, including cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. The PI3K signaling pathway is one of the most frequently mutated pathways in human cancer and is also a major factor in many other human diseases. For example, PI3K signaling is associated with allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diabetic complications, and acute coronary syndrome.

[0004] The PI3K family is divided into three distinct classes: class I, class II, and class III, based on their primary structure, regulation, and lipid substrate specificity (Kalaany et al. 2009 Nature 458 (7239): 725-31; Leevers et al. (1999) Current Opinion in Cell Biology 11 (2): 219-25). Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are activated by tyrosine kinases or G protein-coupled receptors to generate phosphatidylinositol-3,4,5-triphosphate (PIP3). Binding of PIP3 to effectors such as PDPK1 / AKT activates downstream signaling pathways.

[0005] Class IA PI3K p110α (PI3Kα) is mutated in many human cancers. Angiogenesis has been shown to selectively require the PI3Kα isoform in regulating endothelial cell migration. Mutations in the gene encoding PI3Kα (PIK3CA) or upregulation of PI3Kα occur in many human cancers, including ovarian, cervical, breast, colorectal, endometrial, gastric, hepatocellular carcinoma, small-cell and non-small-cell lung cancer, thyroid cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.In cancer, PI3Kα mutations are often hotspot point mutations in the helical or kinase domain, such as E542K, E545K, and H1047R (Graupera et al. 2008 Nature 453: 662-6; Campbell et al. 2004 Cancer Res 64, 7678-7681; Levine et al. 2005 Clin Cancer Res 11, 2875-2878; Wang et al. 2005 Hum Mutat 25, 322; Lee et al. 2005 Gynecol Oncol 97, 26-34; Bachman, et al. 2004 Cancer Biol Ther 3, 772-775; Li et al. 2006 Breast Cancer Res Treat 96, 91-95; Saal et al. 2005 Cancer Res 65, 2554-2559;Samuels and Velculescu 2004 Cell Cycle 3, 1221-1224;Samuels, et al. 2004 Science 304, 554;Velho et al. 2005 Eur J Cancer 41, 1649-1654;Oda et al. 2005 Cancer Res. 65, 10669-10673;Byun et al. 2003 Int J Cancer 104, 318-327;Lee et al. 2005 Oncogene 24, 1477-1480;Tang et al. 2006 Lung Cancer 51, 181-191;Massion et al. 2004 Am J Respir Grit Care Med 170, 1088-1094;Wu et al. 2005 J Clin Endocrinol Metab 90, 4688-4693;Sujobert et al. 1997 Blood 106, 1063-1066;Hickey and Cotter 2006 J Biol Chem 281, 2441-2450;Hartmann et al. 2005 Acta Neuropathol (Berl) 109, 639-642.). Summary of the Invention [Problem to be solved by the invention]

[0006] There remains an urgent unmet need for potent and selective PI3Kα inhibitors that are safe and effective for treating PI3Kα-associated diseases and conditions, such as various types of cancer (e.g., breast cancer, ovarian cancer, colorectal cancer, lung cancer).

[0007] The present invention provides novel tricyclic compounds and derivatives thereof as PI3K alpha inhibitors, which are herein shown to exhibit more advantageous potency and selectivity profiles than known PI3K alpha inhibitors. These novel compounds selectively target, bind to, and inhibit and / or modulate the activity of PI3K alpha. The compounds are also orally available with pharmacokinetic profiles suitable for development into orally administered therapeutic agents for the treatment of various diseases and disorders associated with or related to PI3K alpha activity, such as various types of cancer. [Means for solving the problem]

[0008] In one aspect, the present invention generally provides a compound of structural formula (I): [ka] [In the formula, Ring A is 0 to 10 R a is a 4- to 7-membered monocyclic non-aromatic ring substituted with R 1 is Z B -R B and R 2 is Z C -R C and X is N, CH or CR X and R X is Z X -R X’ and Z B , Z C and ZX each independently represents a covalent bond, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O), NRS(O), S(O)NR, or C(O) optionally and independently substituted with a heteroatom selected from the group consisting of N, S, and O. 1~4 is a linking group selected from saturated or unsaturated divalent hydrocarbon groups, R B , R C and R X each of which independently: H, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR', or -N(R)S(O)2R, or C 1~6 a 5-10 membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from an aliphatic chain, N, O and S, each of which is selected from one or more R b , R c or R x are substituted appropriately with R a , R b , R c and R x each of which independently: H, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR' or -N(R)S(O)2R, or C 1~6 is a substituted or unsubstituted group selected from alkyl or a 4- to 6-membered carbocyclic ring; Each of R and R' is independently H, unsubstituted or substituted C 1~4 alkyl, or an unsubstituted or substituted 4- to 6-membered carbocyclic ring, or when R and R' are attached to the same C or N atom, they together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0009] In another aspect, the invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0010] In yet another aspect, the invention generally relates to unit dosage forms that include the pharmaceutical compositions disclosed herein.

[0011] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.

[0012] In yet another aspect, the invention generally relates to a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0013] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Kα, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0014] In yet another aspect, the present invention generally relates to a method for treating or reducing cancer or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0015] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0017] As used herein, "at least" a particular value is understood to be that value and all values above that value.

[0018] The term "comprising," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term "consisting essentially of," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but exclude other elements of any essential importance to the compositions and methods. For example, "consisting essentially of" refers to the administration of explicitly recited pharmacologically active agents, but excludes pharmacologically active agents not explicitly recited. The term "consisting essentially of" does not exclude pharmacologically non-active or inactive agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, is intended to mean excluding trace elements and substantial method steps of other components. Embodiments defined by each of these transition terms are within the scope of this invention.

[0019] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. About can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein may be modified by the term about.

[0020] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0021] As used herein, the term "administration" or "administering" a disclosed compound includes delivery of a compound described herein, or a prodrug or other pharmaceutically acceptable form thereof, to a subject using any suitable formulation or route of administration described herein.

[0022] As used herein, the term "co-administered" means that two pharmacological agents are present in a subject's body (e.g., in the blood) at the same time. The two pharmacological agents may be administered simultaneously or sequentially.

[0023] Unless otherwise indicated, the terms "disease," "disorder," and "condition" are used interchangeably.

[0024] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a compound or pharmaceutical composition described herein that is sufficient to fulfill its intended use, including, but not limited to, the treatment of diseases, as described below.

[0025] In some embodiments, the amount is sufficient to negatively regulate or inhibit the activity of PI3K alpha. In some embodiments, the amount is effective to reduce or improve symptoms, or to stop or reverse the progression of a disease or disorder, such as cancer. In some embodiments, the amount is effective to detectably reduce or inhibit the growth or spread of cancer cells; the size or number of tumors; or other measures of the level, stage, progression, or severity of cancer.

[0026] The therapeutically effective amount may vary depending on the intended use, or the subject and disease state to be treated, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the patient's weight and age, and can be easily determined by those skilled in the art.Such an amount may be administered as a single dose or according to a regimen.This term also applies to the dose that induces a specific response in target cells, such as reducing cell migration.The specific dose will vary depending on, for example, the specific compound selected, the species of subject and their age / current health condition or risk of health condition, the administration regimen followed, the severity of the disease, whether it is administered in combination with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0027] As used herein, an "inhibitor" of "PI3K alpha" refers to a compound of the present invention that is capable of negatively regulating or inhibiting all or part of the activity of PI3K alpha.

[0028] As used herein, "PI3K alpha-related" disease or disorder refers to a disease or disorder that is related to or mediated by PI3K alpha or has one or more PI3K alpha mutations. Examples of PI3K alpha-related diseases or disorders include various types of cancer. PI3K alpha-related diseases or disorders can also refer to allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diabetic complications, or acute coronary syndrome.

[0029] As used herein, the term "contacting" refers to bringing the indicated moieties together in vitro or in vivo. For example, "contacting" a cell with a compound disclosed herein includes administering the compound to a subject in need thereof, as well as introducing the compound into a sample containing the cell or a purified preparation, for example. In some embodiments, cells in which inhibition of PI3K α activity is desired are contacted with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable form thereof, to negatively regulate PI3K α activity. By negatively regulating PI3K α activity, the methods disclosed herein are designed to inhibit undesired cell proliferation resulting from enhanced PI3K α activity in cells. Cells can be contacted with a single dose or multiple doses according to a specific treatment regimen to achieve the desired negative modulation of PI3K α. The ability of a compound to bind to PI3K α can be monitored in vitro using methods known in the art. The inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring inhibition of PI3K α activity using methods known in the art.

[0030] As used herein, the terms "unsubstituted or substituted" and "optionally substituted" are used interchangeably and refer to a situation in which a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be bonded at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any additional functional groups. Suitable substituents used for appropriate substitution of the described groups include, but are not limited to, halogen, oxo, CN, -COOH, -CHCN, -O-Ci-C alkyl, Ci-C alkyl, -O-Ci-C alkenyl, -O-Ci-C alkynyl, -Ci-C alkenyl, -Ci-C alkynyl, -OH, -O-P(O)(OH), -OC(O)Ci-C alkyl, -C(O)Ci-C alkyl, -OC(O)O-Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), -NHC(O)Ci-C alkyl, -C(O)NHCi-C alkyl, -S(O)-Ci-C alkyl, -S(O)NHCi-C alkyl, and S(O)N(Ci-C alkyl).

[0031] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In some embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0032] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of suitable salts include benzoate, benzoyl peroxide ...In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0033] Salts may be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0034] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to an ester that hydrolyzes in vivo, including those that readily decompose in the human body to leave the parent compound or its salt. Such esters can act as prodrugs, as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids, and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates. Esters may be formed using hydroxy or carboxylic acid groups of the parent compound.

[0035] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be of the disclosed compounds or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that may include, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. The term "compound," as used herein, will be understood to encompass compounds and solvates of compounds, as well as mixtures thereof.

[0036] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to a compound that is converted in vivo to produce a pharmaceutically acceptable form of the disclosed compound or compound. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can increase the bioavailability of a compound when administered to a subject (e.g., by enabling enhanced absorption into the blood after oral administration) or enhance delivery to a desired biological compartment (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced water solubility or active transport across intestinal membranes compared to the parent compound.

[0037] Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated herein by reference). Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or its ability to enhance absorption from the gastrointestinal tract, or its ability to enhance drug stability for long-term storage.

[0038] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0039] As used herein, the term "subject" means any animal (e.g., mammal), including, but not limited to, humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0040] In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder that can be treated with the compounds disclosed herein and / or according to the methods disclosed herein. In some embodiments, the subject has been identified or diagnosed as having a cancer with one or more PI3K alpha mutations. In some embodiments, the subject has a cancer that is positive for PI3K alpha mutations. In some embodiments, the subject is suspected of having a PI3K alpha gene-related cancer.

[0041] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a subject has one or more PI3Kα mutations using a sample from the subject (e.g., a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample)). Various techniques, such as next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR), can be used.

[0042] As used herein, the term "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying, or ameliorating such a condition before or after it has occurred. Treatment can target one or more effects or symptoms of a disease and / or underlying pathology. Treatment is intended to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even though the patient may still be suffering from the underlying disorder. For prophylactic benefit, pharmaceutical compounds and / or compositions can be administered to patients at risk of developing a particular disease or to patients who report one or more physiological symptoms of the disease, even though the disease may not have been diagnosed. Treatment can be any reduction, or can be, but is not limited to, the complete elimination of the disease or symptoms of the disease. Compared to comparable untreated controls, such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0043] As used herein, the term "therapeutic benefit" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0044] After their preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 95% or more by weight of the compound ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the present invention are greater than 99% pure.

[0045] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0046] As used herein, the term "isolated" or "substantially isolated" refers to a molecule (e.g., a polypeptide or polynucleotide) that has been engineered to exist at a higher concentration than in nature or that has been removed from its natural environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified if at least 10%, 20%, 40%, 50%, 70%, or 90% of the non-subject antibody material naturally associated with it has been removed. For example, a polynucleotide or polypeptide that naturally occurs in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated." Furthermore, recombinant DNA molecules contained in a vector are considered isolated for purposes of the present invention. Isolated RNA molecules include the products of in vivo or in vitro RNA replication of DNA and RNA molecules. Isolated nucleic acid molecules further include molecules produced synthetically. Furthermore, vector molecules contained in a recombinant host cell are also isolated. Therefore, not all "isolated" molecules need to be "purified."

[0047] As used herein, the term "purified," when used in reference to a molecule, means that the concentration of the purified molecule is increased relative to the molecules that accompany it in its natural environment or the environment in which it was produced, found, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally exclude water, buffers, and reagents that are added to maintain the integrity of the purified molecule or facilitate its purification. By this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

[0048] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~4 "Alkyl" is C1, C2, C3, C4, C 1~3 , C 1~2 , C 2~4 , C 3~4 and C 2~3 Alkyl groups are intended to be included.

[0049] As used herein, the term "aliphatic" or "aliphatic group" means a straight or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic.

[0050] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 Numerical ranges such as "1 to 10," whenever they appear herein, refer to each integer within the given range, e.g., "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also encompasses the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, "alkyl" refers to C 1~6It may also be an alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight-chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, and saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in this specification, an alkyl group is any of the following: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R x )3, -OR x , -SR x , -OC(O)-R x , -N(R x )2, -C(O)R x , -C(O)OR x , -OC(O)N(R x )2, -C(O)N(R x )2, -N(R x )C(O)OR x , -N(R x )C(O)R x , -N(R x )C(O)N(R x )2, -N(R x )C(NR x )N(R x )2, -N(Rx )S(O) t N(R x )2 (where t is 1 or 2), -P(=O)(R x )(R x ), or -OP(=O)(OR x )2, and each R x are independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. In a non-limiting embodiment, the substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0051] Unless otherwise specifically defined, the terms "aromatic" or "aryl" refer to a cyclic aromatic hydrocarbon group having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, H, halogen, —O—Ci-C alkyl, Ci-C alkyl, —Ci-C alkenyl, —O—Ci-C alkynyl, —Ci-C alkenyl, —Ci-C alkynyl, —OH, —O—P(O)(OH), —OC(O)Ci-C alkyl, —C(O)Ci-C alkyl, —OC(O)O—Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), —S(O)—Ci-C alkyl, —S(O)NHCi-C alkyl, and S(O)N(Ci-C alkyl). The substituents may themselves be optionally substituted. Furthermore, when containing two fused rings, aryl groups as defined herein may have a fully unsaturated ring and a fused unsaturated or partially saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

[0052] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0053] As used herein, the term "heteroaryl" or "hetero-aromatic" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 p-electrons shared in the cyclic array, and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1,2-dihydro-5H-pyrrolo[1,2-a]imidazole ... H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, o Xazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidyl nyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl."Heteroaryl" also means bicyclic ring systems having, in addition to carbon atoms, from 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S, wherein one ring system may be saturated or partially saturated.

[0054] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2)carbonyl. The term "NZ1Z2" as used herein refers to two groups, Z1 and Z2, attached to the parent molecular moiety through a nitrogen atom. Z1 and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0055] As used herein, the term "alkoxy" refers to an --O-alkyl group.

[0056] As used herein, the terms "cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic group that contains only carbon and hydrogen and may be saturated or partially unsaturated. Unless otherwise specified herein, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond or "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3~13Cycloalkyl). Numerical ranges such as "3 to 10," whenever they appear herein, refer to each integer within the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3~8 In some embodiments, "cycloalkyl" is a C 3~5 It may also be a cycloalkyl group. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~7 Examples of carbocyclyl groups include norbornyl (C7). 3~8 Examples of carbocyclyl groups are those listed above. 3~7 Carbocyclyl groups include cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, etc. 3~13 Examples of carbocyclyl groups are those listed above. 3~8Unless otherwise stated in the specification, cycloalkyl groups include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, each R aare independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. The terms "cycloalkenyl" and "cycloalkynyl" reflect the above description of "cycloalkyl," with the prefix "alk" replaced with "alkene" or "alkyne," respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0057] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group having one or more skeletal atoms selected from atoms other than carbon, e.g., O, N, S, P, or combinations thereof. Unless otherwise specified herein, this term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Examples of heterocycloalkyl include 2-hydroxyaziridin-1-yl, 3-oxo-1-oxacyclobutan-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazin-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, and the like.

[0058] As used herein, the terms "heterocycle," "heterocyclic," or "heterocyclo" refer to a fully saturated or partially unsaturated cyclic group, e.g., a 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 15-membered spirocyclic or tricyclic ring system, having at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, where 0, 1, 2, or 3 atoms in each ring may be substituted by a substituent. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may be oxidized and the nitrogen heteroatom may be quaternized. The heterocyclic group may be bonded at any heteroatom or carbon atom in the ring or ring system. The heterocyclic group is optionally substituted. Examples of heterocyclic groups include epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, and azabicyclononanyl (e.g., octahydroindolizinyl). , azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl, diazaspirononanyl, oxazabioctoheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, and tetrahydro-2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide.

[0059] Detailed Description of the Invention The present invention is based in part on the discovery of novel tricyclic compounds and their derivatives as PI3K alpha inhibitors. These compounds are shown herein to selectively target, bind to, inhibit and / or modulate the activity of PI3K alpha. The compounds are orally available and can be used to treat various diseases and disorders associated with or related to PI3K alpha activity, such as various types of cancer.

[0060] In one aspect, the present invention generally provides a compound of structural formula (I): [ka] [In the formula, Ring A is 0 to 10 R a is a 4- to 7-membered monocyclic non-aromatic ring substituted with R 1 is Z B -R B and R 2 is Z C -R C and X is N, CH or CR X and R X is Z X -R X’ and Z B , Z C and Z X each independently represents a covalent bond, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O), NRS(O), S(O)NR, or C(O) optionally and independently substituted with a heteroatom selected from the group consisting of N, S, and O. 1~4 is a linking group selected from saturated or unsaturated divalent hydrocarbon groups, R B , R C and R X each of which independently: H, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR', or -N(R)S(O)2R, or C 1~6 a 5-10 membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from an aliphatic chain, N, O and S, each of which is selected from one or more R b , R c or R x are substituted appropriately with R a , R b , R c and R x each of which independently: H, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR' or -N(R)S(O)2R, or C 1~6 is a substituted or unsubstituted group selected from alkyl or a 4- to 6-membered carbocyclic ring; Each of R and R' is independently H, unsubstituted or substituted C 1~4 alkyl, or an unsubstituted or substituted 4- to 6-membered carbocyclic ring, or when R and R' are attached to the same C or N atom, they together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0061] In certain embodiments of (I), ring A is selected from 0 to 10 R a is a 4- to 7-membered carbocyclic ring with no ring heteroatoms, substituted with

[0062] In certain embodiments of (I), ring A is selected from 0 to 10 R a is a 4-7 membered heterocyclic ring having 1-4 ring heteroatoms selected from N, O and S, substituted with

[0063] In certain embodiments of (I), ring A is selected from 0 to 4 R a and a four-membered non-aromatic ring substituted with a : [ka] (In the formula, Y 1 and Y 2 are independently CH, CH, N, NH, O, or S, with the proviso that Y 1 and Y 2 at least one of is C or CH It has.

[0064] In certain embodiments of (I), ring A is selected from 0 to 6 R a and a five-membered non-aromatic ring substituted with b ): [ka] [In the formula, Y 1 , Y 2 and Y 3 each independently is CH, CH, N, NH, O, S, or C(O), with the proviso that Y 1 , Y 2 and Y 3 At least one of them is neither N nor NH, but Y 1 , Y 2 and Y 3at least one of is C, CH or C(O)] It has.

[0065] In certain embodiments of (I), ring A is selected from 0 to 8 R a and a six-membered non-aromatic ring substituted with c ): [ka] [In the formula, Y 1 , Y 2 , Y 3 and Y 4 each independently is CH, CH, N, NH, O, S, S(O) or C(O), with the proviso that Y 1 , Y 2 , Y 3 and Y 4 At least two of them are neither N nor NH, but Y 1 , Y 2 , Y 3 and Y 4 at least two of are C, CH or C(O)] It has.

[0066] In certain embodiments of (I), ring A is selected from 0 to 8 R a and a seven-membered non-aromatic ring substituted with d ): [ka] [In the formula, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each independently is CH, CH, N, NH, O, S, or C(O), with the proviso that Y 1 , Y 2 , Y 3 , Y 4 and Y 5 At least two of them are neither N nor NH, but Y 1 , Y 2 , Y 3 , Y 4 and Y 5at least two of are C, CH or C(O)] It has.

[0067] In certain embodiments of (I), R B is 0 to 6 R b Ring B having 0-4 ring heteroatoms independently selected from N, O and S, substituted with R C is 0 to 6 R c Ring C, 5-10 membered monocyclic or bicyclic aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from N, O and S, substituted with Structural formula (I e ): [ka] (In the formula, j is 0, 1, 2, 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, 5, or 6) It has.

[0068] In certain embodiments of (I), Z B is NH-C(O), and Z c is a single bond, and the structural formula (I f ): [ka] It has.

[0069] In certain embodiments of (I), Z B is C(O)-NH, and Z c is a single bond, and the structural formula (I g ): [ka] It has.

[0070] (I)~(I g In certain embodiments of), ring A is [ka] is selected from.

[0071] (I)~(I g In certain embodiments of), ring A is [ka] is selected from.

[0072] In certain embodiments, ring A is [ka] (In the formula, R a’ are CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN) is.

[0073] In certain embodiments, each R a are independently H, Cl, F, CN, or CH3.

[0074] In certain embodiments, R a’ is CH2CHF2.

[0075] (I)~(I g In certain embodiments of), ring A is [ka] is selected from.

[0076] (I)~(I g In certain embodiments of), ring A is [ka] [ka] is selected from.

[0077] In certain embodiments, ring A is [ka] (In the formula, R a’ is CH2CHF2 or CH2CF3, Each R a are independently H, Cl, F, CN, or CH3 is selected from.

[0078] In certain embodiments, ring A is [ka] (In the formula, R a’ One of the R is CH2CHF2 or CH2CF3, and the other R a’ is H, CH3 or CD3) is.

[0079] (I)~(I g In certain embodiments of), ring A is [ka] is selected from.

[0080] In certain embodiments, ring A is [ka] (In the formula, R a’ is CH2CHF2 or CH2CF3, and R a is H) is selected from.

[0081] In certain embodiments, ring A is [ka] (In the formula, R a and R a’is selected from H, CH3, CD3, CD2CD3, CH2CN and CH2CHF2, CH2CF3 and CH2CN, and the other R a and / or R a’ is H) is selected from.

[0082] In certain embodiments, ring A is [ka] (In the formula, each R a is H, and each R a’ are independently selected from H, CH3, CD3, CD2CD3, CH2CN and CH2CHF2, CH2CF3 and CH2CN is selected from.

[0083] In certain embodiments, ring A comprises one or more of O, NR, C(O), S(O)2, C(O)O, C(O)NR, and NRC(O)NR, where each R is independently H, CH3, CH2CH3, CD2CD3, CH2CHF2, CH2CF3, or CH2CN.

[0084] (I)~(I g In certain embodiments of ), X is CH.

[0085] (I)~(I g In certain embodiments of X is.

[0086] (I)~(I g In certain embodiments of ), X is N.

[0087] (I)~(I g In certain embodiments of ), Ring B is a substituted or unsubstituted 5- or 6-membered monocyclic carbocyclyl or heterocyclic.

[0088] (I)~(I gIn certain embodiments of ), ring B is a substituted or unsubstituted 5- or 6-membered monocyclic aryl or heteroaryl ring.

[0089] (I)~(I g In certain embodiments of ), Ring B is a substituted or unsubstituted 8-10 membered bicyclic carbocyclyl or heterocyclic.

[0090] (I)~(I g In certain embodiments of ), ring B is a substituted or unsubstituted 8-10 membered bicyclic aryl or heteroaryl ring.

[0091] Non-limiting examples of ring B are: [ka] [ka] Includes.

[0092] (I)~(I e In certain embodiments of), ring B is [ka] is selected from.

[0093] (I)~(I e In certain embodiments of), ring B is [ka] is selected from.

[0094] (I)~(I e In certain embodiments of), ring B is [ka] [ka] is selected from.

[0095] In certain embodiments, ring B is [ka] is.

[0096] (I)~(I e In certain embodiments of ), ring B is substituted or unsubstituted phenyl, pyridyl, pyridazinyl, or pyrazinyl.

[0097] In certain embodiments, Ring B is substituted or unsubstituted phenyl.

[0098] In certain embodiments, Ring B is substituted or unsubstituted pyridyl.

[0099] In certain embodiments, Ring B is substituted or unsubstituted pyridazinyl.

[0100] In certain embodiments, Ring B is substituted or unsubstituted pyrazinyl.

[0101] (I)~(I e In certain embodiments of ), Ring C is substituted or unsubstituted phenyl, pyridyl, pyridazinyl, or pyrazinyl.

[0102] In certain embodiments, Ring C is substituted or unsubstituted phenyl.

[0103] In certain embodiments, Ring C is substituted or unsubstituted pyridyl.

[0104] In certain embodiments, Ring C is substituted or unsubstituted pyridazinyl.

[0105] In certain embodiments, Ring C is substituted or unsubstituted pyrazinyl.

[0106] (I)~(I e In certain embodiments of ), each of ring B and ring C is independently substituted or unsubstituted phenyl.

[0107] Non-limiting examples of ring C are: [ka] [ka] Includes.

[0108] In certain embodiments, ring C is [ka] is.

[0109] In certain embodiments of (I), the compound has structural formula I h : [ka] It has.

[0110] In certain embodiments of (I), the compound has structural formula I h : [ka] It has.

[0111] In certain embodiments of (I), the compound has structural formula I i : [ka] It has.

[0112] In certain embodiments of (I), the compound has structural formula I j : [ka] It has.

[0113] In certain embodiments of (I), the compound has structural formula I k : [ka] It has.

[0114] In certain embodiments of (I), the compound has structural formula I l : [ka] It has.

[0115] In certain embodiments of (I), the compound has structural formula I m : [ka] It has.

[0116] In certain embodiments of (I), the compound has structural formula I n : [ka] It has.

[0117] Non-limiting examples of compounds of the present invention are: [ka] [ka] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0118] Non-limiting examples of compounds of the present invention are: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0119] Non-limiting examples of compounds of the present invention are: [ka] [ka] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0120] Non-limiting examples of compounds of the present invention are: [ka] [ka] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0121] In certain embodiments, the chirality is as follows: [ka]

[0122] In certain embodiments, the chirality is as follows: [ka]

[0123] In certain embodiments, the compounds of the present invention are 2 exhibits the following chirality at the carbon to which it is attached: [ka]

[0124] In certain embodiments, the compounds of the present invention are 2 exhibits the following chirality at the carbon to which it is attached: [ka]

[0125] Non-limiting exemplary compounds of the invention can also be found in Table 1 in the Examples section.

[0126] In certain embodiments, the compounds of the present invention have one or more deuterium atoms in place of hydrogen. In certain embodiments, the compounds of the present invention have one deuterium atom in place of a hydrogen atom.

[0127] In another aspect, the invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0128] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0129] In yet another aspect, the invention generally relates to unit dosage forms that include the pharmaceutical compositions disclosed herein.

[0130] In certain embodiments, the unit dosage form is in the form of a tablet or capsule.

[0131] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, salts or electrolytes such as sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0132] The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.In certain embodiments, the compounds of the formula herein are administered transdermally (for example, using a transdermal patch).Other formulations can be conveniently provided in unit dosage form, for example, tablets and sustained-release capsules, and liposomes, and can be prepared by any method well known in the art of pharmacy.See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[0133] Such preparatory methods include the step of bringing into association the molecule to be administered with ingredients such as the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0134] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or their derivatives are mixed with at least one inert conventional excipient (or carrier) such as sodium citrate or dicalcium phosphate, or (i) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (ii) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (iii) humectants, such as glycerol; (iv) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (v) solution retarders. The formulation may be mixed with (i) an absorbent, such as a sorbent, a sorbent, a sorbent-resistant sorbent, a sorbent-coated sorbent, a sorbent-resistant ...

[0135] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of these substances.In addition to such inert diluents, the composition may also contain additional agents such as wetting, emulsifying, suspending, sweetening, flavoring, or flavoring agents.

[0136] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.

[0137] In yet another aspect, the invention generally relates to a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0138] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Kα, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0139] In certain embodiments, the disease or disorder is a cell proliferative disorder.

[0140] In yet another aspect, the present invention generally relates to a method for treating or reducing cancer or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0141] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0142] Examples of cancers targeted in the present invention include, but are not limited to, head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer and rectal cancer), etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myeloma), sarcoma (e.g., osteosarcoma and soft tissue sarcoma), skin cancer, brain tumor, carcinoma, squamous cell carcinoma, adenocarcinoma, neuroma, melanoma, etc. Examples include lung cancer, pancreatic cancer, rectal cancer, colon cancer, colorectal cancer, and uterine cancer. In certain embodiments, the squamous cell carcinoma is cancer of the cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus. In one embodiment, the adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, or ovary. In certain embodiments, the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, leukemia, or uterine cancer.

[0143] In certain embodiments, the cancer is selected from the group consisting of ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, small cell and non-small cell lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, gastric cancer, bile duct cancer, hepatocellular carcinoma, thyroid cancer, and hematological malignancies.

[0144] In certain embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.

[0145] In certain embodiments, the subject has a mutated class IA PI3K p110α.

[0146] In certain embodiments, the subject has at least one of the following PI3K alpha mutations: H1047R, E542K, and E545K.

[0147] In certain embodiments, the subject does not have a PI3K alpha mutant protein.

[0148] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormonal therapy.

[0149] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder.

[0150] In yet another aspect, the invention relates generally to the use of the compounds disclosed herein for treating a disease or disorder.

[0151] The amount of active compound to be administered depends on the subject being treated, the severity of disorder or condition, route of administration, distribution of compound and the discretion of the prescribing physician.In some cases, the dosage level below the lower limit of the aforementioned range may be more than sufficient, while in other cases, even higher doses can be used without causing harmful side effects, and this higher dose is typically divided into several smaller doses for daily administration.

[0152] Any suitable route of administration may be used, e.g., oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalation, buccal, intraperitoneal, rectal, intrathoracic, and intrathecal. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the treatment and the nature of the active compound used.

[0153] In certain preferred embodiments, compound is orally administered.The pharmaceutical composition of the present invention suitable for oral administration can be provided as individual units such as capsules, sachets or tablets, each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in aqueous liquid or non-aqueous liquid; or as oil-in-water liquid emulsion or water-in-oil liquid emulsion, or packed into liposome, and as a bolus, etc.Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the compound absorption rate.

[0154] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with an appropriate binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored and can be formulated to achieve slow or controlled release of the active ingredient therein. Methods for formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those described herein and other compounds known in the art, are known in the art and are described in several issued U.S. patents, some of which include, but are not limited to, U.S. Pat. Nos. 4,369,172 and 4,842,866, and the references cited therein. Coatings can be used for intestinal compound delivery (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is in the form of enteric-coated pellets, the enteric layer of which comprises hydroxypropylmethylcellulose acetate succinate.

[0155] For oral use tablets, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspension is administered orally, active ingredient is combined with emulsifying and suspending agent.If necessary, certain sweeteners and / or flavors and / or coloring agents can be added.

[0156] Compositions suitable for topical administration include lozenges, which comprise the ingredient in a flavored base, usually sucrose and gum arabic or tragacanth; and pastilles, which comprise the active ingredient in an inert base such as gelatin and glycerin, or sucrose and gum arabic.

[0157] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents.The preparations may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0158] Such injection solutions may be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injections, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0159] The compounds of the present invention may also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes may be used. The composition in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, etc. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0160] The pharmaceutical composition of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compound of this invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0161] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0162] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topical-transdermal patches and iontophoretic administration are also encompassed by this invention.

[0163] The therapeutic methods disclosed herein may be used in combination with or in addition to other treatments. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy.

[0164] Exemplary additional therapeutically active agents include, but are not limited to, drug compounds, small organic molecules such as, for example, compounds approved by the U.S. Food and Drug Administration (FDA) as set forth in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0165] In certain embodiments, compounds of the invention may be administered in combination with endocrine therapy, for example, agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0166] In some embodiments, the compounds of the invention may be administered in combination with chemotherapeutic agents such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, or vinorelbine. In other embodiments, the compounds of the invention may be administered in combination with anti-HER2 agents such as trastuzumab or pertuzumab.

[0167] In certain embodiments, the methods disclosed herein are combined with one or more of immune checkpoint blockade, simultaneous T cell signaling, and tumor-targeted antibody therapy.

[0168] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0169] In certain embodiments, the method further comprises administering radiation therapy to the subject. In certain embodiments, the method further comprises administering targeted therapy to the subject. In certain embodiments, the method further comprises administering immunotherapy to the subject. In certain embodiments, the method further comprises administering hormone therapy to the subject.

[0170] As used herein, the term "chemotherapeutic agent" means a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), and rituximab (TYKERB®, GSK572016, GlaxoSmithKline). Kline], lonafarnib (SCH66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib [IRESSA®, AstraZeneca], alkylating agents such as AG1478, AG1571 (SU 5271; Sugen), thiotepa and CYTOXAN® cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine (t ethylenimines and methylamelamines, including methyltrimethylomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatins; kallistatins; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1);spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; enediyne antibiotics [e.g., calicheamicin, particularly calicheamicin gamma II and calicheamicin omega II (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores], aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilins, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomol Antibiotics such as folino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin, epirubicin, esonibicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamniprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calucelone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid ; Eniluracil; Amsacrine; Bestravsil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diazicon; Elformitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraeline; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS) Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor Free), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France);Examples of anti-inflammatory drugs include chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®), ibandronate, CPT-11, the topoisomerase inhibitor RFS2000, difluoromethylomithine (DMFO), retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0171] Examples of alternative (or additional) agents or treatments include immunotherapy (e.g., PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonists, cell signaling inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, etc.), mitotic inhibitors (e.g., paclitaxel, vincristine, etc.), and / or anti-cancer drugs (e.g., rituximab ... The therapeutic agents may include, but are not limited to, cyclosporine, vinblastine, etc.), alkylating agents (e.g., cisplatin, cyclophosphamide, chlorambucil, carmustine, etc.), antimetabolites (e.g., methotrexate, 5-FU, etc.), intercalating anticancer agents (e.g., actinomycin, anthracyclines, bleomycin, mitomycin-C, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide, etc.), immunotherapeutic agents (e.g., interleukins, interferons, etc.), and antihormonal agents (e.g., tamoxifen, raloxifene, etc.).

[0172] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds as being within its scope, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers and mixtures thereof are intended to be included in this invention.

[0173] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, when only two isomers are combined, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present invention. Those skilled in the art will readily understand that similar ratios are contemplated for more complex isomer mixtures.

[0174] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomer.

[0175] Isotopically labeled compounds are also within the scope of the present disclosure.As used herein, " isotopically labeled compounds " refers to the compounds disclosed herein, including pharmaceutical salts and prodrugs thereof, each of which is described herein, in which one or more atoms are replaced with atoms having atomic masses or mass numbers different from the atomic masses or mass numbers that are normally found in nature.The examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Contains Cl.

[0176] By isotopically labeling the compounds disclosed herein, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred due to their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can afford certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. The isotopically labeled compounds disclosed herein, including pharmaceutical salts, esters, and prodrugs thereof, may be prepared by any means known in the art.

[0177] Furthermore, the normally abundant hydrogen ( 1 Substitution of heavier isotopes, such as deuterium (H), can provide certain therapeutic advantages, for example, due to improved absorption, distribution, metabolism, and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. 12 C 13It may also benefit from substitution by C. (See WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431.)

[0178] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed herein, as well as racemic, diastereomeric and other mixtures of such isomers, are within the scope of this disclosure.

[0179] After their preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 95% or more by weight of the compound ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the present invention are greater than 99% pure.

[0180] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0181] Any suitable route of administration may be used, e.g., parenteral, intravenous, subcutaneous, intramuscular, intracerebroventricular, internal, intraperitoneal, rectal, or oral administration. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the treatment and the nature of the active compound used.

[0182] Compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0183] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0184] The compounds of the present invention may also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes may be used. The composition in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, etc. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0185] The total daily dose of the compositions of the invention administered to a human or other mammalian host in single or divided doses may be, for example, in an amount of 0.0001 to 300 mg / kg body weight, more usually 1 to 300 mg / kg body weight per day. A dose of 0.0001 to 300 mg / kg body weight may also be given twice daily.

[0186] The materials, compositions, and components disclosed herein can be used for, with, in preparation for, or are products of the disclosed methods and compositions. When combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that although specific reference to various individual and collective combinations and permutations of each of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, when a method is disclosed and described, and several modifications that can be made to several molecules included in the method are discussed, unless specifically indicated to the contrary, any and all combinations and permutations of the method and possible modifications are specifically contemplated. Similarly, any subset or combination of these is specifically contemplated and disclosed. This concept applies to all aspects of this disclosure, including, but not limited to, steps in methods using the disclosed compositions. Thus, when there are various additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method step or combination of method steps of the disclosed method, and each such combination or subset of combinations should be considered specifically contemplated and disclosed. [Example]

[0187] The following examples are given for the purpose of illustrating the present invention, and are not intended to limit the scope or spirit of the present invention.

[0188] The compounds of the present invention, including those specifically disclosed hereinabove and hereinafter, can be prepared as described in the following schemes. Although the present invention has been described in detail using preferred embodiments, those skilled in the art should understand that the modifications, variations and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.

[0189] Table 1. Exemplary Compounds [Table 1] TIFF2025526508000055.tif243127 TIFF2025526508000056.tif247127 TIFF2025526508000057.tif253127 TIFF2025526508000058.tif250125 TIFF2025526508000059.tif255125 TIFF2025526508000060.tif17182 TIFF2025526508000061.tif255124 TIFF2025526508000062.tif255125 TIFF2025526508000063.tif255123 TIFF2025526508000064.tif229127 TIFF2025526508000065.tif193127

[0190] Representative synthesis procedure List of abbreviations [Table 2] TIFF2025526508000067.tif255133 TIFF2025526508000068.tif255133 TIFF2025526508000069.tif255133 TIFF2025526508000070.tif255133 TIFF2025526508000071.tif11138

[0191] Common LC-MS methods: Shimadzu LCMS2020, reversed-phase column (Shim-Pack Scepter C18, 33 × 3.0 mm, 3 μm), A: HO / MeCN / FA = 90 / 10 / 0.05; B: elution with MeCN; detection: MS, ELS, UV (100 μL split to MS with in-line UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray-atmospheric pressure ionization.

[0192] General HPLC purification method: Apparatus: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281. Column: YMC-Triart C18, 250 x 20 mm, 5 µm; Welch Ultimate XB-C18, 250 x 21.2 mm, 5 µm. Detection wavelength: 220, 254 nM. Flow rate: 15 ml / min - 20 ml / min; Run time: 8 min; Column temperature: 25°C.

[0193] General synthetic route I [ka]

[0194] General synthetic route II [ka]

[0195] [Example 1] N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized by general synthetic route I. [ka]

[0196] Step A: To a solution of 6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (4.3 g, 22.0 mmol, 1.0 equiv.) in DCE (137 mL) and TFA (27 mL), NBS (4.7 g, 26.4 mmol, 1.2 equiv.), palladium(II) acetate (0.495 g, 2.2 mmol, 0.1 equiv.), and 4-chloro-2-(trifluoromethyl)aniline (TDG) (0.862 g, 4.4 mmol, 0.2 equiv.) were added. The reaction mixture was then stirred at 60 °C for 12 h. Water (50 mL) was added to the mixture, which was then extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated to give a residue. The residue was triturated with petroleum ether / EtOAc=3 / 1 and filtered to give 4-bromo-6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (4.4 g, 73%). 1 H NMR (400 MHz, CDCl3): δ 10.12 (s, 1H), 7.50 (s, 1H), 6.28 (s, 2H).

[0197] Step B: To a solution of 4-bromo-6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (2.4 g, 8.8 mmol, 1.0 equiv.) in THF (40.0 mL) was added (2-chloro-5-fluorophenyl)magnesium bromide (26.2 mL, 13.1 mmol, 0.5 M, 1.5 equiv.) dropwise at −78 °C under a N atmosphere. The reaction mixture was then stirred at room temperature for 30 min. Water (30 mL) was added to the mixture, which was then extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (10 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / EtOAc=15 / 1) to give (4-bromo-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanol (2.0 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 7.50-7.47 (m, 2H), 7.25-7.20 (m, 1H), 7.15-7.11 (m, 1H), 6.62 (d, J = 14.8 Hz, 1H), 6.29 (d, J = 4.4 Hz, 2H), 6.18 (d, J = 5.6 Hz, 1H).

[0198] Step C: To a solution of (4-bromo-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanol (2.0 g, 4.9 mmol, 1.0 equiv.) in DCM (40 mL) was added Dess-Martin (2.5 g, 5.88 mmol, 1.2 equiv.) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. Water (40 mL) was added to the mixture, and the mixture was extracted with DCM (40 mL × 3). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 15 / 1) to give the product (4-bromo-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanone (1.2 g, 60%). 1 H NMR (400 MHz, CDCl3): δ 7.69-7.67 (m, 2H), 7.44-7.41 (m, 1H), 7.24-7.19 (m, 1H), 6.29 (s, 2H).

[0199] Step D: To a solution of (4-bromo-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanone (270 mg, 0.67 mmol, 1.0 equiv.) in N,N-dimethylacetamide (4 mL) was added Zn(CN) (79 mg, 0.67 mmol, 1.0 equiv.) and Pd(PPh) (231 mg, 0.2 mmol, 0.3 equiv.). The reaction mixture was then stirred at 160 °C for 20 min using a microwave. Water (5 mL) was added to the mixture, which was then extracted with EtOAc (5 mL × 3). The combined organic phase was washed with brine (5 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluting with petroleum ether / EtOAc=5:1) to give 5-(2-chloro-5-fluorobenzoyl)-6-nitrobenzo[d][1,3]dioxole-4-carbonitrile (100 mg, 43%). 1 H NMR (300 MHz, CDCl3): δ 7.78 (s, 1H), 7.73-7.70 (m, 1H), 7.44-7.41 (m, 1H), 6.41 (s, 2H).

[0200] Step E: To a solution of 5-(2-chloro-5-fluorobenzoyl)-6-nitrobenzo[d][1,3]dioxole-4-carbonitrile (100 mg, 0.29 mmol, 1.0 equiv.) in can (5 mL) and HO (0.5 mL) was added KOH (5.0 mg, 0.086 mmol, 0.3 equiv.). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was dried over NaSO and concentrated to give the crude product. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / EtOAc = 15 / 1) to give 6-(2-chloro-5-fluorophenyl)-6-hydroxy-5-nitro-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (50 mg, 48%), confirmed by LCMS. LCMS: m / z 365.0 ([M-H] - ).

[0201] Step F: To a solution of 6-(2-chloro-5-fluorophenyl)-6-hydroxy-5-nitro-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (100 mg, 0.273 mmol, 1.0 equiv.) in TFA (4 mL), triethylsilane (127 mg, 1.1 mmol, 4.0 equiv.) was added. The reaction mixture was then stirred at 100° C. for 4 hours. The mixture was concentrated to give the crude product. The residue was triturated with DCM / MeOH=10 / 1 and filtered to give 6-(2-chloro-5-fluorophenyl)-5-nitro-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (50 mg, 25%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.93 (m, 1H), 7.56 (s, 1H), 7.23-7.17 (m, 1H), 6.61-6.45 (m, 4H). LCMS: m / z 351.0 ([M+H] + ).

[0202] Step G: To a solution of 6-(2-chloro-5-fluorophenyl)-5-nitro-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (12 mg, 0.034 mmol, 1.0 equiv) in EtOH (0.5 mL) was added Fe (9 mg, 0.17 mmol, 5.0 equiv). The reaction was heated to 45 °C, and NH Cl (1 mg, 0.017 mmol, 0.5 equiv) and HO (0.2 mL) were added. The reaction mixture was then stirred at 90 °C for 12 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (7 mg, 63.6%). LCMS: m / z 321.0 ([M+H] + ).

[0203] Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (7 mg, 0.022 mmol, 1.0 equiv.) in ACN (0.5 mL) was added pyridine (4 mg, 0.044 mmol, 2.0 equiv.) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (4 mg, 0.018 mmol, 0.8 equiv.). The reaction mixture was then stirred at room temperature for 2 hours. Water (0.5 mL) was added to the mixture, which was then extracted with EtOAc (1 mL × 3). The combined organic phase was washed with brine (1.0 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative TLC (EtOAc) to give the final N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.5 mg, 23%). LCMS: m / z 509.0 ([M+H]). + . 1 H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.00 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.77-7.64 (m, 2H), 7.30-7.27 (m, 1H), 7.10-7.04 (m, 2H), 6.27 (d, J = 14.8 Hz, 2H), 5.91-5.89 (m, 1H).

[0204] [Example 2] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3,6,7,8,9-hexahydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0205] To a solution of N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-1-oxo-2,3,6,7,8,9-hexahydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 0.02 mmol, 1.0 equiv) in TFA (0.5 mL) was added EtSiH (11.6 mg, 0.1 mmol, 5.0 equiv). The reaction mixture was heated to reflux and stirred for 5 h. The reaction mixture was then purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3,6,7,8,9-hexahydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.0 mg, 19.2%). LCMS: m / z 519.0 ([MH] - ). 1 H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.39-7.33 (m, 2H), 7.04-7.00 (m, 1H),6.70 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 6.10 (s, 1H), 5.35 (s, 1H), 3.35 (s, 2H), 2.89 (s, 2H), 1.87 (m, 4H).

[0206] [Example 3] N-(7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized by general route I: [ka] Example 3 LCMS: m / z 525.0 ([M+H] + ). 1H NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.82 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.70-7.63 (m, 2H), 7.30-7.26 (q, J1= 8.7, J2=5.1, 1H), 7.10-7.04 (m, 1H), 5.83 (s, 1H), 4.37 (t, J = 3.6 Hz, 4H).

[0207] [Example 4] N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide [ka]

[0208] Step A: To a solution of 8 (50 mg, 0.16 mmol, 1.0 equiv.) in THF (1 mL) was added triphosgene (47 mg, 0.16 mmol, 1.0 equiv.) and DIEA (20 mg, 0.16 mmol, 1.0 equiv.) under a N2 atmosphere at 0 °C. The reaction mixture was then stirred at 0 °C for 30 min. After adding a solution of 5-fluoro-3-(trifluoromethyl)indolin-3-ol (69 mg, 0.32 mmol, 2.0 equiv.) in pyridine (0.2 mL), the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (2 mL). The mixture was extracted with EtOAc (2 mL × 3). The combined organic layers were washed with brine (2 mL), dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide (32.3 mg, 37%). LCMS: m / z 568.0 ([M+H] + ). 1H NMR (300 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.44 (d, J = 17.4 Hz, 1H), 7.90-7.76 (m, 1H), 7.39-7.01 (m, 5H), 6.97 (d, J = 25.2 Hz, 1H), 6.66 (brs, 1H), 6.24 (d, J = 10.5 Hz, 2H), 5.98-5.92 (m, 1H), 4.13-3.89 (m, 1H), 3.56-3.50 (m, 1H).

[0209] Example 4 was separated into Examples 6, 7, 8 and 9 by the following chiral preparative SFC separation method: Equipment: Waters 150 preparative SFC (SFC-26) Column: (S,S)Whelk O1, 250 x 30 mm ID, 10 μm Mobile phase: A is CO2 and B is ethanol Concentration gradient: B40% Flow rate: 80mL / min Back pressure: 100bar Column temperature: 38℃ Wavelength: 220nm Cycle time: Approximately 25 minutes Sample preparation: Compounds were dissolved in approximately 9 ml of methanol / DCM. Injection: 3ml each injection. Work-up: After separation, the fractions were evaporated to dryness using a rotary evaporator at a bath temperature of 40°C to give P3 and P4, and then the mixture of P1 and P2 was further separated by the following method. Equipment: Waters 150 preparative SFC (SFC-26) Column: ChiralPak AD, 250×30mm ID, 10μm Mobile phase: A is CO2 and B is ethanol Concentration gradient: B35% Flow rate: 80mL / min Back pressure: 100bar Column temperature: 38℃ Wavelength: 220nm Cycle time: Approximately 6 minutes Sample preparation: Compounds were dissolved in approximately 32 ml of methanol / DCM. Injection: 4ml each injection. Work-up: After separation, the fractions were evaporated to dryness by rotary evaporation at a bath temperature of 40° C. to give P1 and P2.

[0210] [ka] P1 Example 6 1 H NMR (400 MHz, CD3OD) δ 7.82 (dd, J = 9.0, 4.5 Hz, 1H), 7.28 (dd, J = 9.0, 5.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15-7.05 (m, 1H), 7.02 - 6.89 (m, 2H), 6.65 (br, 1H), 6.30-6.10 (m, 3H), 4.20 (d, J = 11.8 Hz, 1H), 3.60-3.40 (m, 1H).

[0211] [ka] P2 Example 7 1 H NMR (400 MHz, CD3OD) δ 7.98-7.80 (m, 1H), 7.28 (dd, J = 8.8, 5.0 Hz, 1H), 7.22 - 7.05 (m, 2H), 6.99 (td, J = 8.4, 3.0 Hz, 1H), 6.91 (s, 1H), 6.65 (br, 1H), 6.30 - 6.10 (m, 3H), 3.90 (d, J = 11.4 Hz, 1H), 3.69 - 3.72 (m, 1H).

[0212] [ka] P3 Example 8 1H NMR (400 MHz, CD3OD) δ 7.82 (dd, J = 9.0, 4.5 Hz, 1H), 7.28 (dd, J = 9.0, 5.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15-7.05 (m, 1H), 7.02 - 6.89 (m, 2H), 6.65 (br, 1H), 6.30 - 6.10 (m, 3H), 4.20 (d, J = 11.8 Hz, 1H), 3.60-3.40 (m, 1H).

[0213] [ka] P4 Example 9 1 H NMR (400 MHz, CD3OD) δ 7.98-7.80 (m, 1H), 7.28 (dd, J = 8.8, 5.0 Hz, 1H), 7.22 - 7.05 (m, 2H), 6.99 (td, J = 8.4, 3.0 Hz, 1H), 6.91 (s, 1H), 6.65 (br, 1H), 6.30 - 6.10 (m, 3H), 3.90 (d, J = 11.4 Hz, 1H), 3.69 - 3.72 (m, 1H).

[0214] [Example 5] N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)benzo[d]isothiazole-3-carboxamide was synthesized from the intermediate 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one by general route II: [ka]

[0215] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (50 mg, 0.16 mmol, 1.0 equiv.) in DCM (2 mL) was added benzo[d]isothiazole-3-carbonyl chloride (62 mg, crude) and DIEA (101 mg, 0.780 mmol, 5.0 equiv.) dropwise at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. Water (2 mL) was added to the mixture, which was then extracted with DCM (2 mL × 3). The combined organic phase was washed with brine (2 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative HPLC to give N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)benzo[d]isothiazole-3-carboxamide (5.2 mg, 3.5%). LCMS: m / z 482.0 ([M+H] + ). 1 HNMR (300 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.99 (s, 1H), 8.60 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.70-7.56 (m, 2H), 7.21-7.17 (m, 2H), 7.00-6.93 (m, 1H), 6.26 (d, J = 9.0 Hz, 2H), 6.07 (s, 1H).

[0216] [Example 11] (S)—N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)benzo[d]isothiazole-3-carboxamide and Example 12 (R)—N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)benzo[d]isothiazole-3-carboxamide were isolated from Example 5 using the following preparative SFC method: [ka]

[0217] Equipment: MGII preparative SFC (SFC-14) Column: ChiralCel OD, 250 x 30 mm ID, 10 μm Mobile phase: A is CO2 and B is ethanol Concentration gradient: B30% Flow rate: 80mL / min Back pressure: 100bar Column temperature: 38℃ Wavelength: 220nm Cycle time: Approximately 5.5 minutes Sample preparation: Compounds were dissolved in approximately 120 ml of methanol / DCM. Injection: 4ml each injection. Work-up: After separation, the fractions were evaporated to dryness on a rotary evaporator at a bath temperature of 40° C. to give the desired isomers.

[0218] [Example 10] 3-Chloro-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide was synthesized from the intermediate 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one via general synthetic route II. [ka]

[0219] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (30 mg, 0.10 mmol, 1.0 equiv.) in DCM (1.0 mL) was added 3-chloro-5-fluorobenzoyl chloride (36 mg, 0.20 mmol, 2.0 equiv.) and DIEA (60 mg, 0.50 mmol, 5.0 equiv.) at room temperature. The mixture was then stirred at the same temperature for 2 hours. Water (2 mL) was added to the mixture, and the mixture was extracted with DCM (2 mL × 3). The combined organic phases were washed with brine (2 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative HPLC (35% to 47% acetonitrile in water with 0.1% FA) to give 2.2 mg, 5% yield as a white solid. LCMS: m / z 476.9 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6): δ ppm 10.08 (s, 1H), 9.10 (brs, 1H), 7.73 - 7.60 (m, 1H), 7.55 - 7.28 (m, 3H), 7.20 - 7.09 (m, 1H), 7.04 (s, 1H), 6.90 - 6.50 (m, 1H), 6.36 - 6.15 (m, 2H), 6.05 - 5.80 (m, 1H).

[0220] [Example 13] (S)—N-(7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)benzo[d]isothiazole-3-carboxamide and Example 14 (R)—N-(7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)benzo[d]isothiazole-3-carboxamide were synthesized from the intermediate 6-amino-7-(2-chloro-5-fluorophenyl)-2,3,7,8-tetrahydro-9H-[1,4]dioxino[2,3-e]isoindol-9-one via general synthetic route II. [ka]

[0221] Step A: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-3,7,8,9-tetrahydro-2H-[1,4]dioxino[3,2-e]isoindol-9-one (102 mg, 0.304 mmol) and TEA (92.2 mg, 0.911 mmol) in DCM (2 mL) was added benzo[d][1,2]thiazole-3-carbonyl chloride (60 mg, 0.304 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by preparative HPLC to give N-[7-(2-chloro-5-fluorophenyl)-9-oxo-3,7,8,9-tetrahydro-2H-[1,4]dioxino[3,2-e]isoindol-6-yl]benzo[d][1,2]thiazole-3-carboxamide (25 mg, 50 μmol, 16.6%) as a white solid. The solid was separated by preparative SFC to give P1 Example 13 (S)—N-((S)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide (2.2 mg) as a pale solid. LCMS: ESI m / z 496 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.81 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.31 - 7.09 (m, 3H), 6.97 (t, J = 7.0 Hz, 1H), 6.66 (s, 1H), 6.01 (s, 1H), 4.36 (s, 4H). and P2 Example 14 (R)—N-(7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)benzo[d]isothiazole-3-carboxamide (2.0 mg) was obtained as a pale solid. LCMS: ESI m / z 496 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.81 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.31 - 7.09 (m, 3H), 6.97 (t, J = 7.0 Hz, 1H), 6.66 (s, 1H), 6.01 (s, 1H), 4.36 (s, 4H).

[0222] Preparative SFC separation method: Equipment: Waters Thar 80 preparative SFC Column: ChiralPak IB, 250 x 21.2 mm ID, 5 μm Mobile phase: A is CO2 and B is ETOH + 0.1% NH3H2O Concentration gradient: B40% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 20 minutes Dissolution time: 2 hours

[0223] [Example 15] (R * )-N-((S)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide and Example 16 (R * )-N-((R)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide [ka]

[0224] Step A: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-2,3,7,8-tetrahydro-9H-[1,4]dioxino[2,3-e]isoindol-9-one (25 mg, 0.075 mmol, 1.0 equiv.) in anhydrous THF (0.5 mL) was added DIEA (9.7 mg, 0.075 mmol, 1.0 equiv.). The mixture was stirred and cooled to 0° C. A solution of triphosgene (22.4 mg, 0.076 mmol, 1.01 equiv.) in anhydrous THF (0.5 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 hours. The solution was then added to a solution of (S)-5-fluoro-3-(trifluoromethyl)indolin-3-ol (33.1 mg, 0.15 mmol, 2.0 equiv.) in pyridine (0.5 mL) and DMAP (catalytic amount). The resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with aqueous NH4Cl (10 mL) and extracted with DCM (10 mL x 3). The organic layer was washed with brine (5 mL x 3), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give a mixture (13 mg). The mixture was then separated by chiral separation to give P1 Example 15 (R *)-N-((S)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide (2.9 mg, white solid, 7% yield). LCMS: m / z 582.0 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.77 (brs, 1H), 8.36 (s, 1H), 7.78 (dd, J = 8.8, 4.4 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J = 8.8, 5.2 Hz, 1H), 7.27 - 7.14 (m, 2H), 7.14 - 7.02 (m, 1H), 6.94 (s, 1H), 5.91 (brs, 1H), 4.60 - 4.22 (m, 4H), 4.11 (d, J = 12.0 Hz, 1H), 3.51 (d, J = 11.6 Hz, 1H). and P2 Example 16 (R * )-N-((R)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide (3.5 mg, white solid, 8% yield). LCMS: m / z 582.0 ([M+H] - ). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.75 (brs, 1H), 8.42 (s, 1H), 8.00 - 7.80 (m, 1H), 7.35 (s, 1H), 7.34 - 7.00 (m, 5H), 6.86 (s, 1H), 5.86 (brs, 1H), 4.60 - 4.24 (m, 4H), 3.91 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 11.6 Hz, 1H).

[0225] [Example 17] N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized using general synthetic route I. [ka]

[0226] Step A: To a solution of 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde (10.0 g, 53.7 mmol, 1.0 equiv) in HSO (50 mL) was added HNO (5 mL) dropwise at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 2 h. The mixture was poured into ice water (500 mL) and extracted with DCM (250 mL × 3). The combined organic phases were washed with brine (250 mL), dried over NaSO, and concentrated to give 2,2-difluoro-6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (11.0 g, 89%) as a yellow liquid. 1 H NMR (300 MHz, CDCl3): δ ppm 10.35 (s, 1H), 7.87 (s, 3H), 7.67 (s, 1H).

[0227] Step B: To a solution of 2,2-difluoro-6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (5.0 g, 21.6 mmol, 1.0 equiv.) in HSO (50 mL) was added NBS (5.8 g, 32.4 mmol, 1.5 equiv.) portionwise at 0 °C. The mixture was then stirred at room temperature for 12 h. The mixture was poured into ice-water (200 mL) and extracted with DCM (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative HPLC (55% to 60% acetonitrile in water with 0.1% FA) to give 4-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (1.0 g, 14.9%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ ppm 10.17 (s, 1H), 7.84 (s, 1H).

[0228] Step C: To a solution of 4-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (1.0 g, 3.2 mmol, 1.0 equiv.) in THF (10 mL) was added the magnesium reagent (2-chloro-5-fluorophenyl)magnesium bromide (9.6 mL, 4.8 mmol, 1.5 equiv., 0.5 M) under a N atmosphere at −78 °C. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL), and the mixture was extracted with EtOAc (20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated to give (4-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanol (1.6 g, crude) as a yellow liquid. LCMS: m / z 437.9 ([M-H] - ). 1 H NMR (400 MHz, CDCl3): δ ppm 7.38 (s, 1H), 7.34 - 7.22 (m, 2H), 7.12 - 6.90 (m, 1H), 6.42 (s, 1H), 3.37 (brs, 1H).

[0229] Step D: To a solution of (4-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanol (1.6 g, 3.6 mmol, 1.0 equiv., crude) in DCM (20 mL) was added Dess-Martin (1.8 g, 4.3 mmol, 1.2 equiv.). The reaction mixture was then stirred at room temperature for 2 hours. Water (50 mL) was added to the mixture, which was then extracted with DCM (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5:1) to give (4-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanone (1.0 g, 70.7% yield over two steps) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ ppm 7.99 (s, 1H), 7.75 (dd, J = 8.8, 3.2 Hz, 1H), 7.52 - 7.40 (m, 1H), 7.35 - 7.22 (m, 1H).

[0230] Step E: To a solution of (4-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanone (250 mg, 0.57 mmol, 1.0 equiv) in EtOH (5.0 mL) was added Fe (159 mg, 2.85 mmol, 5.0 equiv). The reaction mixture was heated to 65 °C, and then a solution of NH Cl (15 mg, 0.9 mmol, 0.5 equiv) in HO (1.5 mL) was added. The reaction mixture was then heated to reflux and stirred for 2 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give the crude product. The residue was purified by preparative TLC (petroleum ether / EtOAc = 3:1) to give (6-amino-4-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanone (230 mg, 98.7%) as a yellow solid. LCMS: m / z 407.9, 409.9 ([M+H] + ).

[0231] Step F: To a solution of (6-amino-4-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanone (230 mg, 0.56 mmol, 1.0 equiv.) in DMAc (5 mL) was added Zn(CN) (79 mg, 0.67 mmol, 1.2 equiv.) and Pd(PPh) (195 mg, 0.17 mmol, 0.3 equiv.). The reaction mixture was then stirred in a microwave at 160 °C for 30 min. Water (20 mL) was added to the mixture, which was then extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=3:1) to give 6-amino-5-(2-chloro-5-fluorobenzoyl)-2,2-difluorobenzo[d][1,3]dioxole-4-carbonitrile (110 mg, 55.0%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.17 (s, 2H), 7.65 - 7.57 (m, 1H), 7.52 - 7.38 (m, 2H), 7.18 (s, 1H).

[0232] Step G: To a solution of 6-amino-5-(2-chloro-5-fluorobenzoyl)-2,2-difluorobenzo[d][1,3]dioxole-4-carbonitrile (110 mg, 0.31 mmol, 1.0 equiv.) in ACN (1.0 mL) and HO (0.1 mL) was added KOH (5 mg, 0.093 mmol, 0.3 equiv.) at room temperature. The reaction mixture was then stirred at the same temperature for 2 hours. The mixture was dried over NaSO and concentrated to give a residue. The residue was purified by preparative TLC (petroleum ether / EtOAc = 2:1) to give 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6-hydroxy-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (80 mg, 69.2%) as a yellow solid. LCMS: m / z 371.0 ([M-H] - ).

[0233] Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6-hydroxy-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (80 mg, 0.22 mmol, 1.0 equiv.) in ACN (1.0 mL) was added acyl chloride (49 mg, 0.22 mmol, 1.0 equiv.) and pyridine (34 mg, 0.44 mmol, 2.0 equiv.). The reaction mixture was then stirred at 50° C. for 12 hours. Water (5 mL) was added to the mixture, which was then extracted with EtOAc (5 mL×3). The combined organic phases were washed with brine (5 mL), dried over NaSO, and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6-hydroxy-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (160 mg, crude) as a yellow solid. LCMS: m / z 560.9 ([M-H] - ).

[0234] Step I: To a solution of N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6-hydroxy-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (160 mg, 0.28 mmol, 1.0 equiv., crude) in TFA (2.0 mL) was added triethylsilane (132 mg, 1.14 mmol, 4.0 equiv.). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (45% to 64% acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (18 mg, 15.3% yield over two steps) as a white solid. LCMS: m / z 547.0 ([M+H] + ). 1H NMR (300 MHz, DMSO-d6): δ ppm 10.48 (brs, 1H), 9.38 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.83 - 7.50 (m, 3H), 7.40 - 7.20 (m, 1H), 7.20 - 7.00 (m, 2H), 6.03 (s, 1H).

[0235] [Example 18] N-(6-(2-chloro-5-fluorophenyl)-2,8-dioxo-1,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized from the intermediate 6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde via general synthetic route I. [ka]

[0236] Step A: To a solution of 4-hydroxy-3-nitrobenzaldehyde (45.0 g, 269.3 mmol, 1.0 equiv) and propane-1,3-diol (30.7 g, 403.9 mmol, 1.5 equiv) in toluene (500 mL) was added p-TsOH (5.1 g, 26.9 mmol, 0.1 equiv) at 25 °C. The reaction mixture was heated to reflux for 16 h. The mixture was concentrated, water (300 mL) was added, and the mixture was extracted with EtOAc (200 mL × 2). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether: EtOAc = 5:1) to give 4-(1,3-dioxan-2-yl)-2-nitrophenol (42 g, 69.3%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 10.58 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.8, 2.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 5.46 (s, 1H), 4.37 - 4.10 (m, 2H), 4.09 - 3.70 (m, 2H), 2.30 - 2.10 (m, 1H), 1.57 - 1.40 (m, 1H). LCMS: m / z 224.1 ([MH] - ).

[0237] Step B: To a solution of 4-(1,3-dioxan-2-yl)-2-nitrophenol (40.0 g, 177.6 mmol, 1.0 equiv) in THF (500 mL) under an atmosphere of H was added dropwise a solution of nickel (15 g) at 25 °C. The reaction mixture was stirred at 40 °C for 48 h. The mixture was then filtered and concentrated to give 2-amino-4-(1,3-dioxan-2-yl)phenol (33 g, 95.2%) as a black solid. LCMS: m / z 196.1 ([M+H] + ).

[0238] Step C: To a solution of 2-amino-4-(1,3-dioxan-2-yl)phenol (26.0 g, 133.2 mmol, 1.0 equiv) and TEA (29.6 g, 293.0 mmol, 2.2 equiv) in DCM (500 mL) was added triphosgene (51.4 g, 173.1 mmol, 1.3 equiv) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and then the mixture was stirred at room temperature for 1 h. Water (300 mL) was added to the mixture, which was then extracted with DCM (200 mL × 2). The combined organic phase was washed with brine (300 mL), dried over Na SO , and concentrated to give a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether: EtOAc = 2:1) to give 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (11.2 g, 51.5%) as a white solid. LCMS: m / z 162.1 ([M-H] - ).

[0239] Step D: To a solution of 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (11.2 g, 68.6 mmol, 1.0 equiv) in HSO (98%, 120 mL) at 0 °C was added HNO (5.2 g, 82.4 mmol, 1.2 equiv) dropwise. The reaction mixture was stirred at room temperature for 3 h. The product was then precipitated by pouring the solution onto ice water (600 mL) and collected by vacuum filtration to give 6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (10.0 g, 70.0%) as a red solid. 1 H NMR (300 MHz, DMSO-d6): δ 12.83 (brs, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 7.76 (s, 1H). LCMS: m / z 207.1 ([MH] - ).

[0240] Step E: To a solution of 6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (10.0 g, 48.0 mmol, 1.0 equiv) in HSO (110 mL) at 0 °C was added NBS (12.8 g, 72.1 mmol, 1.5 equiv). The reaction mixture was stirred at 40 °C for 5 h. The product was then precipitated by pouring the solution onto ice water (400 mL) and collected by vacuum filtration to give 4-bromo-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (8.6 g, 62.4%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.24 (s, 1H). LCMS: m / z 284.9, 286.9 ([MH] - ).

[0241] Step F: To a solution of 4-bromo-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (5.5 g, 19.2 mmol, 1.0 equiv.) in THF (70 mL) was added Intermediate A (2-chloro-5-fluorophenyl)magnesium bromide (191.6 mL, 0.5 M in THF, 95.8 mmol, 5.0 equiv.) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Water (200 mL) was then added to the mixture, which was then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc = 1:1) to give 4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-6-nitrobenzo[d]oxazol-2(3H)-one (3.2 g, 40.0%) as a yellow oil. LCMS: m / z 414.9, 416.9 ([MH] - ). 1 H NMR (300 MHz, DMSO-d6): δ 12.61 (brs, 1H), 7.92 (s, 1H), 7.50 (dd, J = 8.8, 5.2 Hz, 1H), 7.42 -7.00 (m, 2H), 6.73 (d, J = 6.0 Hz, 1H), 6.27 (d, J = 5.4 Hz, 1H).

[0242] Step G: To a solution of 4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-6-nitrobenzo[d]oxazol-2(3H)-one (3.0 g, 7.2 mmol, 1.0 equiv) and Fe (2.0 g, 35.9 mmol, 5.0 equiv) in EtOH (60 mL) at 50 °C, NH Cl (192.1 mg, 3.6 mmol, 0.5 equiv) in HO (10 mL) was added dropwise. The reaction mixture was heated to 90 °C and stirred for 1 h. Water (80 mL) and ethyl acetate (30 mL) were then added to the mixture, which was then filtered. The filtrate was then extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over NaSO, and concentrated to give 6-amino-4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)benzo[d]oxazol-2(3H)-one (2.3 g, 82.4%) as a yellow solid. LCMS: m / z 384.9, 386.9 ([M-H] - ).

[0243] Step H: To a solution of 6-amino-4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)benzo[d]oxazol-2(3H)-one (700 mg, 1.8 mmol, 1.0 equiv) in ACN (10 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (818.3 mg, 3.6 mmol, 2.0 equiv) and pyridine (428.6 mg, 5.4 mmol, 3.0 equiv). The reaction mixture was stirred at 30° C. for 2 hours. The solution was then poured onto ice water (30 mL) to precipitate the product, which was collected by vacuum filtration to give N-(4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (600 mg, 57.7%) as a yellow solid. LCMS: m / z 574.9, 576.8 ([M-H] - ).

[0244] Step I: To a solution of N-(4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (200 mg, 0.35 mmol, 1.0 equiv) in DCM (6 mL) was added DMP (440 mg, 1.05 mmol, 3.0 equiv) at 25 °C. The reaction mixture was stirred at room temperature for 2 h. Water (10 mL) was added to the mixture and extracted with DCM (10 mL × 2). The combined organic phase was washed with NaHCO (10 mL × 2), NaSO (10 mL × 2), and brine (20 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether: EtOAc = 5:1) to give N-(4-bromo-5-(2-chloro-5-fluorobenzoyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (70 mg, 34.7%) as a yellow solid. LCMS: m / z 572.8, 574.9 ([M-H] - ).

[0245] Step J: A sealed vial was charged with N-(4-bromo-5-(2-chloro-5-fluorobenzoyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.09 mmol, 1.0 equiv), Zn(CN) (15.4 mg, 0.13 mmol, 1.5 equiv), Pd(PPh) (30.0 mg, 0.03 mmol, 0.3 equiv), and DMAC (1 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. Water (3 mL) was added to the mixture, which was then extracted with EtOAc (2 mL × 2). The combined organic phase was washed with brine (3 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc 2:1) to give N-(5-(2-chloro-5-fluorobenzoyl)-4-cyano-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (40 mg, crude) as a yellow oil. LCMS: m / z 520.0 ([M-H] - ).

[0246] Step K: To a solution of N-(5-(2-chloro-5-fluorobenzoyl)-4-cyano-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (40.0 mg, 0.08 mmol, 1.0 equiv) in MeCN (1 mL) / HO (0.1 mL) at room temperature was added KOH (1.3 mg, 0.02 mmol, 0.3 equiv). The reaction mixture was stirred at 40 °C for 4 h. Water (3 mL) was added to the mixture, and it was extracted with EtOAc (3 mL × 2). The combined organic phase was washed with brine (3 mL × 2), dried over NaSO, and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxo-1,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, crude) as a yellow oil. LCMS: m / z 537.9 ([M-H] - ).

[0247] Step L: To a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxo-1,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.09 mmol, 1.0 equiv) in TFA (5 mL) was added EtSiH (104.7 mg, 0.9 mmol, 10.0 equiv). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-2,8-dioxo-1,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.8 mg, 5.9% yield over three steps) as a white solid. LCMS: m / z 522.0 ([MH] - ). 1 H NMR (400 MHz, DMSO-d6): δ 12.59 (brs, 1H), 10.35 (s, 1H), 9.18 (brs, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.86 - 7.60 (m, 2H), 7.43 (s, 1H), 7.36 - 7.22 (m, 1H), 7.15 - 7.00 (m, 1H), 6.90 - 5.80 (m, 1H).

[0248] [Example 19] N-(4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0249] Step A: To a solution of 4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-6-nitrobenzo[d]oxazol-2(3H)-one (100 mg, 0.24 mmol, 1.0 equiv) in DCM (4 mL) was added DMP (152 mg, 0.36 mmol, 1.5 equiv) at 25° C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give 4-bromo-5-(2-chloro-5-fluorobenzoyl)-6-nitrobenzo[d]oxazol-2(3H)-one (230 mg, crude) as a yellow solid.

[0250] Step B: To a solution of 4-bromo-5-(2-chloro-5-fluorobenzoyl)-6-nitrobenzo[d]oxazol-2(3H)-one (230 mg, 0.55 mmol, 1.0 equiv) and KCO (764.3 mg, 5.5 mmol, 10.0 equiv) in DMF (10 mL) was added CHI (392.5 mg, 2.9 mmol, 5.0 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. Water (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried over NaSO, and concentrated to give 4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (120 mg, crude) as a yellow oil.

[0251] Step C: To a solution of 4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (120 mg, 0.28 mmol, 1.0 equiv) and Fe (78 mg, 1.4 mmol, 5.0 equiv) in EtOH (3 mL) at 50 °C, NH Cl (7.5 mg, 0.14 mmol, 0.5 equiv) in HO (0.3 mL) was added dropwise. The reaction mixture was heated to 90 °C and stirred for 1 h. Water (3 mL) and ethyl acetate (5 mL) were then added to the mixture, which was then filtered. The filtrate was then extracted with ethyl acetate (5 mL). The combined organic phases were washed with brine (5 mL), dried over NaSO, and concentrated to give 6-amino-4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methylbenzo[d]oxazol-2(3H)-one (100 mg, crude) as a yellow solid. LCMS: m / z 398.9, 400.9 ([M+H] + ).

[0252] Step D: To a solution of 6-amino-4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methylbenzo[d]oxazol-2(3H)-one (100 mg, 0.25 mmol, 1.0 equiv.) in ACN (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (86.1 mg, 0.38 mmol, 1.5 equiv.) and pyridine (59.3 mg, 0.75 mmol, 3.0 equiv.). The reaction mixture was stirred at 50 °C for 2 hours. Water (3 mL) was then added to the mixture, which was then extracted with ethyl acetate (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over Na SO , and concentrated to give a residue. The residue was purified by preparative TLC (eluting with petroleum ether / EtOAc = 3:1) to give N-(4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 4-step yield 56.5%) as a yellow solid. LCMS: m / z 586.8, 588.9 ([M-H] - ).

[0253] Step E: A sealed vial was charged with N-(4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.1 mmol, 1.0 equiv.), Zn(CN) (18.1 mg, 0.15 mmol, 1.5 equiv.), Pd(PPh) (36.2 mg, 0.03 mmol, 0.3 equiv.), and DMAc (1.8 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. Water (3 mL) was added to the mixture, which was then extracted with EtOAc (2 mL × 2). The combined organic phase was washed with brine (3 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc 3:1) to give N-(5-(2-chloro-5-fluorobenzoyl)-4-cyano-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (18.7 mg, 34.9%) as a yellow solid. LCMS: m / z 534.0 ([M-H] - ).

[0254] Step F: To a solution of N-(5-(2-chloro-5-fluorobenzoyl)-4-cyano-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.05 mmol, 1.0 equiv.) in MeCN (1 mL) / HO (0.1 mL) at room temperature was added KOH (5.6 mg, 0.1 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 4 hours. Water (2 mL) was added to the mixture, which was then extracted with EtOAc (2 mL × 2). The combined organic phases were washed with brine (2 mL), dried over NaSO, and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-dioxo-1,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, crude) as a yellow oil. LCMS: m / z 551.9 ([M-H] - ).

[0255] Step G: To a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-dioxo-1,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.04 mmol, 1.0 equiv) in TFA (2 mL) was added EtSiH (23.2 mg, 0.2 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-dioxo-1,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (4.4 mg, 16.4% yield over two steps) as a white solid. LCMS: m / z 535.9 ([MH] - ). 1 H NMR (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 9.30 (brs, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.84 - 7.62 (m, 2H), 7.52 (s, 1H), 7.40 - 7.22 (m, 1H), 7.18 - 7.00 (m, 1H), 6.90 - 5.80 (m, 1H), 3.86 (s, 3H).

[0256] [Example 20] N-(6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3,6,7,8-tetrahydro-2H-oxazolo[5,4-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0257] Step A: To a solution of 4-amino-3-methoxybenzoic acid (50.0 g, 299.1 mmol, 1.0 equiv) in EtOAc (2000 mL) was added TFAA (50 mL, 358.92 mmol, 1.2 equiv), which was then mixed with EtOAc (500 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated to give 3-methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (82.0 g, crude) as a yellow solid. LCMS: m / z 262.1 ([M-H] - ).

[0258] Step B: To a solution of 3-methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (82.0 g, crude, 0.31 mol, 1.0 equiv) in HSO (98%, 4100 mL) at 0 °C was added a solution of HNO (27.1 g) and HSO (98%, 197 mL) dropwise. The reaction mixture was stirred at 0 °C for 10 min. The mixture was then slowly poured into ice water (7.0 L) and filtered to give 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (64.0 g, 69.5% yield over two steps) as a brown solid. LCMS: m / z 307.0 ([M-H] - ). 1 H NMR (300 MHz, DMSO-d6): δ ppm 11.13 (s, 1H), 8.27 (s, 1H), 7.46 (s, 1H), 3.99 (s, 3H).

[0259] Step C: To a solution of 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (32.0 g, 103.8 mmol, 1.0 equiv) in THF (400 mL) at 0 °C, BH3-Me2S (2 M) (155.8 mL, 311.5 mmol, 3.0 equiv) was added portionwise. The reaction mixture was stirred at room temperature for 20 h, and then the mixture was stirred at room temperature for 1 h. Water (300 mL) was added to the mixture, which was then extracted with EtOAc (200 mL × 2). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, and concentrated to give 2,2,2-trifluoro-N-(4-(hydroxymethyl)-2-methoxy-5-nitrophenyl)acetamide (25.0 g, crude) as a yellow solid. LCMS: m / z 293.0 ([M−H] - ).

[0260] Step D: To a solution of 2,2,2-trifluoro-N-(4-(hydroxymethyl)-2-methoxy-5-nitrophenyl)acetamide (15.0 g, 50.9 mmol, 1.0 equiv) in DCM (750 mL) was added DMP (32.4 g, 76.49 mmol, 1.5 equiv) at 25 °C. The reaction mixture was stirred at room temperature for 2 h. Water (300 mL) was added to the mixture, and it was extracted with EtOAc (200 mL × 2). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give 2,2,2-trifluoro-N-(4-formyl-2-methoxy-5-nitrophenyl)acetamide (11.0 g, 60.4% yield for two steps) as a yellow solid. LCMS: m / z 291.0 ([M-H] - ).

[0261] Step E: To a solution of 2,2,2-trifluoro-N-(4-(hydroxymethyl)-2-methoxy-5-nitrophenyl)acetamide (11.0 g, 37.6 mmol, 1.0 equiv) in HSO (98%, 190 mL) at 0 °C was added NBS (10.0 g, 56.4 mmol, 1.5 equiv). The reaction mixture was stirred at 25 °C for 2 h. The mixture was poured into ice water (400 mL) and filtered to give a residue which was triturated with petroleum ether / EtOAc (3:1, 60 mL) to give N-(3-bromo-4-formyl-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (12.1 g, 86.6%) as a yellow solid. LCMS: m / z 368.9, 370.9 ([MH] - ). 1 H NMR (300 MHz, DMSO-d6): δ ppm 11.62 (s, 1H), 10.18 (s, 1H), 8.47 (s, 1H), 3.86 (s, 3H).

[0262] Step F: To a solution of N-(3-bromo-4-formyl-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (12.1 g, 32.6 mmol, 1.0 equiv.) in THF (121 mL) was added Intermediate A (2-chloro-5-fluorophenyl)magnesium bromide (326.0 mL, 0.5 M in THF, 163.0 mmol, 5.0 equiv.) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Water (200 mL) was then added to the mixture, which was then extracted with EtOAc (200 mL × 2). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give N-(3-bromo-4-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (11.0 g, 67.3%) as a yellow solid. LCMS: m / z 498.9, 500.9 ([M-H] - ). 1H NMR (400 MHz, DMSO-d6): δ ppm 11.46 (s, 1H), 8.06 (s, 1H), 7.60 - 7.51 (m, 1H), 7.32 - 7.20 (m, 1H), 7.04 (dd, J = 9.6, 3.2 Hz, 1H), 6.82 (d, J = 6.0 Hz, 1H), 6.29 (d, J = 5.2 Hz, 1H), 3.76 (s, 3H).

[0263] Step G: To a solution of N-(3-bromo-4-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (11.0 g, 21.9 mmol, 1.0 equiv) in DCM (440 mL) was added DMP (13.9 g, 32.9 mmol, 1.5 equiv) at 25 °C. The reaction mixture was stirred at room temperature for 2 h. Water (200 mL) was added to the mixture and extracted with DCM (200 mL × 2). The combined organic phase was washed with aqueous NaHCO (200 mL × 2), aqueous NaSO (100 mL × 2), and brine (200 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give N-(3-bromo-4-(2-chloro-5-fluorobenzoyl)-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (6.6 g, 59.9%) as a yellow solid. LCMS: m / z 496.8, 498.8 ([M-H] - ).

[0264] Step H: To a solution of N-(3-bromo-4-(2-chloro-5-fluorobenzoyl)-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (2.0 g, 4.0 mmol, 1.0 equiv) and Fe (1.2 g, 20.0 mmol, 5.0 equiv) in EtOH (40 mL) at 50 °C, NH Cl (107.0 mg, 2.0 mmol, 0.5 equiv) in HO (20 mL) was added dropwise. The reaction mixture was heated to 90 °C and stirred for 1 h. Then, water (80 mL), EtOAc (30 mL) were added to the mixture, which was filtered. The filtrate was then extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (50 mL), dried over NaSO, and concentrated to give N-(5-amino-3-bromo-4-(2-chloro-5-fluorobenzoyl)-2-methoxyphenyl)-2,2,2-trifluoroacetamide (0.9 g, 47.9%) as a yellow solid. LCMS: m / z 466.8, 468.9 ([M-H] - ).

[0265] Step I: To a solution of N-(5-amino-3-bromo-4-(2-chloro-5-fluorobenzoyl)-2-methoxyphenyl)-2,2,2-trifluoroacetamide (900 mg, 1.9 mmol, 1.0 equiv.) in ACN (10 mL) was added Intermediate B 3-fluoro-5-(trifluoromethyl)benzoyl chloride (516.6 mg, 2.3 mmol, 1.2 equiv.) and pyridine (300.6 mg, 5.4 mmol, 2.0 equiv.). The reaction mixture was stirred at 50° C. for 1 hour. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=3:1) to give N-(3-bromo-2-(2-chloro-5-fluorobenzoyl)-4-methoxy-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluoro-5-(trifluoromethyl)benzamide (800 mg, 57.7%) as a yellow solid. LCMS: m / z 656.8, 658.9 ([M-H] - ).

[0266] Step J: A sealed vial was charged with N-(3-bromo-2-(2-chloro-5-fluorobenzoyl)-4-methoxy-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.15 mmol, 1.0 equiv), Zn(CN) (26.4 mg, 0.23 mmol, 1.5 equiv), Pd(PPh) (52.0 mg, 0.05 mmol, 0.3 equiv), and DMAc (3 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. Water (9 mL) was added to the mixture, which was then extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (4 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give N-(2-(2-chloro-5-fluorobenzoyl)-3-cyano-4-methoxy-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluoro-5-(trifluoromethyl)benzamide (47 mg, 51.2%) as a yellow solid. LCMS: m / z 603.9 ([M-H] - ).

[0267] Step K: To a solution of N-(2-(2-chloro-5-fluorobenzoyl)-3-cyano-4-methoxy-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluoro-5-(trifluoromethyl)benzamide (191 mg, 0.32 mmol, 1.0 equiv) in MeCN (12 mL) / HO (1.2 mL) at room temperature was added KOH (35.9 mg, 0.64 mmol, 2.0 equiv). The reaction mixture was stirred at 80 °C for 1 h. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (30 mL × 2), dried over NaSO, and concentrated to give N-(6-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (144 mg, 86.5%) as a brown solid. LCMS: m / z 526.0 ([M-H] - ).

[0268] Step L: To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (160 mg, 0.30 mmol, 1.0 equiv) in TFA (2 mL) was added EtSiH (174 mg, 1.5 mmol, 5.0 equiv). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was then concentrated to give a residue which was purified by preparative TLC (EtOAc) to give N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 52.1%) as a white solid. LCMS: m / z 512.0 ([M+H] + ).

[0269] Step M: To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.02 mmol, 1.0 equiv) in DCM (1 mL) under N was added BBr (7.5 mg, 0.03 mmol, 1.5 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then quenched with MeOH (0.5 mL) and concentrated to give N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, crude) as a yellow oil. LCMS: m / z 498.0 ([M+H] + ).

[0270] Step N: To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.02 mmol, 1.0 equiv) in DCM (2 mL) was added TEA (44 mg, 0.44 mmol, 2.2 equiv). To the mixture was then added triphosgene (71 mg, 0.24 mmol, 1.2 equiv) under N at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was then concentrated to give a residue that was purified by preparative HPLC (30% to 70% acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3,6,7,8-tetrahydro-2H-oxazolo[5,4-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.8 mg, 26.7% yield over two steps) as a white solid. LCMS: m / z 522.0 ([MH] - ). 1 H NMR (300 MHz, DMSO-d6): δ ppm 10.22 (s, 1H), 9.00 (s, 1H), 8.35 - 8.20 (m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.78 - 7.55 (m, 2H), 7.38 - 7.22 (m, 1H), 7.15 - 6.93 (m, 2H), 6.80 - 6.50 (m, 1H), 6.10 - 5.80 (m, 1H).

[0271] [Example 21] (R * )-N-((R)-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide

[0272] [Example 22] (R *)-N-((S)-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide [ka]

[0273] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (200 mg, 0.56 mmol, 1.0 equiv.) in THF (2 mL) was added triphosgene (168 mg, 0.56 mmol, 1.0 equiv.) and DIEA (73 mg, 0.56 mmol, 1.0 equiv.) under a N atmosphere at 0° C. The reaction mixture was then stirred at 0° C. for 30 minutes. A solution of rel-(R)-5-fluoro-3-(trifluoromethyl)indolin-3-ol (248 mg, 1.12 mmol, 2.0 equiv.) in pyridine (1.0 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (2 mL), and the mixture was extracted with EtOAc (2 mL × 3). The combined organic layers were washed with brine (2 mL), dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC (40% to 57% acetonitrile in water containing 0.1% FA) to give rel-(3R)-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide (170 mg, 50.3%) as a white solid. LCMS: m / z 602.0 ([M-H] - ). This (170 mg) was separated through chiral SFC separation to give P1 (R *)-N-((R)-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide (50.0 mg, 29.4%) was obtained as a white solid. LCMS: m / z 602.0 ([MH] - ). 1 H NMR (300 MHz, DMSO-d6): δ ppm 9.32 (s, 1H), 8.79 (s, 1H), 7.99 - 7.80 (m, 1H), 7.60 - 7.37 (m, 2H), 7.37 - 7.07 (m, 4H), 6.82 (brs, 1H), 6.06 (s, 1H), 3.91 (d, J =12.0 Hz, 1H), 3.55 (d, J = 12.0 Hz, 1H). and P2(R * )-N-((S)-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide (41.6 mg, 24.5%) was obtained as a white solid. LCMS: m / z 601.9 ([MH] - ). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.33 (s, 1H), 8.70 (s, 1H), 7.80 (dd, J = 8.8, 4.4 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.8, 4.2 Hz, 1H), 7.30 - 7.16 (m, 2H), 7.15 - 7.04 (m, 1H), 6.77 (brs, 1H), 6.12 (s, 1H), 4.20 - 4.00 (m, 1H), 3.51 (d, J = 12.0 Hz, 1H).

[0274] The preparative SFC separation is as follows: Chiral purity by SFC (area percentage) Principle normal phase HPLC (Principle NP HPLC) with UV detection, evaluated in area % MeOH: HPLC grade, J&K CO2: 99.999% Solvent: ACN Equipment: Equipment Waters SFC Column: CHIRALCEL OD-H 20mm x 250mm, 5um Chromatography conditions: Mobile phase A: CO2 Mobile phase B: MeOH Concentration gradient: B20% Flow rate: 30ml / min Injection capacity: 0.5ml Injection concentration: 20mg / ml Column temperature: 35℃ Preparative SFC cycle time: 11 minutes

[0275] Example 23 (S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide and Example 24 (R)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide [ka]

[0276] Step A: To a solution of 3-chloro-5-fluorobenzoic acid (5.0 g, 28.6 mmol, 1.0 equiv.) in THF (50 mL) was added dropwise (COCl) (10.9 g, 85.8 mmol, 3.0 equiv.) and DMF (0.1 mL) at room temperature. The reaction mixture was then stirred at the same temperature for 2 hours. The mixture was concentrated to give 3-chloro-5-fluorobenzoyl chloride (5.5 g, crude) as a yellow solid, which was used directly.

[0277] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (200 mg, 0.56 mmol, 1.0 equiv.) in ACN (2 mL) was added 3-chloro-5-fluorobenzoyl chloride (130 mg, 0.67 mmol, 1.2 equiv.) and pyridine (89 mg, 1.12 mmol, 2.0 equiv.) at room temperature. The mixture was then stirred at the same temperature for 2 hours. Water (2 mL) was added to the mixture, which was then extracted with EtOAc (2 mL × 3). The combined organic phase was washed with brine (2 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative HPLC (35% to 47% acetonitrile in water with 0.1% FA) to give 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (100.0 mg, 34.8%) as a white solid. LCMS: m / z 510.9 ([M-H] - ). This was separated by chiral SFC using the following conditions to give P1(S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (20.0 mg, 20.0%) as a white solid. LCMS: m / z 510.9 ([M-H] - ). 1H NMR (300 MHz, DMSO-d6): δ ppm 10.33 (s, 1H), 9.37 (s, 1H), 7.77 - 7.63 (m, 1H), 7.60 (s, 1H), 7.48 - 7.23 (m, 3H), 7.23 - 7.05 (m, 1H), 6.85 (brs, 1H), 6.04 (s, 1H). and P2 CAN-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (30.0 mg, 30.0%) were obtained as a white solid. LCMS: m / z 510.9 ([M-H] - ). 1 H NMR (300 MHz, DMSO-d6): δ ppm 10.33 (s, 1H), 9.37 (s, 1H), 7.77 - 7.63 (m, 1H), 7.60 (s, 1H), 7.45 - 7.25 (m, 3H), 7.24 - 7.05 (m, 1H), 6.86 (brs, 1H), 6.04 (s, 1H).

[0278] Chiral SFC separation method: Chiral purity by SFC (area percentage) Principal normal phase HPLC with UV detection, evaluated by area % reagent: MeOH: HPLC grade, J&K CO2: 99.999% Solvent: MeOH+CAN Equipment: Equipment Waters SFC Column: CHIRALCEL AS-H 20mm x 250mm, 5um Chromatography conditions: Mobile phase A: CO2 Mobile phase B: MeOH Concentration gradient: B30% Flow rate: 30ml / min Injection capacity: 1.0ml Injection concentration: 20mg / ml Column temperature: 35℃

[0279] [Example 25] (S)-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)benzo[d]isothiazole-3-carboxamide

[0280] [Example 26] (R)-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)benzo[d]isothiazole-3-carboxamide [ka]

[0281] Step A: To a solution of 3-chloro-5-fluorobenzoic acid (200 mg, 1.12 mmol, 1.0 equiv) in THF (2.0 mL) was added dropwise (COCl) (0.425 g, 3.35 mmol, 3.0 equiv) and DMF (0.1 mL) at room temperature. The reaction mixture was then stirred at the same temperature for 2 hours. The mixture was concentrated to give 3-chloro-5-fluorobenzoyl chloride (250 mg, crude) as a yellow solid, which was used directly crude in the next step.

[0282] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (200 mg, 0.56 mmol, 1.0 equiv.) in ACN (2 mL) was added 3-chloro-5-fluorobenzoyl chloride (133 mg, 0.67 mmol, 1.2 equiv.) and pyridine (89 mg, 1.12 mmol, 2.0 equiv.) at room temperature. The mixture was then stirred at the same temperature for 2 hours. Water (2 mL) was added to the mixture, which was then extracted with EtOAc (2 mL × 3). The combined organic phase was washed with brine (2 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative HPLC (35% to 47% acetonitrile in water with 0.1% FA) to give 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (approximately 60 mg, 20.7%) as a white solid. LCMS: m / z 515.9 ([M-H] - ), which was separated by chiral preparative SFC separation using the following method to give P1(S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (15.7 mg, 39.3%) as a white solid. LCMS: m / z 515.9 ([M-H] - ). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.43 (s, 1H), 9.37 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.90 - 7.52 (m, 3H), 7.50 - 6.60 (m, 3H), 6.22 (brs, 1H). and P2(R)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (17.9 mg, 44.8%) was obtained as a white solid. LCMS: m / z 515.9 ([M-H] - ). 1 H NMR (400 MHz, DMSO-d6): δ ppm 10.43 (s, 1H), 9.37 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.90 - 7.52 (m, 3H), 7.50 - 6.70 (m, 3H), 6.22 (brs, 1H).

[0283] Chiral preparative SFC separation method: Chiral purity by UPCC (area percentage) Principal normal phase HPLC with UV detection, evaluated by area % reagent: MeOH: HPLC grade, MREDA CO2: 99.999% Solvent: MeOH Equipment: Equipment Waters UPCC Column: CHIRALPAK AS-3, 4.6mm x 150mm, 3um Chromatography conditions Mobile phase A: CO2 Mobile phase B: MeOH Concentration gradient: B30% Flow rate: 2.0ml / min Detection UV: 210nm Column temperature: 35℃ Injection capacity: 2.0ul

[0284] [Example 27] N-(3-(2-chloro-5-fluorophenyl)-7-methyl-1,6-dioxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0285] Step A: To a stirred mixture of methyl 3-bromo-5-fluoro-2-methylbenzoate (5 g, 20.2 mmol) in dry THF (30 mL) cooled to −78° C., a solution of LDA (20.2 mL, 40.5 mmol, 2 M) was added dropwise over 0.5 h. The reaction mixture was stirred at −78° C. for 20 min. A solution of 2-chloro-5-fluorobenzene-1-carbaldehyde (4.17 g, 26.3 mmol) in THF (10 mL) was added dropwise over 0.1 h at −78° C. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (NH4CI). The following mixture was subsequently extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0-30% EA in PE) to give methyl 3-bromo-4-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-5-fluoro-2-methylbenzoate (2.2 g, 5.42 mmol, 26.8%) as a yellow oil.

[0286] Step B: To a solution of methyl 3-bromo-4-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-5-fluoro-2-methylbenzoate (2.2 g, 5.42 mmol) in DCM (22 mL) was added 1,1,1-triacetoxy-1,3-dihydro-1λ at 0 °C under N 5-benzo[d][1,2]iodoxol-3-one (4.6 g, 10.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was treated with HO (100 mL) and extracted with EA (3 × 300 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by subsequent column chromatography (0-30% EA in PE) to give methyl 3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-5-fluoro-2-methylbenzoate (1.7 g, 4.21 mmol, 77.6%) as a yellow oil. LCMS: ESI m / z 403 / 405 [M+H] + .

[0287] Step C: To a stirred mixture of methyl 3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-5-fluoro-2-methylbenzoate (1 g, 2.47 mmol) in CCl4 (15 mL) was added NBS (572 mg, 3.23 mmol) and 2-[(1E)-(2-cyanoprop-2-yl)diazenyl]-2-methylpropanenitrile (110 mg, 0.74 mmol). The reaction mixture was stirred at reflux for 2 h. The cooled reaction mixture was diluted with water and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (PE:EA=2:1) to give methyl 3-bromo-2-(bromomethyl)-4-[(2-chloro-5-fluorophenyl)carbonyl]-5-fluorobenzoate (1.1 g, 2.27 mmol, 91.9%) as a white solid.

[0288] Step D: A stirred solution of methyl 3-bromo-2-(bromomethyl)-4-[(2-chloro-5-fluorophenyl)carbonyl]-5-fluorobenzoate (1.1 g, 2.28 mmol) in methanamine (10 mL) was stirred for 0.5 hours. The reaction was concentrated under reduced pressure to give 4-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (650 mg, 1.62 mmol, 71.2%). LCMS: ESI m / z 400 / 402 [M+H]+ .

[0289] Step E: To a solution of 4-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (450 mg, 1.12 mmol) in NMP (5 mL) was added CuCN (100 mg, 1.12 mmol). The reaction mixture was stirred at 120 °C under N for 1 h. The cooled reaction mixture was treated with HO (100 mL) and extracted with EA (3 × 300 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by subsequent column chromatography (PE:EA=2:1) to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (350 mg, 1.01 mmol, 89.9%) as a yellow oil. LCMS: ESI m / z 347 [M+H] + .

[0290] Step F: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (300 mg, 0.87 mmol) in DMSO (4 mL) was added DIEA (112 mg, 0.87 mmol) in a sealed tube. The mixture was refluxed under N for 30 minutes until the starting material was completely consumed. The cooled reaction mixture was poured into water (6 mL) and extracted with EtOAc (6 mL). The organic layer was washed with brine, dried over MgSO, filtered, and concentrated. The crude product was purified by silica gel chromatography eluting with PE:EA=3:1 to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (80 mg, 0.16 mmol, 18.7%) as a yellow solid.

[0291] Step G: To a stirred mixture of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (80 mg, 0.16 mmol) in acetonitrile (4 mL) was added dropwise a solution of KOH (45.5 mg, 0.81 mmol) in HO (1 mL). The solution was stirred at room temperature for an additional 2 h. The reaction was then extracted with DCM (3 × 5.0 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with a solvent mixture consisting of PE:EA = 3:1 to give 3-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-hydroxy-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindole-1,6-dione (40 mg, 0.08 mmol, 48.2%) as a yellow oil. LCMS: ESI m / z 512 [M+H] + .

[0292] Step H: To a solution of 3-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-hydroxy-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindole-1,6-dione (40 mg, 0.08 mmol) in TFA (2 mL) was added triethylsilane (90.7 mg, 0.78 mmol). The reaction mixture was stirred at 50 °C for 1 h. The cooled mixture was concentrated. The residue was diluted with HO (50 mL), adjusted to pH = 8 with saturated aqueous NaHCO solution, and extracted with EA. The organic layer was washed with brine (50 mL), dried over NaSO, and concentrated. The residue was purified by column chromatography (PE:EA=1:1) to give 4-amino-3-(2-chloro-5-fluorophenyl)-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindole-1,6-dione (30 mg, 0.09 mmol, 100%) as a yellow solid. LCMS: ESI m / z 346 [M+H] + .

[0293] Step I: To a stirred mixture of 4-amino-3-(2-chloro-5-fluorophenyl)-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindole-1,6-dione (20 mg, 0.06 mmol) and 5-fluoro-3-(trifluoromethyl)benzoic acid (12 mg, 0.06 mmol) in dry pyridine (1 mL) was added dropwise POCl (8.87 mg, 0.06 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was extracted with EA (15 mL). The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative HPLC to give N-[3-(2-chloro-5-fluorophenyl)-7-methyl-1,6-dioxo-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3.5 mg, 0.007 mmol, 11.3%) as a white solid. LCMS: ESI m / z 536 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 7.66 (dd, J = 16.2, 8.7 Hz, 3H), 7.27 (dd, J = 9.0, 5.0 Hz, 1H), 7.00 (td, J = 8.4, 3.0 Hz, 1H), 6.28 (s, 2H), 4.88 (d, J = 2.6 Hz, 2H), 3.27 (s, 3H).

[0294] [Example 28] N-[3-(2-chloro-5-fluorophenyl)-7-methyl-1-oxo-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0295] Step A: To a solution of methyl 3-bromo-5-fluoro-2-methylbenzoate (1 g, 4.05 mmol) in CCl4 (10 mL) was added 1-bromotetrahydropyrrole-2,5-dione (1.08 g, 6.071 mmol) and perbenzoic anhydride (0.39 g, 1.619 mmol). The reaction mixture was stirred at 90 °C overnight. The cooled mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (gradient 0-5%) to give methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (1.2 g, 3.68 mmol, 90.95%) as a colorless oil.

[0296] Step B: To a solution of methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (1 g, 3.07 mmol) in THF (10 mL) was added methanamine (7.7 mL, 15.3 mmol, 2 M in THF). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (35% gradient) to give 4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (500 mg, 2.049 mmol, 66.78%) as a white solid. LCMS: ESI m / z 244 [M+H] + .

[0297] Step C: To a solution of 4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (1 g, 4.09 mmol) in THF (7.5 mL) was added borane dimethylsulfane (5 mL, 50.0 mmol) at 25 °C, and the reaction mixture was stirred at 60 °C for 4 h. The cooled reaction solution was quenched with methanol, and the pH was adjusted to 1-2 by the addition of 6 M HCl. The mixture was then heated to 80 °C and stirred for 1 h. The reaction was cooled to room temperature, and the pH was adjusted to 7-8 with 6 M NaOH. The reaction solution was extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH (concentration gradient 0-5%) in DCM to give the compound 4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindole (650 mg, 2.825 mmol, 68.95%) as a colorless oil. LCMS: ESI m / z 230 [M+H] + .

[0298] Step D: To a solution of 4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindole (1.5 g, 6.519 mmol) in dry THF (15 mL) was added dropwise lithium di(prop-2-yl)azanide (4.890 mL, 9.779 mmol) at −65° C. The reaction mixture was stirred at −65° C. for 0.5 h under a N atmosphere. A solution of 2-chloro-5-fluorobenzene-1-carbaldehyde (1.55 g, 9.779 mmol) in THF (8 mL) was added dropwise. The reaction mixture was stirred at −65° C. for 1 h. The reaction mixture was quenched by adding saturated aqueous NHCl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel using MeOH in DCM (0→4%, v / v) to give diethyl (4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-5-yl)(2-chloro-5-fluorophenyl)methanol (1 g, 2.573 mmol, 39.47%) as a white solid. LCMS: ESI m / z 388 [M+H] + .

[0299] Step E: To a solution of (4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-5-yl)(2-chloro-5-fluorophenyl)methanol (800 mg, 2.058 mmol) in propan-2-one (10 mL) was added 65272-70-0 (0.5 mL, 2.058 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. After 2 hours, the reaction mixture was quenched with isopropyl alcohol (10 mL). The isopropyl alcohol was removed under vacuum, followed by extraction with EA. All organic phases were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using MeOH in DCM (0→5%, v / v) to give (4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-5-yl)(2-chloro-5-fluorophenyl)methanone (700 mg, 1.811 mmol, 87.96%) as a white solid. LCMS: ESI m / z 386 [M+H] + .

[0300] Step F: To a solution of (4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindol-5-yl)(2-chloro-5-fluorophenyl)methanone (600 mg, 1.55 mmol) in 1-methyltetrahydropyrrol-2-one (10 mL) was added CuCN (278 mg, 3.10 mmol) at 25 °C. The reaction mixture was stirred at 120 °C under a N atmosphere for 4 h. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography eluting with MeOH in DCM (gradient 0-3%) to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-2,3-dihydro-1H-isoindole-4-carbonitrile (250 mg, 0.751 mmol, 48.4%) as a yellow solid. LCMS: ESI m / z 333 [M+H] - .

[0301] Step G: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-2,3-dihydro-1H-isoindole-4-carbonitrile (250 mg, 0.751 mmol) in DMSO (6 mL) was added (2,4-dimethoxyphenyl)methanamine (125 mg, 0.751 mmol) and ethyl[di(prop-2-yl)]amine (194 mg, 1.503 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 1 h. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography eluting with MeOH in DCM (gradient 0-4%) to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-2-methyl-2,3-dihydro-1H-isoindole-4-carbonitrile (160 mg, 0.333 mmol, 44.37%) as a yellow solid. LCMS: ESI m / z 480 [M+H] + .

[0302] Step H: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-2-methyl-2,3-dihydro-1H-isoindole-4-carbonitrile (140 mg, 0.292 mmol) in ACN (5 mL) and HO (0.5 mL) was added NaOH (23.34 mg, 0.583 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography eluting with MeOH (gradient 0-8%) in DCM to give 3-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-hydroxy-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindol-1-one (114 mg, 0.229 mmol, 78.5%) as a yellow solid. LCMS: ESI m / z 498 [M+H] + .

[0303] Step I: To a solution of 3-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-hydroxy-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindol-1-one (100 mg, 0.201 mmol) in 2,2,2-trifluoroacetic acid (3 mL) was added triethylsilane (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. After 0.5 hours, the reaction mixture was diluted with HO. The aqueous layer was extracted with EA. The EA layers were combined, washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give 4-amino-3-(2-chloro-5-fluorophenyl)-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindol-1-one (85 mg, 0.154 mmol, 76.54%) as a yellow oil. LCMS: ESI m / z 332 [M+H] + .

[0304] Step J: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-7-methyl-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindol-1-one (80 mg, 0.145 mmol) in ACN (5 mL) was added pyridine (0.117 mL, 1.447 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (98 mg, 0.434 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 10 minutes and then concentrated. The residue was purified by silica gel column chromatography eluting with EA and further purified by preparative HPLC to give N-[3-(2-chloro-5-fluorophenyl)-7-methyl-1-oxo-1,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (19.1 mg, 0.037 mmol, 25.3%) as a white solid. LCMS: ESI m / z 522 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.26 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.51 (s, 1H), 7.36 - 7.28 (m, 1H), 7.10 (s, 1H), 6.05 (s, 1H), 4.74 (s, 2H), 4.51 (s, 2H), 2.97 (s, 3H).

[0305] [Example 29] N-(6-(2-chloro-5-fluorophenyl)-3,8-dioxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0306] Step A: A solution of N-[6-(2-chloro-5-fluorophenyl)-3-methoxy-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.056 mmol) in HBr (3 mL, 30% HBr in HO) was stirred overnight at 50° C. The cooled reaction mixture was diluted with HO, extracted with EA, washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative HPLC to give the compound N-(6-(2-chloro-5-fluorophenyl)-3,8-dioxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.0 mg, 0.004 mmol, 6.84%) as a white solid. LCMS: ESI m / z 523 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.82 (s, 1H), 10.28 (s, 1H), 9.07 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 14.8 Hz, 4H), 7.29 (dd, J = 8.8, 5.1 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.13 (s, 1H).

[0307] [Example 30] N-[6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3,6,7,8-tetrahydro-1H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0308] Step A: To a stirred solution of 3-bromo-5-fluorobenzene-1,2-diamine (18 g, 87.8 mmol) in DMF (180 mL) was added CDI (10.9 mL, 87.8 mmol) under an argon atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC. The mixture was treated with HO (100 mL) and extracted with EA (3 × 300 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was triturated with DCM (100 mL) and filtered to give 4-bromo-6-fluoro-2,3-dihydro-1H-benzo[d]imidazol-2-one (16.5 g, 71.4 mmol, 81.4%) as a yellow oil.

[0309] Step B: To a suspension of NaH (8.31 g, 208 mmol, 60% in mineral oil) in dry THF (60 mL) at 0 °C, 4-bromo-6-fluoro-2,3-dihydro-1H-benzo[d]imidazol-2-one (16 g, 69.3 mmol) was added batchwise. After the addition was complete, the reaction mixture was stirred at 0 °C for an additional 1.5 h. 4-Methoxybenzyl chloride (28.3 mL, 208 mmol) was added slowly, and the mixture was stirred at 0 °C for 0.5 h and at room temperature for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution. The mixture was subsequently extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0-30% EA in PE) to give 7-bromo-5-fluoro-1-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (7.2 g, 20.5 mmol, 29.6%) as a yellow oil. LCMS: ESI m / z 351 / 353 [M+H] + .

[0310] Step C: To a stirred mixture of 7-bromo-5-fluoro-1-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (7 g, 19.9 mmol) in dry THF (70 mL) cooled to −78° C., a solution of LDA (39.9 mL, 79.7 mmol, 2 M) was added dropwise over 0.5 h. The reaction mixture was stirred at −78° C. for 20 min. A solution of 2-chloro-5-fluorobenzene-1-carbaldehyde (4.74 g, 29.9 mmol) in THF (20 mL) was added dropwise over 0.1 h at −78° C. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution. The mixture was subsequently extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0–30% EA in PE) to give 7-bromo-6-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-5-fluoro-1-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.2 g, 6.28 mmol, 31.5%) as a yellow oil.

[0311] Step D: To a solution of 7-bromo-6-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-5-fluoro-1-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.2 g, 6.28 mmol) in DCM (40 mL) was added 1,1,1-triacetoxy-1,3-dihydro-1λ under N at 0 °C. 5-Benzo[d][1,2]iodoxol-3-one (832 mg, 1.96 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was treated with HO (100 mL) and extracted with EA (3 × 300 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by subsequent column chromatography (0–30% EA in PE) to give 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-5-fluoro-1-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (1.9 g, 3.74 mmol, 59.6%) as a yellow oil. LCMS: ESI m / z 507 / 509 [M+H] + .

[0312] Step E: To a solution of 4-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-1-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (1.7 g, 3.35 mmol) and Zn(CN) (0.47 g, 4.02 mmol) in DMA (20 mL) was added Zn (0.04 g, 0.67 mmol) followed by Pd(dba) (0.31 g, 0.34 mmol) and bis(cyclopentyldiphenylphosphane)iron(0) (0.38 g, 0.67 mmol) under N with stirring. The mixture was refluxed for 3 h until the starting material was completely consumed. The cooled reaction mixture was treated with HO (100 mL) and extracted with EA (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by subsequent column chromatography (0–30% EA in PE) to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-1-[(4-methoxyphenyl)methyl]-2-oxo-3H-benzo[d]imidazole-4-carbonitrile (1.2 g, 2.64 mmol, 78.9%) as a yellow oil.

[0313] Step F: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-3-[(4-methoxyphenyl)methyl]-2-oxo-1H-benzo[d]imidazole-4-carbonitrile (200 mg, 0.308 mmol) in DMSO (5 mL) was added (2,4-dimethoxyphenyl)methanamine (51.5 mg, 0.308 mmol) and DIEA (80 mg, 0.617 mmol) at 25° C. The reaction mixture was stirred at 130° C. for 5 hours. The reaction solution was purified by flash chromatography eluting with ACN (gradient 0-65%) in HO to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-3-[(4-methoxyphenyl)methyl]-2-oxo-1H-benzo[d]imidazole-4-carbonitrile (60 mg, 0.100 mmol, 32.4%) as a yellow solid. LCMS: ESI m / z 601 [M+H] + .

[0314] Step G: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-3-[(4-methoxyphenyl)methyl]-2-oxo-1H-benzo[d]imidazole-4-carbonitrile (60 mg, 0.100 mmol) in ACN (5 mL) and HO (1 mL) was added KOH (28.0 mg, 0.499 mmol) at 25 °C. The reaction mixture was stirred at 30 °C overnight. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography eluting with MeOH (gradient 0-8%) in DCM to give 6-(2-chloro-5-fluorophenyl)-5-{[(2,4-dimethoxyphenyl)methyl]amino}-6-hydroxy-1-[(4-methoxyphenyl)methyl]-1,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (15 mg, 0.024 mmol, 24.27%) as a yellow solid. LCMS: ESI m / z 619 [M+H] + .

[0315] Step H: To a solution of 6-(2-chloro-5-fluorophenyl)-5-{[(2,4-dimethoxyphenyl)methyl]amino}-6-hydroxy-1-[(4-methoxyphenyl)methyl]-1,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (15 mg, 0.024 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was added triethylsilane (5.64 mg, 0.048 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.260 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. TFE and TfOH were removed under vacuum. The mixture was then adjusted to pH 8 with NaHCO (aq) and extracted with EA. The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give 5-amino-6-(2-chloro-5-fluorophenyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (10 mg, 0.021 mmol, 86.85%) as a yellow solid, which was used in the next step without further purification. LCMS: ESI m / z 333 [M+H] - .

[0316] Step I: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (10 mg, 0.021 mmol) in acetonitrile (1 mL) was added Py (0.005 mL, 0.063 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (9.52 mg, 0.042 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 10 min. The ACN and pyridine were removed under vacuum to give the crude product, which was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3,6,7,8-tetrahydro-1H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.2 mg, 0.004 mmol, 20.0%) as a white solid. LCMS: ESI m / z 523 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 11.00 (s, 1H), 10.21 (s, 1H), 8.99 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 9.4 Hz, 1H), 7.66 (s, 1H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.07 (t, J = 6.8 Hz, 1H), 7.03 (s, 1H), 5.98 (s, 1H).

[0317] [Example 32] N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0318] Step A: To a solution of 4-bromo-5-(2-chloro-5-fluorobenzoyl)-6-nitrobenzo[d]oxazol-2(3H)-one (2.0 g, 4.81 mmol, 1.0 equiv) in EtOH (20 mL) was added NaOH (770 mg, 19.25 mmol, 4.0 equiv) in HO (20 mL). The reaction mixture was refluxed for 12 h. The reaction mixture was concentrated, and DCM:MeOH = 10:1 (50 mL) was added. The mixture was then filtered, and the filtrate was concentrated to give (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (2.3 g, crude) as a brown solid. LCMS: m / z 387.0, 388.9 ([M-H] - ).

[0319] Step B: To a solution of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (1.0 g, 2.57 mmol, 1.0 equiv) in DCM (8.5 mL) was added TEA (546 mg, 5.39 mmol, 2.1 equiv) and DMAP (63 mg, 0.51 mmol, 0.2 equiv) under N2 atmosphere at 0 °C. Then, chloroacetyl chloride (304 mg, 2.70 mmol, 1.05 equiv) was added to the system. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to 25 °C, and chloroacetyl chloride (434 mg, 3.85 mmol, 1.5 equiv) was added. The reaction mixture was refluxed for 4 h. The reaction mixture was cooled to 25 °C, quenched with aqueous NaHSO4 (30 mL), and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (30 mL), dried over NaSO, and concentrated to give 5-bromo-6-(2-chloro-5-fluorobenzoyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (1.1 g, crude) as a brown solid. LCMS: m / z 426.9, 428.8 ([M-H] - ).

[0320] Step C: To a solution of 5-bromo-6-(2-chloro-5-fluorobenzoyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (1.1 g, 2.45 mmol, 1.0 equiv) in EtOH (10 mL) was added NH4Cl (520 mg, 9.77 mmol, 4 equiv) in HO (3.5 mL). Then, Fe (410 mg, 7.33 mmol, 3.0 equiv) was added to the system at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Water (15 mL) and ethyl acetate (5 mL) were then added, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated to give the crude product. The residue was purified by preparative TLC (eluted with petroleum ether / EtOAc = 3:1) to give 7-amino-5-bromo-6-(2-chloro-5-fluorobenzoyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (110 mg) as a yellow solid. LCMS: m / z 398.9, 400.9 ([M+H] + ).

[0321] Step D: A sealed vial was charged with 7-amino-5-bromo-6-(2-chloro-5-fluorobenzoyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.13 mmol, 1.0 equiv.), Zn(CN) (15 mg, 0.13 mmol, 1.0 equiv.), Pd(PPh) (44 mg, 0.04 mmol, 0.3 equiv.), and DMAc (0.5 mL). The sealed vial was irradiated in a microwave at 160 °C for 30 min. Water (3 mL) was added to the mixture, which was then extracted with EtOAc (3 mL × 2). The combined organic phase was washed with brine (5 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative TLC (eluted with petroleum ether / EtOAc = 1:1) to give 7-amino-6-(2-chloro-5-fluorobenzoyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (18 mg, 41.5%) as a yellow solid. LCMS: m / z 344.1 ([M-H] - ).

[0322] Step E: To a solution of 7-amino-6-(2-chloro-5-fluorobenzoyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (150 mg, 0.43 mmol, 1.0 equiv.) in ACN (5 mL) / HO (0.5 mL) was added KOH (72.4 mg, 1.29 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred at 50° C. for 1 hour. Water (5 mL) was added to the mixture, which was then extracted with EtOAc (5 mL × 2). The combined organic phases were washed with brine (5 mL), dried over NaSO, and concentrated to give 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-7,8-dihydro-[1,4]oxazino[3,2-e]isoindole-2,9(1H,3H)-dione (150 mg, crude) as a yellow oil. LCMS: m / z 362.0 ([M-H] - ).

[0323] Step F: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-7,8-dihydro-[1,4]oxazino[3,2-e]isoindole-2,9(1H,3H)-dione (150 mg, 0.41 mmol, 1.0 equiv.) in ACN (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (278 mg, 1.23 mmol, 3 equiv.) and pyridine (162.2 mg, 2.05 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (5 mL × 2). The combined organic phases were washed with brine (5 mL) and aqueous NaCO (5 mL), dried over NaSO, and concentrated to give N-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (240 mg, crude) as a yellow oil. LCMS: m / z 551.9 ([M-H] - ).

[0324] Step G: To a solution of N-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (240 mg, 0.41 mmol, 1.0 equiv) in TFA (5 mL) was added EtSiH (238 mg, 2.05 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (19 mg, approx. 8.2% yield over three steps) as a white solid. LCMS: m / z 535.9 ([MH] - ). 1 H NMR (400 MHz, DMSO-d6): δ 10.34 (brs, 1H), 9.51 (brs, 1H), 9.28 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.33 - 7.30 (m, 1H), 7.12 - 7.07 (m, 2H), 6.90 - 6.76 (m, 1H), 5.95 (s, 1H), 4.81 (s, 2H).

[0325] [Example 35] N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide

[0326] [Example 48] (S)-N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide

[0327] [Example 49] (R)-N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0328] Step A: To a solution of N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7 mg, 0.01 mmol) in CD3OD (0.5 mL) was added 40% NaOD (0.26 mg, 0.0026 mmol) in DO. The reaction mixture was stirred at 50 °C for 18 hours. To the cooled mixture was added 1 N HCl to adjust the pH to approximately 7. The reaction mixture was pre-purified by preparative HPLC purification to give N-[7-(2-chloro-5-fluorophenyl)-3,3-dideuterio-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.9 mg, 0.01 mmol, 41.3%) as a white solid. LCMS: ESI m / z 541 [M + H] + . 1 H NMR (400 MHz, CD3OD) 7.67 - 7.58 (m, 3H), 7.25 (dd, J = 8.8, 5.0 Hz, 1H), 7.08 (s, 1H), 7.02 - 6.94 (m, 1H), 6.68 (s, 1H). Another batch of N-[7-(2-chloro-5-fluorophenyl)-3,3-dideuterio-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide, 200 mg, was then subjected to chiral preparative SFC separation using the following method to afford P1 Example 48 (S)—N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide (51.8 mg, 0.096 mmol, 52%) as a white solid. LCMS: ESI m / z 541 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.52 (s, 1H), 9.26 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.31 (dd, J = 8.8, 5.2 Hz, 1H), 7.11 (d, J = 6.4 Hz, 1H), 7.08 (dd, J = 8.6, 2.9 Hz, 1H), 6.86 (brs, 1H). and P2 Example 49 (R)—N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide (62.7 mg, 0.116 mmol, 62%) was obtained as a white solid (R)—N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide. LCMS: ESI m / z 541 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.52 (s, 1H), 9.26 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.31 (dd, J = 8.8, 5.2 Hz, 1H), 7.11 (d, J = 6.4 Hz, 1H), 7.08 (dd, J = 8.6, 2.9 Hz, 1H), 6.86 (brs, 1H).

[0329] Preparative separation method: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 250×20mm ID, 5μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B20% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 6 minutes Dissolution time: 2 hours

[0330] [Example 36] N-[7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0331] [Example 37] N-((3R * ,7R)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0332] [Example 38] N-((3R *,7R)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0333] [Example 39] N-((3R * ,7S)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0334] [Example 40] N-((3R * ,7S)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0335] Step A: To a stirred mixture of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (500 mg, 1.28 mmol) in DCM (5 mL) at room temperature, TEA (0.357 mL, 2.56 mmol), DMAP (31 mg, 0.257 mmol), and 2-chloropropanoyl chloride (325 mg, 2.57 mmol) were added dropwise. The reaction mixture was stirred at 50 °C for an additional 2 h. The cooled reaction was quenched with aqueous NaHSO (10 mL) and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [gradient: 5%] to give 5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-one (450 mg, 1.014 mmol, 78.9%) as a white solid. LCMS: ESI m / z 442 [M+H] - .

[0336] Step B: To a stirred mixture of 5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-one (420 mg, 0.947 mmol) in EtOH / HO (20 mL) was added dropwise NH4Cl (152 mg, 2.84 mmol) and Fe (158 mg, 2.84 mmol). The reaction mixture was stirred at 75 °C for an additional 1 h. Water and ethyl acetate were added, filtered, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [gradient: 6%] to give 7-amino-5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-3-one (380 mg, 0.919 mmol, 97.4%) as a white solid. LCMS: ESI m / z 412 [M+H] - . 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.60 (dd, J = 8.8, 4.9 Hz, 1H), 7.44 (dd, J = 8.2, 3.0 Hz, 1H), 7.24 (dd, J = 8.6, 3.0 Hz, 1H), 6.54 (s, 1H), 6.25 (s, 2H), 4.69 (d, J = 6.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 3H).

[0337] Step C: To a stirred mixture of 7-amino-5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-3-one (700 mg, 1.69 mmol) in NMP (8 mL) was added dropwise CuCN (303 mg, 3.38 mmol). The reaction mixture was stirred at 150 °C for 1 h using a microwave. The resulting cooled mixture was filtered, and the filtrate was washed with EA. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in DCM [gradient: 4%] to give the compound 7-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-5-carbonitrile (480 mg, 1.33 mmol, 78.8%) as a white solid. LCMS: ESI m / z 360 [M+H] - .

[0338] Step D: To a solution of 7-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-5-carbonitrile (350 mg, 0.973 mmol) in CHCN / HO (8 mL) was added potassium hydroxide (273 mg, 4.86 mmol). The reaction mixture was stirred at 50 °C for 30 min. The cooled reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [gradient: 4%] to give 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-3-methyl-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindole-2,9-dione (270 mg, 0.715 mmol, 72.9%) as a white solid. LCMS: ESI m / z 376 [M+H] -

[0339] Step E: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-3-methyl-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindole-2,9-dione (200 mg, 0.529 mmol) in ACN (5 mL) was added pyridine (0.086 mL, 1.06 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (144 mg, 0.635 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [gradient: 5%] to give N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (150 mg, 0.264 mmol, 49.9%) as a white solid. LCMS: ESI m / z 567 [M+H] -

[0340] Step F: To a solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (200 mg, 0.352 mmol) in TFA (4 mL) was added EtSiH (204 mg, 1.76 mmol). The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous NaHCO and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative HPLC to give Example 36: N-[7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.181 mmol, 68.6%) as a white solid. LCMS: ESI m / z 552 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.52 (s, 0.5H), 9.48 (s, 0.5H), 9.27 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.00 (m, 2H), 6.78 (s, 1H), 5.88 (brs, 1H), 5.02 - 4.84 (m, 1H), 1.52 (d, J = 6.8 Hz, 3H).

[0341] Step G: Example 36 (100 mg, 0.181 mmol) was separated by chiral preparative SFC (Waters Thar 80 Prep SFC-Chiral Cel OD, 250 x 21.2 mm ID, 5 μm, 20%, Phase A: CO2, Phase B: MeOH) to give P-1 Example 37 (15 mg, 0.027 mmol, 10.3%) as a white solid; LCMS: ESI m / z 552 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.52 (s, 1H), 9.27 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.00 (m, 2H), 6.78 (s, 1H), 5.88 (brs, 1H), 4.96 (q, J = 6.8 Hz, 1H), 1.51 (d, J = 6.8 Hz, 3H). P-2 Example 38 (15.8 mg, 0.028 mmol, 10.8%) was obtained as a white solid. LCMS: ESI m / z 552 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.48 (s, 0.5H), 9.27 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.69 - 7.66 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.00 (m, 2H), 6.78 (s, 1H), 5.88 (brs, 1H), 4.94 (q, J = 6.8 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H). P-3 Example 39 (16.9 mg, 0.031 mmol, 11.6%) was obtained as a white solid. LCMS: ESI m / z 552 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.52 (s, 1H),, 9.27 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.00 (m, 2H), 6.78 (s, 1H), 5.88 (brs, 1H), 4.96 (q, J = 6.8 Hz, 1H), 1.51 (d, J = 6.8 Hz, 3H). P-4 was obtained as a white solid in Example 40 (12.2 mg, 0.021 mmol, 8.34%). LCMS: ESI m / z 552 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.48 (s, 0.5H), 9.27 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.69 - 7.66 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.00 (m, 2H), 6.78 (s, 1H), 5.88 (brs, 1H), 4.94 (q, J = 6.8 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H).

[0342] Separation method: Device: Waters Thaler 80 min SFC カラム: ChiralPak IH, 250×21.2mm ID, 5μm Mobile phase: AはCO2およびBはMEOH Concentration blend: B20% Flow rate: 40mL / min Reverse pressure: 100bar カラムTemperature:35℃ Wavelength: 220nm サイクル time: 6 minutes Dissolution time: 2 hours

[0343] [Example 41] N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0344] [Example 42] (S)-N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0345] [Example 43] (R)-N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0346] Step A: To a stirred mixture of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (800 mg, 2.05 mmol) in DCM (10 mL) under a N atmosphere at 0 °C, TEA (0.571 mL, 4.10 mmol), DMAP (50 mg, 0.411 mmol), and 2-bromo-2,2-difluoroacetyl chloride (794 mg, 4.10 mmol) were added dropwise. The reaction mixture was stirred at 50 °C for an additional 2 h. The cooled reaction was quenched with aqueous NaHSO (10 mL) and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 35%] to obtain the compound 2-bromo-N-(2-bromo-3-(2-chloro-5-fluorobenzoyl)-6-hydroxy-4-nitrophenyl)-2,2-difluoroacetamide (650 mg, 1.19 mmol, 58%) as a white solid. LCMS: ESI m / z 545 [M+H] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 11.10 (s, 1H), 7.82 (s, 1H), 7.75 - 7.65 (m, 2H), 7.65 - 7.55 (m, 1H).

[0347] Step B: To a solution of 2-bromo-N-(2-bromo-3-(2-chloro-5-fluorobenzoyl)-6-hydroxy-4-nitrophenyl)-2,2-difluoroacetamide (650 mg, 1.19 mmol) in DMF (10 mL) was added potassium carbonate (493 mg, 3.57 mmol), (2-methylprop-2-yl)oxidanecarboxylic anhydride (51 mg, 0.237 mmol), and DMAP (1.45 mg, 0.012 mmol). The reaction mixture was stirred at 50 °C under N overnight. The cooled reaction mixture was diluted with HO and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with EA in PE [concentration gradient: 25%] to give the compound 5-bromo-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 1.07 mmol, 90%) as a white solid. LCMS: ESI m / z 465 [M+H] +

[0348] Step C: To a stirred mixture of 5-bromo-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 1.074 mmol) in EtOH / HO (20 mL) was added dropwise NH4Cl (172 mg, 3.222 mmol) and iron(0) (179 mg, 3.22 mmol) at room temperature under a N2 atmosphere. The reaction mixture was stirred at 80 °C for 1 h. The cooled reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with EA. The combined organic layers were washed with brine 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 in PE [concentration gradient: 30%] to give the compound 7-amino-5-bromo-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (410 mg, 0.941 mmol, 88%) as a white solid. LCMS: ESI m / z 436 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.64 (dd, J = 8.8, 4.8 Hz, 1H), 7.49 (td, J = 8.4, 3.2 Hz, 1H), 7.35 (dd, J = 8.8, 3.0 Hz, 1H), 6.77 (s, 1H), 6.09 (s, 2H).

[0349] Step D: To a stirred mixture of 7-amino-5-bromo-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (400 mg, 0.918 mmol) in NMP (6 mL) was added dropwise CuCN (164 mg, 1.837 mmol). The reaction mixture was stirred at 150 °C in a microwave under N for 1 h. The cooled reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with EA in PE [concentration gradient: 35%] to obtain the compound 7-amino-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (220 mg, 0.576 mmol, 63%) as a white solid. LCMS: ESI m / z 380 [M+H] -

[0350] Step E: To a solution of 7-amino-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile (220 mg, 0.552 mmol) in CHCN / HO (8 mL) was added potassium hydroxide (97 mg, 1.73 mmol). The reaction mixture was stirred at 50 °C for 30 min. The cooled reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EA in PE [concentration gradient: 40%] to obtain the compound 6-amino-7-(2-chloro-5-fluorophenyl)-3,3-difluoro-7-hydroxy-7,8-dihydro-[1,4]oxazino[3,2-e]isoindole-2,9(1H,3H)-dione (120 mg, 0.30 mmol, 52%) as a white solid. LCMS: ESI m / z 398 [M+H] -

[0351] Step F: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-3,3-difluoro-7-hydroxy-7,8-dihydro-[1,4]oxazino[3,2-e]isoindole-2,9(1H,3H)-dione (100 mg, 0.25 mmol) in CAN (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (68 mg, 0.300 mmol) and pyridine (0.04 mL, 0.500 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 35%] to obtain the compound N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-7-hydroxy-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.153 mmol, 61%) as a white solid. LCMS: ESI m / z 588 [M+H]-

[0352] Step G: To a solution of N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-7-hydroxy-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.153 mmol) in TFA (4 mL) was added EtSiH (88 mg, 0.763 mmol). The reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was diluted with aqueous NaHCO and extracted with EA. The organic phase was washed with brine, dried over NaSO and concentrated. The residue was purified by preparative HPLC to give N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25.5 mg, 0.044 mmol, 29%) as a white solid. LCMS: ESI m / z 574 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.50 (s, 1H), 9.44 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 2.8 Hz, 1H), 6.96 (s, 1H), 6.10 - 6.00 (brs, 1H).

[0353] Step H: N-[7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25.5 mg) was purified by preparative SFC (Waters Thar 80 Prep SFC-Chiral Cel OD, 250 × 21.2 mm ID, 5 μm, 20%, A: CO , Phase B: IPA) to give compound: P-1 Example 42 (9.3 mg, 0.016 mmol, 73%) was obtained as a white solid. LCMS: ESI m / z 574 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.50 (s, 1H), 9.44 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 2.8 Hz, 1H), 6.96 (s, 1H), 6.10 - 6.00 (brs, 1H). P-2 Example 43 (7.2 mg, 0.012 mmol, 56%) was obtained as a white solid. LCMS: ESI m / z 574 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.50 (s, 1H), 9.44 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 2.8 Hz, 1H), 6.96 (s, 1H), 6.10 - 6.00 (brs, 1H).

[0354] [Example 44] N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,2,4,7,8,9-hexahydro-[1,3]oxazino[4,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0355] Step A: A mixture of 2-bromo-1-fluoro-3-methyl-4-nitrobenzene (1.0 g, 4.3 mmol), BPO (104 mg, 0.43 mmol), and NBS (800 mg, 4.5 mmol) in CCl (15 mL) was stirred at 80 °C under a N atmosphere for 18 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluted with EA / PE = 0 to 20%) to give the crude product, 2-bromo-3-(bromomethyl)-1-fluoro-4-nitrobenzene (1.0 g, 3.2 mmol, 75%), as a colorless oil.

[0356] Step B: A solution of 2-bromo-3-(bromomethyl)-1-fluoro-4-nitrobenzene (1.0 g, 3.2 mmol) and NMO (560 mg, 4.8 mmol) in CH3CN (15 mL) was stirred at 80 °C for 1 h. TLC and LCMS indicated the reaction was complete. The reaction was cooled, poured into ice water, and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA / PE = 0 to 40%) to give the desired product, 2-bromo-3-fluoro-6-nitrobenzene-1-carbaldehyde (800 mg, 3.2 mmol, 100%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.33 (dd, J = 9.2, 4.4 Hz, 1H), 7.89 - 7.77 (m, 1H).

[0357] Step C: A solution of 2-bromo-3-fluoro-6-nitrobenzene-1-carbaldehyde (800 mg, 3.2 mmol, 100%), DIEA (1.12 g, 8.9 mmol), and DMBNH2 (1.0 g, 5.9 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 1 h. TLC and LCMS indicated the reaction was complete. The reaction was cooled, poured into ice water, and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in THF (10 mL) and 6 N HCl (10 mL). The solution was stirred at 60 °C for 1 h. The reaction was cooled to 0 °C, the pH was adjusted to 7-8 with NaHCO3, and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA / PE = 0 to 50%) to give the desired product 3-amino-2-bromo-6-nitrobenzene-1-carbaldehyde (500 mg, 2.0 mmol, 68%) as a yellow solid. LCMS: ESI m / z 246 / 248 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.24 (s, 2H), 6.97 (d, J = 9.2 Hz, 1H).

[0358] Step D: To a mixture of 2-bromo-3-methyl-4-nitroaniline (800 mg, 3.2 mmol) and AgSO (1.4 g, 4.5 mmol) in MeOH (20 mL) was added I (1.07 g, 4.2 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The mixture was poured into H2O. The mixture was filtered, and the filtrate was extracted with EA. The organic layer was concentrated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA / PE = 0-50%) to give the desired product, 3-amino-2-bromo-4-iodo-6-nitrobenzene-1-carbaldehyde (700 mg, 1.9 mmol, 58%) as a yellow solid. LCMS: ESI m / z 371.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.47 (s, 1H), 6.87 (s, 2H).

[0359] Step E: To a solution of 3-amino-2-bromo-4-iodo-6-nitrobenzene-1-carbaldehyde (1.6 g, 4.31 mmol) in THF (30 mL) was added 2-chloro-5-fluorophenyl)magnesium chloride (0.5 M, 30 mL) at 0 °C. The mixture was stirred at room temperature for 1 h and then diluted with EA and aqueous NH4Cl. The organics were separated and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA / PE = 0-30%) to give (3-amino-2-bromo-4-iodo-6-nitrophenyl)(2-chloro-4-fluorophenyl)methanol (1.7 g, 3.39 mmol, 79%) as a brown solid. LCMS: ESI m / z 503 [M+H+2] + .

[0360] Step F: To a solution of (3-amino-2-bromo-4-iodo-6-nitrophenyl)(2-chloro-4-fluorophenyl)methanol (1.7 g, 3.39 mmol) in DCM (35 mL) was added DMP (2.88 g, 6.78 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was treated with HO (20 mL) and extracted with DCM (2 × 20 mL). The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography to give (3-amino-2-bromo-4-iodo-6-nitrophenyl)(2-chloro-4-fluorophenyl)methanone (1.5 g, 3.00 mmol, 89%) as a brown solid. LCMS: ESI m / z 501 [M+H+2] + .

[0361] Step G: In a sealed vial, add (3-amino-2-bromo-4-iodo-6-nitrophenyl)(2-chloro-4-fluorophenyl)methanone (500 mg, 1.00 mmol), potassium trifluoro(vinyl)-λ 5 A mixture of 161 mg (1.21 mmol), pd(dppf)Cl2 (73.3 mg, 100 μmol), K2CO3 (414 mg, 3.01 mmol), dioxane (10 mL), and H2O (2 mL) was added. The mixture was stirred at 85 °C under N2 for 2 h. The mixture was diluted with water (ca. 10 mL) and extracted with EtOAc (ca. 20 mL × 2). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give a residue. The residue was purified by column elution (EA:PE = 30%) to give (3-amino-2-bromo-6-nitro-4-vinylphenyl)(2-chloro-4-fluorophenyl)methanone (270 mg, 0.676 mmol, 67%) as a yellow solid. LCMS: ESI m / z 401 [M+H] + .

[0362] Step H: A sealed vial was charged with (3-amino-2-bromo-6-nitro-4-vinylphenyl)(2-chloro-4-fluorophenyl)methanone (480 mg, 1.20 mmol), Zn(CN) (705 mg, 6.01 mmol), Pd(PPh) (139 mg, 0.120 mmol), and DMA (10 mL). The mixture was stirred under N at 170 °C (microwave) for 3 h. The mixture was diluted with water (ca. 10 mL) and extracted with EtOAc (ca. 20 mL × 2). The combined organic phase was washed with brine, dried over NaSO, and concentrated to give a residue. The residue was purified by column elution (EA:PE=30%) to give 6-amino-2-[(2-chloro-4-fluorophenyl)carbonyl]-3-nitro-5-vinylbenzene-1-carbonitrile (170 mg, 0.492 mmol, 41%) as a brown solid. LCMS: ESI m / z 346 [M+H] + .

[0363] Step I: To a solution of 6-amino-2-[(2-chloro-4-fluorophenyl)carbonyl]-3-nitro-5-vinylbenzene-1-carbonitrile (170 mg, 0.492 mmol) in ACN (4 mL) and HO (0.5 mL) was added KOH (138 mg, 2.46 mmol). The reaction mixture was stirred at 40 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL × 2), dried over NaSO, and concentrated to give 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-4-nitro-6-vinyl-2,3-dihydro-1H-isoindol-1-one (170 mg, 0.467 mmol, 95%) as a brown solid. LCMS: ESI m / z 364 [M+H] + .

[0364] Step J: To a solution of 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-4-nitro-6-vinyl-2,3-dihydro-1H-isoindol-1-one (70 mg, 0.192 mmol) in dioxane (2 mL) and HO (0.2 mL) was added NaIO (123 mg, 0.577 mmol) and potassium citrate (7.09 mg, 19 μmol). The mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated NaHCO solution and extracted with ethyl acetate. The organic layers were combined and concentrated to give 4-amino-1-(2-chloro-4-fluorophenyl)-1-hydroxy-7-nitro-3-oxo-2,3-dihydro-1H-isoindole-5-carbaldehyde (60 mg, 0.164 mmol, 85%) as a brown solid. LCMS:ESI m / z 366[M+H] + .

[0365] Step K: To a solution of 4-amino-1-(2-chloro-4-fluorophenyl)-1-hydroxy-7-nitro-3-oxo-2,3-dihydro-1H-isoindole-5-carbaldehyde (50 mg, 0.137 mmol) in THF (2 mL) was added NaBH (10.3 mg, 0.273 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (approximately 10 mL) and extracted with EtOAc (approximately 20 mL × 2). The combined organic phase was washed with brine, dried over NaSO, and concentrated to give a residue. The residue was purified by column chromatography (eluted with (MeOH:DCM=10%)) to give 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-4-nitro-2,3-dihydro-1H-isoindol-1-one (40 mg, 0.109 mmol, 80%) as a brown solid. LCMS: ESI m / z 368 [M+H] + .

[0366] Step L: To a solution of 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-4-nitro-2,3-dihydro-1H-isoindol-1-one (70 mg, 0.190 mmol) in THF (1 mL) was added CDI (34.0 mg, 0.209 mmol). The mixture was stirred at 95 °C for 2 days. The cooled mixture was diluted with HO and extracted with EA. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH:DCM = 1:10) to give 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-4-nitro-2,3-dihydro-1H-isoindol-1-one (20 mg, 54 μmol, 29%) as a brown solid. LCMS:ESI m / z 394[M+H] + .

[0367] Step M: To a solution of 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-4-nitro-2,3-dihydro-1H-isoindol-1-one (30 mg, 82 μmol) and Fe (21.3 mg, 0.381 mmol) in EtOH (1 mL) was added NH4Cl (20.4 mg, 0.381 mmol) in HO (0.3 mL). The reaction mixture was heated to 85 °C for 2 h. The mixture was then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (MeOH:DCM = 1:10) to give 4,7-diamino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-2,3-dihydro-1H-isoindol-1-one (20 mg, 59 μmol, 73%) as a brown solid. LCMS:ESI m / z 364[M+H] + .

[0368] Step N: To a solution of 6-amino-7-(2-chloro-4-fluorophenyl)-7-hydroxy-1,2,4,7,8,9-hexahydro[1,3]oxazino[4,5-e]isoindole-2,9-dione (20 mg, 55 μmol) in ACN (3 mL) was added Py (21.7 mg, 0.275 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (16.2 mg, 71 μmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was then diluted with water (approximately 20 mL) and extracted with ethyl acetate (approximately 20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over NaSO, and concentrated to give N-[5-(5-chloro-2-fluorophenyl)-3-cyano-5-hydroxy-2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]indazol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 45 μmol, 82%) as a brown solid. LCMS: ESI m / z 554 [M+H] + .

[0369] Step O: To a solution of N-[7-(2-chloro-4-fluorophenyl)-7-hydroxy-2,9-dioxo-1,2,4,7,8,9-hexahydro[1,3]oxazino[4,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 18 μmol) in TFA (1 mL) was added EtSiH (0.2 mL, 18 μmol). The reaction mixture was stirred at 60° C. for 30 minutes. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give N-[7-(2-chloro-4-fluorophenyl)-2,9-dioxo-1,2,4,7,8,9-hexahydro[1,3]oxazino[4,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3.5 mg, 7 μmol, 36%) as a white solid. LCMS: ESI m / z 538 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.31 (s, 1H), 8.91 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.34 (d, J = 4.4 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.10 (dd, J = 8.4, 5.2 Hz, 1H), 6.70 - 6.50 (s, 0.5H), 6.00 (brs, 1H), 5.52 (s, 2H).

[0370] [Example 45] N-[7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-2,3,4,7,8,9-hexahydro[1,3]oxazino[6,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0371] Step A. To a solution of 2,6-dibromo-3-methyl-4-nitrophenol (10 g, 32.1 mmol) in CHCN (100 mL) was added KCO (8.89 g, 64.3 mmol) and CHCl (3.9 mL, 48.2 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0–15%] to give 1,3-dibromo-2-methoxy-4-methyl-5-nitrobenzene (10 g, 30.7 mmol, 96%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 3.87 (s, 3H), 2.46 (s, 3H).

[0372] Step B. To a solution of 1,3-dibromo-2-methoxy-4-methyl-5-nitrobenzene (10 g, 30.7 mmol) in CCl4 (120 mL) was added NBS (6.30 g, 36.9 mmol) and AIBN (0.25 g, 1.53 mmol). The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was diluted with HO and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0–20%] to give 1,3-dibromo-4-(bromomethyl)-2-methoxy-5-nitrobenzene (10 g, 24.7 mmol, 80%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 4.80 (s, 2H), 3.90 (s, 3H).

[0373] Step C. To a solution of 1,3-dibromo-4-(bromomethyl)-2-methoxy-5-nitrobenzene (10 g, 24.7 mmol) in CH3CN (60 mL) was added NMO (5.80 g, 49.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0-30%] to obtain the compound 2,4-dibromo-3-methoxy-6-nitrobenzene-1-carbaldehyde (8.1 g, 24.0 mmol, 97%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.56 (s, 1H), 3.93 (s, 3H).

[0374] Step D. To a solution of 2,4-dibromo-3-methoxy-6-nitrobenzene-1-carbaldehyde (8.1 g, 24.0 mmol) in THF (100 mL) was added bromo(2-chloro-5-fluorophenyl)magnesium (126 mL, 126 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with NH4Cl and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0-40%] to obtain the compound (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanol (7.1 g, 14.9 mmol, 59%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.54 (dd, J = 8.8, 5.2 Hz, 1H), 7.25 (td, J = 8.4, 3.2 Hz, 1H), 7.06 (dd, J = 9.6, 3.2 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), 6.24 (d, J = 5.6 Hz, 1H), 3.84 (s, 4H).

[0375] Step E. To a stirred solution of (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanol (10 g, 21.3 mmol) in DCM (120 mL) at 0 °C, Dess-Martin (9.1 g, 21.3 mmol) was slowly added. After stirring at room temperature for 3 h, the mixture was poured into ice-water (20 mL) and extracted with DCM (10 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–50%, EtOAc in PE) to give (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanone (8.4 g, 17.9 mmol, 84%) as a yellow solid. LCMS: m / z 468 [M+H] - . 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.81 (dd, J = 9.2, 3.2 Hz, 1H), 7.74 (dd, J = 8.8, 4.8 Hz, 1H), 7.65 - 7.58 (m, 1H), 3.95 (s, 3H).

[0376] Step F. To a stirred solution of (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanone (4.2 g, 8.9 mmol) in dioxane (16 mL) / HO (4 mL) at room temperature was added (2,2-dimethyl-4-oxo-5-aza-3-oxahex-6-yl)trifluoro-λ 5 To the mixture were added 2.6 g (13.5 mmol), Pd(dppf)Cl (660 mg, 0.89 mmol), and KCO (3.7 g, 26.9 mmol). After stirring overnight at 70 °C under N, the cooled mixture was poured into ice-water (20 mL) and extracted with DCM (10 mL × 3). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–50%, EtOAc in PE) to give 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]methanoate (930 mg, 1.8 mmol, 20%) as a yellow solid. LCMS: m / z 517 [M+H] + .

[0377] Step G. To a stirred solution of 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]methanoate (900 mg, 1.7 mmol) in DMF (20 mL) was slowly added NaH (125 mg, 5.2 mmol, 60% in mineral oil) at −20° C. After stirring at −20° C. for 1 h, CHI (0.2 mL, 2.6 mmol) was added to the mixture. After stirring at room temperature for 2 h, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(methyl)amino]methanoate (430 mg, 0.81 mmol, 46%) as a yellow solid. LCMS: m / z 531 [M+H] + .

[0378] Step H. To a stirred solution of 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(methyl)amino]methanoate (400 mg, 0.752 mmol) in EtOH (12 mL) / HO (3 mL) at room temperature was added NHCl (161 mg, 3.1 mmol) and Fe (420 mg, 7.5 mmol). After stirring at 80 °C for 2 h, the mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0–50%, EtOAc in PE) to afford 2-methylpropan-2-yl[({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)(methyl)amino]methanoate (300 mg, 0.59 mmol, 79%) as a yellow solid. LCMS: m / z 502 [M+H] + .

[0379] Step I. To a stirred solution of 2-methylpropan-2-yl[({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)(methyl)amino]methanoate (280 mg, 0.56 mmol) in NMP (3 mL) was added CuCN (150 mg, 1.7 mmol) at room temperature. After stirring at 130 °C under N for 2 h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated to no further drop. The residue was purified by preparative HPLC (C18, 40-90% MeCN in HO with 0.1% FA) to give 2-methylpropan-2-yl[({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(methyl)amino]methanoate (230 mg, 0.51 mmol, 92%) as a yellow solid. LCMS: m / z 448 [M+H] + .

[0380] Step J. To a stirred solution of 2-methylpropan-2-yl[({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(methyl)amino]methanoate (230 mg, 0.51 mmol) in ACN (2 mL) / HO (1 mL) was added KOH (288 mg, 5.1 mmol) slowly at room temperature. After stirring at room temperature for 1 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to afford 2-methylpropan-2-yl ({[7-amino-1-(2-chloro-5-fluorophenyl)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(methyl)amino)methanoate (170 mg, 0.36 mmol, 71%) as a white solid. LCMS: m / z 466 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.96 (dd, J = 10.4, 3.2 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.29 - 7.18 (m, 1H), 6.99 (s, 1H), 6.53 (s, 1H), 4.47 (s, 2H), 4.34 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H), 2.75 (s, 3H), 1.41 (d, J = 19.4 Hz, 10H).

[0381] Step K. To a stirred solution of 2-methylpropan-2-yl ({[7-amino-1-(2-chloro-5-fluorophenyl)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(methyl)amino)methanoate (150 mg, 0.32 mmol) in ACN (2 mL) was added pyridine (76 mg, 0.97 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (145 mg, 0.64 mmol) slowly at room temperature. After stirring at room temperature for 1 hour, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 2-methylpropan-2-yl ({[1-(2-chloro-5-fluorophenyl)-7-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(methyl)amino)methanoate (180 mg, 0.27 mmol, 85%) as a brown solid. LCMS: m / z 656 [M+H] + .

[0382] Step L. To a stirred solution of 2-methylpropan-2-yl ({[1-(2-chloro-5-fluorophenyl)-7-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(methyl)amino)methanoate (170 mg, 0.26 mmol) in TFA (5 mL) at room temperature was added EtSiH (1 mL). After stirring at 70 °C for 2 h, the cooled mixture was concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-6-[(methylamino)methyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (120 mg, 0.22 mmol, 86%) as a white solid. LCMS: m / z 540 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.17 (s, 1H), 8.82 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.68-7.60 (m, 2H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.11 (td, J = 8.4, 2.8 Hz, 1H), 5.96 (brs, 1H), 4.25 (d, J = 7.7 Hz, 2H), 4.19 (s, 3H), 2.62 (s, 3H).

[0383] Step M-N: To a stirred solution of [3-(2-chloro-5-fluorophenyl)-7-methoxy-6-[(methylamino)methyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (110 mg, 0.21 mmol) in ACN (6 mL) was added TMSCl (110 mg, 1.1 mmol) and NaI (152 mg, 1.1 mmol) at room temperature. After stirring at 90 °C for 4 h, the cooled mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-12%, MeOH in DCM) to give N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-6-[(methylamino)methyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.17 mmol, 87%) as a white solid. LCMS: m / z 526 [M+H] + .

[0384] Step 1: To a stirred solution of N-N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-6-[(methylamino)methyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.17 mmol) in dioxane (5 mL) was added CDI (42 mg, 0.26 mmol) at room temperature. After stirring at 50 °C for 1 hour, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN in HO with 0.1% TFA) to give N-[7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-2,3,4,7,8,9-hexahydro[1,3]oxazino[6,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (24 mg, 0.04 mmol, 25%) as a white solid. LCMS: m / z 552 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.05 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.37 - 7.27 (m, 2H), 7.09 (td, J = 8.4, 2.8 Hz, 1H), 5.92 (brs, 1H), 4.68 - 4.55 (m, 2H), 3.03 (s, 3H).

[0385] [Example 46] N-(7-(2-chloro-5-fluorophenyl)-9-oxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0386] Step A: To a solution of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (450 mg, 1.15 mmol) in DMSO (5 mL) was added K2CO3 (319 mg, 2.31 mmol) and 1,2-dibromoethane (0.150 mL, 1.73 mmol). The reaction mixture was stirred at 80 °C under N2 for 1 h. The reaction was complete and monitored by TLC. The cooled reaction mixture was dissolved in EA (20 mL), washed with HO (20 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-100% EA in PE) to give (5-bromo-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.481 mmol, 42%) as a yellow solid. LCMS: ESI m / z 415.6 / 417.6 [M+H] + .

[0387] Step B: To a solution of (5-bromo-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.481 mmol) in DMF (5 mL) was added KCO (199 mg, 1.44 mmol) and 4-methoxybenzyl chloride (150 mg, 0.962 mmol). The reaction mixture was stirred at 60 °C under N for 3 h. The reaction was complete and monitored by TLC. The cooled reaction mixture was dissolved in EA (20 mL), washed with HO (20 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 0–100% EA in PE) to give (5-bromo-4-(4-methoxybenzyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.373 mmol, 78%) as a yellow oil.

[0388] Step C: To a solution of (5-bromo-4-(4-methoxybenzyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (100 mg, 0.187 mmol) in EtOH (3 mL) and HO (1 mL) was added NHCl (29.9 mg, 0.560 mmol) and Fe (104 mg, 1.87 mmol). The reaction mixture was stirred at 45 °C under N for 1 h. The reaction was complete and monitored by TLC. The cooled reaction mixture was filtered and concentrated. It was then dissolved in EA (10 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to give (7-amino-5-bromo-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (55.0 mg, 0.109 mmol, 58%) as a yellow solid. LCMS: ESI m / z 505.77 / 507.55 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (dd, J = 8.8, 4.8 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.38 (dd, J = 8.8, 3.2 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.37 (s, 1H), 5.97 (s, 2H), 4.23 - 4.16 (m, 2H), 3.92 (s, 2H), 3.73 (s, 3H), 2.83 - 2.77 (m, 2H).

[0389] Step D: To a solution of (7-amino-5-bromo-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (50.0 mg, 0.0990 mmol) in ACN (3 mL) was added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (22.4 mg, 0.0990 mmol) and Py (0.024 mL, 0.297 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The reaction was complete and monitored by LCMS. The cooled reaction mixture was dissolved in EA (10 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-20% EA in PE) to give N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50.0 mg, 0.0720 mmol, 73%) as a yellow oil. LCMS: ESI m / z 695.87 / 697.87 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.04 - 7.98 (m, 3H), 7.93 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 11.6 Hz, 2H), 7.51 (t, J = 2.4 Hz, 1H), 7.49 (t, J = 2.4 Hz, 1H), 7.38 - 7.30 (m, 2H), 6.98 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 4.29 - 4.23 (m, 2H), 4.14 (s, 2H), 3.76 (s, 3H), 2.98 - 2.91 (m, 2H).

[0390] Step E: To a solution of N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.158 mmol) in NMP (5 mL) was added CuCN (21.2 mg, 0.237 mmol). The reaction mixture was stirred at 120 °C under N for 3 h. The reaction was complete and monitored by LCMS. The cooled reaction mixture was dissolved in EA (20 mL), washed with HO (15 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to give N-(6-(2-chloro-5-fluorobenzoyl)-5-cyano-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80.0 mg, 0.125 mmol, 79%) as a yellow oil. LCMS: ESI m / z 642.98 [M+H] + .

[0391] Step F: To a solution of N-(6-(2-chloro-5-fluorobenzoyl)-5-cyano-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80.0 mg, 0.125 mmol) in ACN (3 mL) and HO (1 mL) was added KOH (34.9 mg, 0.623 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was complete and monitored by TLC. The reaction mixture was dissolved in EA (20 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, and concentrated to give N-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-1-(4-methoxybenzyl)-9-oxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80.0 mg, 0.121 mmol, 97%) as a yellow solid. LCMS: ESI m / z 660.99 [M+H]+ .

[0392] Step G: To a solution of N-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-1-(4-methoxybenzyl)-9-oxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80.0 mg, 0.121 mmol) in TFA (2 mL) was added EtSiH (400 μL, 2.50 mmol) and TfOH (80 μL, 0.904 mmol). The reaction mixture was stirred at 70 °C for 1 h. The reaction was complete and monitored by LCMS. The reaction mixture was concentrated and purified by preparative HPLC (C18, 30-95% ACN in HO with 0.1% TFA) to give N-(7-(2-chloro-5-fluorophenyl)-9-oxo-1,2,3,7,8,9-hexahydro-[1,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (42.3 mg, 0.0810 mmol, 67%) as a white solid. LCMS: ESI m / z 524.07 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.73 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.63 (s, 1H), 7.27 (dd, J = 8.8, 5.2 Hz, 1H), 7.06 (td, J = 8.4, 2.8 Hz, 1H), 6.73 (s, 1H), 6.64 (brs, 1H), 5.82 (brs, 1H), 4.23 (dd, J = 11.2, 4.6 Hz, 2H), 3.40 - 3.36 (m, 2H).

[0393] [Example 47] N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-2,9-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3,4-f]quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0394] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl)methanone (10 g, 22.0 mmol) in dioxane (100 mL) was added DIEA (3.8 mL, 22.0 mmol) and 2,2-difluoroethan-1-amine (1.5 mL, 22.0 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (100 mL × 3). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 5–8%) to give (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}methanone (1.9 g, 3.7 mmol, 17%) as a green oil. LCMS: m / z 455 [M+H] + .

[0395] Step B: To a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}methanone (1.9 g, 3.68 mmol) in EtOH (15 mL) was added Fe (2.05 g, 36.8 mmol) and saturated NH4Cl (5 mL). The reaction was stirred at 80 °C for 3 h. The cooled reaction mixture was filtered and concentrated. The residue was diluted with water and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (20% gradient) to give {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (1.78 g, 3.66 mmol, 99%) as an orange solid. LCMS: m / z 487 [M+H] +

[0396] Step C: To a solution of {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (1.26 g, 2.59 mmol) in DMF (10 mL) was added pyridine (1.05 mL, 12.9 mmol) and chloroacetyl chloride (320 mg, 2.85 mmol). The mixture was stirred at 20 °C for 1 h. The residue was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na SO , and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-30%) to give 2-chloro-N-{2,4-dibromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-[(2,2-difluoroethyl)amino]phenyl}acetamide (900 mg, 1.60 mmol, 62%) as a yellow solid. LCMS: ESI m / z 563.1 [M+H] + .

[0397] Step D: To a solution of 2-chloro-N-{2,4-dibromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-[(2,2-difluoroethyl)amino]phenyl}acetamide (900 mg, 1.60 mmol) in CH3CN (50 mL) was added DIEA (619 mg, 4.80 mmol) and NaI (479 mg, 3.20 mmol). The mixture was stirred at 130 °C for 30 min (neat). The cooled residue was purified by silica gel chromatography (20 g column) using 0-30% PE / EA to give 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1,2,3,4-tetrahydroquinoxalin-2-one (360 mg, 0.684 mmol, 43%) as a brown solid. LCMS:ESI m / z 527.2[M+H] + .

[0398] Step E: To a solution of 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1,2,3,4-tetrahydroquinoxalin-2-one (240 mg, 0.456 mmol) in THF (24 mL) was added NaH (54.7 mg, 1.37 mmol, 60% in mineral oil). The mixture was stirred at 20 °C for 10 min. SEMCl (152 mg, 0.912 mmol) was added, and the mixture was stirred at 20 °C for 30 min. The mixture was diluted with ice water (30 mL) and extracted with EA (30 mL × 3). The organic layer was washed with brine, dried over Na SO , and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0–30% EtOAc / hexanes to give 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,4-tetrahydroquinoxalin-2-one (180 mg, 0.274 mmol, 60%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 8.9, 5.0 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.65 (s, 1H), 7.49 (dd, J = 8.8, 2.8 Hz, 1H), 6.25-6.42 (m, 1H), 5.64 (s, 2H), 4.12 - 4.00 (m, 4H), 3.37 - 3.32 (m, 2H), 0.80 - 0.73 (m, 2H), 0.00 (s, 9H).

[0399] Step F: To a solution of 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,4-tetrahydroquinoxalin-2-one (180 mg, 0.274 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (85.1 mg, 0.411 mmol) in dioxane (9 mL) was added CsCO (268 mg, 0.822 mmol), Xant-PHOS (31.7 mg, 0.055 mmol), and Pd(dba) (25.1 mg, 0.027 mmol). The mixture was stirred at 95 °C under N for 12 h. The cooled mixture was concentrated, and the residue was purified by silica gel chromatography (5 g column) using 0–30% EtOAc / hexanes to give N-{8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl}-5-fluoro-3-(trifluoromethyl)benzamide (75 mg, 0.096 mmol, 35%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 14.4 Hz, 2H), 7.61 (dd, J = 8.8, 4.8 Hz, 1H), 7.49 - 7.39 (m, 2H), 7.27 (s, 1H), 6.51 - 6.20 (m, 1H), 5.62 (s, 2H), 4.08 (s, 2H), 4.02 - 3.91 (m, 2H), 3.34 (d, J = 8.4 Hz, 2H), 0.81 - 0.73 (m, 2H), 0.02 - 0.02 (m, 9H).

[0400] Step G: To a solution of N-{8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl}-5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.128 mmol) in DMA (4 mL) was added Zn(CN) (22.5 mg, 0.192 mmol) and Pd(PPh) (14.8 mg, 0.013 mmol). The mixture was stirred at 150 °C in a microwave under N for 1 h. The mixture was purified by preparative TLC (PE / EA=7:3) to give N-{7-[(2-chloro-5-fluorophenyl)carbonyl]-8-cyano-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl}-5-fluoro-3-(trifluoromethyl)benzamide (35 mg, 0.048 mmol, 38%) as a brown solid. LCMS: ESI m / z 727 [MH] - .

[0401] Step H: To a solution of N-{7-[(2-chloro-5-fluorophenyl)carbonyl]-8-cyano-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl}-5-fluoro-3-(trifluoromethyl)benzamide (35 mg, 0.048 mmol) in CHCN (3 mL) and HO (1 mL) was added KOH (8.08 mg, 0.144 mmol). The mixture was stirred at 20 °C for 30 min. The reaction mixture was diluted with water and extracted with EA (10 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated to give N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-7-hydroxy-2,9-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[4,3-f]quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (35 mg, 0.042 mmol, 88%) as a brown solid. LCMS: ESI m / z 745 [MH] - .

[0402] Step I: A solution of N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-7-hydroxy-2,9-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[4,3-f]quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.040 mmol) in HCl / dioxane (3 mL) was stirred at 20° C. for 30 minutes. The mixture was concentrated in vacuo to give N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-7-hydroxy-2,9-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[4,3-f]quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.039 mmol, 97%) as a brown solid. LCMS: ESI m / z 615 [MH] - .

[0403] Step J: To a solution of N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-7-hydroxy-2,9-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[4,3-f]quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.049 mmol) in TFA (2 mL) was added EtSiH (0.5 mL, 0.008 mmol), and the mixture was stirred at 70° C. for 30 min. The cooled mixture was concentrated. The residue was purified by preparative HPLC to give N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-2,9-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3,4-f]quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2 mg, 0.003 mmol, 7%) as a white solid. LCMS: ESI m / z 601 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.62 (s, 1H), 9.22 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.66 (s, 1H), 7.30 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (td, J = 8.4, 3.2 Hz, 1H), 6.91 (s, 1H), 6.76 (brs, 1H), 6.52-6.20 (m, 1H), 5.89 (brs, 1H), 4.16 (s, 2H), 3.87 - 3.71 (m, 2H).

[0404] [Example 50] N-(7'-(2-chloro-5-fluorophenyl)-2',9'-dioxo-1',7',8',9'-tetrahydro-2'H-spiro[cyclopropane-1,3'-[1,4]oxazino[3,2-e]isoindol]-6'-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0405] Step A: To a solution of ethyl 1-hydroxycyclopropane-1-carboxylate (2.06 g, 15.8 mmol) in THF (20 mL) was added NaH (0.470 g, 19.7 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min under N 2 . 15-Crown-5 (0.580 g, 2.63 mmol) and (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl)methanone (6.00 g, 13.1 mmol) in THF (20 mL) were added. The reaction mixture was stirred at room temperature under N 2 for 1 h. The reaction was complete and monitored by TLC. The cooled reaction mixture was quenched with water and extracted with EA (80 mL). The organic phase was washed with HO (50 mL) and brine, dried over Na 2 SO 4 , and concentrated. The residue was purified by silica gel chromatography (eluting with 0-30% EA in PE) to give ethyl 1-({3,5-dibromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-nitrophenyl}oxy)cyclopropane-1-carboxylate (5.50 g, 9.72 mmol, 73%) as a yellow solid. LCMS: ESI m / z 564.57 / 566.57 / 568.57 [M+H] + .

[0406] Step B: To a solution of ethyl 1-({3,5-dibromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-nitrophenyl}oxy)cyclopropane-1-carboxylate (3.00 g, 5.30 mmol) in EtOH (30 mL) and HO (30 mL) was added NHCl (0.850 g, 15.9 mmol) and Fe (2.96 g, 53.0 mmol). The reaction mixture was stirred at 45 °C under N for 1 h. The reaction was complete and monitored by TLC. The cooled reaction mixture was filtered, concentrated, diluted with water, and extracted with EA (80 mL). The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to give ethyl 1-({2-amino-3,5-dibromo-4-[(2-chloro-5-fluorophenyl)carbonyl]phenyl}oxy)cyclopropane-1-carboxylate (1.90 g, 3.54 mmol, 66%) as a yellow solid. LCMS: ESI m / z 534.59 / 536.59 / 538.59 [M+H] + .

[0407] Step C: To a solution of ethyl 1-({2-amino-3,5-dibromo-4-[(2-chloro-5-fluorophenyl)carbonyl]phenyl}oxy)cyclopropane-1-carboxylate (1.90 g, 3.54 mmol) in THF (20 mL) was added LiHMDS (7.09 mL, 7.09 mmol) at −78° C. The reaction mixture was stirred at room temperature under N for 1 h. The reaction was complete and monitored by TLC. The reaction mixture was quenched with water and extracted with EA (80 mL). The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-10% EA in PE) to give 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropan]-3-one (1.70 g, 3.47 mmol, 97%) as a white solid. LCMS: ESI m / z 488.52 / 490.52 / 492.52 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.72 (dd, J = 8.8, 4.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 1.36 (s, 2H), 1.28 (s, 2H).

[0408] Step D: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3,4-dihydrospiro[benzo[1,4]oxazin-2,1'-cyclopropan]-3-one (850 mg, 1.73 mmol) in DMF (15 mL) was added NaH (208 mg, 5.20 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C under N for 30 min. SEM-Cl (0.922 mL, 5.20 mmol) was added. The reaction mixture was stirred at room temperature under N for 1 h. The reaction was complete and monitored by TLC. The reaction mixture was quenched with water and extracted with EA (80 mL). The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (eluting with 0–30% EA in PE) to give 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-3,4-dihydrospiro[benzo[1,4]oxazine-2,1′-cyclopropan]-3-one (700 mg, 1.12 mmol, 64%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 8.8, 4.8 Hz, 1H), 7.64 (dd, J =8.0, 3.2 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 6.0 Hz, 1H), 5.60 (s, 2H), 3.40 (t, J = 8.0 Hz, 2H), 0.90 - 0.84 (m, 2H), 0.84 - 0.76 (m, 2H), 0.74 (t, J = 8.0 Hz, 2H), 0.00 - -0.02 (m, 9H).

[0409] Step E: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-{[2-(trimethylsilyl)ethyl]oxy}-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropan]-3-one (150 mg, 0.248 mmol) in dioxane (20 mL) was added 5-fluoro-3-(trifluoromethyl)benzene-1-carboxamide (0.430 g, 2.09 mmol), CsCO (2.05 g, 6.29 mmol), Pd(dba) (0.190 g, 0.210 mmol), and Xantphos (0.240 g, 0.420 mmol). The reaction mixture was stirred at 100 °C under N for 1 h. The reaction was complete and monitored by TLC. The cooled reaction mixture was diluted with water and extracted with EA (80 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (eluting with 20 to 100% EA in PE) to give N-{5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-3-oxo-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropan]-7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (820 mg, 1.09 mmol, 52%) as a yellow solid. LCMS: ESI m / z 744.00 / 746.00 [M+H] + .

[0410] Step F: To a solution of N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-3-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydrospiro[benzo[1,4]oxazine-2,1′-cyclopropan]-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (435 mg, 0.583 mmol) in dioxane (5 mL) was added HCl / dioxane (5 mL). The reaction mixture was stirred at 60° C. overnight. The reaction was complete and monitored by LCMS. The cooled reaction mixture was concentrated. The residue was purified by silica gel chromatography (eluting with 0-100% EA in PE) to give N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-3-oxo-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropan]-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.162 mmol, 27%) as a yellow solid. LCMS: ESI m / z 615.74 / 617.74 [M+H] + .

[0411] Step G: To a solution of N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-3-oxo-3,4-dihydrospiro[benzo[1,4]oxazine-2,1′-cyclopropan]-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.162 mmol) in NMP (3 mL) was added CuCN (21.8 mg, 0.244 mmol). The reaction mixture was stirred at 130° C. under N for 3 h. The reaction was complete and monitored by LCMS. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-100% EA in PE) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-3-oxo-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropan]-7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (90.0 mg, 0.160 mmol, 98%) as a yellow oil. LCMS: ESI m / z 562.85 [M+H]+ .

[0412] Step H: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-3-oxo-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropan]-7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (90.0 mg, 0.160 mmol) in ACN (1 mL) and HO (1 mL) was added KOH (8.99 mg, 0.160 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was complete and monitored by LCMS. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated to give N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,9-dioxo-2,7,8,9-tetrahydro-1H-spiro[[1,4]oxazino[3,2-e]isoindol-3,1'-cyclopropan]-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (90.0 mg, 0.155 mmol, 96%) as a yellow oil. LCMS: ESI m / z 580.86 [M+H] + .

[0413] Step I: To a solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,9-dioxo-2,7,8,9-tetrahydro-1H-spiro[[1,4]oxazino[3,2-e]isoindol-3,1'-cyclopropan]-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.155 mmol) in TFA (1 mL) was added EtSiH (0.200 mL). The reaction mixture was stirred at 50° C. for 0.5 h. The reaction was complete and monitored by LCMS. The reaction mixture was concentrated and purified by preparative HPLC (C18, 30-95% ACN in HO with 0.1% TFA) to give N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-2,7,8,9-tetrahydro-1H-spiro[[1,4]oxazino[3,2-e]isoindol-3,1'-cyclopropan]-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (22.7 mg, 0.0402 mmol, 23%) as a yellow solid. LCMS: ESI m / z 564.87 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.60 (s, 1H), 9.32 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.08 (td, J = 8.4, 3.2 Hz, 1H), 7.04 (s, 1H), 5.96 (brs, 1H), 1.41 - 1.31 (m, 4H).

[0414] [Example 51] N-[6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-[1,3]oxazolo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0415] Step A: To a stirred solution of N-{3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}-2,2,2-trifluoroacetamide (1.2 g, 2.40 mmol) in THF (6 mL) was added borane-methyl sulfide complex (0.36 mL, 3.60 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 2 h. The cooled mixture was quenched with water (100 mL) and extracted with EA (100 mL × 2). The combined organic phase was washed with brine (100 mL), dried over Na SO , and concentrated. The residue was purified by silica gel chromatography (PE / EA = 1 / 100 to 100 / 1) to give {2-bromo-3-methoxy-6-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (170 mg, 0.35 mmol, 15%) as a yellow oil. LCMS: m / z 486.2 [M+H] + .

[0416] Step B: To a solution of {2-bromo-3-methoxy-6-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (330 mg, 0.68 mmol) in EtOH / HO (5:1) (10 mL) was added Fe (190 mg, 3.40 mmol) and NHCl (182 mg, 3.40 mmol). The reaction was stirred at 80 °C for 2 h. The cooled reaction mixture was filtered, concentrated, diluted with water, and extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated to give the crude compound {6-amino-2-bromo-3-methoxy-4-[(2,2,2-trifluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (250 mg, 0.549 mmol, 81%) as a yellow oil. LCMS: m / z 457.2 [M+H] + .

[0417] Step C: To a solution of {6-amino-2-bromo-3-methoxy-4-[(2,2,2-trifluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (200 mg, 0.439 mmol) in ACN (5 mL) was added pyridine (0.107 mL, 1.317 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (150 mg, 0.658 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated to give crude compound N-{3-bromo-2-[(2-chloro-5-fluorophenyl)carbonyl]-4-methoxy-5-[(2,2,2-trifluoroethyl)amino]phenyl}-3-fluoro-5-(trifluoromethyl)benzamide (200 mg, 0.310 mmol, 71%) as a yellow oil. LCMS: m / z 646.9 [M+H] + .

[0418] Step D: To a solution of N-{3-bromo-2-[(2-chloro-5-fluorophenyl)carbonyl]-4-methoxy-5-[(2,2,2-trifluoroethyl)amino]phenyl}-3-fluoro-5-(trifluoromethyl)benzamide (180 mg, 0.279 mmol) in DMA (2 mL) was added Zn(CN) (39.3 mg, 0.335 mmol) and Pd(PPh) (32.2 mg, 0.028 mmol). The reaction mixture was degassed with N and stirred at 130 °C for 1 h under N using a microwave. The cooled reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with EA / PE (1 / 100 to 2 / 1) to obtain the compound N-{2-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-4-methoxy-5-[(2,2,2-trifluoroethyl)amino]phenyl}-3-fluoro-5-(trifluoromethyl)benzamide (130 mg, 0.22 mmol, 79%) as a yellow oil. LCMS: m / z 592.1 [M+H] + .

[0419] Step E: To a solution of N-{2-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-4-methoxy-5-[(2,2,2-trifluoroethyl)amino]phenyl}-3-fluoro-5-(trifluoromethyl)benzamide (140 mg, 0.237 mmol) in ACN (5 mL) and HO (1.00 mL) was added KOH (66.4 mg, 1.18 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1% to 60%) to give the compound N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-1-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (140 mg, 0.23 mmol, 97%) as a white solid. LCMS: m / z 608.0 [MH] - .

[0420] Step F: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-1-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (140 mg, 0.230 mmol) in TFA (5 mL) was added EtSiH (267 mg, 2.30 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction was concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in DCM (0% to 10%) to give the compound N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (130 mg, 0.219 mmol, 95%) as a yellow oil. LCMS m / z: 594.3 [M+H] + .

[0421] Step G: To a solution of N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (130 mg, 0.219 mmol) in DCM (5 mL) under N was added tribromoborane (0.042 mL, 0.438 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with MeOH (2 mL) and concentrated to give crude N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.172 mmol, 78%) as a pale red solid. LCMS: m / z 580.1 [M+H] + .

[0422] Step H: To a solution of N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.034 mmol) in dioxane (2 mL) was added CDI (8.39 mg, 0.052 mmol). The reaction was stirred at 100° C. for 5 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC (30% to 70% acetonitrile in water with 0.1% FA) to give N-[6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-[1,3]oxazolo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.017 mmol, 48%) as a white solid. LCMS: m / z 606.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.28 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.35 - 7.24 (m, 1H), 7.16 - 7.01 (m, 1H), 6.68 (brs, 1H), 6.05 (brs, 1H), 5.03 - 4.74 (m, 2H).

[0423] [Example 52] N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2,8-dioxo-7,8-dihydro-6H-[1,3]oxazolo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0424] Step A: To a solution of 4-amino-3-methoxybenzoic acid (25 g, 149 mmol) in 800 mL of EtOAc was added a solution of TFAA (24.9 mL, 179 mmol) in 100 mL of EtOAc at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated to give 3-methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (40 g, 152 mmol, 100%) as a yellow solid. LCMS: m / z 262.1 [M−H] - .

[0425] Step B: To a solution of 3-methoxy-4-[(trifluoroacetyl)amino]benzoic acid (40 g, 152 mmol) in concentrated HSO (98%, 1000 mL) at 0 °C was added dropwise a solution of concentrated HNO (13.6 g). The reaction mixture was stirred at 0 °C for 1 h. The mixture was then slowly poured into ice water (2000 mL) and filtered to give 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (40 g, 129 mmol, 85%) as a brown solid. LCMS: m / z 307.0 [M−H] - .

[0426] Step C: To a solution of 5-methoxy-2-nitro-4-[(trifluoroacetyl)amino]benzoic acid (40 g, 129 mmol) in THF (400 mL) was added BH3-Me2S (10 M, 39.0 mL, 390 mmol, 3.0 equiv) portionwise at 0 °C. The reaction mixture was stirred at room temperature for 20 h. Water (100 mL) was added to the mixture, and it was extracted with EtOAc (300 mL × 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated to give 2,2,2-trifluoro-N-(4-(hydroxymethyl)-2-methoxy-5-nitrophenyl)acetamide (9.0 g, 30.6 mmol, 24%) as a yellow solid. LCMS: m / z 293.0 [M−H] - . 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.30 (s, 1H), 7.55 (s, 1H), 5.70 (t, J = 5.6 Hz, 1H), 4.90 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H).

[0427] Step D: To a solution of 2,2,2-trifluoro-N-[4-(hydroxymethyl)-2-methoxy-5-nitrophenyl]acetamide (9.0 g, 30.6 mmol) in DCM (20 mL) was added DMP (19.5 g, 45.9 mmol) at 25 °C. The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the mixture, and the mixture was extracted with DCM (50 mL × 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give 2,2,2-trifluoro-N-(4-formyl-2-methoxy-5-nitrophenyl)acetamide (8.4 g, 28.8 mmol, 94%) as a yellow solid. LCMS: m / z 291 [M−H] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 10.30 (s, 1H), 8.45 (s, 1H), 7.49 (s, 1H), 4.04 (s, 3H).

[0428] Step E: To a solution of 2,2,2-trifluoro-N-(4-formyl-2-methoxy-5-nitrophenyl)acetamide (8.4 g, 28.8 mmol) in HSO (98%, 100 mL) was added NBS (7.7 g, 43.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into ice water (200 mL) and filtered to give a residue that was triturated with petroleum ether / EtOAc (3:1, 300 mL) to give N-(3-bromo-4-formyl-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (8.4 g, 22.6 mmol, 79%) as a yellow solid. LCMS: m / z 368.9 / 370.9 [M−H] - .

[0429] Step F: To a solution of N-(3-bromo-4-formyl-2-methoxy-5-nitrophenyl)-2,2,2-trifluoroacetamide (4.3 g, 11.6 mmol) in THF (125 mL) was added bromo(2-chloro-5-fluorophenyl)magnesium (0.5 M, 130 mL, 13.6 g, 57.9 mmol). The reaction was stirred at room temperature under N for 2 hours. LCMS showed the reaction was complete. The reaction mixture was quenched with aqueous NH4Cl and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to give N-{3-bromo-4-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-2-methoxy-5-nitrophenyl}-2,2,2-trifluoroacetamide (5.5 g, 10.9 mmol, 95%) as a red oil. LCMS: ESI m / z 501 / 503 [M+H] + .

[0430] Step G: To a solution of N-{3-bromo-4-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-2-methoxy-5-nitrophenyl}-2,2,2-trifluoroacetamide (6 g, 11.9 mmol) in CHCl (200 mL) was added Dess-Martin periodinane (10.1 g, 23.9 mmol). The mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The reaction was diluted with DCM and HO. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 15–25%) to give N-{3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}-2,2,2-trifluoroacetamide (5.9 g, 11.8 mmol, 98%) as a red solid. LCMS:ESI m / z 499 / 501[M+H] + .

[0431] Step H: To a solution of N-{3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}-2,2,2-trifluoroacetamide (5 g, 10.0 mmol) in MeOH (50 mL) was added KOH (3.37 g, 60.0 mmol). The reaction was stirred at 80 °C under N for 1 h. LCMS showed the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 20-30%) to give (4-amino-2-bromo-3-methoxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (2.5 g, 6.19 mmol, 62%) as a yellow solid. LCMS:ESI m / z 403 / 405[M+H] + .

[0432] Step I: To a solution of (4-amino-2-bromo-3-methoxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (500 mg, 1.24 mmol) in EtOAc (40 mL) was added 2,2-difluoroacetic anhydride (0.172 mL, 1.49 mmol). The reaction was stirred at room temperature under N for 18 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The organic layer was separated and concentrated to give N-{3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}-2,2-difluoroacetamide (595 mg, 1.23 mmol, 100%) as an orange solid. LCMS: ESI m / z 429 / 431 [M+H] + .

[0433] Step J: To a solution of N-{3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}-2,2-difluoroacetamide (400 mg, 0.831 mmol) in THF (15 mL) was added borane dimethylsulfane (10 M, 0.125 mL, 1.24 mmol). The reaction was stirred at 70 °C under N for 2 h. LCMS showed the reaction was complete. The cooled reaction mixture was quenched with MeOH, diluted with H O, and extracted with EA. The organic phase was washed with brine, dried over Na SO , and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to give {2-bromo-4-[(2,2-difluoroethyl)amino]-3-methoxy-6-nitrophenyl}(2-chloro-5-fluorophenyl)methanone (250 mg, 0.535 mmol, 64%) as a yellow solid. LCMS: ESI m / z 467 / 469 [M+H] + .

[0434] Step K: To a solution of {2-bromo-4-[(2,2-difluoroethyl)amino]-3-methoxy-6-nitrophenyl}(2-chloro-5-fluorophenyl)methanone (200 mg, 0.428 mmol) in EtOH (15 mL) and HO (3 mL) was added Fe (119 mg, 2.13 mmol) and NHCl (114 mg, 2.14 mmol). The reaction was stirred at 80 °C under N for 2 h. LCMS showed the reaction was complete. The cooled reaction mixture was filtered, concentrated, diluted with water, and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to give {6-amino-2-bromo-4-[(2,2-difluoroethyl)amino]-3-methoxyphenyl}(2-chloro-5-fluorophenyl)methanone (165 mg, 0.377 mmol, 88%) as a yellow solid. LCMS: ESI m / z 437 / 439 [M+H] + .

[0435] Step L: To a solution of {6-amino-2-bromo-4-[(2,2-difluoroethyl)amino]-3-methoxyphenyl}(2-chloro-5-fluorophenyl)methanone (140 mg, 0.320 mmol) in DMA (10 mL) was added Zn(CN) (56.3 mg, 0.480 mmol) and Pd(PPh) (36.9 mg, 0.032 mmol). The reaction was stirred at 130 °C for 1.5 h using a microwave under N. LCMS showed the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in dichloroform (gradient: 10-20%) to give 3-amino-2-[(2-chloro-5-fluorophenyl)carbonyl]-5-[(2,2-difluoroethyl)amino]-6-methoxybenzene-1-carbonitrile (90 mg, 0.235 mmol, 73%) as a yellow oil. LCMS: ESI m / z 384 / 386 [M+H] + .

[0436] Step M: To a solution of 3-amino-2-[(2-chloro-5-fluorophenyl)carbonyl]-5-[(2,2-difluoroethyl)amino]-6-methoxybenzene-1-carbonitrile (100 mg, 0.261 mmol) in ACN (10 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (0.060 mL, 0.391 mmol) and Py (0.063 mL, 0.782 mmol). The reaction was stirred at room temperature under N for 2 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to give N-{2-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-5-[(2,2-difluoroethyl)amino]-4-methoxyphenyl}-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.192 mmol, 74%) as a yellow oil. LCMS: ESI m / z 574 [M+H] + .

[0437] Step N: To a solution of N-{2-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-5-[(2,2-difluoroethyl)amino]-4-methoxyphenyl}-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.192 mmol) in ACN (6 mL) and HO (2 mL) was added KOH (32.2 mg, 0.575 mmol). The reaction was stirred at room temperature under N for 1 h. LCMS showed the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The organic layer was separated and concentrated to give N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-3-hydroxy-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (110 mg, 0.186 mmol, 97%) as a yellow solid. LCMS: ESI m / z 590 [MH]- .

[0438] Step O: To a solution of N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-3-hydroxy-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (110 mg, 0.186 mmol) in TFA (5 mL) was added EtSiH (21.6 mg, 0.186 mmol). The reaction was stirred at 70 °C for 1 h. LCMS showed the reaction was complete. The cooled reaction mixture was concentrated, diluted with aqueous NaHCO and extracted with EA. The organic phase was washed with brine, dried over NaSO and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to give N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.139 mmol, 75%) as a yellow solid. LCMS: ESI m / z 576 [M+H] + .

[0439] Step P: To a solution of N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.139 mmol) in DCM (4 mL) and tribromoborane (69.6 mg, 0.278 mmol) was added. The reaction was stirred at room temperature for 18 hours. LCMS showed the reaction was complete. The reaction was diluted with EA and NaHCO. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative TLC eluting with ethyl acetate in petroleum ether (gradient: 40-50%) to give the compound N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (71 mg, 0.126 mmol, 91%) as a yellow solid. LCMS: ESI m / z 562 [M+H] + .

[0440] Step Q: To a solution of N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.071 mmol) in dioxane (3 mL) was added CDI (23 mg, 0.142 mmol). The reaction was stirred at 100° C. for 1 h. LCMS showed the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2,8-dioxo-7,8-dihydro-6H-[1,3]oxazolo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3.2 mg, 0.005 mmol, 8%) as a white solid. LCMS: ESI m / z 588 [M + H] +. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.26 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.34 - 7.25 (m, 1H), 7.15 - 7.05 (m, 1H), 6.60 - 6.30 (m, 1H), 6.02 (brs, 1H), 4.54 - 4.27 (m, 2H).

[0441] [Example 53] N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-3,9-dioxo-1,3,4,7,8,9-hexahydro[1,3]oxazino[5,4-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0442] Step A: To a solution of 2,6-dibromo-4-fluorobenzene-1-carbaldehyde (10 g, 35.5 mmol) in 1,2-dichloroethane (80 mL) at 25 °C was added ethylene glycol (9.9 mL, 177.4 mmol), triethoxymethane (5.0 mL, 30.5 mmol), and 4-methylbenzenesulfonic acid (0.06 g, 0.36 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled to 20 °C, washed successively with saturated NaHCO (100 mL) and brine (2 × 100 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (0% to 5%) to give 2-(2,6-dibromo-4-fluorophenyl)-1,3-dioxolane (7.8 g, 23.9 mmol, 67%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.0 Hz, 2H), 6.22 (s, 1H), 4.22 (m, 2H), 4.01 (m, 2H).

[0443] Step B: To a solution of 2-(2,6-dibromo-4-fluorophenyl)-1,3-dioxolane (11.3 g, 34.7 mmol) in THF (110 mL) was added 2N LDA (22.5 mL, 45.1 mmol) dropwise at −78° C. and stirred at −78° C. for 30 minutes. Hexahydropyridine-1-carbaldehyde (5.9 g, 52.0 mmol) was then slowly added. The reaction mixture was stirred at −78° C. for an additional 30 minutes. The mixture was then added to saturated NH4Cl (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel (10% EtOAc in PE) to give 2,4-dibromo-3-(1,3-dioxolan-2-yl)-6-fluorobenzene-1-carbaldehyde (8 g, 22.6 mmol, 65%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 6.35 (s, 1H), 4.27 - 4.21 (m, 2H), 4.07 - 4.01 (m, 2H).

[0444] Step C: To a solution of 2,4-dibromo-3-(1,3-dioxolan-2-yl)-6-fluorobenzene-1-carbaldehyde (3.9 g, 11.0 mmol) in dioxane (40 mL), DIEA (1.9 mL, 11.0 mmol) and 2,2-difluoroethan-1-amine (3.11 mL, 44.1 mmol) were added, sealed, and stirred at 80 °C overnight. The reaction mixture was quenched with 1 N HCl (50 mL) and extracted with EtOAc (70 mL × 3). The organic layer was separated, and 4-methyl-benzenesulfonic acid (2.28 g, 13.2 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes (monitored by LCMS). Brine was added, and the organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 5-10%) to give 2,4-dibromo-6-[(2,2-difluoroethyl)amino]-3-(1,3-dioxolan-2-yl)benzene-1-carbaldehyde (2.7 g, 6.5 mmol, 59%) as a yellow solid. LCMS: m / z 416 [M+H] + .

[0445] Step D: To a solution of 2,4-dibromo-6-[(2,2-difluoroethyl)amino]-3-(1,3-dioxolan-2-yl)benzene-1-carbaldehyde (760 mg, 1.83 mmol) in MeOH (7 mL) was added NaBH (83.1 mg, 2.2 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL × 3). The organic layer was separated, dried over NaSO, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 10-15%) to give {2,4-dibromo-6-[(2,2-difluoroethyl)amino]-3-(1,3-dioxolan-2-yl)phenyl}methanol (0.3 g, 0.72 mmol, 39%) as a white solid. LCMS: m / z 418 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 7.04 (s, 1H), 6.34 - 5.97 (m, 3H), 5.38 (t, J = 5.2 Hz, 1H), 4.73 (d, J = 5.2 Hz, 2H), 4.16 (t, J = 6.8 Hz, 2H), 3.94 (t, J = 6.8 Hz, 2H), 3.76 - 3.58 (m, 2H).

[0446] Step E: To a solution of {2,4-dibromo-6-[(2,2-difluoroethyl)amino]-3-(1,3-dioxolan-2-yl)phenyl}methanol (3 g, 7.2 mmol) in dioxane (10 mL) was added CDI (4.67 g, 28.8 mmol) at room temperature. The reaction mixture was stirred at 130 °C until solvent-free. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL × 3). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 0-15%) to give 5,7-dibromo-1-(2,2-difluoroethyl)-6-(1,3-dioxolan-2-yl)-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-one (1.2 g, 2.71 mmol, 38%) as a white solid. LCMS: m / z 444 [M+H] + .

[0447] Step F: To a solution of 5,7-dibromo-1-(2,2-difluoroethyl)-6-(1,3-dioxolan-2-yl)-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-one (700 mg, 1.58 mmol) in THF (7 mL) was added concentrated HCl (0.3 mL, 3.20 mmol) at room temperature. The reaction mixture was stirred for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL × 3). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 20%) to give 5,7-dibromo-1-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-6-carbaldehyde (0.6 g, 1.5 mmol, 95%) as a yellow solid. LCMS: m / z 400 [M+H] + .

[0448] Step G: To a solution of 5,7-dibromo-1-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-6-carbaldehyde (600 mg, 1.51 mmol) in THF (2 mL) was added dropwise bromo(2-chloro-5-fluorophenyl)magnesium (15.0 mL, 7.52 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was then added to saturated NH4Cl (15 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried over Na2SO4, and concentrated to give a residue. The residue was purified on silica gel (eluted with 0-15% EtOAc in petroleum ether) to give 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-one (630 mg, 1.2 mmol, 80%) as a yellow solid. LCMS: m / z 528, 530, 532 [M+H] + .

[0449] Step H: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-1-(2,2-difluoroethyl)-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-one (650 mg, 1.23 mmol) in DCM (7 mL) was added Dess-Martin periodinane (624.8 mg, 1.47 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was added to ice water (10 mL) and extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried over Na SO , and concentrated to give a residue. The residue was purified by silica gel (PE / EtOAc=15%) to give 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-one (540 mg, 1.0 mmol, 83%) as a white solid. LCMS (ESI): m / z 528 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (m, 2H), 7.65 - 7.59 (m, 1H), 7.55 (m, 1H), 6.33 (m, 1H), 5.38 (d, J = 7.2 Hz, 2H), 4.49 (m, 2H).

[0450] Step I: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-one (50 mg, 0.1 mmol), CsCO (61.8 mg, 0.19 mmol), Xant-phos (5.48 mg, 0.01 mmol), and 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (21.60 mg, 0.10 mmol) in anhydrous dioxane (2 mL) was added Pd(dba) (8.7 mg, 0.01 mmol). The mixture was stirred at 100 °C under N for 2 h. The cooled mixture was diluted with water and extracted with EA (10 mL × 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel (PE / EtOAc=10%) to give N-{5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-7-yl}-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.015 mmol, 16%) as a brown oil. LCMS (ESI): m / z 651, 653 [MH] - .

[0451] Step J: To a solution of N-{5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-7-yl}-5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.15 mmol) and Zn(CN) (26.9 mg, 0.23 mmol) in anhydrous DMA (2 mL) was added Pd(PPh) (17.7 mg, 0.02 mmol). The mixture was stirred at 150 °C under N for 2 h. The cooled mixture was diluted with water and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative TLC (PE / EtOAc=2:1) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-1-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-7-yl}-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.033 mmol, 22%) as a yellow solid. LCMS (ESI): m / z 600 [M+H] +

[0452] Step K: To a stirred solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-1-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-7-yl}-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.03 mmol) in CHCN (1 mL) was added KOH (2.86 mg, 0.05 mmol) and HO (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was treated with HO (10 mL) and extracted with EA (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated to give N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-3-hydroxy-7-(hydroxymethyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (5 mg, 0.01 mmol, 25%) as a yellow oil, which was used without further purification. LCMS (ESI): m / z 590 [MH] -

[0453] Step L: To a stirred solution of N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-3-hydroxy-7-(hydroxymethyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (5 mg, 0.01 mmol) in dioxane (1 mL) was added CDI (4 mg, 0.03 mmol) at room temperature. The mixture was stirred at 80 °C overnight. The mixture was treated with HO (5 mL) and extracted with EA (3 × 8 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated to give N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-7-hydroxy-3,9-dioxo-1,3,4,7,8,9-hexahydro[1,3]oxazino[5,4-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (5 mg, 0.002 mmol, 28%) as a yellow oil, which was used without further purification. LCMS (ESI): m / z 616 [MH] -

[0454] Step M: To a stirred solution of N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-7-hydroxy-3,9-dioxo-1,3,4,7,8,9-hexa-hydro[1,3]oxazino[5,4-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.02 mmol) in TFA (1 mL) was added triethylsilane (6 mg, 0.05 mmol) at room temperature. The mixture was stirred at 60° C. for 1 hour. The mixture was concentrated to give a residue. The residue was purified by preparative TLC (DCM / MeOH=10:1) and preparative HPLC to give N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-3,9-dioxo-1,3,4,7,8,9-hexa-hydro[1,3]oxazino[5,4-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (1 mg, 0.002 mmol, 10%) as a white solid. LCMS (ESI): m / z 602 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.76 - 7.53 (m, 3H), 7.37 (s, 1H), 7.27 (dd, J = 8.8, 5.2 Hz, 1H), 7.04 - 6.95 (m, 1H), 6.41 - 6.07 (m, 2H), 5.92 (d, J = 2.4 Hz, 2H), 4.45 - 4.32 (m, 2H).

[0455] [Example 54] N-(7-(2-chloro-5-fluorophenyl)-2,2-dioxide-9-oxo-1,7,8,9-tetrahydro-3H-[1,3,4]oxathiazino[5,6-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0456] Step A: To a solution of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (3.5 g, 8.98 mmol) and imidazole (1.22 g, 18 mmol) in DMF (25 mL) was added TBSCl (TBSCI) (2.71 g, 18 mmol). The resulting mixture was stirred at 23 °C for 2 h. The mixture was treated with HO (100 mL) and extracted with EA (3 × 300 mL). The organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether and dried to give the compound (3-amino-2-bromo-4-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (2 g, 3.97 mmol, 44%) as a yellow oil. LCMS: m / z 501 [MH] - .

[0457] Step B: To a solution of (3-amino-2-bromo-4-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (2 g, 3.97 mmol) in Py (13 mL) and THF (13 mL) was added chloromethanesulfonyl chloride (0.9 mL, 9.92 mmol). The reaction mixture was refluxed for 1 h. The reaction mixture was cooled to 25 °C, quenched with aqueous HO (30 mL), and extracted with EA (20 mL × 3). The combined organic phase was washed with brine (30 mL), dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether and dried to give the compound N-{2-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-4-nitrophenyl}-1-chloromethanesulfonamide (1.6 g, 2.6 mmol, 65%) as a yellow oil. LCMS: m / z 613 [MH] - .

[0458] Step C: A solution of N-{2-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-4-nitrophenyl}-1-chloromethanesulfonamide (1.6 g, 2.6 mmol) in DMF (6 mL) was stirred at 50 °C for 2 h. The cooled mixture was treated with HO (100 mL) and extracted with EtOAc (3 × 300 mL). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by subsequent column chromatography (PE:EA = 2:1) to give 8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-6-nitro-1H-2λ. 6 -benzo[2,1-e][1,3,4]oxathiazine-2,2-dione (700 mg, 1.5 mmol, 57.9%) was obtained as a yellow oil. LCMS: ESI m / z 465 [M+H] + .

[0459] Step D: 8-Bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-6-nitro-1H-2λ 6 To a solution of 1,2-benzo[2,1-e][1,3,4]oxathiazine-2,2-dione (700 mg, 1.5 mmol) in EtOH (28 mL) and HO (7 mL) was added Fe (420 mg, 7.52 mmol) and NHCl (402 mg, 7.52 mmol). The reaction mixture was stirred at 80 °C for 3 h. The cooled reaction mixture was filtered through a Buchner funnel and washed with EA (200 mL). The filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to give the compound 6-amino-8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-1H-2λ. 6 -benzo[2,1-e][1,3,4]oxathiazine-2,2-dione (500 mg, 1.15 mmol, 76%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 7.62 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.46 (td, J = 8.0 Hz, 4.0 Hz, 1H), 7.23 (dd, J = 8.4, 3.2 Hz, 1H), 6.54 (s, 1H), 6.02 (s, 2H), 5.18 (s, 2H).

[0460] Step E: 6-amino-8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-1H-2λ 6To a solution of 100 mg (0.23 mmol) of benzo[2,1-e][1,3,4]oxathiazine-2,2-dione in DMA (1 mL) was added Zn(CN) (80.9 mg (0.689 mmol) and Pd(PPh) (53.0 mg (0.046 mmol). The mixture was stirred at 150 °C under N for 4 h. The cooled mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give the compound 6-amino-7-[(2-chloro-5-fluorophenyl)carbonyl]-2,2-dioxo-1H-2λ. 6 -benzo[2,1-e][1,3,4]oxathiazine-8-carbonitrile (80 mg, 0.21 mmol, 91%) was obtained as a yellow solid. LCMS: ESI m / z 382 [M+H] + .

[0461] Step F: 6-amino-7-[(2-chloro-5-fluorophenyl)carbonyl]-2,2-dioxo-1H-2λ 6 To a solution of 1,3-benzo[2,1-e][1,3,4]oxathiazine-8-carbonitrile (70 mg, 0.183 mmol) in CH3CN (3 mL) and HO (0.3 mL) was added KOH (30.9 mg, 0.55 mmol). The mixture was stirred at 50 °C for 1 h. The cooled mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to give compound 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-1,7,8,9-tetrahydro-2λ 6 -[1,3,4]oxathiazino[5,6-e]isoindole-2,2,9-trione (40 mg, 0.1 mmol, 55%) was obtained as a yellow solid.

[0462] Step G: 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-1,7,8,9-tetrahydro-2λ 6To a solution of -[1,3,4]oxathiazino[5,6-e]isoindole-2,2,9-trione (40 mg, 0.1 mmol) in MeCN (1 mL) was added pyridine (0.04 mL, 0.5 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (68 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated to give N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,2,9-trioxo-1,7,8,9-tetrahydro-2λ]. 6 -[1,3,4]oxathiazino[5,6-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.034 mmol, 34%) was obtained as a yellow solid. LCMS: ESI m / z 588 [M−H] - .

[0463] Step H: N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,2,9-trioxo-1,7,8,9-tetrahydro-2λ] 6 To a solution of -[1,3,4]oxathiazino[5,6-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.034 mmol) in TFA (1.5 mL) was added triethylsilane (0.3 mL). The mixture was stirred at 70° C. for 1 hour. The cooled mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give N-[7-(2-chloro-5-fluorophenyl)-2,2,9-trioxo-1,7,8,9-tetrahydro-2λ]. 6 -[1,3,4]oxathiazino[5,6-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (1.1 mg, 0.002 mmol, 6%) was obtained as a white solid. LCMS: ESI m / z 574 [M + H] + . 1H NMR (400 MHz, CD3OD) δ 7.68 - 7.60 (m, 3H), 7.38 - 7.16 (m, 2H), 6.99 (t, J = 8.0 Hz, 1H), 6.67 (brs, 1H), 6.10 (brs, 1H), 5.22 (s, 2H).

[0464] [Example 55] N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-3-(trideuteriomethyl)-2,3,4,7,8,9-hexahydro[1,3]oxazino[6,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0465] [Example 56] (S)-N-(7-(2-chloro-5-fluorophenyl)-3-(methyl-d3)-2,9-dioxo-2,3,4,7,8,9-hexahydro-[1,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0466] [Example 57] (R)-N-(7-(2-chloro-5-fluorophenyl)-3-(methyl-d3)-2,9-dioxo-2,3,4,7,8,9-hexahydro-[1,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0467] Step A. To a stirred solution of 3-methyl-4-nitrophenol (31.2 g, 203 mmol) in DMF (300 mL) was added NBS (43.5 g, 244 mmol) at 0 °C. After stirring at 65 °C for 3 h, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–20%, EtOAc in PE) to give 2,6-dibromo-3-methyl-4-nitrophenol (45.1 g, 145 mmol, 71%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 2.51 (s, 3H).

[0468] Step B. To a solution of 2,6-dibromo-3-methyl-4-nitrophenol (44.2 g, 142 mmol) in CHCN (450 mL) was added KCO (29.5 g, 213 mmol) and CHCl (13.8 mL, 171 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0–10%] to obtain the compound 3,5-dibromo-4-methoxy-2-methyl-1-nitrobenzene (41 g, 126 mmol, 89%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 3.87 (s, 3H), 2.47 (s, 3H).

[0469] Step C. To a solution of 3,5-dibromo-4-methoxy-2-methyl-1-nitrobenzene (41 g, 126 mmol) in CCl4 (300 mL) was added NBS (20.4 g, 114 mmol) and BPO (2.3 g, 9.54 mmol). The reaction mixture was stirred at 85 °C overnight. The reaction mixture was diluted with HO and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0–15%] to obtain the compound 3,5-dibromo-2-(bromomethyl)-4-methoxy-1-nitrobenzene (46.1 g, 89 mmol, 94%) as a white solid.

[0470] Step D. To a solution of 3,5-dibromo-2-(bromomethyl)-4-methoxy-1-nitrobenzene (46.1 g, 89 mmol) in CH3CN (400 mL) was added NMO (20.9 g, 178 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0-30%] to obtain the compound 2,4-dibromo-3-methoxy-6-nitrobenzene-1-carbaldehyde (35.1 g, 74 mmol, 83%) as a yellow solid.

[0471] Step E. To a solution of 2,4-dibromo-3-methoxy-6-nitrobenzene-1-carbaldehyde (30.5 g, 89 mmol) in THF (400 mL) was added bromo(2-chloro-5-fluorophenyl)magnesium (89 mL, 135 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with NH4Cl and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [concentration gradient: 0-40%] to obtain the compound (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanol (40.2 g, 85.6 mmol, 95%) as a white solid.

[0472] Step F. To a stirred solution of (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanol (40.2 g, 85.6 mmol) in DCM (420 mL) was slowly added Dess-Martin (40 g, 94.2 mmol) at 0 °C. After stirring at room temperature for 3 h, the mixture was poured into ice-water (500 mL) and extracted with DCM (200 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–30%, EtOAc in PE) to give (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanone (35.5 g, 75.9 mmol, 89%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.82 - 7.60 (m, 3H), 3.95 (s, 3H).

[0473] Step G. To a stirred solution of (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanone (10 g, 21.4 mmol) in dioxane (80 mL) / HO (20 mL) at room temperature, add (2,2-dimethyl-4-oxo-5-aza-3-oxahex-6-yl)trifluoro-λ 5The resulting mixture was mixed with 100 mL of dimethyl ether (DMSO) and 1.25 g of dimethyl ether (DMSO). The resulting mixture was then stirred overnight at 70 °C under N2, and the cooled mixture was poured into ice-water (100 mL) and extracted with DCM (80 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–50%, EtOAc in PE) to give 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]methanoate (2.5 g, 4.83 mmol, 22%) as a brown solid. LCMS: m / z 517 [M+H] + .

[0474] Step H. To a stirred solution of 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]methanoate (1.6 g, 3.09 mmol) in DMF (20 mL) was slowly added NaH (370 mg, 9.27 mmol, 60% in mineral oil) at −20° C. After stirring at −20° C. for 1 h, CD3I (2.24 g, 15.452 mmol) was added to the mixture. After stirring at room temperature for 2 h, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(trideuteriomethyl)amino]methanoate (1 g, 1.87 mmol, 61%) as a yellow solid. LCMS: m / z 535 [M+H] + .

[0475] Step I. To a stirred solution of 2-methylpropan-2-yl[({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(trideuteriomethyl)amino]methanoate (1 g, 1.87 mmol) in EtOH (16 mL) / HO (4 mL) was added NH4Cl (300 mg, 5.61 mmol) and Fe (835 mg, 14.9 mmol) at room temperature. After stirring at 80 °C for 2 h, the mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give crude 2-methylpropan-2-yl[({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)(trideuteriomethyl)amino]methanoate (820 mg, 1.62 mmol, 87%) as a yellow solid. LCMS: m / z 505 [M+H] + .

[0476] Step J. To a stirred solution of 2-methylpropan-2-yl[({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)(trideuteriomethyl)amino]methanoate (820 mg, 1.62 mmol) in NMP (10 mL) was added CuCN (291 mg, 3.25 mmol) at room temperature. After stirring at 130 °C for 5 h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 2-methylpropan-2-yl[({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(trideuteriomethyl)amino]methanoate (550 mg, 1.22 mmol, 75%) as a yellow solid. LCMS: m / z 451 [M+H] + .

[0477] Step K. To a stirred solution of 2-methylpropan-2-yl[({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(trideuteriomethyl)amino]methanoate (500 mg, 1.1 mmol) in ACN (3 mL) / HO (1 mL) was added KOH (622 mg, 11.1 mmol) slowly at room temperature. After stirring at room temperature for 1 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 2-methylpropan-2-yl ({[7-amino-1-(2-chloro-5-fluorophenyl)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(trideuteriomethyl)amino)methanoate (480 mg, 1.02 mmol, 92%) as a white solid. LCMS: m / z 469 [M+H] + .

[0478] Step L. To a stirred solution of 2-methylpropan-2-yl ({[7-amino-1-(2-chloro-5-fluorophenyl)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(trideuteriomethyl)amino)methanoate (480 mg, 1.02 mmol) in ACN (10 mL) was slowly added pyridine (0.3 mL, 3.1 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (348 mg, 1.54 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 2-methylpropan-2-yl ({[1-(2-chloro-5-fluorophenyl)-7-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(trideuteriomethyl)amino)methanoate (420 mg, 0.637 mmol, 62%) as a brown solid. LCMS: m / z 659 [M+H] + .

[0479] Step M. To a stirred solution of 2-methylpropan-2-yl ({[1-(2-chloro-5-fluorophenyl)-7-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-1-hydroxy-4-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}(trideuteriomethyl)amino)methanoate (420 mg, 0.637 mmol) in TFA (5 mL) at room temperature was added EtSiH (2 mL). After stirring at 70 °C for 2 h, the cooled mixture was concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-6-{[(trideuteriomethyl)amino]methyl}-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (320 mg, 0.589 mmol, 92%) as a white solid. LCMS: m / z 543 [M+H] + .

[0480] Step 1: To a stirred solution of N-N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-6-{[(trideuteriomethyl)amino]methyl}-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (150 mg, 0.276 mmol) in ACN (6 mL) was added TMSCl (150 mg, 1.38 mmol) and NaI (207 mg, 1.38 mmol) at room temperature. After stirring at 90 °C for 5 h, the cooled mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-12%, MeOH in DCM) to give crude N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-6-{[(trideuteriomethyl)amino]methyl}-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (110 mg, 0.21 mmol, 75%) as a white solid. LCMS: m / z 529 [M+H] + .

[0481] Step 1: To a stirred solution of ON-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-6-{[(trideuteriomethyl)amino]methyl}-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.189 mmol) in dioxane (5 mL) was added CDI (33 mg, 0.21 mmol) at room temperature. After stirring at 50 °C for 1 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN in HO with 0.1% TFA) to give N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-3-(trideuteriomethyl)-2,3,4,7,8,9-hexahydro[1,3]oxazino[6,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (55 mg, 0.09 mmol, 47%) as a white solid. LCMS: m / z 555 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.20 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.12 - 7.06 (m, 1H), 5.92 (brs, 1H), 4.62 (t, 2H).

[0482] Step PN-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-3-(trideuteriomethyl)-2,3,4,7,8,9-hexahydro[1,3]oxazino[6,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.090 mmol) was purified by SFC to give P1 Example 56: (R)—N-(7-(2-chloro-5-fluorophenyl)-3-(methyl-d3)-2,9-dioxo-2,3,4,7,8,9-hexahydro-[1,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10.9 mg, 22%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.04 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 7.32 (s, 1H), 7.08 (s, 1H), 6.64 (brm, 1H), 5.96 (s, 1H), 4.60 (s, 2H). P2 Example 57: (S)—N-(7-(2-chloro-5-fluorophenyl)-3-(methyl-d3)-2,9-dioxo-2,3,4,7,8,9-hexahydro-[1,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (19.5 mg, 39%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.04 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 7.32 (s, 1H), 7.08 (s, 1H), 6.64 (brm, 1H), 5.96 (s, 1H), 4.60 (s, 2H).

[0483] Preparative separation method: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IA, 250 x 30 mm ID, 5 μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B45% Flow rate: 60mL / min...

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