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 the treatment of diseases and conditions, such as various types of cancer.

Description

[0001] Priority claims and related applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 393,570, filed on July 29, 2022, the entire contents of each of which are incorporated herein by reference for all purposes. Technical Field

[0003] The present invention generally relates to novel compounds and their therapeutic uses. More particularly, the present invention provides novel tricyclic compounds that have been shown to be potent and selective inhibitors of phosphoinositide 3-kinase alpha (PI3Kα). The present invention also provides pharmaceutical compositions comprising the compounds of the invention and methods for treating diseases and conditions associated with or related to PI3Kα activity, such as various types of cancer. Background Art

[0004] Phosphoinositide 3-kinases (PI3Ks) are a family of related intracellular signaling enzymes that phosphorylate the 3-hydroxyl group of the inositol ring of phosphatidylinositol (PtdIn). PI3Ks have been implicated in a diverse array of cellular functions, including cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. The PI3K signaling pathway is one of the most commonly mutated in human cancers and a major factor in many other human diseases. For example, PI3K signaling has been implicated in allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetic complications, and acute coronary syndromes.

[0005] Based on their primary structure, regulation, and lipid substrate specificity, the PI3K family is divided into three distinct classes: class I, class II, and class III. (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). Effectors such as PDPK1 / AKT bind to PIP3 and activate downstream signaling pathways.

[0006] Mutations in the class IA PI3K p110α (PI3Kα) occur in many human cancers. Angiogenesis has been shown to selectively require the PI3Kα isoform in controlling 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, small-cell and non-small-cell lung cancers, thyroid cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma. In cancer, PI3Kα mutations are often hotspot point mutations within the helical or kinase domains, 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 CareMed 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. ).

[0007] There remains an urgent and unmet need for potent and selective PI3Kα inhibitors that are safe and effective in treating diseases and disorders associated with PI3Kα, such as various types of cancer (e.g., breast cancer, ovarian cancer, colorectal cancer, lung cancer). Summary of the Invention

[0008] The present invention provides novel tricyclic compounds and derivatives thereof that are PI3Kα inhibitors and are demonstrated herein to exhibit advantageous potency and selectivity compared to known PI3Kα inhibitors. These novel compounds selectively target, bind to, inhibit, and / or modulate the activity of PI3Kα. The compounds are also orally administered and have pharmacokinetic properties suitable for development as orally administered therapeutics for the treatment of various diseases and conditions associated with or related to PI3Kα activity, such as various types of cancer.

[0009] In one aspect, the present invention generally relates to compounds having structural formula (I):

[0010]

[0011] or a pharmaceutically acceptable form or isotopic derivative thereof,

[0012] in

[0013] Ring A is surrounded by 0-10 R a 'Substituted 4- to 7-membered monocyclic non-aromatic ring;

[0014] R 1 It's Z B -R B ;

[0015] R 2 It's Z C -R C ;

[0016] X is N, CH or CR X ;

[0017] R X It's Z X -R X’ ;

[0018] Z B , Z C and Z X Each is independently a covalent bond, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O)2, NRS(O)2, S(O)2NR or selected from C 1-4 a linking group of a saturated or unsaturated divalent hydrocarbon radical, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S, and O;

[0019] R B 、R C and R X Each independently is

[0020] 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( OR

[0021] C having 0-4 ring heteroatoms independently selected from 1-6 an aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclic, heterocyclic, aryl or heteroaryl ring, each optionally substituted by one or more R b 、R c or R x replace;

[0022] R a 、R b 、R c and R x Each independently is

[0023] 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( OR

[0024] Substituted or unsubstituted selected from C 1-6 an alkyl group or a 4- to 6-membered carbocyclic group;

[0025] R and R' are each independently selected from: H, unsubstituted or substituted C 1-4 alkyl or an unsubstituted or substituted 4- to 6-membered carbocyclic ring, or wherein R and R' are attached to the same C or N atom and together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; and

[0026] i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0027] In another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0028] In yet another aspect, the present invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0029] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with an effective amount of a compound disclosed herein.

[0030] In yet another aspect, the invention generally relates to a method for inhibiting PI3K alpha activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0031] In yet another aspect, the present invention generally relates to a method for treating a disease or condition mediated by PI3Kα, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0032] In yet another aspect, the present invention generally relates to a method for treating or ameliorating cancer or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0033] In yet another aspect, the present 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 condition.

[0034] definition

[0035] 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. The 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.

[0036] As used herein, "at least" a particular value is understood to mean that value and all values ​​greater than that value.

[0037] When used to define compositions and methods, the term "comprising" is intended to mean that the compositions and methods include the stated elements, but do not exclude other elements. When used to define compositions and methods, the term "consisting essentially of shall mean that the compositions and methods include the stated elements and exclude other elements that are of any importance to the compositions and methods. For example, "consisting essentially of" refers to the administration of the pharmacologically active agents explicitly stated and excludes pharmacologically active agents that are not explicitly stated. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. When used to define compositions and methods, the term "consisting of" shall mean excluding minor elements and substantial method steps of other ingredients. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0038] Unless otherwise specified or obvious from the context, as used herein, the term "about" is understood to be within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. About can be understood to be 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 the context clearly dictates otherwise, all numerical values ​​provided herein may be modified by the term about.

[0039]

[0026] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0040] As used herein, the terms "administration" or "administering" of a disclosed compound encompasses delivering a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, to a subject using any suitable dosage form or route of administration as discussed herein.

[0041] As used herein, the term "co-administered" refers to the simultaneous presence of two agents in a subject's body (eg, in the blood). The two agents can be administered simultaneously or sequentially.

[0042] Unless otherwise indicated, the terms "disease," "disorder," and "condition" are used interchangeably.

[0043] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to affect the intended application, including but not limited to disease treatment as set forth below.

[0044] In some embodiments, the amount is sufficient to negatively regulate or inhibit the activity of PI3Kα. In some embodiments, the amount is effective to alleviate or ameliorate symptoms to stop or reverse the progression of a disease or condition (such as cancer). In some embodiments, the amount is effective to kill or inhibit the growth or spread of detectable cancer cells; tumor size or number; or other indicators of the level, stage, progression, or severity of the cancer.

[0045] The therapeutically effective amount can vary depending on the intended application or the subject and disease condition being treated, for example, the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient's weight and age, which can be easily determined by one of ordinary skill in the art. The amount can be administered in a single dose or according to a regimen. The term also applies to doses that will induce a specific response in target cells, for example, to reduce cell migration. The specific dose will vary depending on, for example, the specific compound selected, the species of the subject and their age / existing health condition or the risk of a health condition, the dosing regimen to be followed, the severity of the disease, whether to be administered in combination with other agents, the time of administration, the tissue to which it is administered, and the physiological delivery system in which it is carried.

[0046] As used herein, an "inhibitor" of "PI3Kα" refers to a compound of the present invention that is capable of negatively regulating or inhibiting all or part of the activity of PI3Kα.

[0047] As used herein, a "PI3Kα-associated" disease or condition refers to a disease or condition that is associated with or mediated by PI3Kα or has one or more PI3Kα mutations. Examples of PI3Kα-associated diseases or conditions include various types of cancer. PI3Kα-associated diseases or conditions may also refer to allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetic complications, or acute coronary syndrome.

[0048] As used herein, the term "contact" refers to bringing specified parts 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, and, for example, introducing the compound into a sample containing cells or a purified preparation. In some embodiments, cells in which PI3Kα activity needs to be inhibited are contacted with an effective amount of a compound disclosed herein or a pharmaceutically acceptable form thereof to negatively regulate the activity of PI3Kα. By negatively regulating the activity of PI3Kα, the methods disclosed herein are designed to inhibit the desired cell proliferation caused by enhanced PI3Kα activity in the cell. Depending on the specific treatment regimen, cells can be contacted with a single dose or multiple doses to achieve the desired negative regulation of PI3Kα. The ability of a compound to bind to PI3Kα can be monitored in vitro using methods known in the art. For example, the inhibition of PI3Kα activity can be measured using methods known in the art to monitor the inhibitory activity of exemplary compounds in cells.

[0049] As used herein, the terms "unsubstituted or substituted" and "optionally substituted" can be used interchangeably and refer to a given chemical moiety (e.g., an alkyl group) that can be (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., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. 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 other functional groups. Suitable substituents for use in the optional substitution of the groups include, but are not limited to, halogen, oxo, CN, -COOH, -CH2CN, -O-C1-C6 alkyl, C1-C6 alkyl, -OC1-C6 alkenyl, -OC1-C6 alkynyl, -C1-C6 alkenyl, -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -S(O)2-C1-C6 alkyl, -S(O)NHC1-C6 alkyl and S(O)N(C1-C6 alkyl)2.

[0050] 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.

[0051] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissue of a subject without excessive toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. 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 with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, phenylsulfonate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. 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.

[0052] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, for example, by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4alkyl) 4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate to form. The organic base from which the salt can be derived includes, 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, pharmaceutically acceptable base addition salts can be selected from ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts.

[0053] 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 and includes an ester that readily decomposes in the human body and leaves the parent compound or its salt. This type of ester can be used as a prodrug 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 acid, phosphoric acid, phosphinic acid, sulfinic acid, sulfonic acid, and boric acid). Examples of esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinate. Esters can form with the hydroxyl or carboxylic acid groups of the parent compound.

[0054] 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 a solvent bound by non-covalent intermolecular forces. The solvate can be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that can, for example, contain 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0055] In some embodiments, pharmaceutically acceptable form is a prodrug. As used in this article, the term "prodrug" (or "prodrug") refers to a compound that is converted in vivo to produce a pharmaceutically acceptable form of the disclosed compound or the compound. Prodrugs may be inactive when administered to a subject, but are converted into active compounds in vivo by, for example, hydrolysis (e.g., hydrolysis in the blood). In some cases, prodrugs have improved physical and / or delivery properties compared to the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by enhancing absorption into the blood after oral administration) or enhance delivery to a biological compartment of interest (e.g., brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds with enhanced water solubility or active transport by intestinal membranes relative to the parent compound.

[0056] Prodrug compounds typically provide solubility, tissue compatibility, or delayed release benefits in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs 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 incorporated herein by reference in their entireties. Exemplary benefits of a prodrug may include, but are not limited to, its physical properties, such as enhanced water solubility at physiological pH for parenteral administration compared to the parent compound, or enhanced absorption from the digestive tract, or enhanced drug stability during long-term storage.

[0057] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to 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 the subject pharmaceutical agent 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 glycerol, 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; ethanol; phosphate buffered saline; and other nontoxic, compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyoxyethylene-polyoxypropylene copolymers, as well as coloring agents, release agents, coating agents, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0058] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is to receive a particular treatment. Generally, the terms "subject" and "patient" are used interchangeably herein to refer to a human subject.

[0059] In some embodiments, the subject has experienced and / or displays at least one symptom of a disease or condition to 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 PI3Kα mutations. In some embodiments, the subject has a PI3Kα mutation-positive cancer. In some embodiments, the subject is suspected of having a PI3Kα gene-associated cancer.

[0060] In some embodiments of any of the methods or uses described herein, a sample from a subject (e.g., a biological sample or a tissue biopsy sample (e.g., a paraffin-embedded tissue biopsy sample)) is used to perform an assay to determine whether the subject has one or more PI3Kα mutations. Various techniques can be used, such as next-generation sequencing, immunohistochemistry, fluorescence microscopy, decomposed FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).

[0061] As used herein, the term "treating" or "treating" a disease or condition refers to a method of alleviating, delaying or improving the condition before or after the disease or condition occurs. Treatment can be directed to one or more effects or symptoms of the disease and / or underlying pathology. Treatment is intended to obtain a benefit or desired outcome, including but not limited to therapeutic benefit and / or preventive benefit. Therapeutic benefit means eradicating or improving the underlying condition being treated. In addition, therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition so that improvement is observed in the patient, even if the patient may still be suffering from the underlying condition. In order to obtain a preventive benefit, a pharmaceutical compound and / or composition can be administered to a patient at risk of developing a specific disease, or to a patient reporting one or more physiological symptoms of a disease, even if the disease may not yet be diagnosed. Treatment can be any alleviation of the disease or disease symptoms, and can be, but is not limited to, the complete elimination of the disease or disease symptoms. Compared to an equivalent untreated control, such alleviation or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100%, as measured by any standard technique.

[0062] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0063] After their preparation, the compounds of the invention are preferably isolated and purified to obtain compositions containing 95% or more by weight ("substantially pure") and then used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0064] Also contemplated herein are solvates and polymorphs of the compounds of the present invention. Solvates of the compounds of the present invention include, for example, hydrates.

[0065] As used herein, the term "isolated" or "substantially isolated" molecules (such as polypeptides or polynucleotides) are molecules that have been manipulated to exist at a higher concentration than in nature or have been removed from their natural environment. For example, the target antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of the non-test antibody material related to it in nature has been removed. For example, a polynucleotide or polypeptide naturally occurring in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials in its natural state is "isolated." In addition, for the purposes of the present invention, recombinant DNA molecules contained in a vehicle are considered to be isolated. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules also include synthetically produced molecules. In addition, vehicle molecules contained in recombinant host cells are also isolated. Therefore, not all "isolated" molecules need to be "purified."

[0066] As used herein, when the term "purified" is used to refer to a molecule, it means that the concentration of the purified molecule is increased relative to the molecule associated with it in its natural environment or the environment in which it is produced, found or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids and sugars, but generally do not include water, buffers and reagents added to maintain integrity or promote purification of the purified molecule. According to this definition, a substance can 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.

[0067] The 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 every value and subrange within that range. For example, "C 1-4 "Alkyl" is intended to encompass C1, C2, C3, C4, C 1-3 、C 1-2 、C 2-4 、C 3-4 and C 2-3 Alkyl group.

[0068] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic.

[0069] As used herein, the term "alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-10 Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 10 carbon atoms, but this definition also encompasses the presence of the term "alkyl" where no numerical range is specified. In some embodiments, "alkyl" can be C 1-6 Alkyl groups. 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 alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched-chain alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl group is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl ring, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, sulfhydryl, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silanyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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(R x )S(O) t N(Rx )2(wherein t is 1 or 2), -P(=O)(R x )(R x ) or -OP(=O)(OR x )2, where each R x In one embodiment, the alkyl radicals of the present invention are substituted alkyl radicals, ...

[0070] Unless otherwise specifically defined, the term "aromatic" or "aryl" refers to a cyclic, aromatic hydrocarbon group having 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. In the case of groups containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted with one or more substituents (e.g., 1 to 5 substituents) at any point of attachment. Exemplary substituents include, but are not limited to, H, halogen, -O-C-C alkyl, C-C alkyl, -C-C alkenyl, -OC-C alkynyl, -C-C alkenyl, -C-C alkynyl, -OH, -OP(O)(OH)2, -OC(O)C-C alkyl, -C(O)C-C alkyl, -OC(O)OC-C alkyl, NH2, NH(C-C alkyl), N(C-C alkyl)2, -S(O)2-C-C alkyl, -S(O)NHC-C alkyl, and S(O)N(C-C alkyl). The substituents themselves may be optionally substituted. In addition, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthyl, and tetrahydrobenzoannulyl.

[0071] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0072] As used herein, the term "heteroaryl ring" or "heteroaromatic" 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 in common in the cyclic arrangement; and having one to three heteroatoms per ring other than carbon atoms selected from N, O and S. Examples of heteroaryl ring groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydrobenzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo[1,1-d]-benzo -dihydro-5H-pyrrolo[1,2-a]imidazole, furyl, furanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl oxazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrinyl, phenazinyl, phenothiazinyl, phenanthrothiocyanate, phenanthroxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolyl The term "heteroaryl ring" also refers to a bicyclic ring system having one to three heteroatoms selected from N, O and S in each ring in addition to carbon atoms, wherein one of the ring systems may be saturated or partially saturated.

[0073] The heteroaryl ring can be substituted by 0, 1, 2, 3 or 4 substituents independently selected from the following: alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxyl, carboxylalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfhydryl, nitro, -NZ1Z2 and (NZ1Z2) carbonyl. As used in this article, the term "NZ1Z2" means two groups Z1 and Z2 attached to the parent molecular part by a nitrogen atom. Z1 and Z2 are each independently selected from hydrogen, alkyl, alkylcarbonyl and formyl. Representative examples of NZ1Z2 include but are not limited to amino, methylamino, acetylamino and acetylmethylamino.

[0074] As used herein, the term "alkoxy" refers to an -O-alkyl group.

[0075] As used in this article, the terms "cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic group containing only carbon and hydrogen, and can be saturated or partially unsaturated. Unless otherwise stated in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyl" when the carbocycle contains at least one double bond, or as "cycloalkynyl" when the carbocycle contains at least one triple bond. Cycloalkyl includes groups with 3 to 13 ring atoms (i.e., C 3-13 Cycloalkyl). Whenever it appears in this article, a numerical range such as "3 to 10" refers to each integer in the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can be composed of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged or 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 aromatic groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" can be C 3-8 In some embodiments, the "cycloalkyl" may be C 3-5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. 3-7 Examples of carbocyclic groups include norbornyl (C7). 3-8 Examples of the carbocyclic group include the aforementioned C 3-7Carbocyclyl groups and cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, etc. 3-13 Examples of the carbocyclyl group include the aforementioned C 3-8 Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted with one or more substituents independently comprising: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl ring, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, sulfhydryl, sulfhydryl, alkylsulfanyl, arylsulfanyl, thiocarbonyl, nitro, oxo, phosphonate, phosphonate, phosphinate, silanyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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(wherein t is 1 or 2), -P(=O)(R a )(R a ) or -OP(=O)(OR a )2, where each R aIn some embodiments, the cycloalkenyl group comprises 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, the cycloalkenyl group comprises 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, the cycloalkenyl group comprises 5 to 13 ring atoms.

[0076] As used in this article, term " heterocycloalkyl " refers to the cycloalkyl with one or more main chain atoms selected from the atom (for example, O, N, S, P or its combination) except carbon.Unless otherwise stated in the specification, the term is intended to include substituted and unsubstituted heterocycloalkyl groups.The illustrative examples of heterocycloalkyl include 2-hydroxy-aziridine-1-base, 3-oxo-1-oxetanes-2-base, 2,2-dimethyl-tetrahydrofuran-3-base, 3-carboxyl-morpholine-4-base, 1-cyclopropyl-4-methyl-piperazine-2-base, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4] oxazine etc.

[0077] As used in this article, the term "heterocycle", "heterocyclic" or "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group, for example, a 3 to 8-membered monocyclic, 7 to 12-membered bicyclic or 10 to 15-membered spirocyclic or tricyclic ring system having at least one heteroatom (selected from N, O and S) in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system. The heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroindole),

[0014] In some embodiments, the present invention includes but is not limited to oxazolidinyl, ... DETAILED DESCRIPTION

[0078] The present invention is based, in part, on the discovery of novel tricyclic compounds and their derivatives that are PI3Kα inhibitors. These compounds are shown herein to selectively target, bind to, inhibit, and / or modulate the activity of PI3Kα. The compounds are orally administrable and can be used to treat various diseases and conditions associated with or related to PI3Kα activity, such as various types of cancer.

[0079] In one aspect, the present invention generally relates to compounds having structural formula (I):

[0080]

[0081] or a pharmaceutically acceptable form or isotopic derivative thereof,

[0082] in

[0083] Ring A is surrounded by 0-10 R a 'Substituted 4- to 7-membered monocyclic non-aromatic ring;

[0084] R 1 It's Z B -R B ;

[0085] R 2 It's Z C -R C ;

[0086] X is N, CH or CR X ;

[0087] R X It's Z X -R X’ ;

[0088] Z B 、Z C and Z X Each is independently a covalent bond, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O)2, NRS(O)2, S(O)2NR or selected from C 1-4 a linking group of a saturated or unsaturated divalent hydrocarbon radical, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S, and O;

[0089] R B 、R C and R X Each independently is

[0090] 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( OR

[0091] C having 0-4 ring heteroatoms independently selected from N, O and S 1-6 an aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclic, heterocyclic, aryl or heteroaryl ring, each optionally substituted by one or more R b 、R c or R x replace;

[0092] R a 、R b 、R c and R x Each independently is

[0093] 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( OR

[0094] Substituted or unsubstituted selected from C 1-6 an alkyl group or a 4- to 6-membered carbocyclic group;

[0095] R and R' are each independently selected from: H, unsubstituted or substituted C 1-4 alkyl or an unsubstituted or substituted 4- to 6-membered carbocyclic ring, or wherein R and R' are attached to the same C or N atom and together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; and

[0096] i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0097] In certain embodiments of (I), Ring A is surrounded by 0-10 R a Substituted 4- to 7-membered carbocyclic ring having no ring heteroatoms.

[0098] In certain embodiments of (I), Ring A is surrounded by 0-10 R a Substituted 4- to 7-membered heterocyclic ring having 1-4 ring heteroatoms selected from N, O and S.

[0099] In certain embodiments of (I), Ring A is a member having the structural formula I a 0-4 R a Substituted 4-membered non-aromatic ring:

[0100]

[0101] where Y 1 and Y 2 are each independently CH, CH2, N, NH, O or S, provided that Y 1 and Y 2 At least one of is C or CH.

[0102] In certain embodiments of (I), Ring A has the structural formula (I b ) is 0-6 R a The substituted 5-membered non-aromatic ring is:

[0103]

[0104]

[0105] where Y 1 、Y 2 and Y 3 are each independently CH, CH2, N, NH, O, S or C(O), provided that Y 1 、Y 2 and Y 3 At least one is not N or NH and Y 1 、Y 2 and Y 3 At least one of is C, CH or C(O).

[0106] In certain embodiments of (I), Ring A has the structural formula (I c ) is 0-8 R a The replacement is a 6-membered non-aromatic ring:

[0107]

[0108] where Y 1 、Y 2 、Y 3 and Y 4 are each independently CH, CH2, N, NH, O, S, S(O)2 or C(O), provided that Y 1 、Y 2 、Y 3 and Y 4 At least two of them are not N or NH, and Y 1 、Y 2 、Y 3 and Y 4 At least two of are C, CH or C(O).

[0109] In certain embodiments of (I), Ring A is a member having the structural formula (I d ) is 0-8 R a Substituted 7-membered non-aromatic ring:

[0110]

[0111] where Y 1 、Y 2 、Y 3 、Y 4 and Y5 are each independently CH, CH2, N, NH, O, S or C(O), provided that Y 1 、Y 2 、Y 3 、Y 4 and Y 5 At least two of them are not N or NH, and Y 1 、Y 2 、Y 3 、Y 4 and Y 5 At least two of are C, CH or C(O).

[0112] In certain embodiments of (I), R B It is ring B, surrounded by 0-6 R b a substituted 5- to 10-membered monocyclic or bicyclic carbocyclyl, heterocyclyl, aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from N, O and S; and R C It is a ring C, surrounded by 0-6 R c a substituted 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from N, O and S,

[0113] The compound has the structural formula (I e ):

[0114]

[0115] in

[0116] j is 0, 1, 2, 3, 4, 5, or 6; and

[0117] k is 0, 1, 2, 3, 4, 5, or 6.

[0118] In certain embodiments of (I), Z B is NH-C(O) and Z c is a single bond, which has the structural formula (I f ):

[0119]

[0120] In certain embodiments of (I), Z B is C(O)-NH and Z c is a single bond, which has the structural formula (I g ):

[0121]

[0122] in(I)-(I g ), in certain embodiments, Ring A is selected from:

[0123]

[0124] in(I)-(I g ), in certain embodiments, Ring A is selected from:

[0125]

[0126] In certain embodiments, Ring A is:

[0127]

[0128] where R a’ is CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN. In certain embodiments, each R a are independently H, Cl, F, CN or CH3. In certain embodiments, R a’ It is CH2CHF2.

[0129] in(I)-(I g ), in certain embodiments, Ring A is selected from:

[0130]

[0131] in(I)-(I g ), in certain embodiments, Ring A is selected from:

[0132]

[0133] In certain embodiments, Ring A is selected from:

[0134]

[0135] in

[0136] R a’ is CH2CHF2 or CH2CF3; and

[0137] Each R a are independently H, Cl, F, CN or CH3.

[0138] In certain embodiments, Ring A is

[0139]

[0140] where R a’ One is CH2CHF2 or CH2CF3, and the other R a’ It is H, CH3 or CD3.

[0141] in(I)-(I g ), in certain embodiments, Ring A is selected from:

[0142]

[0143] In certain embodiments, Ring A is selected from:

[0144]

[0145] where R a’ is CH2CHF2 or CH2CF3, and R a It’s H.

[0146] In certain embodiments, Ring A is selected from:

[0147]

[0148] where R a and R a’ One of the following is selected from H, CH3, CD3, CD2CD3, CH2CN, CH2CHF2, CH2CF3 and CH2CN; and R a and / or R a’ The other one is H.

[0149] In certain embodiments, Ring A is selected from:

[0150]

[0151] Each R a’ Independently selected from H, CH3, CD3, CD2CD3, CH2CN and CH2CHF2, CH2CF3 and CH2CN.

[0152] 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, wherein each R is independently H, CH3, CH2CH3, CD2CD3, CH2CHF2, CH2CF3, or CH2CN.

[0153] in(I)-(I g ), in certain embodiments, X is CH.

[0154] in(I)-(I g ) in certain embodiments, X is CR X .

[0155] in(I)-(I g ), in certain embodiments, X is N.

[0156] in(I)-(I g ), in certain embodiments of the present invention, Ring B is a substituted or unsubstituted 5-membered or 6-membered monocyclic carbocyclyl or heterocycle.

[0157] in(I)-(I g ), in certain embodiments, Ring B is a substituted or unsubstituted 5-membered or 6-membered monocyclic aryl or heteroaryl ring.

[0158] in(I)-(I g ), in certain embodiments of the present invention, Ring B is a substituted or unsubstituted 8- to 10-membered bicyclic carbocyclyl or heterocycle.

[0159] in(I)-(I g ), in certain embodiments of the present invention, Ring B is a substituted or unsubstituted 8- to 10-membered bicyclic aryl or heteroaryl ring.

[0160] Non-limiting examples of Ring B include:

[0161]

[0162] in(I)-(I e ), in certain embodiments, Ring B is selected from:

[0163]

[0164] in(I)-(I e ), in certain embodiments, Ring B is selected from:

[0165]

[0166] in(I)-(I e ), in certain embodiments, Ring B is selected from:

[0167]

[0168] In certain embodiments, Ring B is:

[0169]

[0170] in(I)-(I e ), in certain embodiments of the present invention, Ring B is substituted or unsubstituted phenyl, pyridyl, pyridazinyl, or pyrazinyl.

[0171] In certain embodiments, Ring B is substituted or unsubstituted phenyl.

[0172] In certain embodiments, Ring B is substituted or unsubstituted pyridinyl.

[0173] In certain embodiments, Ring B is a substituted or unsubstituted pyridazinyl.

[0174] In certain embodiments, Ring B is substituted or unsubstituted pyrazinyl.

[0175] in(I)-(I e ), in certain embodiments of the present invention, Ring C is substituted or unsubstituted phenyl, pyridyl, pyridazinyl, or pyrazinyl.

[0176] In certain embodiments, Ring C is substituted or unsubstituted phenyl.

[0177] In certain embodiments, Ring C is substituted or unsubstituted pyridinyl.

[0178] In certain embodiments, Ring C is a substituted or unsubstituted pyridazinyl.

[0179] In certain embodiments, Ring C is substituted or unsubstituted pyrazinyl.

[0180] in(I)-(I e ), in certain embodiments of the present invention, Ring B and Ring C are each independently substituted or unsubstituted phenyl.

[0181] Non-limiting examples of Ring C include:

[0182]

[0183] In certain embodiments, Ring C is:

[0184]

[0185] In certain embodiments of (I), the compound has the structural formula I h :

[0186]

[0187] In certain embodiments of (I), the compound has the structural formula I h :

[0188]

[0189] In certain embodiments of (I), the compound has the structural formula I i :

[0190]

[0191] In certain embodiments of (I), the compound has the structural formula I j :

[0192]

[0193] In certain embodiments of (I), the compound has the structural formula I k :

[0194]

[0195] In certain embodiments of (I), the compound has the structural formula I l :

[0196]

[0197] In certain embodiments of (I), the compound has the structural formula I m :

[0198]

[0199] In certain embodiments of (I), the compound has the structural formula I n :

[0200]

[0201] Non-limiting examples of compounds of the present invention include:

[0202]

[0203]

[0204]

[0205] or a pharmaceutically acceptable form or isotopic derivative thereof. Non-limiting examples of compounds of the present invention include:

[0206]

[0207]

[0208]

[0209]

[0210] or a pharmaceutically acceptable form or isotopic derivative thereof. Non-limiting examples of compounds of the present invention include:

[0211]

[0212]

[0213] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0214] Non-limiting examples of compounds of the present invention also include:

[0215]

[0216]

[0217] or a pharmaceutically acceptable form or isotopic derivative thereof. In certain embodiments, the chirality is as follows:

[0218]

[0219] In certain embodiments, the chirality is as follows:

[0220]

[0221] In certain embodiments, the compounds of the present invention are 2 The carbon to which it is bonded exhibits the following chirality:

[0222]

[0223] In certain embodiments, the compounds of the present invention are 2 The carbon to which it is bonded exhibits the following chirality:

[0224]

[0225] Non-limiting exemplary compounds of the invention can also be found in Table 1 in the Examples section.

[0226] In certain embodiments, the compounds of the invention have one or more deuterium atoms replacing a hydrogen. In certain embodiments, the compounds of the invention have one deuterium atom replacing a hydrogen atom.

[0227] In another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0228] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0229] In yet another aspect, the present invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0230] In certain embodiments, the unit dosage form is in the form of a tablet or capsule.

[0231] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present 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, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0232] The pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral, nasal, topical (including oral and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the chemical formula herein is transdermally administered (e.g., using a transdermal patch). Other preparations can conveniently exist in unit dosage forms (e.g., tablets and sustained-release capsules) and liposomes, and can be prepared by any method well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th edition, 1985).

[0233] Such preparation methods include the step of bringing into association one or more auxiliary ingredients (e.g., carriers) with the molecule to be administered. In general, the compositions are prepared by uniformly and intimately combining the active ingredient with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0234] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound described herein or its derivative is blended with at least one inert conventional excipient (or carrier) such as sodium citrate or calcium hydrogen phosphate or the following substances: (i) fillers or extenders, such as, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid, (ii) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic, (iii) humectants, such as, for example, glycerol, (iv) disintegrants, such as, for example Such as, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain composite silicates and sodium carbonate, (v) solution retarders, such as, for example, paraffin, (vi) absorption promoters, such as, for example, quaternary ammonium compounds, (vii) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate, (viii) adsorbents, such as, for example, kaolin and bentonite and (ix) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or its mixture. In the case of capsules, tablets and pills, the dosage form may also include a buffer. Using such excipients as lactose or milk sugar and high molecular weight polyethylene glycol etc., similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules. Solid dosage forms, such as tablets, lozenges, capsules, pills and granules, can be made with coatings and shells, such as enteric coatings and other coatings and shells known in the art.

[0235] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (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 etc. In addition to these inert diluents, the composition can also include other agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavorings or aromatics.

[0236] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with an effective amount of a compound disclosed herein.

[0237] In yet another aspect, the invention generally relates to a method for inhibiting PI3K alpha activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0238] In yet another aspect, the present invention generally relates to a method for treating a disease or condition mediated by PI3Kα, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0239] In certain embodiments, the disease or disorder is a cell proliferative disorder.

[0240] In yet another aspect, the present invention generally relates to a method for treating or ameliorating cancer or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0241] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0242] Examples of target cancers in the present invention include, but are not particularly limited to, head and neck cancer, digestive organ cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, gallbladder 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, reproductive cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urinary system cancer (e.g., kidney cancer, bladder cancer, prostate and testicular cancer), hematological tumors (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, pancreatic cancer, rectal cancer, colon cancer, colorectal cancer and uterine cancer. In certain embodiments, the squamous cell carcinoma is a cancer of the cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus. In one embodiment, the adenocarcinoma is a 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.

[0243] 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 carcinoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, thyroid cancer, and hematological malignancies.

[0244] In certain embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.

[0245] In certain embodiments, the subject has mutant Class IA PI3K p110α.

[0246] In certain embodiments, the subject has at least one of the following PI3Kα mutations: H1047R, E542K, and E545K.

[0247] In certain embodiments, the subject does not have a PI3Kα mutant protein.

[0248] In certain embodiments, the treated subject is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormonal therapy.

[0249] In yet another aspect, the present 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 condition.

[0250] In yet another aspect, the invention generally relates to the use of the compounds disclosed herein for treating a disease or condition.

[0251] The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the route of administration, the disposition of the compound, and the discretion of the prescribing physician. In some cases, dosage levels below the lower limit of the aforementioned range may be more appropriate, while in other cases, larger doses may also be used without producing any adverse side effects, wherein such larger doses are generally divided into several smaller doses for administration throughout the day.

[0252] Any suitable route of administration may be employed, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, intranasal, intrapulmonary, inhalation, intrabuccal, intraperitoneal, rectal, intrapleural and intrathecal administration. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition to be treated or the nature of the therapy used, as well as the nature of the active compound.

[0253] In certain preferred embodiments, the compound is administered orally. Pharmaceutical compositions of the present invention suitable for oral administration can be in the form of discrete units, such as capsules, sachets, or tablets, each containing a predetermined amount of active ingredient; in the form of a powder or granules; in the form of a solution or suspension in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or encapsulated in liposomes and in the form of a bolus injection, etc. Soft gelatin capsules can be used to contain such suspensions, which can advantageously increase the absorption rate of the compound.

[0254] Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing a free-flowing active ingredient in a powder or granule optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds lubricated with an inert liquid in a suitable machine. Tablets can be optionally coated or scored and can be formulated to provide a sustained release or controlled release of the active ingredient therein. Methods for preparing such sustained release or controlled release compositions of pharmaceutical active ingredients (such as those herein and other compounds known in the art) are known in the art and are described in several authorized U.S. patents and references cited therein, some of which include but are not limited to U.S. Patent Nos. 4,369,172; and 4,842,866. Coatings can be used to deliver compounds to the intestine (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 the invention is in the form of enteric granules in which the enteric layer comprises hydroxypropyl methylcellulose acetate succinate.

[0255] In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added.

[0256] Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and arabinose or tragacanth; and lozenges comprising the active ingredient in an inert basis such as gelatin and glycerol, or sucrose and arabinose.

[0257] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations can be provided in unit dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0258] Such injectable solutions can be in the form of, for example, sterile injectable aqueous or oily suspensions. Such suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (such as, for example, Tween 80) and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent (e.g., as a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are typically used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can be used to prepare injectables, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants.

[0259] The compounds of the present invention can also be administered in liposome form. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, the compositions of the present invention in liposome form may also contain stabilizers, preservatives, excipients, etc. Preferred lipids are 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), page 33 and following pages.

[0260] The pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present 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 substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0261] The pharmaceutical compositions of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may employ benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0262] When the desired treatment involves easily accessing an area or organ by topical application, topical application of the pharmaceutical composition of the present invention is particularly useful. For topical application to the skin, the pharmaceutical composition should be formulated into a suitable ointment containing an active ingredient suspended or dissolved in a carrier. Carriers for topical application of the compound of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing an 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 composition of the present invention can also be topically applied to the lower intestinal tract via rectal suppository formulations or in suitable enema formulations. Topical transdermal patches and iontophoretic administration are also included in the present invention.

[0263] The treatment methods disclosed herein can be used in combination or together with other therapies. In certain embodiments, the treated subject is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy.

[0264] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules, such as pharmaceutical compounds, e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as provided in the U.S. Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, 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.

[0265] In certain embodiments, the compounds of the invention can be administered in combination with endocrine therapy, for example, agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0266] In some embodiments, the compounds of the present invention can be administered in combination with chemotherapeutic agents, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine. In other embodiments, the compounds of the present invention can be administered in combination with anti-HER2 agents, such as trastuzumab or pertuzumab.

[0267] In certain embodiments, the methods disclosed herein are combined with one or more of immune checkpoint blockade, T cell co-signaling, and tumor-targeted antibody therapy.

[0268] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0269] 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.

[0270] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSIPharm.), bortezomib ( Millennium Pharm.), Fulvestrant ( AstraZeneca), Sutent (SU11248, Pfizer), Letrozole ( Novartis), imatinib mesylate ( Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin ( Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, Wyeth), lapatinib ( GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs) and gefitinib ( AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and Cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, tamiprofen, and euridopa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trishydroxymethylmelamine; annonaceous lactones (particularly bratacin and brataconone); camptothecins (including the synthetic analogue topotecan); bryostatin; marastatin; CC-1065 (including its synthetic analogues adolesin, carzelesin, and biszelesin); cryptophytotoxins (particularly cryptophytotoxin 1 and cryptophytotoxin 8); dolastatin; pyrocatechol. chlorambucil, chlorambucil, chlorambucil, estramustine, ifosfamide, dimethyl(chloroethyl)amine, dimethyl(chloroethyl)amine oxide hydrochloride, melphalan, chlorambucil, phenylephrine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin omega II (Angewandte), chlorambucil, chlorambucil, chlorambucil, estramustine, ifosfamide, dimethyl(chloroethyl)amine, dimethyl(chloroethyl)amine oxide hydrochloride, melphalan, chlorambucil, phenylephrine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine); Chem. Intl. Ed. Engl. (1994) 33: 183-186); ethynamicins, including ethynamicin A; bisphosphonates, such as clodronate; esperamicins; and new tumor suppressor protein chromophores and related chromophores (enediyne antibiotic chromophores), aclarubicin, actinomycin, anthramycin, azaserine, bleomycin, actinomycin C, calabikine, caminamicin, carbomycin, chromomycin, actinomycin D, daunomycin, detoximcin, 6-diazo-5-oxo-L-norleucine, (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and deoxydoxorubicin, epirubicin, esubicin, idarubicin, mexilomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olivomycin, peplomycin, porfibrinocin, puromycin, quinamycin, rhodorubicin, streptozocin, streptozocin, tuberculin, ubenimex, zoloft, daunorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethylfolate, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, Cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calutosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; antiadreners such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglucuronolide; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; amustine; bisantrene; idarubicin Datrol; defosfamide; colcemid; diazocine; eflumicin; elliptonium acetate; epsilon; etoglucagon; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoxantrone; mitoxantrone; mopidarol; nivetidine; pentostatin; methambucil; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizobactin; sizolan; spirogermanamine; tricholomanic acid; triazoline quinone; 2,2',2"-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, verrucomycin A, myclosan A, and serpentin); urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gasitopide; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g., (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (without polyoxyethylene hydrogenated castor oil), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.) and (docetaxel; Rhone-Poulenc Rorer, Antony, France); chlorambucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (Vinorelbine); tumor-killing; teniposide; edatrexate; daunorubicin; aminopterin; capecitabine Ibandronate; CPT-11; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); a retinoid, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the foregoing.

[0271] Examples of second (or additional) agents or therapies can include, but are not limited to, immunotherapies (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, pegatinib, panitumumab, etc.), mitotic inhibitors (e.g., paclitaxel, vincristine, vinblastine, etc.), alkylating agents (e.g., cisplatin, cyclophosphamide, chlorambucil, carmustine, etc.), antimetabolites (e.g., methotrexate, 5-FU, etc.), intercalating anticancer agents (e.g., actinomycin, anthracycline, bleomycin, mitomycin C, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide, etc.), immunotherapeutics (e.g., interleukins, interferons, etc.), and antihormonal agents (e.g., tamoxifen, raloxifene, etc.).

[0272] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all such compounds within the scope of the present invention, including cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Other asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0273] Mixtures of isomers containing any of a variety of isomer ratios can be used according to 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 encompassed by the present invention. Those of ordinary skill in the art will readily appreciate that similar ratios are contemplated for more complex mixtures of isomers.

[0274] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by this symmetrical synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with appropriate optically active acids or bases, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0275] Isotopically labeled compounds are also within the scope of the present disclosure. As used herein, "isotopically labeled compound" refers to a compound disclosed herein, including pharmaceutical salts and prodrugs thereof, each as described herein, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0276] By isotopically labeling the compounds disclosed in the present invention, the compounds can be used for drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 Compounds labeled with deuterium (C) are particularly preferred because they are easy to prepare and detect. 2 H)) substitutions may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may be preferred in some circumstances. The presently disclosed isotopically labeled compounds, including pharmaceutically acceptable salts, esters, and prodrugs thereof, may be prepared by any means known in the art.

[0277] In addition, the normal abundance of hydrogen is replaced by heavier isotopes such as deuterium ( 1 H) Certain therapeutic advantages may be obtained, for example resulting from improved absorption, distribution, metabolism and / or excretion (ADME) properties, thereby resulting in a drug with improved efficacy, safety and / or tolerability. 13 C replaces the normal abundance 12C may also benefit. (See WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361 and WO 2007 / 016431.)

[0278] Stereoisomers (eg, cis and trans isomers) and all optical isomers (eg, R and S enantiomers) of the compounds of the present disclosure, as well as racemic, diastereomeric and other mixtures of such isomers, are within the scope of the present disclosure.

[0279] The compounds of the present invention are preferably isolated and purified after their preparation to obtain compositions containing an amount equal to or greater than 95% ("substantially pure") by weight, which are then used or formulated as described herein. In certain embodiments, the purity of the compounds of the present invention exceeds 99%.

[0280] Also contemplated herein are solvates and polymorphs of the compounds of the present invention. Solvates of the compounds of the present invention include, for example, hydrates.

[0281] Any suitable route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracerebroventricular, in vivo, 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 to be treated or the nature of the therapy used and the nature of the active compound.

[0282] 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 before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, Polyethylene Glycol etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate. For example, coating materials such as lecithin can be used, in the case of dispersions, required particle diameter can be maintained and suitable mobility can be maintained using a surfactant.

[0283] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. By adding various antibacterial and antifungal agents, for example, benzene, chlorobutanol, phenol sorbic acid, etc., it is possible to ensure that the action of microorganisms is prevented. It may also be necessary to include isotonic agents, such as sugars, sodium chloride, etc. The prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0284] The compounds of the present invention can also be administered in liposome form. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, the compositions of the present invention in liposome form may contain stabilizers, preservatives, excipients, etc. Preferred lipids are 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), page 33 and following pages.

[0285] The total daily dose of the composition of the present invention administered to a human or other mammalian host in single or divided doses can be, for example, from 0.0001 to 300 mg / kg body weight and more typically 1 to 300 mg / kg body weight per day. Doses of 0.0001 to 300 mg / kg body weight can be provided twice daily.

[0286] The materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used to prepare the disclosed methods and compositions, or are products of the disclosed methods and compositions. It should be understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed, although specific reference to each of the various individual and collective combinations and arrangements of these compounds may not be explicitly disclosed, each combination and arrangement is specifically contemplated and described herein. For example, if a method is disclosed and discussed and various modifications that can be made to the multiple molecules included in the method are discussed, each combination and arrangement of the method and possible modifications are specifically contemplated unless specifically stated to the contrary. Similarly, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of the present disclosure, including but not limited to steps in the method using the disclosed compositions. Therefore, if various additional steps can be performed, it is understood that each of these additional steps can be performed using any specific method step or combination of method steps of the disclosed method, and each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

[0287] Example

[0288] The following examples are given for the purpose of illustrating the present invention but are not intended to limit the scope or spirit of the present invention.

[0289] The compounds of the present invention, including those specifically disclosed herein above and below, can be prepared as described in the following routes. Although the present invention has been described in detail by preferred embodiments, it will be understood by those skilled in the art that modifications, variations, and equivalent substitutions of the present invention within the scope of the present invention fall within the scope of the present invention.

[0290] Table 1 Exemplary compounds

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] Exemplary synthetic procedures

[0306] List of abbreviations

[0307]

[0308]

[0309]

[0310]

[0311]

[0312] General LC-MS method:

[0313] Shimadzu LCMS2020, reversed-phase column (Shim-Pack Scepter C18, 33 x 3.0 mm, 3 μm), eluted with the following: A: H2O / MeCN / FA = 90 / 10 / 0.05; B: MeCN; detection: MS, ELS, UV (100 μL split to MS and inline UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray-atmospheric pressure ionization.

[0314] General HPLC purification method:

[0315] Instruments: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281. Columns: YMC-Triart C18, 250 x 20 mm, 5 μm; Welch Ultimate XB-C18, 250 x 21.2 mm, 5 μm. Detection wavelengths: 220, 254 nm. Flow rate: 15 ml / min-20 ml / min; Run time: 8 min; Column temperature: 25°C.

[0316] General synthetic route I

[0317]

[0318] General synthetic route II

[0319]

[0320] 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, synthesized via general synthetic route I

[0321]

[0322] Step A: To a solution of 6-nitrobenz[d][1,3]dioxole-5-carbaldehyde (4.3 g, 22.0 mmol, 1.0 eq) in DCE (137 mL) and TFA (27 mL) was added NBS (4.7 g, 26.4 mmol, 1.2 eq), palladium(II) acetate (0.495 g, 2.2 mmol, 0.1 eq), and 4-chloro-2-(trifluoromethyl)aniline (TDG) (0.862 g, 4.4 mmol, 0.2 eq). The reaction mixture was then stirred at 60°C for 12 h. Water (50 mL) was added to the mixture and extracted with EtOAc (50 mL x 3). The combined organic phases were 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 (400MHz, CDCl3): δ10.12(s,1H),7.50(s,1H),6.28(s,2H).

[0323] Step B: To a solution of 4-bromo-6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (2.4 g, 8.8 mmol, 1.0 eq) in THF (40.0 mL) was added (2-chloro-5-fluorophenyl)magnesium bromide (26.2 mL, 13.1 mmol, 0.5 M, 1.5 eq) dropwise at -78 ° C under N2 atmosphere. The reaction mixture was then stirred at room temperature for 30 min. Water (30 mL) was added to the mixture and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 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%). 1 HNMR (400MHz, DMSO-d6): δ7.50-7.47(m,2H),7.25-7.20(m,1H),7.15-7.11( m, 1H), 6.62 (d, J = 14.8Hz, 1H), 6.29 (d, J = 4.4Hz, 2H), 6.18 (d, J = 5.6Hz, 1H).

[0324] 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 eq) in DCM (40 mL) at 0°C was added Dess-Martin (2.5 g, 5.88 mmol, 1.2 eq). The reaction mixture was then stirred at room temperature for 2 h. Water (40 mL) was added to the mixture and extracted with DCM (40 mL x 3). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, and concentrated to a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 15 / 1) to afford the product (4-bromo-6-nitrobenzo[d][1,3]dioxol-5-yl)(2-chloro-5-fluorophenyl)methanone (1.2 g, 60%). 1 H NMR (400MHz, CDCl3): δ7.69-7.67(m,2H),7.44-7.41(m,1H),7.24-7.19(m,1H),6.29(s,2H).

[0325] 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 eq) in N,N-dimethylacetamide (4 mL) was added Zn(CN)2 (79 mg, 0.67 mmol, 1.0 eq) and Pd(PPh3)4 (231 mg, 0.2 mmol, 0.3 eq). The reaction mixture was then stirred at 160 ° C in a microwave for 20 min. Water (5 mL) was added to the mixture and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted 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 (300MHz, CDCl3): δ7.78(s,1H),7.73-7.70(m,1H),7.44-7.41(m,1H),6.41(s,2H).

[0326] 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 eq) in can (5 mL) and H2O (0.5 mL) was added KOH (5.0 mg, 0.086 mmol, 0.3 eq). The reaction mixture was then stirred at room temperature for 2 h. The mixture was dried over Na2SO4 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%), which was confirmed by LCMS. LCMS: m / z 365.0 ([MH] - ).

[0327] 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 eq) in TFA (4 mL) was added triethylsilane (127 mg, 1.1 mmol, 4.0 eq). The reaction mixture was then stirred at 100°C for 4 h. 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 (300MHz, DMSO-d6): δ9.39(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] + ).

[0328] 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 eq) in EtOH (0.5 mL) was added Fe (9 mg, 0.17 mmol, 5.0 eq). The reaction was heated to 45°C, and NHCl (1 mg, 0.017 mmol, 0.5 eq) and H2O (0.2 mL) were added. The reaction mixture was then stirred at 90°C for 12 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to afford 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] + ).

[0329] Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxol[4,5-e]isoindol-8-one (7 mg, 0.022 mmol, 1.0 eq) in ACN (0.5 mL) was added pyridine (4 mg, 0.044 mmol, 2.0 eq) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (4 mg, 0.018 mmol, 0.8 eq). The reaction mixture was then stirred at room temperature for 2 h. Water (0.5 mL) was added to the mixture and extracted with EtOAc (1 mL x 3). The combined organic phases were 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 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 (400MHz, DMSO-d6): δ10.20 (s, 1H), 9.00 (brs, 1H), 7.92 (d, J = 8.0Hz, 1H), 7.77-7.64 (m,2H),7.30-7.27(m,1H),7.10-7.04(m,2H),6.27(d,J=14.8Hz,2H),5.91-5.89(m,1H).

[0330] 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

[0331]

[0332] 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 eq) in TFA (0.5 mL) was added Et3SiH (11.6 mg, 0.1 mmol, 5.0 eq). The reaction mixture was heated to reflux and stirred for 5 h. The reaction mixture was then subjected to preparative HPLC (acetonitrile in water with 0.1% FA) to afford 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 (400MHz, CDCl3): δ7.77 (s, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.39-7.33 (m, 2H), 7.04-7.00 (m, 1H), 6. 70(d,J=8.0Hz,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).

[0333] 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 via General Route I:

[0334]

[0335] LCMS: m / z 525.0 ([M+H] + ). 1H NMR (300MHz, DMSO-d6): δ10.16(s,1H),8.82(s,1H),7.91(d,J=8.4Hz,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=3.6Hz,4H).

[0336] 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

[0337]

[0338] Step A: To a solution of 8 (50 mg, 0.16 mmol, 1.0 eq) in THF (1 mL) was added triphosgene (47 mg, 0.16 mmol, 1.0 eq) and DIEA (20 mg, 0.16 mmol, 1.0 eq) at 0 ° C under N2 atmosphere. 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 eq) in pyridine (0.2 mL), the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (2 mL), and the mixture was extracted with EtOAc (2 mL x 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] + ). 1 H NMR (300MHz, DMSO-d6): δ8.95(s,1H),8.44(d,J=17.4Hz,1H),7.90-7.76(m,1H),7.39-7.01(m,5H),6.97(d,J =25.2Hz,1H),6.66(brs,1H),6.24(d,J=10.5Hz,2H),5.98-5.92(m,1H),4.13-3.89(m,1H),3.56-3.50(m,1H).

[0339] Example 4 was separated into Examples 6, 7, 8 and 9 by the following chiral preparative SFC separation method:

[0340] Instrument: Waters 150 Preparative SFC (SFC-26)

[0341] Column: (S,S)Whelk O1, 250×30mm ID, 10μm

[0342] Mobile phase: A is CO2 and B is ethanol

[0343] Gradient: B 40%

[0344] Flow rate: 80 mL / min

[0345] Back pressure: 100 bar

[0346] Column temperature: 38°C

[0347] Wavelength: 220nm

[0348] Cycle time: ~25min

[0349] Sample preparation: Dissolve the compound in ~9 ml methanol / DCM

[0350] Injection: 3 ml each time.

[0351] Workup: After separation, the fractions were dried by rotary evaporator at a bath temperature of 40°C to obtain P3 and P4, and then the mixture of P1 & P2 was further separated using the following method.

[0352] Instrument: Waters 150 Preparative SFC (SFC-26)

[0353] Column: ChiralPak AD, 250×30mm ID, 10μm

[0354] Mobile phase: A is CO2 and B is ethanol

[0355] Gradient: B 35%

[0356] Flow rate: 80 mL / min

[0357] Back pressure: 100 bar

[0358] Column temperature: 38°C

[0359] Wavelength: 220nm

[0360] Cycle time: ~6 minutes

[0361] Sample preparation: Dissolve the compound in ~32 ml methanol / DCM

[0362] Injection: 4 ml each time.

[0363] Workup: After separation, the fractions were dried by rotary evaporation at a bath temperature of 40°C to give P1 and P2.

[0364]

[0365] 1 H NMR (400MHz, CD3OD) δ7.82(dd,J=9.0,4.5Hz,1H),7.28(dd,J=9.0,5.0Hz,1H),7.18(d,J=8.0Hz,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=11.8Hz,1H),3.60-3.40(m,1H).

[0366]

[0367] 1 H NMR (400MHz, CD3OD) δ7.98-7.80(m,1H),7.28(dd,J=8.8,5.0Hz,1H),7.22–7.05(m,2H),6.99(td,J=8. 4,3.0Hz,1H),6.91(s,1H),6.65(br,1H),6.30–6.10(m,3H),3.90(d,J=11.4Hz,1H),3.69–3.72(m,1H).

[0368]

[0369] 1 H NMR (400MHz, CD3OD) δ7.82(dd,J=9.0,4.5Hz,1H),7.28(dd,J=9.0,5.0Hz,1H),7.18(d,J=8.0Hz,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=11.8Hz,1H),3.60-3.40(m,1H).

[0370]

[0371] 1H NMR (400MHz, CD3OD) δ7.98-7.80(m,1H),7.28(dd,J=8.8,5.0Hz,1H),7.22–7.05(m,2H),6.99(td,J=8. 4,3.0Hz,1H),6.91(s,1H),6.65(br,1H),6.30–6.10(m,3H),3.90(d,J=11.4Hz,1H),3.69–3.72(m,1H).

[0372] 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 via general route II:

[0373]

[0374] Step A: Benzo[d]isothiazole-3-carbonyl chloride (62 mg, crude) and DIEA (101 mg, 0.780 mmol, 5.0 eq) were added dropwise to a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxol[4,5-e]isoindole-8-one (50 mg, 0.16 mmol, 1.0 eq) in DCM (2 mL) at 0 ° C. The reaction mixture was then stirred at room temperature for 2 h. Water (2 mL) was added to the mixture and extracted with DCM (2 mL x 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 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 (300MHz, DMSO-d6): δ10.17(s,1H),8.99(s,1H),8.60(d,J=8.1Hz,1H),8.30(d,J=8.4Hz,1 H),7.70-7.56(m,2H),7.21-7.17(m,2H),7.00-6.93(m,1H),6.26(d,J=9.0Hz,2H),6.07(s,1H).

[0375] 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:

[0376]

[0377] Instrument: MG II preparative SFC (SFC-14)

[0378] Column: ChiralCel OD, 250×30mm ID, 10μm

[0379] Mobile phase: A is CO2 and B is ethanol

[0380] Gradient: B 30%

[0381] Flow rate: 80 mL / min

[0382] Back pressure: 100 bar

[0383] Column temperature: 38°C

[0384] Wavelength: 220nm

[0385] Cycle time: ~5.5min

[0386] Sample preparation: Dissolve the compound in ~120 ml methanol / DCM

[0387] Injection: 4 ml each time.

[0388] Work-up: After separation, the fractions were dried by rotary evaporation at a bath temperature of 40°C to give the desired isomer.

[0389] 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.

[0390]

[0391] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1,3]dioxol[4,5-e]isoindol-8-one (30 mg, 0.10 mmol, 1.0 eq) in DCM (1.0 mL) was added 3-chloro-5-fluorobenzoyl chloride (36 mg, 0.20 mmol, 2.0 eq) and DIEA (60 mg, 0.50 mmol, 5.0 eq) at room temperature. The mixture was then stirred at the same temperature for 2 h. Water (2 mL) was added to the mixture and extracted with DCM (2 mL x 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 (acetonitrile in water containing 0.1% FA, 35% to 47%) to give 2.2 mg, 5% as a white solid. LCMS: m / z 476.9 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6): δppm 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).

[0392] 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.

[0393]

[0394] 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 h. 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 gray 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). 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 gray solid. LCMS:ESI m / z 496[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.81(s,1H),8.60(d,J=8.2Hz,1H),8.28(d,J=8.2Hz,1H),7 .66–7.58(m,2H),7.31–7.09(m,3H),6.97(t,J=7.0Hz,1H),6.66(s,1H),6.01(s,1H),4.36(s,4H).

[0395] Preparative SFC separation method:

[0396] Instrument: Waters Thar 80 preparative SFC

[0397] Column: ChiralPak IB, 250×21.2 mm ID, 5 μm

[0398] Mobile phase: A is CO2 and B is ETOH + 0.1% NH3H2O

[0399] Gradient: B 40%

[0400] Flow rate: 40 mL / min

[0401] Back pressure: 100 bar

[0402] Column temperature: 35°C

[0403] Wavelength: 220nm

[0404] Cycle time: 20 minutes

[0405] Elution time: 2 hours

[0406] 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

[0407]

[0408] 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 eq) in anhydrous THF (0.5 mL) was added DIEA (9.7 mg, 0.075 mmol, 1.0 eq). The mixture was stirred and cooled to 0°C. A solution of triphosgene (22.4 mg, 0.076 mmol, 1.01 eq) in anhydrous THF (0.5 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 h. 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 eq) 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 an aqueous solution of 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 a 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 (400MHz, DMSO-d6): δppm 8.77(brs,1H),8.36(s,1H),7.78(dd,J=8.8,4.4Hz,1H),7.34(s,1H),7.30(dd,J=8.8,5.2Hz,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=12.0Hz,1H),3.51(d,J=11.6Hz,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, yield 8%). LCMS: m / z 582.0 ([M+H]- ). 1 H NMR (400MHz, DMSO-d6): δppm8.75(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=12.0Hz,1H),3.54(d,J=11.6Hz,1H).

[0409] 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 Synthesis Route I

[0410]

[0411] Step A: To a solution of 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde (10.0 g, 53.7 mmol, 1.0 eq) in H2SO4 (50 mL) was added HNO3 (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 x 3). The combined organic phases were washed with brine (250 mL), dried over Na2SO4, and concentrated to afford 2,2-difluoro-6-nitrobenz[d][1,3]dioxole-5-carbaldehyde (11.0 g, 89%) as a yellow liquid. 1 H NMR (300MHz, CDCl3): δppm 10.35 (s, 1H), 7.87 (s, 3H), 7.67 (s, 1H).

[0412] Step B: To a solution of 2,2-difluoro-6-nitrobenz[d][1,3]dioxole-5-carbaldehyde (5.0 g, 21.6 mmol, 1.0 eq) in H2SO4 (50 mL) at 0°C was added NBS (5.8 g, 32.4 mmol, 1.5 eq) portionwise. 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 x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative HPLC (0.1% FA in acetonitrile, 55% to 60%) to give 4-bromo-2,2-difluoro-6-nitrobenz[d][1,3]dioxole-5-carbaldehyde (1.0 g, 14.9%) as a yellow solid. 1 H NMR (300MHz, CDCl3): δppm 10.17 (s, 1H), 7.84 (s, 1H).

[0413] Step C: At -78 ° C under N2 atmosphere, 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 eq) in THF (10 mL) was added magnesium reagent (2-chloro-5-fluorophenyl) magnesium bromide (9.6 mL, 4.8 mmol, 1.5 eq, 0.5 M). The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (20 mL). 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]dioxole-5-yl)(2-chloro-5-fluorophenyl)methanol (1.6 g, crude product) as a yellow liquid. LCMS: m / z 437.9 ([MH] - ).

[0414] 1 H NMR (400MHz, CDCl3): δppm 7.38 (s, 1H), 7.34-7.22 (m, 2H), 7.12-6.90 (m, 1H), 6.42 (s, 1H), 3.37 (brs, 1H).

[0415] 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 eq, crude) in DCM (20 mL) was added Dess-Martin (1.8 g, 4.3 mmol, 1.2 eq). The reaction mixture was then stirred at room temperature for 2 h. Water (50 mL) was added to the mixture and extracted with DCM (50 mL x 3). The combined organic phases were 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 2 steps) as a yellow solid. 1 HNMR (400MHz, CDCl3): δppm 7.99 (s, 1H), 7.75 (dd, J = 8.8, 3.2Hz, 1H), 7.52-7.40 (m, 1H), 7.35-7.22 (m, 1H).

[0416] 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 eq) in EtOH (5.0 mL) was added Fe (159 mg, 2.85 mmol, 5.0 eq). After heating the reaction mixture to 65°C, a solution of NH4Cl (15 mg, 0.9 mmol, 0.5 eq) 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 pad of celite, 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] + ).

[0417] 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 eq) in DMAc (5 mL) was added Zn(CN) (79 mg, 0.67 mmol, 1.2 eq) and Pd(PPh) (195 mg, 0.17 mmol, 0.3 eq). The reaction mixture was then stirred at 160 ° C in a microwave for 30 min. Water (20 mL) was added to the mixture and extracted with EtOAc (10 mL x 3). The combined organic phases were 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.

[0418] 1 H NMR (400MHz, DMSO-d6): δppm 8.17 (s, 2H), 7.65-7.57 (m, 1H), 7.52-7.38 (m, 2H), 7.18 (s, 1H).

[0419] 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 eq) in ACN (1.0 mL) and H₂O (0.1 mL) was added KOH (5 mg, 0.093 mmol, 0.3 eq) at room temperature. The reaction mixture was then stirred at the same temperature for 2 h. The mixture was dried over Na₂SO₄ and concentrated to a residue. The residue was purified by preparative TLC (petroleum ether / EtOAc = 2:1) to afford 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 ([MH] - ).

[0420] 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 eq) in ACN (1.0 mL) was added acyl chloride (49 mg, 0.22 mmol, 1.0 eq) and pyridine (34 mg, 0.44 mmol, 2.0 eq). The reaction mixture was then stirred at 50° C. for 12 h. Water (5 mL) was added to the mixture and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4 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 ([MH] - ).

[0421] 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 eq, crude) in TFA (2.0 mL) was added triethylsilane (132 mg, 1.14 mmol, 4.0 eq). The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated to a residue. The residue was purified by preparative HPLC (0.1% FA in acetonitrile, 45% to 64%) 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% over 2 steps) as a white solid. LCMS: m / z 547.0 ([M+H] + ). 1 H NMR (300MHz, DMSO-d6): δppm10.48(brs,1H),9.38(s,1H),7.95(d,J=7.8Hz ,1H),7.83-7.50(m,3H),7.40-7.20(m,1H),7.20-7.00(m,2H),6.03(s,1H).

[0422] 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.

[0423]

[0424] Step A: To a solution of 4-hydroxy-3-nitrobenzaldehyde (45.0 g, 269.3 mmol, 1.0 eq) and propane-1,3-diol (30.7 g, 403.9 mmol, 1.5 eq) in toluene (500 mL) was added p-TsOH (5.1 g, 26.9 mmol, 0.1 eq). The reaction mixture was heated to reflux for 16 h. The mixture was concentrated, water (300 mL) was added, and extracted with EtOAc (200 mL x 2). The combined organic phases were washed with brine (200 mL), dried over NaSO, and concentrated to a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether:EtOAc = 5:1) to afford 4-(1,3-dioxan-2-yl)-2-nitrophenol (42 g, 69.3%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ10.58(s,1H),8.22(d,J=2.0Hz,1H),7.69(dd,J=8.8,2.0Hz,1H),7.13(d,J=8 .8Hz,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] - ).

[0425] Step B: To a solution of 4-(1,3-dioxane-2-yl)-2-nitrophenol (40.0 g, 177.6 mmol, 1.0 eq) in THF (500 mL) was added nickel solution (15 g) dropwise at 25°C under H2 atmosphere. 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-dioxane-2-yl)phenol (33 g, 95.2%) as a black solid. LCMS: m / z 196.1 ([M+H] + ).

[0426] Step C: To a solution of 2-amino-4-(1,3-dioxan-2-yl)phenol (26.0 g, 133.2 mmol, 1.0 eq) and TEA (29.6 g, 293.0 mmol, 2.2 eq) in DCM (500 mL) at 0°C was added triphosgene (51.4 g, 173.1 mmol, 1.3 eq) portionwise. The reaction mixture was stirred at 0°C for 1 h, then at room temperature for 1 h. Water (300 mL) was added to the mixture and extracted with DCM (200 mL x 2). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, and concentrated to a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether:EtOAc = 2:1) to afford 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (11.2 g, 51.5%) as a white solid. LCMS: m / z 162.1 ([MH] - ).

[0427] Step D: To a solution of 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (11.2 g, 68.6 mmol, 1.0 eq) in HSO (98%, 120 mL) was added HNO (5.2 g, 82.4 mmol, 1.2 eq) dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h. The solution was then poured onto ice water (600 mL) to precipitate the product, which was collected by vacuum filtration to afford 6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (10.0 g, 70.0%) as a red solid. 1 H NMR (300MHz, DMSO-d6): δ12.83(brs,1H),8.55(s,1H),8.43(s,1H),7.76(s,1H). LCMS:m / z207.1([MH] - ).

[0428] 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 eq) in H2SO4 (110 mL) was added NBS (12.8 g, 72.1 mmol, 1.5 eq) at 0°C. The reaction mixture was stirred at 40°C for 5 h. The solution was then poured onto ice water (400 mL) to precipitate the product, which was collected by vacuum filtration to afford 4-bromo-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (8.6 g, 62.4%) as a yellow solid. 1H NMR (300MHz, DMSO-d6): δ10.17(s,1H),8.24(s,1H). LCMS:m / z 284.9,286.9([MH] - ).

[0429] 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 eq) in THF (70 mL) was added Int-A (2-chloro-5-fluorophenyl) magnesium bromide (191.6 mL, 0.5 M in THF, 95.8 mmol, 5.0 eq) dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 2 h. Water (200 mL) was then added to the mixture and extracted with ethyl acetate (100 mL x 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 (300MHz, DMSO-d6): δ12.61 (brs, 1H), 7.92 (s, 1H), 7.50 (dd, J = 8.8, 5.2Hz, 1H), 7.42 -7.00 (m, 2H), 6.73 (d, J = 6.0Hz, 1H), 6.27 (d, J = 5.4Hz, 1H).

[0430] 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 eq) and Fe (2.0 g, 35.9 mmol, 5.0 eq) in EtOH (60 mL) was added dropwise NH4Cl (192.1 mg, 3.6 mmol, 0.5 eq) in HO (10 mL) at 50°C. The reaction mixture was heated to 90°C and stirred for 1 h. Then, water (80 mL) and ethyl acetate (30 mL) were added to the mixture, filtered, and the filtrate was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4 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 ([MH]- ).

[0431] 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 eq) in ACN (10 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (818.3 mg, 3.6 mmol, 2.0 eq) and pyridine (428.6 mg, 5.4 mmol, 3.0 eq). The reaction mixture was stirred at 30°C for 2 h. The solution was then poured onto ice water (30 mL) to precipitate the product which was collected by vacuum filtration to afford 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 ([MH] - ).

[0432] 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 eq) in DCM (6 mL) at 25°C was added DMP (440 mg, 1.05 mmol, 3.0 eq). 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 x 2). The combined organic phases were washed with NaHCO (10 mL x 2), NaS0 (10 mL x 2), and brine (20 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel chromatography (eluted 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 ([MH] - ).

[0433] 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 eq), Zn(CN)2 (15.4 mg, 0.13 mmol, 1.5 eq), Pd(PPh3)4 (30.0 mg, 0.03 mmol, 0.3 eq) 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 and extracted with EtOAc (2 mL x 2). The combined organic phases were washed with brine (3 mL x 2), dried over Na2SO4 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 product) as a yellow oil. LCMS: m / z 520.0 ([MH] - ).

[0434] 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 eq) in MeCN (1 mL) / HO (0.1 mL) was added KOH (1.3 mg, 0.02 mmol, 0.3 eq) at room temperature. The reaction mixture was stirred at 40° C. for 4 h. Water (3 mL) was added to the mixture and extracted with EtOAc (3 mL x 2). The combined organic phases were washed with brine (3 mL x 2), dried over Na2SO4 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 ([MH] - ).

[0435] 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 eq) in TFA (5 mL) was added Et3SiH (104.7 mg, 0.9 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated to a residue. The residue was purified by preparative HPLC (0.1% FA in acetonitrile) 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 (400MHz, DMSO-d6): δ12.59(brs,1H),10.35(s,1H),9.18(brs,1H),7.93(d,J=7.6Hz,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).

[0436] 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

[0437]

[0438]

[0439] 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 eq) in DCM (4 mL) was added DMP (152 mg, 0.36 mmol, 1.5 eq) at 25°C. The reaction mixture was stirred at room temperature for 2 h. 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.

[0440] 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 eq) and KCO (764.3 mg, 5.5 mmol, 10.0 eq) in DMF (10 mL) was added CHI (392.5 mg, 2.9 mmol, 5.0 eq) at 25°C. The reaction mixture was stirred at 25°C for 2 h. Water (20 mL) was added to the mixture and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over NaSO, and concentrated to afford 4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (120 mg, crude) as a yellow oil.

[0441] 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 eq) and Fe (78 mg, 1.4 mmol, 5.0 eq) in EtOH (3 mL) was added dropwise NH4Cl (7.5 mg, 0.14 mmol, 0.5 eq) in HO (0.3 mL) at 50°C. 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, filtered, and the filtrate was extracted with ethyl acetate (5 mL). The combined organic phases were washed with brine (5 mL), dried over Na2SO4 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] + ).

[0442] 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 eq) in ACN (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (86.1 mg, 0.38 mmol, 1.5 eq) and pyridine (59.3 mg, 0.75 mmol, 3.0 eq). The reaction mixture was stirred at 50 ° C for 2 h. Then, water (3 mL) was added to the mixture and extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with brine (5 mL), dried over Na2SO4 and concentrated to give a residue. The residue was purified by preparative TLC (eluted 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, 56.5% yield over four steps) as a yellow solid. LCMS: m / z 586.8, 588.9 ([MH] - ).

[0443] 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 eq), Zn(CN)2 (18.1 mg, 0.15 mmol, 1.5 eq), Pd(PPh3)4 (36.2 mg, 0.03 mmol, 0.3 eq) 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 and extracted with EtOAc (2 mL x 2). The combined organic phases were washed with brine (3 mL x 2), dried over Na2SO4 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 ([MH] - ).

[0444] 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 eq) in MeCN (1 mL) / HO (0.1 mL) was added KOH (5.6 mg, 0.1 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 4 h. Water (2 mL) was added to the mixture and extracted with EtOAc (2 mL x 2). The combined organic phases were washed with brine (2 mL), dried over Na2SO4 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 ([MH] - ).

[0445] 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 eq) in TFA (2 mL) was added Et3SiH (23.2 mg, 0.2 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated to a residue. The residue was purified by preparative HPLC (0.1% FA in acetonitrile) 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 (400MHz, DMSO-d6): δ10.37(s,1H),9.30(brs,1H),7.93(d,J=8.8Hz,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).

[0446] 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

[0447]

[0448]

[0449] Step A: To a solution of 4-amino-3-methoxybenzoic acid (50.0 g, 299.1 mmol, 1.0 eq) in EtOAc (2000 mL) was added TFAA (50 mL, 358.92 mmol, 1.2 eq) at 25°C and mixed with EtOAc (500 mL). The reaction mixture was stirred at 25°C for 16 h. The mixture was concentrated to give 3-methoxy-4-(2,2,2-trifluoroacetylamino)benzoic acid (82.0 g, crude) as a yellow solid. LCMS: m / z 262.1 ([MH] - ).

[0450] Step B: To a solution of 3-methoxy-4-(2,2,2-trifluoroacetylamino)benzoic acid (82.0 g, crude, 0.31 mol, 1.0 eq) in H2SO4 (98%, 4100 mL) was added dropwise a solution of HNO3 (27.1 g) and H2SO4 (98%, 197 mL) at 0°C. 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 afford 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetylamino)benzoic acid (64.0 g, 69.5% yield over 2 steps) as a brown solid. LCMS: m / z 307.0 ([MH] - ). 1 H NMR (300MHz, DMSO-d6): δppm 11.13 (s, 1H), 8.27 (s, 1H), 7.46 (s, 1H), 3.99 (s, 3H).

[0451] 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 eq) in THF (400 mL) was added BH3-Me2S (2M) (155.8 mL, 311.5 mmol, 3.0 eq) portionwise at 0°C. 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 and extracted with EtOAc (200 mL x 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 ([MH] - ).

[0452] 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 eq) in DCM (750 mL) was added DMP (32.4 g, 76.49 mmol, 1.5 eq) at 25°C. The reaction mixture was stirred at room temperature for 2 h. Water (300 mL) was added to the mixture and extracted with EtOAc (200 mL x 2). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, and concentrated to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to obtain 2,2,2-trifluoro-N-(4-formyl-2-methoxy-5-nitrophenyl)acetamide (11.0 g, 60.4% yield over 2 steps) as a yellow solid. LCMS: m / z 291.0 ([MH] - ).

[0453] 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 eq) in H2SO4 (98%, 190 mL) was added NBS (10.0 g, 56.4 mmol, 1.5 eq) at 0°C. 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] - ). 1H NMR (300MHz, DMSO-d6): δppm 11.62 (s, 1H), 10.18 (s, 1H), 8.47 (s, 1H), 3.86 (s, 3H).

[0454] Step F: At 0 ° C, 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 eq) in THF (121 mL) was added dropwise Int-A (2-chloro-5-fluorophenyl) magnesium bromide (326.0 mL, 0.5 M in THF, 163.0 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 1 h. Then, water (200 mL) was added to the mixture and extracted with EtOAc (200 mL x 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 (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 ([MH] - ). 1 H NMR (400MHz, DMSO-d6): δppm 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, 3.2Hz, 1H), 6.82 (d, J = 6.0Hz, 1H), 6.29 (d, J = 5.2Hz, 1H), 3.76 (s, 3H).

[0455] 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 eq) in DCM (440 mL) was added DMP (13.9 g, 32.9 mmol, 1.5 eq) 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 x 2). The combined organic phases were washed with aqueous NaHCO3 (200 mL x 2), aqueous Na2S2O3 (100 mL x 2), and 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-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 ([MH] - ).

[0456] 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 eq) and Fe (1.2 g, 20.0 mmol, 5.0 eq) in EtOH (40 mL) was added dropwise NH4Cl (107.0 mg, 2.0 mmol, 0.5 eq) in HO (20 mL) at 50°C. The reaction mixture was heated to 90°C and stirred for 1 h. Then, water (80 mL) and EtOAc (30 mL) were added to the mixture and filtered, and the filtrate was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4 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 ([MH] - ).

[0457] 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 eq) in ACN (10 mL) was added Int.B 3-fluoro-5-(trifluoromethyl)benzoyl chloride (516.6 mg, 2.3 mmol, 1.2 eq) and pyridine (300.6 mg, 5.4 mmol, 2.0 eq) at 50° C. The reaction mixture was stirred at 50° C. for 1 h. 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-trifluoroacetylamino)phenyl)-3-fluoro-5-(trifluoromethyl)benzamide (800 mg, 57.7%) as a yellow solid. LCMS: m / z 656.8, 658.9 ([MH] - ).

[0458] 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 eq), Zn(CN)2 (26.4 mg, 0.23 mmol, 1.5 eq), Pd(PPh3)4 (52.0 mg, 0.05 mmol, 0.3 eq) 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 and extracted with EtOAc (5 mL x 2). The combined organic phase was washed with brine (4 mL x 2), 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-(2-(2-chloro-5-fluorobenzoyl)-3-cyano-4-methoxy-5-(2,2,2-trifluoroacetylamino)phenyl)-3-fluoro-5-(trifluoromethyl)benzamide (47 mg, 51.2%) as a yellow solid. LCMS: m / z 603.9 ([MH] - ).

[0459] 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 eq) in MeCN (12 mL) / HO (1.2 mL) was added KOH (35.9 mg, 0.64 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 80° C. for 1 h. Water (20 mL) was added to the mixture and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried over Na2SO4 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 ([MH] - ).

[0460] 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 eq) in TFA (2 mL) was added Et3SiH (174 mg, 1.5 mmol, 5.0 eq). The reaction mixture was stirred at 50°C for 12 h. The reaction mixture was then concentrated to a residue, which was purified by preparative TLC (EtOAc) to afford 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] + ).

[0461] 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 eq) in DCM (1 mL) was added BBr (7.5 mg, 0.03 mmol, 1.5 eq) dropwise under N 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] + ).

[0462] 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 eq) in DCM (2 mL) was added TEA (44 mg, 0.44 mmol, 2.2 eq). Triphosgene (71 mg, 0.24 mmol, 1.2 eq) was then added to the mixture 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, which was purified by preparative HPLC (0.1% FA in acetonitrile, 30% to 70%) 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% over 2 steps) as a white solid. LCMS: m / z 522.0 ([MH] - ). 1 H NMR (300MHz, DMSO-d6): δppm10.22(s,1H),9.00(s,1H),8.35-8.20(m,1H),7.91(d,J=8.4Hz,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).

[0463] 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

[0464] 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

[0465]

[0466] 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 eq) in THF (2 mL) was added triphosgene (168 mg, 0.56 mmol, 1.0 eq) and DIEA (73 mg, 0.56 mmol, 1.0 eq) at 0°C under N2 atmosphere. The reaction mixture was then stirred at 0°C for 30 min. A solution of rel-(R)-5-fluoro-3-(trifluoromethyl)indolin-3-ol (248 mg, 1.12 mmol, 2.0 eq) in pyridine (1.0 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl (2 mL) and the mixture was extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (2 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA, 40% to 57%) 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 ([MH] - ). This (170 mg) was separated by chiral SFC separation to provide 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%) as a white solid. LCMS: m / z 602.0 ([MH] - ). 1H NMR (300MHz, DMSO-d6): δppm9.32(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=12.0Hz,1H),3.55(d,J=12.0Hz,1H). and white solid 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%). LCMS: m / z 601.9 ([MH] - ). 1 H NMR (400MHz, DMSO-d6): δppm 9.33(s,1H),8.70(s,1H),7.80(dd,J=8.8,4.4Hz,1H),7.54(s,1H),7.39(d,J=2.0Hz,1H),7.33(dd,J=8.8,4.2Hz, 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=12.0Hz,1H).

[0467] The preparative SFC separation is shown below:

[0468] Chiral purity was determined by SFC (area normalized)

[0469] Principle NP HPLC, UV detection, evaluation by area %

[0470] MeOH: HPLC grade, J&K

[0471] CO2: 99.999%

[0472] Solvent: ACN

[0473] Equipment: Waters SFC

[0474] Column: CHIRALCEL OD-H 20mm*250mm, 5μm

[0475] Chromatographic conditions:

[0476] Mobile phase A: CO2

[0477] Mobile phase B: MeOH

[0478] Gradient: B 20%

[0479] Flow rate: 30ml / min

[0480] Injection volume: 0.5 ml

[0481] Injection concentration: 20 mg / ml

[0482] Column temperature: 35°C

[0483] Preparative SFC cycle time: 11 min

[0484] 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

[0485]

[0486] Step A: To a solution of 3-chloro-5-fluorobenzoic acid (5.0 g, 28.6 mmol, 1.0 eq) in THF (50 mL) was added (COCl) (10.9 g, 85.8 mmol, 3.0 eq) and DMF (0.1 mL) dropwise at room temperature. The reaction mixture was then stirred at the same temperature for 2 h. The mixture was concentrated to give 3-chloro-5-fluorobenzoyl chloride (5.5 g, crude) as a yellow solid and used directly.

[0487] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6,7-dihydro-8H-[1,3]dioxol[4,5-e]isoindol-8-one (200 mg, 0.56 mmol, 1.0 eq) in ACN (2 mL) was added 3-chloro-5-fluorobenzoyl chloride (130 mg, 0.67 mmol, 1.2 eq) and pyridine (89 mg, 1.12 mmol, 2.0 eq) at room temperature. The mixture was then stirred at the same temperature for 2 h. Water (2 mL) was added to the mixture and extracted with EtOAc (2 mL x 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 (0.1% FA in acetonitrile, 35% to 47%) 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 ([MH] - ). It 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 ([MH] - ). 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), 7.48-7.23 (m, 3H), 7.23-7.05 (m, 1H), 6.85 (brs, 1H), 6.04 (s, 1H). And white solid 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%). LCMS: m / z 510.9 ([MH] - ). 1H NMR (300MHz, DMSO-d6): δppm 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).

[0488] Chiral SFC separation method:

[0489] Chiral purity was determined by SFC (area normalized)

[0490] Principle NP HPLC, UV detection, evaluation by area %

[0491] Reagents:

[0492] MeOH: HPLC grade, J&K

[0493] CO2: 99.999%

[0494] Solvent: MeOH+CAN

[0495] Equipment: Waters SFC

[0496] Column: CHIRALCEL AS-H 20mm*250mm, 5μm

[0497] Chromatographic conditions:

[0498] Mobile phase A: CO2

[0499] Mobile phase B: MeOH

[0500] Gradient: B 30%

[0501] Flow rate: 30ml / min

[0502] Injection volume: 1.0 ml

[0503] Injection concentration: 20 mg / ml

[0504] Column temperature: 35°C

[0505] 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

[0506] 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

[0507]

[0508] Step A: At room temperature, to a solution of 3-chloro-5-fluorobenzoic acid (200 mg, 1.12 mmol, 1.0 eq) in THF (2.0 mL) was added (COCl) (0.425 g, 3.35 mmol, 3.0 eq) and DMF (0.1 mL). The reaction mixture was then stirred at the same temperature for 2 h. The mixture was concentrated to give 3-chloro-5-fluorobenzoyl chloride (250 mg, crude) as a yellow solid and used directly in the next step in crude form.

[0509] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6,7-dihydro-8H-[1,3]dioxol[4,5-e]isoindol-8-one (200 mg, 0.56 mmol, 1.0 eq) in ACN (2 mL) was added 3-chloro-5-fluorobenzoyl chloride (133 mg, 0.67 mmol, 1.2 eq) and pyridine (89 mg, 1.12 mmol, 2.0 eq) at room temperature. The mixture was then stirred at the same temperature for 2 h. Water (2 mL) was added to the mixture and extracted with EtOAc (2 mL x 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 (0.1% FA in acetonitrile, 35% to 47%) 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 as a white solid (~60 mg, 20.7%). LCMS: m / z 515.9 ([MH] - ). It was separated by chiral preparative SFC using the following method to obtain P1(S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[1,3]dioxol[4,5-e]isoindol-5-yl)-5-fluorobenzamide (15.7 mg, 39.3%) as a white solid. LCMS: m / z 515.9 ([MH] - ). 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 ([MH] - ). 1 H NMR (400MHz, DMSO-d6): δppm 10.43(s,1H),9.37(s,1H),8.61(d,J=8.4Hz,1H),8.31(d,J=8.4Hz,1H),7.90-7.52(m,3H),7.50–6.70(m,3H),6.22(brs,1H).

[0510] Chiral preparative SFC separation method:

[0511] Chiral purity was determined by UPCC (area normalization).

[0512] Principle NP HPLC, UV detection, evaluation by area %

[0513] Reagents

[0514] MeOH: HPLC grade, MREDA

[0515] CO2: 99.999%

[0516] Solvent: MeOH

[0517] Equipment: Waters UPCC

[0518] Column: CHIRALPAK AS-3, 4.6mm*150mm, 3μm

[0519] Chromatographic conditions

[0520] Mobile phase A: CO2

[0521] Mobile phase B: MeOH

[0522] Gradient: B 30%

[0523] Flow rate: 2.0ml / min

[0524] Detection UV: 210nm

[0525] Column temperature: 35°C

[0526] Injection volume: 2.0 μl

[0527] 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

[0528]

[0529] Step A: To a stirred mixture of methyl 3-bromo-5-fluoro-2-methylbenzoate (5 g, 20.2 mmol) in anhydrous THF (30 mL) cooled to -78 ° C was added LDA solution (20.2 mL, 40.5 mmol, 2 M) dropwise for 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 at -78 ° C for 0.1 h. The resulting mixture was stirred at -78 ° C for 2 h. The reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl. The following mixture was 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.

[0530] 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-1λ5-benzo[d][1,2]iodooxolane-3-one (4.6 g, 10.8 mmol) at 0 ° C under N2. The reaction mixture was stirred at room temperature for 1 hour. The mixture was treated with H2O (100 mL) and extracted with EA (3 x 300 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by 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] + .

[0531] 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)diazepine]-2-methylpropionitrile (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.

[0532] Step D: A solution of methyl 3-bromo-2-(bromomethyl)-4-[(2-chloro-5-fluorophenyl)carbonyl]-5-fluorobenzoate (1.1 g, 2.28 mmol) in methylamine (10 mL) was stirred for 0.5 h. 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] + .

[0533] 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 N₂ for 1 hour. The cooled reaction mixture was treated with H₂O (100 mL) and extracted with EA (3 x 300 mL). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by 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] + .

[0534] Step F: In a sealed tube, DIEA (112 mg, 0.87 mmol) was added 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). 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.

[0535] Step G: To a stirred solution 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 x 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 using a solvent mixture consisting of PE:EA = 3:1 as eluent 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] + .

[0536] 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 hour. The cooled mixture was concentrated. The residue was diluted with H 2 O (50 ml), adjusted to pH = 8 with saturated aqueous NaHCO 3 and extracted with EA. The organic layer was washed with brine (50 mL), dried over Na 2 SO 4 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] + .

[0537] 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 anhydrous pyridine (1 mL) was added POCl (8.87 mg, 0.06 mmol) dropwise 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 (400MHz, CD3OD) δ7.82(s,1H),7.66(dd,J=16.2,8.7Hz,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).

[0538] 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

[0539]

[0540] 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 benzoyl peroxide (0.39 g, 1.619 mmol). The reaction mixture was stirred at 90°C overnight. The cooled mixture was diluted with water, extracted with EA, and 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 (0-5% gradient) to afford methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (1.2 g, 3.68 mmol, 90.95%) as a colorless oil.

[0541] Step B: To a solution of methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (1 g, 3.07 mmol) in THF (10 mL) was added methylamine (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 using petroleum ether with ethyl acetate (35%) 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] + .

[0542] Step C: Borane dimethylsulfane (5 mL, 50.0 mmol) was added 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) at 25 ° C, and the reaction mixture was stirred at 60 ° C for 4 h. The cooled reaction solution was quenched with methanol and 6M HCl was added to adjust the pH to 1-2. The mixture was then heated to 80 ° C and stirred for 1 h. The reactants were cooled to room temperature and the pH was adjusted to 7-8 using 6M 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 in DCM (0-5% gradient) to give 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] + .

[0543] Step D: To a solution of 4-bromo-6-fluoro-2-methyl-2,3-dihydro-1H-isoindole (1.5 g, 6.519 mmol) in anhydrous THF (15 mL) was added lithium di(propyl-2-yl)amide (4.890 mL, 9.779 mmol) dropwise at -65 ° C. The reaction mixture was stirred at -65 ° C for 0.5 h under an N2 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 a saturated aqueous solution of NH4Cl and extracted with EA. The combined organic phases were 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→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] + .

[0544] 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) at 0°C was added 65272-70-0 (0.5 mL, 2.058 mmol). The reaction mixture was stirred at 0°C for 2 hr. After 2 h, the reaction mixture was quenched with isopropanol (10 mL). The isopropanol 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] + .

[0545] 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 N2 atmosphere for 4 hr. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography eluting with MeOH in DCM (0-3% gradient) 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] + .

[0546] 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(propan-2-yl)]amine (194 mg, 1.503 mmol) at 25° C. The reaction mixture was stirred at 120° C. for 1 hr. The reaction solution was diluted with EA, water, and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography eluting with MeOH in DCM (0-4% gradient) to afford 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] + .

[0547] 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 H2O (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, water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with MeOH in DCM (0-8% gradient) to afford 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] + .

[0548] 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 h. After 0.5 h, the reaction mixture was diluted with H₂O. The aqueous layer was extracted with EA. The combined EA layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford 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] + .

[0549] 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 min 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] + . 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),9.26(s,1H),7.96(d,J=7.6Hz,1H),7.75(d,J=8.8Hz,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).

[0550] 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

[0551]

[0552] Step A: 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) was stirred in a solution of HBr (3 mL, 30% HBr in H2O) at 50°C overnight. The cooled reaction mixture was diluted with H2O, extracted with EA, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give 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] + . 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),10.82(s,1H),10.28(s,1H),9.07(s,1H),7.93(d,J=8.2H z, 1H), 7.70 (d, J = 14.8Hz, 4H), 7.29 (dd, J = 8.8, 5.1Hz, 1H), 7.10 (d, J = 7.8Hz, 1H), 6.13 (s, 1H).

[0553] 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

[0554]

[0555]

[0556] 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) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC. The mixture was treated with H2O (100 mL) and extracted with EA (3 x 300 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, 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.

[0557] Step B: To a suspension of NaH (8.31 g, 208 mmol, 60% in mineral oil) in anhydrous THF (60 mL) was added 4-bromo-6-fluoro-2,3-dihydro-1H-benzo[d]imidazol-2-one (16 g, 69.3 mmol) portionwise at 0°C. After the addition was complete, the reaction mixture was stirred at 0°C for an additional 1.5 hours. 4-Methoxybenzyl chloride (28.3 mL, 208 mmol) was slowly added, and the mixture was stirred at 0°C for 0.5 hours and at room temperature for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl. The mixture was 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] + .

[0558] 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 anhydrous THF (70 mL) cooled to -78°C was added LDA solution (39.9 mL, 79.7 mmol, 2 M) dropwise for 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 at -78°C for 0.1 h. The resulting mixture was stirred at -78°C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl. The mixture was 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.

[0559] 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-1λ5-benzo[d][1,2]iodooxolane-3-one (832 mg, 1.96 mmol) at 0 ° C under N2. The reaction mixture was stirred at room temperature for 1 hour. The mixture was treated with H2O (100m) and extracted with EA (3x300 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (PE containing 0-30% EA) 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] + .

[0560] 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), bis(cyclopentyldiphenylphosphine)iron(0) (0.38 g, 0.67 mmol) under N2 with stirring. The mixture was refluxed for 3 h until the starting material was completely consumed. The cooled mixture was treated with H2O (100 mL) and extracted with EA (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by 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.

[0561] 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 hr. The reaction solution was purified by flash chromatography using ACN in H2O (0-65% gradient) to afford 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] + .

[0562] 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 H2O (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, water, and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography using MeOH in DCM (0-8% gradient) to afford 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] + .

[0563] 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 pH of the mixture was then adjusted to 8 with NaHCO3 (aq.) and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 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] + .

[0564] 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. ACN and pyridine were removed under vacuum to give a 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] + . 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),11.00(s,1H),10.21(s,1H),8.99(s,1H),7.92(d,J=8.2Hz,1H),7.71 (d, J = 9.4Hz, 1H), 7.66 (s, 1H), 7.29 (dd, J = 8.8, 5.2Hz, 1H), 7.07 (t, J = 6.8Hz, 1H), 7.03 (s, 1H), 5.98 (s, 1H).

[0565] 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

[0566]

[0567]

[0568] 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 eq) in EtOH (20 mL) was added HO (20 mL) containing NaOH (770 mg, 19.25 mmol, 4.0 eq). 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 ([MH] - ).

[0569] Step B: at 0 ° C under N2 atmosphere, to a solution of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl) (2-chloro-5-fluorophenyl) ketone (1.0 g, 2.57 mmol, 1.0 eq) in DCM (8.5 mL) was added TEA (546 mg, 5.39 mmol, 2.1 eq) and DMAP (63 mg, 0.51 mmol, 0.2 eq). Chloroacetyl chloride (304 mg, 2.70 mmol, 1.05 eq) was then 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 eq) was added. The reaction mixture was heated to reflux for 4 h. The reaction mixture was cooled to 25 ° C, quenched with NaHSO4 aqueous solution (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 and filtered 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 ([MH] - ).

[0570] 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 eq) in EtOH (10 mL) was added NH4Cl (520 mg, 9.77 mmol, 4 eq) in H2O (3.5 mL). Fe (410 mg, 7.33 mmol, 3.0 eq) was then 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 x 2). The combined organic phases were 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] + ).

[0571] 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 eq), Zn(CN)2 (15 mg, 0.13 mmol, 1.0 eq), Pd(PPh3)4 (44 mg, 0.04 mmol, 0.3 eq) 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 and extracted with EtOAc (3 mL x 2). The combined organic phase was washed with brine (5 mL x 2), dried over Na2SO4 and concentrated to give a residue. The residue was purified by preparative TLC (extraction 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 ([MH] - ).

[0572] 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 eq) in ACN (5 mL) / H₂O (0.5 mL) was added KOH (72.4 mg, 1.29 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 50°C for 1 h. Water (5 mL) was added to the mixture and extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, and concentrated to afford 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 ([MH] - ).

[0573] 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 eq) in ACN (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (278 mg, 1.23 mmol, 3 eq) and pyridine (162.2 mg, 2.05 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 1 h. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with brine (5 mL) and aqueous Na2CO3 solution (5 mL), dried over Na2SO4 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 ([MH] - ).

[0574] 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 eq) in TFA (5 mL) was added Et3SiH (238 mg, 2.05 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated to a residue. The residue was purified by preparative HPLC (0.1% FA in acetonitrile) 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, ~8.2% over three steps) as a white solid. LCMS: m / z 535.9 ([MH] - ). 1 H NMR (400MHz, DMSO-d6): δ10.34(brs,1H),9.51(brs,1H),9.28(s,1H),7.93(d,J=8.0Hz,1H),7.70(d,J=8. 8Hz,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).

[0575] 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

[0576] 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

[0577] 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

[0578]

[0579] 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 in D2O (0.26 mg, 0.0026 mmol). The reaction mixture was stirred at 50° C. for 18 h. 1 N HCl was added to the cooled mixture and the pH was adjusted to approximately 7. The reaction mixture was pre-purified by preparative HPLC to give N-[7-(2-chloro-5-fluorophenyl)-3,3-dideutero-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 (400MHz, CD3OD)7.67–7.58(m,3H),7.25(dd,J=8.8,5.0Hz,1H),7.08(s,1H),7.02–6.94(m,1H),6.68(s,1H). Then another batch of 200 mg of N-[7-(2-chloro-5-fluorophenyl)-3,3-dideutero-2,9-dioxo-1,2,3,7,8,9-hexahydro[1,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide was 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] + . 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.52(s,1H),9.26(s,1H),7.91(d,J=8.0Hz,1H),7.72(s,1H),7.6 6(s,1H),7.31(dd,J=8.8,5.2Hz,1H),7.11(d,J=6.4Hz,1H),7.08(dd,J=8.6,2.9Hz,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 as a white solid (62.7 mg, 0.116 mmol, 62%). (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] + . 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.52(s,1H),9.26(s,1H),7.91(d,J=8.0Hz,1H),7.72(s,1H),7.6 6(s,1H),7.31(dd,J=8.8,5.2Hz,1H),7.11(d,J=6.4Hz,1H),7.08(dd,J=8.6,2.9Hz,1H),6.86(brs,1H).

[0580] Preparative separation methods:

[0581] Instrument: SHIMADZU PREP SOLUTION SFC

[0582] Column: ChiralPak IH, 250×20mm ID, 5μm

[0583] Mobile phase: A is CO2 and B is MEOH

[0584] Gradient: B 20%

[0585] Flow rate: 40 mL / min

[0586] Back pressure: 100 bar

[0587] Column temperature: 35°C

[0588] Wavelength: 220nm

[0589] Cycle time: 6 minutes

[0590] Elution time: 2h

[0591] 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

[0592] 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

[0593] 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

[0594] 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

[0595] 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

[0596]

[0597]

[0598] Step A: To a stirred solution of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (500 mg, 1.28 mmol) in DCM (5 mL) was added TEA (0.357 mL, 2.56 mmol), DMAP (31 mg, 0.257 mmol) and 2-chloropropionyl chloride (325 mg, 2.57 mmol) dropwise at room temperature. The reaction mixture was stirred at 50 ° C for another 2 h. The cooled reaction was quenched with a NaHSO4 aqueous solution (10 mL) and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with MeOH in DCM [gradient: 5%] to afford 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] - .

[0599] 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 / H2O (20 mL) was added NH4Cl (152 mg, 2.84 mmol) and Fe (158 mg, 2.84 mmol) dropwise. 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 by silica gel column chromatography eluting with MeOH in DCM [gradient: 6%] to afford 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] - . 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),7.60(dd,J=8.8,4.9Hz,1H),7.44(dd,J=8.2,3.0Hz,1H),7. 24(dd,J=8.6,3.0Hz,1H),6.54(s,1H),6.25(s,2H),4.69(d,J=6.8Hz,1H),1.42(d,J=6.8Hz,3H).

[0600] 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 CuCN (303 mg, 3.38 mmol) dropwise. The reaction mixture was stirred at 150 ° C. in a microwave for 1 h. The cooled mixture was filtered and the filtrate was washed with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH in DCM [gradient: 4%] to afford 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] - .

[0601] 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 / H0 (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 H0 and extracted with EA. The organic phase was washed with brine, dried over Na0 and concentrated. The residue was purified by silica gel column chromatography eluting with MeOH in DCM [gradient: 4%] to afford 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] - .

[0602] 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 min. The reaction mixture was washed with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with MeOH in DCM [gradient: 5%] to afford 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] - .

[0603] 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 Et3SiH (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 NaHCO3 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 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] + . 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.52(s,0.5H),9.48(s,0.5H),9.27(s,1H),7.93(d,J=8.4Hz,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=6.8Hz,3H).

[0604] Step G: Example 36 (100 mg, 0.181 mmol) was separated by chiral preparative SFC (Waters Thar 80 preparative SFC-chiral Cel OD, 250×21.2 mm ID, 5 μm, 20%, phase A: CO 2 , phase B: MeOH) to afford 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 (400MHz, DMSO-d6) δ10.34(s,1H),9.52(s,1H),9.27(s,1H),7.93(d,J=8.4Hz,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=6.8Hz,1H),1.51(d,J=6.8Hz,3H).

[0605] 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 HNMR(400MHz,DMSO-d6)δ10.34(s,1H),9.48(s,0.5H),9.27(s,1H),7.93(d,J=8.4Hz,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=6.8Hz,1H),1.52(d,J=6.8Hz,3H).

[0606] 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] + .1 HNMR (400MHz, DMSO-d6) δ10.34(s,1H),9.52(s,1H),9.27(s,1H),7.93(d,J=8.4Hz,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=6.8Hz,1H),1.51(d,J=6.8Hz,3H).

[0607] P-4 Example 40 (12.2 mg, 0.021 mmol, 8.34%) was obtained as a white solid. LCMS: ESI m / z 552 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.34(s,1H),9.48(s,0.5H),9.27(s,1H),7.93(d,J=8.4Hz,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=6.8Hz,1H),1.52(d,J=6.8Hz,3H).

[0608] Preparative separation methods:

[0609] Instrument: Waters Thar 80 preparative SFC

[0610] Column: ChiralPak IH, 250×21.2 mm ID, 5 μm

[0611] Mobile phase: A is CO2 and B is MEOH

[0612] Gradient: B 20%

[0613] Flow rate: 40 mL / min

[0614] Back pressure: 100 bar

[0615] Column temperature: 35°C

[0616] Wavelength: 220nm

[0617] Cycle time: 6 minutes

[0618] Elution time: 2 hours

[0619] 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

[0620] 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

[0621] 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

[0622]

[0623] 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) was added 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) dropwise at 0 ° C under N2 atmosphere. The reaction mixture was stirred at 50 ° C for another 2 h. The cooled reaction was quenched with NaHSO4 (10 mL) aqueous solution and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with PE containing EA [gradient: 35%] to give 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 (400MHz, DMSO-d6) δ11.86(s,1H),11.10(s,1H),7.82(s,1H),7.75–7.65(m,2H),7.65–7.55(m,1H).

[0624] 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)oxanecarboxylic anhydride (51 mg, 0.237 mmol) and DMAP (1.45 mg, 0.012 mmol). The reaction mixture was stirred at 50 ° C under N2 overnight. The cooled reaction mixture was washed with H2O and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with PE containing EA [gradient: 25%] to give 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] + .

[0625] 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 / H2O (20 mL) was added dropwise NH4Cl (172 mg, 3.222 mmol) and iron (0) (179 mg, 3.22 mmol) at room temperature under 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 PE containing EA [gradient: 30%] to give 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 (400MHz, DMSO-d6) δ11.21(s,1H),7.64(dd,J=8.8,4.8Hz,1H),7.49(td,J=8.4,3.2Hz,1H),7.35(dd,J=8.8,3.0Hz,1H),6.77(s,1H),6.09(s,2H).

[0626] 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 CuCN (164 mg, 1.837 mmol) dropwise. The reaction mixture was stirred at 150 ° C. under N2 in a microwave 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 Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with PE containing EA [gradient: 35%] to give 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] - .

[0627] 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 / H0 (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 washed with H0 and extracted with EA. The organic phase was washed with brine, dried over Na0, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with PE containing EA [gradient: 40%] to give 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] - .

[0628] 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 ACN (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 h. The reaction mixture was washed with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with PE containing EA [gradient: 35%] to give 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] - .

[0629] 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 Et3SiH (88 mg, 0.763 mmol). The reaction mixture was stirred at 60°C for 30 min. The reaction mixture was diluted with aqueous NaHCO3 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-(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] + . 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),10.50(s,1H),9.44(s,1H),7.95(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.6 3(s,1H),7.47(s,1H),7.32(dd,J=8.8,5.2Hz,1H),7.10(td,J=8.4,2.8Hz,1H),6.96(s,1H),6.10–6.00(brs,1H).

[0630] 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 Thall 80 Preparative SFC-Chiral Cel OD, 250×21.2 mm ID, 5 μm, 20%, A: CO2, Phase B: IPA) to give compound:

[0631] 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 HNMR (400MHz, DMSO-d6) δ10.81(s,1H),10.50(s,1H),9.44(s,1H),7.95(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7. 63(s,1H),7.47(s,1H),7.32(dd,J=8.8,5.2Hz,1H),7.10(td,J=8.4,2.8Hz,1H),6.96(s,1H),6.10–6.00(brs,1H).

[0632] P-2 Example 43 (7.2 mg, 0.012 mmol, 56%) was obtained as a white solid. LCMS: ESI m / z 574 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ10.81(s,1H),10.50(s,1H),9.44(s,1H),7.95(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7. 63(s,1H),7.47(s,1H),7.32(dd,J=8.8,5.2Hz,1H),7.10(td,J=8.4,2.8Hz,1H),6.96(s,1H),6.10–6.00(brs,1H).

[0633] 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

[0634]

[0635]

[0636] 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 CCl4 (15 mL) was stirred at 80°C under an N2 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 = 0-20%) to give the crude product 2-bromo-3-(bromomethyl)-1-fluoro-4-nitrobenzene (1.0 g, 3.2 mmol, 75%) as a colorless oil.

[0637] 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 and 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 (eluting with EA / PE = 0-40%) 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 (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.33 (dd, J = 9.2, 4.4Hz, 1H), 7.89–7.77 (m, 1H).

[0638] 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 and 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 6N 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 = 0-50%) 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 (400MHz, DMSO-d6) δ10.23 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.24 (s, 2H), 6.97 (d, J = 9.2 Hz, 1H).

[0639] 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 indicated that the reaction was complete. The mixture was poured into H O. The mixture was filtered and the filtrate was extracted with EA. The organic layer was concentrated and washed with brine, dried over Na SO, 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 (400MHz, DMSO-d6) δ10.13(s,1H),8.47(s,1H),6.87(s,2H).

[0640] 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] + .

[0641] 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 H2O (20 mL) and extracted with DCM (2x20 mL). The organic layer was washed with brine, dried over Na2SO4, 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] + .

[0642] Step G: A sealed vial was charged with (3-amino-2-bromo-4-iodo-6-nitrophenyl)(2-chloro-4-fluorophenyl)methanone (500 mg, 1.00 mmol), trifluoro(vinyl)-λ 5 Potassium borohydride (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). The mixture was stirred at 85°C under N2 for 2 h. The mixture was diluted with water (~10 mL) and extracted with EtOAc (~20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (eluting with 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] + .

[0643] 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)2 (705 mg, 6.01 mmol), Pd(PPh3)4 (139 mg, 0.120 mmol) and DMA (10 mL). The mixture was stirred at 170°C (MW) under N2 for 3 h. The mixture was diluted with water (~10 mL) and extracted with EtOAc (~20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified by column (eluting with 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 / z346[M+H] + .

[0644] 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 H₂O (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 x 2). The combined organic phases were washed with brine (20 mL x 2), dried over Na₂SO₄, and concentrated to afford 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] + .

[0645] 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 H2O (0.2 mL) was added NaIO4 (123 mg, 0.577 mmol) and potassium citrate (7.09 mg, 19 μmol). The mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated NaHCO3 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]+ .

[0646] 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 NaBH4 (10.3 mg, 0.273 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (~10 mL) and extracted with EtOAc (~20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to a residue. The residue was purified by column chromatography (eluting with MeOH:DCM = 10%) to give 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-4-nitro-2,3-dihydro-1H-isoindole-1-one (40 mg, 0.109 mmol, 80%) as a brown solid. LCMS:ESI m / z 368[M+H] + .

[0647] 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 d. The cooled mixture was washed with H 2 O and extracted with EA. The organic layer was washed with brine, dried over Na 2 SO 4 , 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] + .

[0648] 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 H2O (0.3 mL). The reaction mixture was heated to 85°C and stirred for 2 h. The mixture was then filtered and the filtrate 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] + .

[0649] 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 min. The mixture was then diluted with water (~20 mL) and extracted with ethyl acetate (~20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated to afford 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] + .

[0650] 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 Et3SiH (0.2 mL, 18 μmol). The reaction mixture was stirred at 60°C for 30 min. The reaction mixture was concentrated to a residue. The residue was purified by preparative HPLC to afford 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] + . 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.31(s,1H),8.91(s,1H),7.94(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.65(s,1H) ,7.34(d,J=4.4Hz,1H),7.33–7.25(m,1H),7.10(dd,J=8.4,5.2Hz,1H),6.70–6.50(s,0.5H),6.00(brs,1H),5.52(s,2H).

[0651] 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

[0652]

[0653] Step A: To a solution of 2,6-dibromo-3-methyl-4-nitrophenol (10 g, 32.1 mmol) in CH3CN (100 mL) was added K2CO3 (8.89 g, 64.3 mmol) and CHI (3.9 mL, 48.2 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with EA in PE [Gradient: 0-15%] to give 1,3-dibromo-2-methoxy-4-methyl-5-nitrobenzene (10 g, 30.7 mmol, 96%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.31(s,1H),3.87(s,3H),2.46(s,3H).

[0654] 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 H₂O and extracted with DCM. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography eluting with EA in PE [Gradient: 0-20%] to afford 1,3-dibromo-4-(bromomethyl)-2-methoxy-5-nitrobenzene (10, 24.7 mmol, 80%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),4.80(s,2H),3.90(s,3H).

[0655] Step C: To a solution of 1,3-dibromo-4-(bromomethyl)-2-methoxy-5-nitrobenzene (10 g, 24.7 mmol) in CHCN (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 washed with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluting with EA in PE [Gradient: 0-30%] to afford 2,4-dibromo-3-methoxy-6-nitrobenzene-1-carbaldehyde (8.1 g, 24.0 mmol, 97%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.56(s,1H),3.93(s,3H).

[0656] 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 by silica gel column chromatography, eluting with PE containing EA [gradient: 0-40%] to give (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 (400MHz, DMSO-d6) δ8.30(s,1H),7.54(dd,J=8.8,5.2Hz,1H),7.25(td,J=8.4,3.2Hz,1 H), 7.06 (dd, J=9.6, 3.2Hz, 1H), 6.81 (d, J=6.0Hz, 1H), 6.24 (d, J=5.6Hz, 1H), 3.84 (s, 4H).

[0657] 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 was slowly added Dess-MARTIN (9.1 g, 21.3 mmol). 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 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-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] + . 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),7.81(dd,J=9.2,3.2Hz,1H),7.74(dd,J=8.8,4.8Hz,1H),7.65–7.58(m,1H),3.95(s,3H).

[0658] 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) / H2O (4 mL) was added (2,2-dimethyl-4-oxo-5-aza-3-oxahexan-6-yl)trifluoro-λ 5Potassium borohydride (2.6 g, 13.5 mmol), Pd(dppf)Cl2 (660 mg, 0.89 mmol), and K2CO3 (3.7 g, 26.9 mmol). After stirring overnight at 70°C under N2, 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 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%, PE containing EtOAc) to give 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]formate (930 mg, 1.8 mmol, 20%) as a yellow solid. LCMS: m / z 517 [M+H] + .

[0659] 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]formate (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 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, 0-30%, EtOAc in PE) to give 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(methyl)amino]formate (430 mg, 0.81 mmol, 46%) as a yellow solid. LCMS: m / z 531 [M+H] + .

[0660] 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]formate (400 mg, 0.752 mmol) in EtOH (12 mL) / HO (3 mL) was added NH4Cl (161 mg, 3.1 mmol) and Fe (420 mg, 7.5 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%, PE with EtOAc) to give 2-methylpropan-2-yl [({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)(methyl)amino]formate (300 mg, 0.59 mmol, 79%) as a yellow solid. LCMS: m / z 502 [M+H] + .

[0661] 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]formate (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 2 for 2 h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL * 3). The combined organic phases were washed with brine, dried over Na 2 SO 4, filtered and concentrated until no droplets remained. The residue was purified by preparative HPLC (C18, 40-90% MeCN and 0.1% FA in H2O) to afford 2-methylpropan-2-yl [({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(methyl)amino]carboxylate (230 mg, 0.51 mmol, 92%) as a yellow solid. LCMS: m / z 448 [M+H] + .

[0662] 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]formate (230 mg, 0.51 mmol) in ACN (2 mL) / HO (1 mL) was slowly added KOH (288 mg, 5.1 mmol) 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 phases were 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)carboxylate (170 mg, 0.36 mmol, 71%) as a white solid. LCMS: m / z 466 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),7.96(dd,J=10.4,3.2Hz,1H),7.35(d,J=5.2Hz,1H),7.29–7.18(m,1H),6. 99(s,1H),6.53(s,1H),4.47(s,2H),4.34(d,J=6.0Hz,2H),3.80(s,3H),2.75(s,3H),1.41(d,J=19.4Hz,10H).

[0663] 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)formate (150 mg, 0.32 mmol) in ACN (2 mL) was slowly added pyridine (76 mg, 0.97 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (145 mg, 0.64 mmol) 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*3). The combined organic phases were 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)carboxylate (180 mg, 0.27 mmol, 85%) as a brown solid. LCMS: m / z 656 [M+H] + .

[0664] 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)carboxylate (170 mg, 0.26 mmol) in TFA (5 mL) was added EtSiH (1 mL) at room temperature. 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 afford 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] + . 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),9.17(s,1H),8.82(s,2H),7.97(d,J=8.4Hz,1H),7.73(d,J=8.4Hz,1H),7.68-7.60(m,2 H),7.32(dd,J=8.8,5.2Hz,1H),7.11(td,J=8.4,2.8Hz,1H),5.96(brs,1H),4.25(d,J=7.7Hz,2H),4.19(s,3H),2.62(s,3H).

[0665] Step M: To a stirred solution of 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 (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 phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-12%, MeOH in DCM) to afford 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] + .

[0666] Step N: To a stirred solution of 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 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN and 0.1% TFA in H2O) to afford 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 HNMR (400MHz, DMSO-d6) δ10.37(s,1H),9.05(s,1H),7.94(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.65 (s,1H),7.37–7.27(m,2H),7.09(td,J=8.4,2.8Hz,1H),5.92(brs,1H),4.68–4.55(m,2H),3.03(s,3H).

[0667] 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

[0668]

[0669] 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 KCO (319 mg, 2.31 mmol) and 1,2-dibromoethane (0.150 mL, 1.73 mmol). The reaction mixture was stirred at 80°C under N for 1 hr. The reaction was complete and monitored by TLC. The cooled reaction mixture was dissolved in EA (20 mL), washed with H0 (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] + .

[0670] 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 hr. The reaction was complete and monitored by TLC. The cooled reaction mixture was dissolved in EA (20 mL), washed with H O (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.

[0671] 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 H2O (1 mL) was added NH4Cl (29.9 mg, 0.560 mmol) and Fe (104 mg, 1.87 mmol). The reaction mixture was stirred at 45 °C under N2 for 1 hr. 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 H2O (10 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted 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 (400MHz, DMSO-d6) δ7.56(dd,J=8.8,4.8Hz,1H),7.44–7.41(m,2H),7.38(dd,J=8.8,3.2Hz,1H),7.23–7.19(m,1 H),6.88(d,J=8.8Hz,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).

[0672] 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 hr. 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 (400MHz, DMSO-d6) δ10.42(s,1H),8.04–7.98(m,3H),7.93(d,J=8.4Hz,1H),7.78(d,J=11.6Hz,2H),7.51(t,J=2.4Hz,1H),7.49(t ,J=2.4Hz,1H),7.38–7.30(m,2H),6.98(s,1H),6.94(d,J=8.8Hz,2H),4.29–4.23(m,2H),4.14(s,2H),3.76(s,3H),2.98–2.91(m,2H).

[0673] 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 2 for 3 hr. 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] + .

[0674] 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 hr. The reaction mixture was complete and monitored by TLC. The reaction mixture was dissolved in EA (20 mL), washed with H2O (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] + .

[0675] 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 Et3SiH (400 μL, 2.50 mmol) and TfOH (80 μL, 0.904 mmol). The reaction mixture was stirred at 70°C for 1 hr. The reaction mixture was complete and monitored by LCMS. The reaction mixture was concentrated and purified by preparative HPLC (C18, 30-95% ACN and 0.1% TFA in H2O) to afford 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 (400MHz, DMSO-d6) δ9.98(s,1H),8.73(s,1H),7.88(d,J=8.0Hz,1H),7.67(d,J=9.2Hz,1H),7.63(s,1H),7.27(dd,J=8.8,5.2 Hz,1H),7.06(td,J=8.4,2.8Hz,1H),6.73(s,1H),6.64(brs,1H),5.82(brs,1H),4.23(dd,J=11.2,4.6Hz,2H),3.40–3.36(m,2H).

[0676] 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]quinoxaline-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0677]

[0678] 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 EtOAc (100 mL*3). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by 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] + .

[0679] 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 by silica gel column chromatography, eluting with petroleum ether containing ethyl acetate (gradient: 20%) to provide {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] + .

[0680] 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 hour. The residue was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, 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] + .

[0681] 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] + .

[0682] Step E: To a solution of 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1,2,3,4-tetrahydroquinoxaline-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 x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0-30% EtOAc / hexanes to afford 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahexan-1-yl)-1,2,3,4-tetrahydroquinoxalin-2-one (180 mg, 0.274 mmol, 60%) as a brown oil. 1 H NMR(400MHz, DMSO-d6)δ7.85(dd,J=8.9,5.0Hz,1H),7.74–7.68(m,1H),7.65(s,1H),7.49(dd,J=8.8,2.8Hz ,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).

[0683] 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-silahexan-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 afford N-{8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahexan-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. 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),8.04(d,J=8.4Hz,1H),7.90(d,J=14.4Hz,2H),7.61(dd,J=8.8,4.8Hz,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=8.4Hz,2H),0.81–0.73(m,2H),0.02–0.02(m,9H).

[0684] 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-silahexan-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. under N in a microwave 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-silanhexan-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] - .

[0685] 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-silahexan-1-yl)-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl}-5-fluoro-3-(trifluoromethyl)benzamide (35 mg, 0.048 mmol) in CH3CN (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 x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahexan-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] - .

[0686] Step I: A solution of N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-1-(5,5-dimethyl-2-oxa-5-silahexan-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 added and the mixture was stirred at 20° C. for 30 min. The mixture was concentrated under vacuum 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] - .

[0687] 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 Et3SiH (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 (400MHz, DMSO-d6) δ10.30(s,1H),9.62(s,1H),9.22(s,1H),7.92(d,J=8.4Hz,1H),7.73(d,J=9.2Hz,1H),7.66(s,1H),7.30(dd,J=8. 8,5.2Hz,1H),7.09(td,J=8.4,3.2Hz,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).

[0688] 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

[0689]

[0690] 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 under N2 for 30 min. 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 N2 for 1 hr. 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 H2O (50 mL) and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (eluted 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] + .

[0691] 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 H2O (30 mL) was added NH4Cl (0.850 g, 15.9 mmol) and Fe (2.96 g, 53.0 mmol). The reaction mixture was stirred at 45 ° C under N2 for 1 hr. 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 Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted 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] + .

[0692] 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 N2 for 1 hr. 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 Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted 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'-cyclopropane]-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] + . 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),7.72(dd,J=8.8,4.8Hz,1H),7.64(d,J=8.0Hz,1H),7.56(d,J=8.8Hz,1H),7.40(s,1H),1.36(s,2H),1.28(s,2H).

[0693] Step D: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropane]-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 N2 for 30 min. SEM-Cl (0.922 mL, 5.20 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 1 hr. 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 Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with 0-30% EA in PE) to give 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-(5,5-dimethyl-2-oxa-5-silahexan-1-yl)-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropane]-3-one (700 mg, 1.12 mmol, 64%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.76(dd,J=8.8,4.8Hz,1H),7.64(dd,J=8.0,3.2Hz,1H),7.60(d,J=2.8Hz,1H),7.48(d,J=6.0Hz, 1H),5.60(s,2H),3.40(t,J=8.0Hz,2H),0.90–0.84(m,2H),0.84–0.76(m,2H),0.74(t,J=8.0Hz,2H),0.00–-0.02(m,9H).

[0694] 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'-cyclopropane]-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 hr. 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 20-100% EA in PE) to afford N-{5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-(5,5-dimethyl-2-oxa-5-silanhexan-1-yl)-3-oxo-3,4-dihydrospiro[benzo[1,4]oxazine-2,1'-cyclopropane]-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] + .

[0695] 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'-cyclopropane]-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 afford N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-3-oxo-3,4-dihydrospiro[benzo[1,4]oxazin-2,1'-cyclopropane]-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] + .

[0696] 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'-cyclopropane]-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 2 for 3 hr. 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 Na 2 SO 4 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'-cyclopropane]-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] + .

[0697] 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'-cyclopropane]-7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (90.0 mg, 0.160 mmol) in ACN (1 mL) and H2O (1 mL) was added KOH (8.99 mg, 0.160 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture 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 Na2SO4 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'-cyclopropane]-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] + .

[0698] 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'-cyclopropane]-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.155 mmol) in TFA (1 mL) was added Et3SiH (0.200 mL). The reaction mixture was stirred at 50°C for 0.5 hr. The reaction mixture was complete and monitored by LCMS. The reaction mixture was concentrated and purified by preparative HPLC (C18, 30-95% ACN and 0.1% TFA in H2O) to afford 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'-cyclopropane]-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 (400MHz, DMSO-d6) δ10.36(s,1H),9.60(s,1H),9.32(s,1H),7.94(d,J=8.0Hz,1H),7.68(d,J=8.4Hz,1H),7.6 4(s,1H),7.32(dd,J=8.8,5.2Hz,1H),7.08(td,J=8.4,3.2Hz,1H),7.04(s,1H),5.96(brs,1H),1.41–1.31(m,4H).

[0699] 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

[0700]

[0701] 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 hours. The cooled mixture was quenched with water (100 mL) and extracted with EA (100 mL*2). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, 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] + .

[0702] 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 / H₂O (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 hr. The cooled reaction mixture was filtered, concentrated, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄ 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] + .

[0703] 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 hr. The reaction mixture was concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the 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] + .

[0704] 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. under N atmosphere using microwaves for 1 hr. 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 by silica gel column chromatography using EA / PE (1 / 100 to 2 / 1) as the eluent to afford 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] + .

[0705] 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 H2O (1.00 mL) was added KOH (66.4 mg, 1.18 mmol). The reaction was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether containing ethyl acetate (1% to 60%), to obtain 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] - .

[0706] 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 Et3SiH (267 mg, 2.30 mmol). The reaction mixture was stirred at 70°C for 2 hr. The reaction was concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in DCM (0% to 10%) to afford 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] + .

[0707] 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) was added tribromoborane (0.042 mL, 0.438 mmol) dropwise under N at 0° C. The reaction mixture was stirred at room temperature for 18 hr. 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 light red solid. LCMS: m / z 580.1 [M+H] + .

[0708] 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 hr. The reaction mixture was concentrated. The residue was purified by preparative HPLC (0.1% FA in acetonitrile, 30% to 70%) to afford 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 (400MHz, DMSO-d6) δ10.50(s,1H),9.28(s,1H),7.95(d,J=8.4Hz,1H),7.74(d,J=8.4Hz,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).

[0709] 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

[0710]

[0711]

[0712] Step A: To a solution of 4-amino-3-methoxybenzoic acid (25 g, 149 mmol) in EtOAc (800 mL) was added a solution of TFAA (24.9 mL, 179 mmol) in EtOAc (100 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 h. The mixture was concentrated to afford 3-methoxy-4-(2,2,2-trifluoroacetylamino)benzoic acid (40 g, 152 mmol, 100%) as a yellow solid. LCMS: m / z 262.1 [MH] - .

[0713] Step B: To a solution of 3-methoxy-4-[(trifluoroacetyl)amino]benzoic acid (40 g, 152 mmol) in concentrated H2SO4 (98%, 1000 mL) at 0°C was added concentrated HNO3 (13.6 g) dropwise. 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 afford 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetylamino)benzoic acid (40 g, 129 mmol, 85%) as a brown solid. LCMS: m / z 307.0 [MH] - .

[0714] 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 eq) portionwise at 0°C. The reaction mixture was stirred at room temperature for 20 h. Water (100 mL) was added to the mixture and extracted with EtOAc (300 mL x 2). The combined organic phases were 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 [MH] - . 1H NMR (400MHz, DMSO-d6) δ 11.01 (s, 1H), 8.30 (s, 1H), 7.55 (s, 1H), 5.70 (t, J = 5.6Hz, 1H), 4.90 (d, J = 5.6Hz, 2H), 3.98 (s, 3H).

[0715] 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 h. Water (30 mL) was added to the mixture and extracted with DCM (50 mL x 2). The combined organic phases were 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 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.30(s,1H),8.45(s,1H),7.49(s,1H),4.04(s,3H).

[0716] 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 H2SO4 (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, which 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 [MH] - .

[0717] 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 N₂ for 2 hours. LCMS indicated 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 by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to afford 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] + .

[0718] 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 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with DCM and H2O. The organic layer was separated and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 15-25%) to afford 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 / z499 / 501[M+H] + .

[0719] 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 N2 for 1 hr. LCMS indicated the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by 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] + .

[0720] 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 N2 for 18 hr. LCMS indicated the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The organic layer was separated and concentrated to afford 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] + .

[0721] 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 N2 for 2 hr. LCMS indicated the reaction was complete. The cooled reaction mixture was quenched with MeOH, diluted with H2O, and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by 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] + .

[0722] 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 H₂O (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 N₂ for 2 hr. LCMS indicated 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 Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to afford {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] + .

[0723] 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. under N using a microwave for 1.5 hr. LCMS indicated 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 by silica gel column chromatography, eluting with ethyl acetate in chloroform (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] + .

[0724] 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 hr. LCMS indicated 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 by 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] + .

[0725] 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 H₂O (2 mL) was added KOH (32.2 mg, 0.575 mmol). The reaction was stirred at room temperature under N₂ for 1 hr. LCMS indicated the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, 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] - .

[0726] 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 Et3SiH (21.6 mg, 0.186 mmol). The reaction was stirred at 70°C for 1 hr. LCMS indicated the reaction was complete. The cooled reaction mixture was concentrated, diluted with aqueous NaHCO3, and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (gradient: 30-40%) to afford 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] + .

[0727] 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 indicated the reaction was complete. The reaction was diluted with EA and NaHCO₃. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by preparative TLC using petroleum ether containing ethyl acetate (gradient: 40-50%) to give 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] + .

[0728] 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 hr. LCMS indicated 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 (400MHz, DMSO-d6) δ10.48(s,1H),9.26(s,1H),7.95(d,J=8.4Hz,1H),7.74(d,J=8.8Hz,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).

[0729] 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

[0730]

[0731] 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 sequentially with saturated NaHCO₃ (100 mL) and brine (2 x 100 mL), dried over Na₂SO₄, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0% to 5%), to afford 2-(2,6-dibromo-4-fluorophenyl)-1,3-dioxolane (7.8 g, 23.9 mmol, 67%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.75 (d, J = 8.0Hz, 2H), 6.22 (s, 1H), 4.22 (m, 2H), 4.01 (m, 2H).

[0732] 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 min. Hexahydropyridine-1-carboxaldehyde (5.9 g, 52.0 mmol) was slowly added. The reaction mixture was stirred at -78°C for an additional 30 min. The mixture was then added to saturated NH4Cl (100 mL) and extracted with ethyl acetate (80 mL*3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified on silica gel (EtOAc in PE = 10%) 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. 1H NMR (400MHz, DMSO-d6) δ10.19(s,1H),7.93(d,J=9.2Hz,1H),6.35(s,1H),4.27–4.21(m,2H),4.07–4.01(m,2H).

[0733] Step C: To a solution of 2,4-dibromo-3-(1,3-dioxolane-2-yl)-6-fluorobenzene-1-carbaldehyde (3.9 g, 11.0 mmol) in dioxane (40 mL) was added DIEA (1.9 mL, 11.0 mmol) and 2,2-difluoroethane-1-amine (3.11 mL, 44.1 mmol) and sealed, and stirred at 80 ° C overnight. The reaction mixture was quenched with 1N 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 min (monitored by LCMS). Brine was added, the organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by 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] + .

[0734] 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) at 0°C was added NaBH₄ (83.1 mg, 2.2 mmol). The reaction mixture was allowed to warm 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 Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 10-15%) to afford {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 (400MHz, DMSO-d6) δ7.04 (s, 1H), 6.34–5.97 (m, 3H), 5.38 (t, J = 5.2Hz, 1H), 4.7 3(d,J=5.2Hz,2H), 4.16(t,J=6.8Hz,2H), 3.94(t,J=6.8Hz,2H), 3.76–3.58(m,2H).

[0735] 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 clear. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layer was separated, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (gradient: 0-15%) to afford 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] + .

[0736] 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 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 by silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 20%) to afford 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] + .

[0737] 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 bromo(2-chloro-5-fluorophenyl)magnesium (15.0 mL, 7.52 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 30 min. The mixture was then added to saturated NH4Cl (15 mL) and extracted with ethyl acetate (20 mL*2). The combined organic phases were washed with brine (20 mL*2), dried over Na2SO4, and concentrated to a residue. The residue was purified on silica gel (eluted with EtOAc in petroleum ether = 0-15%) 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 (630 mg, 1.2 mmol, 80%) as a yellow solid. LCMS: m / z 528, 530, 532 [M+H] + .

[0738] 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) at 0°C was added Dess-Martin periodinane (624.8 mg, 1.47 mmol). 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 x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2SO4 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] + .

[0739] 1 H NMR (400MHz, DMSO-d6) δ7.75(m,2H),7.65–7.59(m,1H),7.55(m,1H),6.33(m,1H),5.38(d,J=7.2Hz,2H),4.49(m,2H).

[0740] 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 x 3). The combined organic phases were washed with brine, dried over NaSO and concentrated. The residue was purified on 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] - .

[0741] 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 x 3). The combined organic phases were 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] + .

[0742] Step K: To a 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 H2O (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was treated with H2O (10 mL) and extracted with EA (3*10 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, 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] - .

[0743] 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 H 2 O (5 mL) and extracted with EA (3*8 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford 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] - .

[0744] Step M: To a solution of 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 (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 hr. The mixture was concentrated to 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-hexahydro[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] + . 1 H NMR (400MHz, CD3OD) δ7.76–7.53(m,3H),7.37(s,1H),7.27(dd,J=8.8,5.2Hz,1H) ,7.04–6.95(m,1H),6.41–6.07(m,2H),5.92(d,J=2.4Hz,2H),4.45–4.32(m,2H).

[0745] Example 54: N-(7-(2-chloro-5-fluorophenyl)-2,2-dioxo-9-oxo-1,7,8,9-tetrahydro-3H-[1,3,4]oxathiazino[5,6-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0746]

[0747]

[0748] 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 TBSCI (2.71 g, 18 mmol). The resulting mixture was stirred at 23°C for 2 h. The mixture was treated with H₂O (100 mL) and extracted with EA (3 x 300 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether containing 0-50% ethyl acetate and drying to give (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] - .

[0749] 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 chloromethylsulfonyl chloride (0.9 mL, 9.92 mmol). The reaction mixture was refluxed for 1 h. The reaction mixture was cooled to 25 ° C. It was quenched with H2O (30 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether containing 0-50% ethyl acetate, and dried to give N-{2-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[dimethyl(2-methylprop-2-yl)silanyl]oxy}-4-nitrophenyl}-1-chloromethanesulfonamide (1.6 g, 2.6 mmol, 65%) as a yellow oil. LCMS: m / z 613 [MH] - .

[0750] 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 H2O (100 mL) and extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=2:1) ​​to give 8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-6-nitro-1H-2λ as a yellow oil.6 -Benzo[2,1-e][1,3,4]oxathiazine-2,2-dione (700 mg, 1.5 mmol, 57.9%). LCMS: ESI m / z 465 [M+H] + .

[0751] Step D: To 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) was added to a solution of EtOH (28 mL) and H2O (7 mL) with Fe (420 mg, 7.52 mmol) and NH4Cl (402 mg, 7.52 mmol). The reaction mixture was stirred at 80 ° C for 3 hours. 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 by silica gel column chromatography and eluted with chloroform containing 0-10% methanol to give a yellow solid 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%). 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 7.62 (dd, J = 8.0Hz, 4.0Hz, 1H), 7.46 (td, J = 8.0 Hz, 4.0Hz, 1H), 7.23 (dd, J = 8.4, 3.2Hz, 1H), 6.54 (s, 1H), 6.02 (s, 2H), 5.18 (s, 2H).

[0752] Step E: To 6-amino-8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-1H-2λ 6 -Benzo[2,1-e][1,3,4]oxathiazine-2,2-dione (100 mg, 0.23 mmol) in DMA (1 mL) was added Zn(CN)2 (80.9 mg, 0.689 mmol) and Pd(PPh3)4 (53.0 mg, 0.046 mmol). The mixture was stirred at 150 ° C under N2 for 4 hours. 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 by silica gel column chromatography, eluting with petroleum ether containing 0-50% ethyl acetate to give the compound 6-amino-7-[(2-chloro-5-fluorophenyl)carbonyl]-2,2-dioxo-1H-2λ as a yellow solid. 6-Benzo[2,1-e][1,3,4]oxathiazine-8-carbonitrile (80 mg, 0.21 mmol, 91%). LCMS: ESI m / z 382 [M+H] + .

[0753] Step F: To 6-amino-7-[(2-chloro-5-fluorophenyl)carbonyl]-2,2-dioxo-1H-2λ 6 -Benzo[2,1-e][1,3,4]oxathiazine-8-carbonitrile (70 mg, 0.183 mmol) was added KOH (30.9 mg, 0.55 mmol) in a solution of CH3CN (3 mL) and H2O (0.3 mL). 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 by silica gel column chromatography, eluting with chloroform containing 0-10% methanol to obtain a yellow solid 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%).

[0754] Step G: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-1,7,8,9-tetrahydro-2λ6-[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 hr. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated to afford N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,2,9-trioxo-1,7,8,9-tetrahydro-2λ6-[1,3,4]oxathiazino[5,6-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.034 mmol, 34%) as a yellow solid. LCMS: ESI m / z 588 [MH] - .

[0755] Step H: To a solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,2,9-trioxo-1,7,8,9-tetrahydro-2λ6-[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-2λ6-[1,3,4]oxathiazino[5,6-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide as a white solid. 6 -[1,3,4]oxathiazino[5,6-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (1.1 mg, 0.002 mmol, 6%). LCMS: ESI m / z 574 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.68–7.60(m,3H),7.38–7.16(m,2H),6.99(t,J=8.0Hz,1H),6.67(brs,1H),6.10(brs,1H),5.22(s,2H).

[0756] 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

[0757] 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

[0758] 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

[0759]

[0760] 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 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, 0-20%, PE containing EtOAc) to give 2,6-dibromo-3-methyl-4-nitrophenol (45.1 g, 145 mmol, 71%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 2.51 (s, 3H).

[0761] Step B: To a solution of 2,6-dibromo-3-methyl-4-nitrophenol (44.2 g, 142 mmol) in CH3CN (450 mL) was added K2CO3 (29.5 g, 213 mmol) and CH3I (13.8 mL, 171 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluting with PE containing EA [gradient: 0-10%]. The compound 3,5-dibromo-4-methoxy-2-methyl-1-nitrobenzene (41 g, 126 mmol, 89%) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),3.87(s,3H),2.47(s,3H).

[0762] 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 H2O and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with PE containing EA [gradient: 0-15%] to give 3,5-dibromo-2-(bromomethyl)-4-methoxy-1-nitrobenzene (46.1 g, 89 mmol, 94%) as a white solid.

[0763] Step D: To a solution of 3,5-dibromo-2-(bromomethyl)-4-methoxy-1-nitrobenzene (46.1 g, 89 mmol) in CHCN (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 washed with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluting with EA in PE [Gradient: 0-30%] to afford 2,4-dibromo-3-methoxy-6-nitrobenzene-1-carbaldehyde (35.1 g, 74 mmol, 83%) as a yellow solid.

[0764] 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 by silica gel column chromatography eluting with EA in PE [Gradient: 0-40%] to give (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6-nitrophenyl)methanol (40.2 g, 85.6 mmol, 95%) as a white solid.

[0765] 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) at 0°C was slowly added DESS-MARTIN (40 g, 94.2 mmol). After stirring at room temperature for 3 h, the mixture was poured into ice water (500 mL) and extracted with DCM (200 mL x 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, 0-30%, EtOAc in PE) to afford (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 (400MHz, DMSO-d6) δ8.68(s,1H),7.82–7.60(m,3H),3.95(s,3H).

[0766] 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) / H2O (20 mL) was added (2,2-dimethyl-4-oxo-5-aza-3-oxahexan-6-yl)trifluoro-λ 5 Potassium borohydride (5 g, 25.7 mmol), Pd(dppf)Cl2 (1.25 g, 1.71 mmol), and K2CO3 (5.91 g, 42.8 mmol). After stirring overnight at 70°C under N2, 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%, PE containing EtOAc) to give 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]formate (2.5 g, 4.83 mmol, 22%) as a brown solid. LCMS: m / z 517 [M+H] + .

[0767] 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]formate (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 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, 0-30%, EtOAc in PE) to give 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(trideuteriomethyl)amino]formate (1 g, 1.87 mmol, 61%) as a yellow solid. LCMS: m / z 535 [M+H] + .

[0768] 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]carboxylate (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]carboxylate (820 mg, 1.62 mmol, 87%) as a yellow solid. LCMS: m / z 505 [M+H] + .

[0769] 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]formate (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 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 [({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(trideuteriomethyl)amino]carboxylate (550 mg, 1.22 mmol, 75%) as a yellow solid. LCMS: m / z 451 [M+H] + .

[0770] 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]formate (500 mg, 1.1 mmol) in ACN (3 mL) / HO (1 mL) was slowly added KOH (622 mg, 11.1 mmol) 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 phases were 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)carboxylate (480 mg, 1.02 mmol, 92%) as a white solid. LCMS: m / z 469 [M+H] + .

[0771] 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)formate (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 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to afford 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)carboxylate (420 mg, 0.637 mmol, 62%) as a brown solid. LCMS: m / z 659 [M+H] + .

[0772] 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)carboxylate (420 mg, 0.637 mmol) in TFA (5 mL) was added EtSiH (2 mL) at room temperature. 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 afford N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-6-{[(trideuteromethyl)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] + .

[0773] Step N: To a stirred solution of 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 phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-12%, MeOH in DCM) to afford crude N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-6-{[(trideuteromethyl)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] + .

[0774] Step O: To a stirred solution of 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 (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 phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN and 0.1% TFA in H2O) to afford 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 (400MHz, DMSO-d6) δ10.40(s,1H),9.20(s,1H),8.00(d,J=8.4Hz,1H),7.68(d,J=8.8Hz,1H),7. 64(s,1H),7.36(s,1H),7.32(dd,J=8.8,5.2Hz,1H),7.12–7.06(m,1H),5.92(brs,1H),4.62(t,2H).

[0775] Step P: 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 (50 mg, 0.090 mmol) was purified by SFC to give P1 as a white solid. 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%). 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.04(s,1H),7.96(d,J=7.2Hz,1H),7.72(d,J=7.6Hz,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).

[0776] P2 Example 57 as a white solid: (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%). 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.04(s,1H),7.96(d,J=7.2Hz,1H),7.72(d,J=7.6Hz,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).

[0777] Preparative separation methods:

[0778] Instrument: SHIMADZU PREP SOLUTION SFC

[0779] Column: ChiralPak IA, 250×30mm ID, 5μm

[0780] Mobile phase: A is CO2 and B is MEOH

[0781] Gradient: B 45%

[0782] Flow rate: 60 mL / min

[0783] Back pressure: 100 bar

[0784] Column temperature: 35°C

[0785] Wavelength: 220nm

[0786] Cycle time: 12 minutes

[0787] Elution time: 2 hours

[0788] Example 58: N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-2,3,4,7,8,9-hexahydro-[1,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0789]

[0790] Step A: To a stirred solution of 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]formate (800 mg, 1.54 mmol) in EtOH (12 mL) / HO (3 mL) was added NH4Cl (248 mg, 4.64 mmol) and Fe (690 mg, 12.3 mmol) at room temperature. After stirring at 80 °C for 2 h, the cooled mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give crude 2-methylpropan-2-yl [({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)amino]formate (660 mg, 1.35 mmol, 87%) as a yellow solid. LCMS: m / z 488[M+H] + .

[0791] Step B: To a stirred solution of 2-methylpropan-2-yl [({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)amino]formate (650 mg, 1.33 mmol) in NMP (10 mL) was added CuCN (358 mg, 3.99 mmol) at room temperature. After stirring at 130° C. for 3 h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL*3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated until no droplets remained. The residue was purified by chromatography (silica gel, 0-60%, EtOAc in PE) to give crude 2-methylpropan-2-yl [({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)amino]carboxylate (300 mg, 0.69 mmol, 52%) as a yellow solid. LCMS: m / z 434 [M+H] + .

[0792] Step C: To a stirred solution of 2-methylpropan-2-yl [({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)amino]formate (300 mg, 0.69 mmol) in ACN (3 mL) / HO (1 mL) was slowly added KOH (194 mg, 3.45 mmol) 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 phases were washed with brine, dried over NaSO, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give crude 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}amino)carboxylate (300 mg, 0.66 mmol, 96%) as a yellow solid. LCMS: m / z 452 [M+H] + .

[0793] Step D: 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}amino)formate (250 mg, 0.55 mmol) in ACN (5 mL) was slowly added pyridine (0.2 mL, 1.67 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (188 mg, 0.83 mmol) at room temperature. After stirring at room temperature for 2 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to afford 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}amino)carboxylate (160 mg, 0.25 mmol, 45%) as a white solid. LCMS: m / z 642 [M+H] + .

[0794] Step E: 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}amino)carboxylate (160 mg, 0.25 mmol) in TFA (4 mL) was added EtSiH (1 mL) at room temperature. 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 afford N-[6-(aminomethyl)-3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (120 mg, 0.23 mmol, 91%) as a white solid. LCMS: m / z 526 [M+H] + .

[0795] Step F: To a stirred solution of N-[6-(aminomethyl)-3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.152 mmol) in ACN (3 mL) was added TMSCl (83 mg, 0.76 mmol) and NaI (114 mg, 0.76 mmol) at room temperature. After stirring at 100°C for 5 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-12%, MeOH in DCM) to give crude N-[6-(aminomethyl)-3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.063 mmol, 42%) as a yellow oil. LCMS: m / z 512 [M+H] + .

[0796] Step G: To a stirred solution of N-[6-(aminomethyl)-3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.06 mmol) in THF (2 mL) was added TEA (24 mg, 0.23 mmol) and triphosgene (46 mg, 0.16 mmol) 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 phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN and 0.1% TFA in H2O) to afford N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-2,3,4,7,8,9-hexahydro[1,3]oxazino[6,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2 mg, 0.004 mmol, 5%) as a white solid. LCM...

Claims

1. A compound having structural formula I: or a pharmaceutically acceptable form or isotopic derivative thereof, in Ring A is surrounded by 0-10 R a 'Substituted 4 to 7 membered monocyclic non-aromatic ring; R 1 It's Z B -R B ; R 2 It's Z C -R C ; X is N, CH or CR X ; R X It's Z X -R X’ ; Z B , Z C and Z X Each is independently a covalent bond, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O)2, NRS(O)2, S(O)2NR or selected from C 1-4 a linking group of a saturated or unsaturated divalent hydrocarbon radical, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S and O; R B , R C and R X Each independently is 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( OR C having 0-4 ring heteroatoms independently selected from N, O and S 1-6 an aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclic, heterocyclic, aryl or heteroaryl ring, which is optionally each substituted by one or more R b , R c or R x replace; R a , R b , R c and R x Each independently is 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( OR Substituted or unsubstituted selected from C 1-6 an alkyl group or a 4- to 6-membered carbocyclic group; R and R' are each independently selected from H, unsubstituted or substituted C 1-4 alkyl or an unsubstituted or substituted 4 to 6 membered carbocyclic ring, or wherein R and R' are attached to the same C or N atom and together form an unsubstituted or substituted 4 to 6 membered heterocyclic ring; and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

2. The compound according to claim 1, wherein ring A is surrounded by 0-10 R a Substituted 4- to 7-membered carbocyclic ring having no ring heteroatoms.

3. The compound according to claim 1, wherein ring A is surrounded by 0-10 R a Substituted 4- to 7-membered heterocyclic ring having 1-4 ring heteroatoms selected from N, O and S.

4. The compound according to any one of claims 1 to 3, wherein Ring A is a compound having the structural formula I a 0-4 R a Substituted 4-membered non-aromatic ring: in Y 1 and Y 2 are each independently CH, CH2, N, NH, O or S, provided that Y 1 and Y 2 At least one of is C or CH.

5. The compound according to any one of claims 1 to 3, wherein Ring A is a compound having the structural formula I b 0-6 R a Substituted 5-membered non-aromatic ring: in Y 1 , Y 2 and Y 3 are each independently CH, CH2, N, NH, O, S or C(O), provided that Y 1 , Y 2 and Y 3 At least one of them is not N or NH, and Y 1 , Y 2 and Y 3 At least one of is C, CH or C(O).

6. The compound according to any one of claims 1 to 3, wherein Ring A is a compound having the structural formula I c 0-8 R a Substituted 6-membered non-aromatic ring: in Y 1 , Y 2 , Y 3 and Y 4 are each independently CH, CH2, N, NH, O, S, S(O)2 or C(O), provided that Y 1 , Y 2 , Y 3 and Y 4 At least two of them are not N or NH, and Y 1 , Y 2 , Y 3 and Y 4 At least two of are C, CH or C(O).

7. The compound according to any one of claims 1 to 3, wherein Ring A is a compound having the structural formula I d 0-8 R a Substituted 7-membered non-aromatic ring: in Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently CH, CH2, N, NH, O, S or C(O), provided that Y 1 , Y 2 , Y 3 , Y 4 and Y 5 At least two of them are not N or NH, and Y 1 , Y 2 , Y 3 , Y 4 and Y 5 At least two of are C, CH or C(O).

8. A compound according to any one of claims 1 to 7, wherein R B It is a ring B, surrounded by 0-6 R b substituted 5- to 10-membered monocyclic or bicyclic carbocyclyl, heterocyclic, aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from N, O and S; and R C It is a ring C, surrounded by 0-6 R c a substituted 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from N, O and S, The compound has the structural formula I e : in j is 0, 1, 2, 3, 4, 5, or 6; and k is 0, 1, 2, 3, 4, 5 or 6.

9. The compound according to claim 8, wherein Z B is NH-C(O) and Z c is a single bond, which has the structural formula I f :

10. The compound according to claim 8, wherein Z B is C(O)-NH and Z c is a single bond, which has the structural formula I g :

11. The compound according to any one of claims 1-4 and 8-10, wherein ring A is selected from:

12. The compound according to any one of claims 1-4 and 8-10, wherein ring A is selected from:

13. The compound according to any one of claims 1-4 and 8-10, wherein ring A is selected from: Where R a’ They are CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN.

14. The compound according to claim 13, wherein R a’ It is CH2CHF2.

15. The compound according to claim 13 or 14, wherein each R a are independently H, Cl, F, CN or CH3.

16. The compound according to any one of claims 1-3, 5 and 8-10, wherein ring A is selected from:

17. The compound according to any one of claims 1-3, 5 and 8-10, wherein Ring A is selected from:

18. The compound according to any one of claims 1-3, 5 and 8-10, wherein Ring A is selected from: in R a’ is CH2CHF2 or CH2CF3; and Each R a are independently H, Cl, F, CN or CH3.

19. The compound according to any one of claims 1-3, 5 and 8-10, wherein ring A is Where R a’ One is CH2CHF2 or CH2CF3, and the other R a’ It is H, CH3 or CD3.

20. The compound according to any one of claims 1-3, 6 and 8-10, wherein Ring A is selected from:

21. The compound according to any one of claims 1-3, 6 and 8-10, wherein Ring A is selected from: Where R a’ is CH2CHF2 or CH2CF3 and R a It's H.

22. The compound according to any one of claims 1-3, 6 and 8-10, wherein Ring A is selected from: Where R a and R a’ one of which is selected from the group consisting of H, CH3, CD3, CD2CD3, CH2CN, CH2CHF2, CH2CF3, and CH2CN; and R a and / or R a’ The other one is H.

23. The compound according to any one of claims 1-3, 6 and 8-10, wherein Ring A is selected from: Each R a’ Independently selected from H, CH3, CD3, CD2CD3, CH2CN and CH2CHF2, CH2CF3 and CH2CN.

24. A compound according to any one of claims 1-3 and 7-10, wherein ring A comprises one or more of O, NR, C(O), S(O)2, C(O)O, C(O)NR and NRC(O)NR, wherein each R is independently H, CH3, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 or CH2CN.

25. The compound of any one of claims 1-24, wherein X is N.

26. A compound according to any one of claims 1-24, wherein X is CH.

27. A compound according to any one of claims 1 to 24, wherein X is CR X , where R X It is C 1-3 alkyl.

28. The compound according to any one of claims 1 to 27, wherein Ring B is selected from:

29. The compound according to any one of claims 1-27, wherein Ring B is selected from:

30. The compound according to any one of claims 1-27, wherein Ring B is selected from:

31. The compound according to any one of claims 1-27, wherein Ring B is selected from:

32. The compound according to claim 31, wherein Ring B is:

33. The compound according to any one of claims 1 to 27, wherein Ring B is substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

34. The compound according to claim 33, wherein Ring B is substituted or unsubstituted phenyl.

35. The compound according to claim 33, wherein Ring B is substituted or unsubstituted pyridinyl.

36. The compound according to claim 33, wherein Ring B is a substituted or unsubstituted pyridazinyl.

37. The compound according to claim 33, wherein Ring B is substituted or unsubstituted pyrazinyl.

38. A compound according to any one of claims 1-9 and 11-27, wherein Z B It is NH-C(O).

39. The compound according to any one of claims 1 to 38, wherein Ring C is substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

40. The compound according to claim 39, wherein Ring C is substituted or unsubstituted phenyl. The compound according to claim 39 , wherein Ring C is substituted or unsubstituted pyridinyl.

42. The compound according to claim 39, wherein Ring C is a substituted or unsubstituted pyridazinyl.

43. The compound according to claim 39, wherein Ring C is substituted or unsubstituted pyrazinyl.

44. The compound according to claim 34 or 40, wherein Ring B and Ring C are each independently substituted or unsubstituted phenyl.

45. The compound according to any one of claims 1-34, 40 and 44, wherein ring C is selected from:

46. ​​The compound according to claim 45, wherein Ring C is:

47. The compound according to claim 1, having the structural formula I h :

48. The compound according to claim 1, having the structural formula I h :

49. The compound according to claim 1, having the structural formula I i :

50. The compound according to claim 1, having the structural formula I j :

51. The compound according to claim 1, having the structural formula I k :

52. The compound according to claim 1, having the structural formula I l :

53. The compound according to claim 1, having the structural formula I m :

54. The compound according to claim 1, having the structural formula I n :

55. A compound having a structural formula selected from the group consisting of: or a pharmaceutically acceptable form or isotopic derivative thereof.

56. A compound having a structural formula selected from the group consisting of: or a pharmaceutically acceptable form or isotopic derivative thereof.

57. A compound having a structural formula selected from the group consisting of: or a pharmaceutically acceptable form or isotopic derivative thereof.

58. A compound having a structural formula selected from the group consisting of: or a pharmaceutically acceptable form or isotopic derivative thereof.

59. according to the compound described in any one of claims 51-54, 57 and 58, it is in R 1 Has the following chirality:

60. according to the compound described in any one of claims 51-54, 57 and 58, it is in R 1 Has the following chirality:

61. according to the compound described in any one of claims 1-60, it is in R 2 The carbon to which it is bonded has the following chirality:

62. according to the compound described in any one of claims 1-60, it is in R 2 The carbon to which it is bonded has the following chirality:

63. A compound selected from Table 1, or a pharmaceutically acceptable form or isotopic derivative thereof.

64. A compound according to any one of claims 1-63 having one or more deuterium atoms replacing hydrogen.

65. A compound according to any one of claims 1-64 having a deuterium atom replacing a hydrogen atom.

66. A pharmaceutical composition comprising a compound according to any one of claims 1-65 and a pharmaceutically acceptable excipient, carrier or diluent.

67. The pharmaceutical composition of claim 66, which is suitable for oral administration.

68. A unit dosage form comprising the pharmaceutical composition according to claim 66 or 67.

69. The unit dosage form according to claim 68, which is in the form of a tablet or a capsule.

70. A method for inhibiting cell proliferation in vitro or in vivo, comprising contacting the cells with an effective amount of a compound according to any one of claims 1-65.

71. A method for inhibiting phosphoinositide 3-kinase alpha (PI3Kα) activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-65.

72. A method for treating a disease or condition mediated by phosphoinositide 3-kinase alpha (PI3Kα), comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-65.

73. The method of claim 72, wherein the disease or disorder is a cell proliferative disease.

74. A method for treating or ameliorating cancer or a related disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-65.

75. The method of claim 74, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

76. The method of claim 74 or 75, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, bile duct carcinoma, bladder urothelial carcinoma, gastric cancer, cholangiocarcinoma, and hematological malignancies.

77. The method of any one of claims 74-76, wherein the subject has a mutated Class IA PI3Kp110α.

78. The method of any one of claims 74-77, wherein the subject has at least one of the following PI3Kα mutations: H1047R, E542K, and E545K.

79. The method of any one of claims 74-78, wherein the treated subject is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

80. Use of a compound according to any one of claims 1-65 and a pharmaceutically acceptable excipient, carrier or diluent in the preparation of a medicament for treating a disease or condition.

81. The use of claim 80, wherein the disease or disorder is a cell proliferative disease.

82. The use according to claim 81, wherein the disease or disorder is cancer.

83. The use according to claim 82, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma and lymphoma.

84. The use of claim 82, wherein 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, bile duct carcinoma, bladder urothelial carcinoma, gastric cancer, cholangiocarcinoma, hepatocellular carcinoma, thyroid cancer, and hematological malignancies.

85. The use according to claim 82, wherein the cancer is selected from the group consisting of: acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and glioblastoma.

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