Tricyclic aryl derivatives, and compositions and methods thereof

Abstract

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

Description

TRICYCLIC ARYL DERIVATIVES, AND COMPOSITIONS AND METHODSTHEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 393,570, filed July 29, 2022, the entire content of each of which is incorporated herein by reference for all purposes.Technical Fields of the Invention

[0002] The invention generally relates to novel compounds and therapeutic uses thereof. More particularly, the invention provides novel tricyclic compounds that are shown to be potent and selective phosphoinositide 3-kinase a (PI3Ka) inhibitors. The invention also provides pharmaceutical compositions comprising compounds of the invention and methods for treating diseases and disorders associated with or related to PI3Ka activities, such as various types of cancer.Background of the Invention

[0003] Phosphoinositide 3 -kinases (PI3Ks) are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 -position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdins). PI3Ks have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3K signaling pathway is one of the most frequently mutated in human cancer and is also a major factor in many other diseases in humans. For examples, PI3K signaling is associated with allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diabetic complications and acute coronary syndrome.

[0004] The PI3K family is divided into three different classes: Class I, Class II, and Class III, based on their primary structure, regulation, and lipid substrate specificity. (Kalaany et al. 2009 Nature 458 (7239): 725-31; Leevers et al. (1999) Current Opinion in Cell Biology 11 (2): 219-25.) Class I PI3Ks (pl 10a, pl 10p, pl 108 and pl 10y) are activated by tyrosine kinases or G protein-coupled receptors to produce phosphatidylinositol-3,4,5-triphosphate (PIP 3). Association of effectors such as PDPK1 / AKT with PIP3 activates downstream signaling pathways.

[0005] The class IA PI3K pl 10a (PI3Ka) is mutated in many human cancers. Angiogenesis has been shown to selectively require the PI3Ka isoform in the control of endothelial cell migration. Mutations in the gene encoding PI3Ka (PIK3CA) or PI3Ka up-regulation occurs in many human cancers such as ovarian cancer, cervical cancer, breast cancer, colorectal cancer, endometrial cancer, gastric carcinomas, hepatocellular carcinoma, small and non-small cell lung cancer, thyroid carcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas. In cancer, PI3Ka mutations are often hotspot point mutations in the helical or kinase domain, such as E542K, E545K and H1047R. (Graupera et al. 2008 Nature 453: 662-6; Campbell et al 2004 Cancer Res 64, 7678-7681; Levine et al. 2005 Clin Cancer Res 1 1 , 2875-2878; Wang et al 2005 Hum Mulat 25, 322; Lee et al. 2005 Gynecol Oncol 97, 26-34; Bachman, et al. 2004 Cancer Biol Ther 3, 772-775; Li el al. 2006 Breast Cancer Res Treat 96, 91-95; Saal e t al. 2005 Cancer Res 65, 2554-2559; Samuels and Velculescu 2004 Ceil Cycle 3, 1221-1224, Samuels, et al 2004 Science 304, 554; Velho e / a / . 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 el al. 2005 Oncogene 24, 1477- 1480; Tang el al. 2006 Lung Cancer 51, 181 -191;Massion et al. 2004 Am JRespir Grit Care Med 170, 1088-1094; Wu el al. 2005 J Clin Endocrinol1Me tab 90, 4638-4693; Sujobert et al. 1997 Blood 106, 1063-1066, Hickey and Cotter 2006 J Biol Cheni 281, 2441-2450; Hartmann et al. 2005 Acta Neuropathol (Berl) 109, 639-642.)

[0006] There remains an urgent and unmet need for potent and selective PI3Ka inhibitors that are safe and effective in treating diseases and conditions associated with PI3Ka, such as various types of cancer (e.g , breast cancer, ovarian cancer, colorectal cancer, lung cancer).Summary of the Invention

[0007] The invention provides novel tricyclic compounds and derivatives thereof as PI3Ka inhibitors, which are shown herein to exhibit favorable potency and selectivity profiles over known PI3Ka inhibitors. These novel compounds selectively target, bind to, inhibit and / ormodulate the activity of PI3Ka. The compounds are also orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for treating various diseases and disorders associated with or related to PI3Ku activities, such as various types of cancer.

[0008] In one aspect, the invention generally relates to a compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered monocyclic non-aromatic ring, substituted with 0-10 Ra’s;R1is ZB-RB;R2is Zc-Rc;X is N, CH or CRX;Rxis Zx-Rx; each of ZB, Zcand Zxis 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 a linking group selected from Ci-4 saturated or unsaturated bivalent hydrocarbon radicals, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S and O; each of RB, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)N(R)OR, -OC(O)R, - OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, -N(R)C(NR)NRR’, - N(R)S(O)2NRR’, or -N(R)S(O)2R; or a Ci-6 aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, optionally substituted with one or more Rb, Rcor Rx, respectively;each of Ra, Rb, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)N(R)OR, -OC(O)R, - OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, -N(R)C(NR)NRR’, - N(R)S(O)2NRR’ or -N(R)S(O)2R; or a substituted or unsubstituted group selected from C1-6 alkyl or 4- to 6-membered carbocyclic ring; each of R and R’ is independently selected from H, unsubstituted or substituted C1-4 alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same C or N atom, together form an unsubstituted or substituted 4- to 6- membered heterocyclic ring; and z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

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

[0010] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

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

[0012] In yet another aspect, the invention generally relates to a method for inhibiting PI3Ka activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0013] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Ka, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

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

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

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

[0017] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0018] The term “comprising”, when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term “consisting essentially of’, when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

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

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

[0021] As used herein, the terms “administration” of or “administering” a disclosed compound encompasses the delivery to a subject of a compound as described herein, or aprodrug or other pharmaceutically acceptable form thereof, using any suitable formulation or route of administration, as discussed herein.

[0022] As used herein, the term “co-administer” refers to the presence of two pharmacological agents in a subject’s body (e.g., in the blood) at the same time. The two pharmacological agents can be administered concurrently or sequentially.

[0023] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0024] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below.

[0025] In some embodiments, the amount is that is sufficient to negatively modulate or inhibit the activity of PI3Ka. In some embodiments, the amount is that effective for reduction or amelioration of a symptom to stop or reversion of progression of a disease or disorder such as cancer. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer.

[0026] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. Such amount may be administered as a single dosage or according to a regimen. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age / existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0027] As used herein, an “inhibitor” of “PI3Ka” refers to a compound of the invention capable of negatively modulating or inhibiting all or a portion of the activity of PI3Ka.

[0028] As used herein, a “PI3Ka-associated” disease or disorder refers to diseases or disorders associated with or mediated by PI3Ka or having one or more PI3K& mutations. Examples of PI3Ka-associated diseases or disorders include various cancer types. A PI3Ka- associated disease or disorder may also refer allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diabetic complications, or acute coronary syndrome.

[0029] used herein, the term contacting reters to the bringing togethei cd indicated moi eties in vitro or in vivo. For example, “contacting” a cell with a compound disclosed herein includes the administration of the compound to a subject in need thereof, as well as, for example, introducing the compound into a sample containing a cellular or purified preparation. In some embodiments, a ceil in which inhibition of PI3Ka activity is desired is contacted with an effective amount of a compound disclosed herein or pharmaceutically acceptable form thereof to negatively modulate the activity of PI3Ka. By negatively modulating the activity of PI3Ka, the methods disclosed herein are designed to inhibit undesired cellular proliferation resulting from enhanced PI3Ka activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of PI3Ka The ability of compounds to bind PI3Ka may be monitored in vitro using methods known in the art. The inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of PI3Ka activity using methods known in the art.

[0030] As used herein, the terms “unsubstituted or substituted” and “optionally substituted” are used interchangeably and refer to where a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e. a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, - COOH, -CH2CN, -O-C1-C6 alkyl, Ci-C6alkyl, -OCi-C6alkenyl, -OCi-C6alkynyl, -Ci-C6alkenyl, -Ci-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi-C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -NHC(O)CI-C6alkyl, -C(O)NHCI-C6alkyl, - S(O)2-Ci-C6alkyl, -S(O)NHCI-C6alkyl, and S(O)N(CI-C6alkyl)2.

[0031] As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

[0032] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes 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, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Insome embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0033] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0034] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act 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 acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

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

[0036] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and / or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0037] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (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," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0038] 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, involved in carrying or transportingthe subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. 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 which 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

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

[0040] In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated with a compound disclosed herein and / or according to a herein disclosed method. In some embodiments, the subject has been identified or diagnosed as having a cancer having one or more PI3Ka mutations. In some embodiments, the subject has a cancer that is positive for a PI3Ka mutation. In some embodiments, the subject is suspected of having a PI3Ka gene-associated cancer.

[0041] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the subject has one or more PI3Ka mutations using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject. Various techniques may be employed, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis. Southern blotting,Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e g., RT-PCR and quantitative real-time RT-PCR).

[0042] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0043] As used herein, the term "therapeutic 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, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0044] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

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

[0046] As used herein, the term an “isolated” or “substantially isolated” molecule (such as a polypeptide or polynucleotide) is one that has been manipulated to exist in a higher concentrationthan in nature or has been removed from its native environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of non-subject-antibody materials with which it is associated in nature have been removed. For example, a polynucleotide or a polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated." Further, recombinant DNA molecules contained in a vector are considered isolated for the purposes of the present invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include synthetically produced molecules. Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

[0047] As used herein, the term “purified” when used in reference to a molecule, it means that the concentration of the molecule being purified has been increased relative to molecules associated with it in its natural environment, or environment in which it was 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 the integrity or facilitate the purification of the molecule being purified. According to this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

[0048] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-4 alkyl” is intended to encompass, Ci, C2, C3, C4, C1-3, C1-2, C2-4, C3-4 and C2-3 alkyl groups.

[0049] As used herein, the term “aliphatic” or “aliphatic group” refers to a linear or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic.

[0050] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having fromone to ten carbon atoms (c. ., Ci-io alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a Ci-6 alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, - ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3- methylbutyl, 2-m ethylpentyl, 3 -methylpentyl, 4-m ethylpentyl, 2-methylhexyl, 3 -methylhexyl, 4- methylhexyl, 5 -methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Rx)3 , -ORX, -SRX, -OC(O)-RX, -N(RX)2, - C(O)RX, -C(O)ORX, -OC(O)N(RX)2, -C(O)N(RX)2, -N(RX)C(O)ORX, -N(RX)C(O)RX, - N(RX)C(O)N(RX)2, -N(RX)C(NRX)N(RX)2, -N(Rx)S(O)tN(Rx)2(where t is 1 or 2), -P(=O)(RX)(RX), or -O-P(=O)(ORX)2wherein each Rxis independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 3- hydroxypropyl, benzyl, and phenethyl.

[0051] Unless otherwise specifically defined, the term “aromatic” or “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by 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-Ci-Ce alkyl, Ci-Ce alkyl, -Ci-Ce alkenyl, -OCi-Ce alkynyl, -Ci-Ce alkenyl, -Ci-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi- C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -S(O)2-Ci-C6alkyl, -S(O)NHCi-C6alkyl, and S(O)N(Ci-Ce alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

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

[0053] As used herein, the terms “heteroaryl” or “hetero-aromatic” refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azoci nyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3FI-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedi oxyphenyl, naphlhyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazoiyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxaihiinyl, phenoxazinyl, phthal azinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyi, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadi azinyl, 1 ,2,3 -thiadi azolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazoiyi, thienooxazolyl, thi enoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1 ,2,4-tiiazolyl, 1,2,5-tri azolyl, 1,3,4-triazolyl, and xanthenyl.“Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one tothree heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated

[0054] Heteroaryl groups maybe substituted with 0, 1 , 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkyl carbonyl, alky {carbonyl alkyl, alkyl carbonyl oxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZiZ2)carbonyl. The term "NZ1Z2" as used herein, means two groups, Zj and Z?, which are appended to the parent molecular moiety through a nitrogen atom. Zi and Z> are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ3Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0055] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0056] As used herein, the terms “cycloalkyl” and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moi eties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 carbocyclyl groups include norbornyl (C7). Examples of C3-8 carbocyclyl groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl(C7), cycloheptadienyl (C?), cycloheptatrienyl (C?), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-lH indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3 , -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tN(Ra)2(where t is 1 or 2), - P(=O)(Ra)(Ra), or -O-P(=O)(ORa)2where each Rais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0057] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., O, N, S, P or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl include 2-hydroxy-aziridin-l-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2-dimethyl- tetrahydrofuran-3-yl, 3 -carboxy -morpholin-4-yl, l-cyclopropyl-4-methyl-piperazin-2-yl. 2- pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H- [l,4]oxazine, etc.

[0058] As used herein, the terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fully saturated or partially unsaturated cyclic groups, for example, 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered spirocyclic or tricyclic ring systems, which haveat least one heteroatom (selected from the group consisting of 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 a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. A heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but not limited to, epoxy, azetidinyl, aziridinyl, letrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorphoiinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepaoyl, azabicyclohexanyls. azabicycloheptanyl, azabicyclooctanyls. azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-lH,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 1 'H,3'H- spiro[cyclopropane-1 ,2’-pyrro1izine], hexahydro- IH-pyrrolizinyl, hexahydro- 1H-pyrrolo[2,1 - c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, and tetrahydro- 2H-thiopyranyl 1 -oxi de and tetra hydro-2H- thi opy rany 1 1 , 1 -di oxi d e .Detailed Description of the Invention

[0059] The invention is based in part on the discovery of novel tricyclic compounds and derivatives thereof as PI3Ka inhibitors. These compounds are shown herein to selectively target, bind to, inhibit and / or modulate the activity of PI3Ku. The compounds are orally available and can be used for treating various diseases and disorders associated with or related to PI3Ka activities, such as various types of cancer.

[0060] In one aspect, the invention generally relates to a compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered monocyclic non-aromatic ring, substituted with 0-10 Ra’s;R1is ZB-RB;R2is Zc-Rc;X is N, CH or CRX;Rxis Zx-Rx; each of ZB, Zcand Zxis 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 a linking group selected from Ci-4 saturated or unsaturated bivalent hydrocarbon radicals, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S and O; each of RB, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)N(R)OR, -OC(O)R, - OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, -N(R)C(NR)NRR’, - N(R)S(O)2NRR’, or -N(R)S(O)2R; or a Ci-6 aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, optionally substituted with one or more Rb, Rcor Rx, respectively; each of Ra, Rb, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)N(R)OR, -OC(O)R, - OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, -N(R)C(NR)NRR’, - N(R)S(O)2NRR’ or -N(R)S(O)2R; ora substituted or unsubstituted group selected from Ci-6 alkyl or 4- to 6-membered carbocyclic ring; each of R and R’ is independently selected from H, unsubstituted or substituted C1-4 alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same C or N atom, together form an unsubstituted or substituted 4- to 6- membered heterocyclic ring; and z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

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

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

[0063] In certain embodiments of (I), Ring A is a 4-membered non-aromatic ring, substituted with 0-4 Ras, having the structural formula Ia:wherein each of Y1and Y2is independently CH, CH2, N, NH, O or S, provided that at least one of Y1and Y2is C or CH.

[0064] In certain embodiments of (I), Ring A is a 5-membered non-aromatic ring, substituted with 0-6 Ras, having the structural formula (lb):wherein each of Y1, Y2and Y3is independently CH, CH2, N, NH, O, S or C(O), provided that at least one of Y1, Y2and Y3is not N or NH and at least one of Y1, Y2and Y3is C, CH or C(O).

[0065] In certain embodiments of (I), Ring A is a 6-membered non-aromatic ring, substituted with 0-8 Ras, having the structural formula (Ic):wherein each of Y1, Y2, Y3and Y4is independently CH, CH2, N, NH, O, S, S(O)2, or C(O), provided that at least two of Y1, Y2, Y3and Y4is notN or NH and at least two of Y1, Y2, Y3and Y4is C, CH or C(O).

[0066] In certain embodiments of (I), Ring A is a 7-membered non-aromatic ring, substituted with 0-8 Ras, having the structural formula (Id):wherein each of Y1, Y2, Y3, Y4and Y5is independently CH, CH2, N, NH, O, S or C(O), provided that at least two of Y1, Y2, Y3, Y4and Y5is not N or NH and at least two of Y1, Y2, Y3, Y4and Y5is C, CH or C(O).

[0067] In certain embodiments of (I), RBis Ring B, a 5- to 10-membered monocyclic or bicyclic carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, substituted with 0-6 Rbs; and Rcis Ring C, a 5- to 10- membered monocyclic or bicyclic aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, substituted with 0-6 Rcs, having the structural formula (Ie):wherein j is 0, 1, 2, 3, 4, 5 or 6; andA; is 0, 1, 2, 3, 4, 5 or 6.

[0068] In certain embodiments of (I), ZBis NH-C(O) and Zcis a single bond, having the structural formula (If):

[0069] In certain embodiments of (I), ZBis C(O)-NH and Zcis a single bond, having the structural formula (Ig):

[0070] In certain embodiments of (I)-(Ig), Ring A is selected from:

[0071] In certain embodiments of (I)-(Ig), Ring A is selected from:

[0072] In certain embodiments, Ring A is:wherein Rais CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN.

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

[0074] In certain embodiments, Rais CH2CHF2.

[0075] In certain embodiments of (I)-(Ig), Ring A is selected from:

[0076] In certain embodiments of (I)-(Ig), Ring A is selected from:

[0077] In certain embodiments, Ring A is selected from:whereinRais CH2CHF2 or CH2CF3; and each Rais independently H, Cl, F, CN or CH3.

[0078] In certain embodiments, Ring A iswherein one of Rais CH2CHF2 or CH2CF3, and the other Rais H, CH3 or CD3.

[0079] In certain embodiments of (I)-(Ig), Ring A is selected from:

[0080] In certain embodiments, Ring A is selected from:wherein Rais CH2CHF2 or CH2CF3, and Rais H.

[0081] In certain embodiments, Ring A is selected from:wherein one of Raand Rais selected from H, CH3, CD3, CD2CD3, CH2CN and CH2CHF2, CH2CF3 and CH2CN; and the other Raand / or Rais H.

[0082] In certain embodiments, Ring A is selected from:wherein each Rais H, and each Rais independently selected from H, CH3, CD3, CD2CD3,CH2CN and CH2CHF2, CH2CF3 and CH2CN.

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

[0084] In certain embodiments of (I)-(Ig), X is CH.

[0085] In certain embodiments of (I)-(Ig), X is CRX.

[0086] In certain embodiments of (I)-(Ig), X is N.

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

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

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

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

[0091] Non-limiting examples of Ring B include:

[0092] In certain embodiments of (I)-(Ie), Ring B is selected from:

[0093] In certain embodiments of (I)-(Ie), Ring B is selected from:

[0094] In certain embodiments of (I)-(Ie), Ring B is selected from:

[0095] In certain embodiments, Ring B is:

[0096] In certain embodiments of (I)-(Ie), Ring B is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

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

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

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

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

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

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

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

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

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

[0106] In certain embodiments of (I)-(Ie), each of Ring B and Ring C is independently a substituted or unsubstituted phenyl.

[0107] Non-limiting examples of Ring C include:

[0108] In certain embodiments, Ring C is:

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

[0110] In certain embodiments of (I), the compound has the structural formula Ih:

[0111] In certain embodiments of (I), the compound has the structural formula L:

[0112] In certain embodiments of (I), the compound has the structural formula Ij:

[0113] In certain embodiments of (I), the compound has the structural formula Ik:

[0114] In certain embodiments of (I), the compound has the structural formula Ii:

[0115] In certain embodiments of (I), the compound has the structural formula Im

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

[0117] Non-limiting examples of compounds of the invention include:or a pharmaceutically acceptable form or an isotope derivative thereof.

[0118] Non-limiting examples of compounds of the invention include:or a pharmaceutically acceptable form or an isotope derivative thereof.

[0119] Non-limiting examples of compounds of the invention include:or a pharmaceutically acceptable form or an isotope derivative thereof

[0120] Non-limiting examples of compounds of the invention also include:or a pharmaceutically acceptable form or an isotope derivative thereof.

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

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

[0123] In certain embodiments, a compound of the invention exhibits the following chirality at the carbon to which R2is bond:

[0124] In certain embodiments, a compound of the invention exhibits the following chirality at the carbon to which R2is bond:

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

[0126] In certain embodiments, a compound of invention has one or more deuterium atoms in place of hydrogen. In certain embodiments, a compound of invention has one deuterium atom in place of a hydrogen atom.

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

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

[0129] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

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

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

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

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

[0134] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv)disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[0135] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Tn addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

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

[0137] In yet another aspect, the invention generally relates to a method for inhibiting PI3Ka activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0138] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Ka, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

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

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

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

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

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

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

[0145] In certain embodiments, the subject has a mutated class IA PI3K pl 10a.

[0146] In certain embodiments, the subject has at least one of the following PI3Ka mutations: H1047R, E542K, and E545K.

[0147] In certain embodiments, the subject does not have a PI3Ka mutant protein

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

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

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

[0151] The amount of the active compound administered will be dependent on the subj ect 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 instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

[0152] Any appropriate route of administration can be employed, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalational, buccal, intraperintoneal, rectal, intrapleural, and intrathecal administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

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

[0154] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of 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 this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[0155] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0156] Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0157] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

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

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

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

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

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

[0163] Methods of treatment disclosed herein may be employed in combination with or in addition to other therapies. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

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

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

[0166] In some embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine. In other embodiments, a compound of the invention may be administered in combination with an anti-HER2 agent, e.g., trastuzumab or pertuzumab.

[0167] In certain embodiments, the method disclosed herein is in combination with one or more of immune check point blockade, co-signaling of T cells, and tumor targeting antibody therapies.

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

[0169] In certain embodiments, the method further comprises administering a radiotherapy to the subject. Tn certain embodiments, the method further comprises administering a targeted therapy to the subject. In certain embodiments, the method further comprises administering an immunotherapy to the subject. In certain embodiments, the method further comprises administering hormonal therapy to the subject.

[0170] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin;CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophy cins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L- norleucine, ADRTAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes(especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difhioromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0171] Examples of the second (or further) agent or therapy may include, but are not limited to, immunotherapies (e.g. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonist, cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab and the like), mitosis inhibitors (e.g., paclitaxel, vincristine, vinblastine and the like), alkylating agents (e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and the like), anti -metabolites (e.g., methotrexate, 5-FU and the like), intercalating anticancer agents, (e.g., actinomycin, anthracycline, bleomycin, mitomycin-C and the like), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide and the like), immunotherapic agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0172] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cisand trcms- somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

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

[0174] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0175] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which 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 compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively.

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

[0177] Further, substitution of normally abundant hydrogen (1H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption,distribution, metabolism and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. Benefits may also be obtained from replacement of normally abundant12C with13C. (See, WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.)

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

[0179] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

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

[0181] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[0182] Compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

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

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

[0185] Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg / kg body weight daily and more usually 1 to 300 mg / kg body weight. The dose, from 0.0001 to 300 mg / kg body, may be given twice a day.

[0186] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that eachsuch combination or subset of combinations is specifically contemplated and should be considered disclosed.Examples

[0187] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0188] Compounds of the invention, including those specifically disclosed herein above and herein below, may be prepared as described in the following schemes. Although the present invention has been described in detail with preferred embodiments, those of ordinary skill in the art should understand that modifications, variations, and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.Table 1. Exemplary CompoundsExemplary Synthetic ProceduresList of Abbreviations aq: aqueousAc = AcetylAcO = AcetateAC2O = Acetic anhydrideAIBN = a,a'-AzoisobyronitrileAll = AllylAlloc = AllyloxycarbonylAm = Amyl (Pentyl)Ar = ArylB2Pin2 = bis(pinacolato)diboron9-BBN = 9-BorabicyclononaneBHT = tert-ButylhydroxytolueneBINAP = 2,2'-Bis(diphenylphosphino)-l,l'-binaphthylBMS = Borane-methylsulphide complexBn = BenzylBoc = tert-Butoxy carbonylBOP = Bis(2-oxo-3-oxazolidinyl)phosphineBu or n-Bu = n-Butyl s-Bu or sBu = sec-Butyl t-Bu or tBu = tert-ButylBuOH = ButanolBz = BenzoylBzl = BenzylCAN = Ceric ammonium nitrate cataCXium A Pd G3 = mesylate [(di(l-adamantyl)-n-butylphosphine)-2-(2’- amino-1, 1 ’biphenyl)]palladium(II)CBS = Corey -Bashki-ShibatCbz = BenzyloxycarbonylCbzCl = Benzyl chloroformate oxCod = CyclooctadieneCp = CyclopentadienylCSA = Camphorsulphonic acidDABCO = 1,4-Diazabicyclo[2.2.2]octane, Tri ethyl endiamineDAST = Diethylaminosulphur trifluoride dba = DibenzylideneacetoneDBU = l,8-Diazabyciclo[5.4.0]undec-7-eneDCC = 1,3 -DicyclohexylcarbodiimideDCM = DichloromethaneDDQ = 2,3-Dichloro-5,6-dicyano-l,4-benzoquinoneDEAD = Diethyl azodicarboxylateDHP = DihydropiranDHQD = DihydroquinidineDIBAL = Diisobutylaluminium hydrideDIBAL-H = Diisobutylaluminium hydrideDIC = DiisopropylcarbodiimideDIPEA = DiisopropylethylamineDMA = N,N-DimethylacetamideDMAC = N,N-DimethylacetamideDMAP = 4-DimethylaminopyridineDME = 1,2-Dimethoxy ethaneDMF = N,N-DimethylformamideDMP = Dess-Martin periodinaneDMPU = l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pirimidoneDMS = DimethylsulphideDMSO = DimethylsulphoxideDPA = DiisopropylamineDPPA = Diphenylphosphoryl azideDdpb = l,4-bis(diphenylphosphino)butaneDppe = l,2-bis(diphenylphosphino)ethaneDppf = 1 ,2-bis(diphenylphosphino)ferrocene dppp = l,3-bis(diphenylphosphino)propaneDtbbpy = 4, 4’ -di-tert-butyl-2, 2’ -dipyridylEA = Ethyl acetateEDC = l-Ethyl-3-(3-dimethylaminopropy)carbodiimideEDCI = l-Ethyl-3-(3-dimethylaminopropy)carbodiimide hydrochlorideEq = equivalentESI or ES = Electrospray ionizationEt = ethylEt2O = Diethyl etherEtOAc = Ethyl acetateFMOC = 9-FluorenylmethoxycarbonylHATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3 -oxide hexafluorophosphateHMDS = HexamethyldisilazaneHMPA = HexamethylphosphoramideHOAt = 7-Aza-l-hydroxybenzotriazoleHOBt = 1 -HydroxybenzotriazoleHPLC = high pressure liquid chromatographyIPA = Isopropyl alcoholIm = ImidazoleKHMDS = Potassium bis(trimethylsilyl)amideKO Ac = Potassium acetateLAH = Lithium aluminium hydrideLDA= Lithium diisopropylamideLHMDS = Lithium bis(trimethylsilyl)amideMCPBA = meta-chloroperoxybenzoic acidMe = MethylMeCN = AcetonitrileMeOH = MethanolMOM = MethoxymethylMg = magnesiumMS = Molecular sievesMs = MethanesulphonylMTBE = Methyl tert-butyl ether m / z = mass divided by chargeNa2SO4 = Sodium SulphateNaHMDS = Sodium bis(trimethylsilyl)amideNaCNBHs = Sodium cyanoborohydrideNBS = N-BromosuccinimideNCS = N-ChlorosuccinimideNIS = N-IodosuccinimideNMM = N-MethylmorpholineNMO = N-Methylmorpholine-N-oxideNMP = N-MethylpyrrolidoneNMR = Nuclear magnetic resonanceNs = p-Nitrophenyl sulphonylPd(dppf)C12 = [l,l’-bis(diphenylphosphino)ferrocene]di chloropalladiumPd(PPh3)4 = tetrakis(triphenylphosphine)palladiumPDC = Pyridinium dichlorochromatePCC = Pyridinium chlorochromatePE = Petroleum etherPh = PhenylPiv = Pivaloyl, 2,2-dimethylacetylPMB = p-MethoxybenzylPPA = Polyphosphoric acidPPTS = Pyridinium p-toluensulphonate n-Pr = n-PropylPr = Propyl i-Pr or iPr = iso-propiloPTC = Phase transfer catalystPTSA = p-Toluenesulphonic acidPv = Pivaloyl, 2,2-dimethylacetylPy = PyridineRed-Al® = Sodium bis(2-methoxyethoxy)aluminium hydrideRT = room temperatureSFC = supercritical fluid chromatographyPrep-SFC = Preparative SFCSEM = 2-(Trimethylsilyl)ethoxymethylTBAF = Tetrabutylammonium fluorideTBDMS = tert-Butyldimethyl silylTBDPS = tert-ButyldiphenylsilylTBHP = tert-ButylhydroperoxydeTBS = tert-ButyldimethylsilylTEA = TriethylamineTES = TriethylsilylTf = TrifluoromethanesulfonylTfO = TrifluoromethanesulfonateTf2O = Trifluoromethanesulfonyl anhydrideTfOH = Trifluoromethanesulfonic acidTFA= Trifluoroacetic acidTFAA = Trifluoroacetic anhydrideThexyl = 2,3-dimethyl-2-butylTHF = TetrahydrofuraneTHP = TetrahydropyranylTIPS = Triisopropyl silylTMEDA = N,N,N',N'-TetramethylethylendiamineTMG = TetramethylguanidineTMS = Trimethyl silylTol = p-ToluylTPAP = Tetra-n-propylammonium perruthenateTPS = Tripropyl silylTr = Trityl, triphenylmethylTroc = 2,2,2-TrichloroethoxycarbonylTrt = Trityl, triphenylmethylTs = p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acidUV = ultravioletZ = BenzyloxycarbonyUV: ultravioletGeneral LC-MS Method:

[0189] Shimadzu LCMS2020, Reverse-phase column (Shim-Pack Scepter Cl 8, 33 x 3.0 mm, 3um), elution with A: H2O / MeCN / FA = 90 / 10 / 0.05; B: MeCN; Detection: MS, ELS, UV (100 pL split to MS with in-line UV detector); MS ionization method: Electrospray (positive and negative ion). ES-API = electrospray-atmospheric pressure ionization.General HPLC Purification Method:

[0190] Instrument = Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8 A; GX-281. Column = YMC-Triart C18, 250*20 mm, 5um; Welch Ultimate XB-C18, 250*21.2 mm, 5um.Detection wavelength = 220, 254 nM. Flow rate = 15ml / min-20ml / min; Run time = 8 min;Column temperature = 25 °C.General Synthetic Route IExample 1 N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5- e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized via GeneralSynthesis Route I

[0191] Step A: To a solution of 6-nitrobenzo[d][l ,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). Then the reaction mixture was stirred at 60 °C for 12 h. The mixture was added water (50 mL) and extracted with EtOAc (50 rnL x 3). The combined organic phases were washed with brine (20 mL), dried over Na?.S()4 and concentrated to give a residue. The residue was triturated with petroleum ether / EtOAc = 3 / 1 and filtered to afford 4-bromo-6- nitrobenzo[d][ 1 ,3 ]dioxole-5-carbaldehyde (4.4 g, 73%). ^ NMR (400 MHz, CDCh): 8 10.12 (s, 1H), 7.50 (s, 1H), 6.28 (s, 2H).

[0192] Step B: To a solution of 4-bromo-6-nitrobenzo[d][l ,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 Ny atmosphere Then the reaction mixture was stirred at room temperature for 30 mins. The mixture was added waler (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over NajSCE 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][l,3]dioxol-5-yl)(2-cbloro-5-fluorophenyl)methanol (2.0 g, 57%).!H NMR (400 MHz, DMSO-^): 8 7.50-7.47 (m, 2H), 7.25-7.20 (m, 1H), 7.15-7.11 (m, 1H), 6.62 (d, J= 14.8 Hz, 1H), 6.29 (d, J= 4.4 Hz, 2H), 6.18 (d, J= 5.6 Hz, 1H).

[0193] Step C: To a solution of (4-bromo-6-nitrobenzo[d][l,3]dioxol-5-yl)(2-chloro-5- fluorophenyl)methanol (2.0 g, 4.9 mmol, 1.0 eq) in DCM (40 mL) was added Dess-Martin (2.5 g, 5 88 mmol, 1 .2 eq) at 0 °C. Then the reaction mixture was stirred at room temperature for 2 h.The mixture was added with water (40 ml) and extracted with DCM (40 mL x 3), The combmed organic phases were washed with brine (40 mL), dried over NaiSOi and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc:::15 / 1) to give product (4-bromo-6-nitrobenzo[dl[1,3]dioxoi-5-yl)(2-chloro-5- fluorophenyljmethanone (1.2 g, 60%). ’H NMR (400 MHz, CDCh): 8 7.69-7.67 (m, 2H), 7.44- 7.41 (m, 1H), 7.24-7.19 (m, 1H), 6.29 (s, 2H).

[0194] Step D: To a solution of (4-bromo-6-nitrobenzo[d][l,3]dioxol-5-yl)(2-chloro-5- fluorophenyl)methanone (270 mg, 0.67 mmol, 1.0 eq) in iV,7V-Dimethylacetamjde (4 mL) was added Zn(CN)2 (79 mg, 0.67 mmol, 1.0 eq) and Pd(PPhs)4 (231 mg, 0.2 mmol, 0.3 eq). Then the reaction mixture was stirred at 160 °C for 20 min with M.W. The mixture was added with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL). dried over NajSOi 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-fiuorobenzoyl)-6-nitrobenzo[d][1 ,3]dioxole-4-carbonitrile (I 00 mg, 43%). ’H NMR (300 MHz, CDCh): 5 7.78 (s, 1H), 7.73-7.70 (m, 1H), 7.44-7.41 (m, 1H), 6.41 (s, 2H).

[0195] Step E: To a solution of 5-(2-chloro-5-fluorobenzoyl)-6-nitrobenzo[d][l,3]dioxole-4- carbonitrile (100 mg, 0.29 mmol, 1.0 eq) in can (5 mL) and HzO (0.5 mL) was added KOH (5.0 nig, 0.086 mmol, 0.3 eq). Then the reaction mixture was stirred at room temperature for 2 h. The mixture was dried over NazSOi and concentrated to give crude. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / EtOAc = 15 / I) to give 6-(2- cbloro-5-fluorophenyl)-6-hydroxy-5-nitro-6(7-dihydro-8H-[1,3]dioxo1o[4,5-e]isoindol-8-one (50 mg, 48%) confirmed by LCMS. LCMS: m / z 365.0 ([M-H]').

[0196] Step F: To a solution of 6~(2-chloro-5-fluorophenyl)-6-hydroxy-5-nitro-6,7-dihydro- 8H-[l ,3]dioxolo[4,5-e]isoindol-8-one (100 mg, 0.273 mmol, 1 .0 eq) in TFA (4 mL) was added Triethyl silane (127 mg, 1 1 mmol, 4 0 eq). Then the reaction mixture was stirred at 100 °C for 4 h. The mixture was concentrated to afford the crude product. The residue was triturated with DCM / MeOH= 10 / I and filtered to afford 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.JHNMR (300 MHz, DMSO-t / e): 8 9.39 (s, 1H), 7.93 (m, 1H), 7.56 (s, 1H), 7.23-7.17 (m, 1H), 6.61-6.45 (m, 4H). LCMS: m / z 351.0 ([M+H]+).

[0197] Step G: To a solution of 6-(2-chloro-5-fluorophenyl)-5-nitro-6,7-dibydro-8H-[1.3]dioxolo[4,5-e]isoindol-8-one (12 mg, 0.034 mmol, 1.0 eq) in EtOH (0.5 mL) and was added Fe (9 mg, 0. 17 mmol, 5 0 eq) The reaction was heated to 45 °C was added NH4CI (1 mg, 0.017 mmol, 0.5 eq) and H2O (0.2 mL). Then the reaction mixture w7as stirred at 90 °C for 12 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give 5-amino- 6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[l ,3]dioxolo[4,5-e]isoindol-8-one (7 mg, 63.6%). LCMS: m / z 321.0 ([M+H]+).

[0198] Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1.3]dioxolo[4,5-e]isoindol-8”one (7 mg, 0.022 mmol, 1.0 eq) in ACN (0.5 mL) was added Pyridine (4 mg, 0.044 mmol, 2.0 eq) and 3-fIuoro-5-(trifluorometbyl)benzoyl chloride (4 mg, 0.018 mmol, 0.8 eq). Then the reaction mixture was stirred at room temperature for 2 h. The mixture was added water (0.5 ml.) and extracted with EtOAc (1 mL x 3). The combined organic phases were washed with brine (1.0 mL), dried over NaaSCL and concentrated to give a residue. The residue was purified by Prep-TLC (EtOAc) to give final N-(6-(2-chloro-5-fluorophenyl)-8- oxo-7, 8-dihydro-6H-[l ,3]dioxolo[4,5-e]isoindol-5-yl)~3-fluoro-5-(tritluoromethyl)benzamide (2.5 mg, 23%). LCMS: m / z 509.0 ([M+H])+. 'HNMR (400 MHz, DMSO-t / q): 8 10.20 (s, 1H), 9.00 (brs, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.77-7.64 (m, 2H), 7.30-7.27 (m, 1H), 7.10-7.04 (m, 2H), 6.27 (d, J= 14.8 Hz, 2H), 5.91-5.89 (m, 1H).Example 2 N-(3-(2-chloro-5-fluorophenyl)-l-oxo-2,396,7,8,9-hexahydro-lH- benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0199] To a solution of N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-l- oxo-2,3,6,7,8,9-hexahydro-lH-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 EtsSiH (11.6 mg, 0.1 mmol, 5.0 eq). The reaction mixture was heated to reflux and stirred for 5 h. Then the reaction mixture was by prep- HPLC (acetonitrile with 0.1% FA in water) to give N-(3-(2-chloro-5-fluorophenyl)-l-oxo-2,3,6,7,8,9-hexahydro-lH-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.0 mg, 19.2%). LCMS: m / z 519.0 ([M-H]’). ’H NMR (400 MHz, CDCh): 5 7.77 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.39-7.33 (m, 2H), 7.04-7.00 (m, 1H),6.7O (d, . / = 8.0 Hz, 1H), 6.31 (s, 1H), 6.10 (s, 1H), 5.35 (s, 1H), 3.35 (s, 2H), 2.89 (s, 2H), 1.87 (m, 4H).Example 3 N-(7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[l,4]dioxino[2,3- e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized via general route I:

[0200] LCMS: m / z 525.0 ([M+H]+). 'H NMR (300 MHz, DMSO-t / s): 5 10.16 (s, 1H), 8.82 (s, 1H), 7.91 (d, J= 8.4 Hz, 1H), 7.70-7.63 (m, 2H), 7.30-7.26 (q, Ji = 8.7, J2=5.1, 1H), 7.10- 7.04 (m, 1H), 5.83 (s, 1H), 4.37 (t, J= 3.6 Hz, 4H).Example 4 N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5- e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-l-carboxamide

[0201] 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 N2atmosphere. Then the reaction mixture was stirred at 0 °C for 30 min. After a solution of 5- fluoro-3-(trifluoromethyl)indolin-3-ol (69 mg, 0.32 mmol, 2.0 eq) in Pyridine (0.2 mL) was added. The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched by the addition of the saturated aqueous NH4CI (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 Prep-HPLC to give N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3- hydroxy-3 -(trifluoromethyl)indoline-l -carboxamide (32.3 mg, 37%). LCMS: m / z 568.0 ([M+H]+). ^ NMR (300 MHz, DMSO-^): 8 8.95 (s, 1H), 8.44 (d, J= 17.4 Hz, 1H), 7.90-7.76 (m, 1H), 7.39-7.01 (m, 5H), 6.97 (d, .7 25.2 Hz, 1H), 6.66 (brs, 1H), 6.24 (d, 7 = 10.5 Hz, 2H), 5.98-5.92 (m, 1H), 4.13-3.89 (m, 1H), 3.56-3.50 (m, 1H).

[0202] Example 4 was separated to Example 6, 7, 8 and 9 via the chiral prep-SFC separation method below:Instrument: Waters 150 preparative SFC(SFC-26) Column: (S, S) Whelk 01, 250x30mm I.D., 10pm Mobile phase: A for CO2 and B for Ethanol Gradient: B 40%Flow rate: 80 mL / minBack pressure: 100 barColumn temperature: 38°CWavelength: 220nmCycle time: ~25 minSample preparation: Compound was dissolved in ~9 ml methanol / DCMInjection: 3 ml per injection.Work up: After separation, the fractions were dried off via rotary evaporator at bath temperature 40°C to get the P3 and P4, the mixture of P1&P2 was then further separated with the method below.Instrument: Waters 150 preparative SFC(SFC-26) Column: ChiralPak AD , 250x30mm I.D., 10pm Mobile phase: A for CO2 and B for Ethanol Gradient: B 35%Flow rate: 80 mL / minBack pressure: 100 barColumn temperature: 38°CWavelength: 220nmCycle time: ~6 minSample preparation: Compound was dissolved in ~32 ml methanol / DCMInjection: 4 ml per injection.Work up: After separation, the fractions were dried off via rotary evaporator at bath temperature 40°C to get the Pl and P2.P1 Example 6

[0203] ‘HNMR (400 MHz, CD3OD) 8 7.82 (dd, J= 9.0, 4.5 Hz, 1H), 7.28 (dd, J= 9.0, 5.0 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 7.15-7.05 (m, 1H), 7.02 - 6.89 (m, 2H), 6.65 (br, 1H), 6.30- 6.10 (m, 3H), 4.20 (d, J= 11.8 Hz, 1H), 3.60-3.40 (m, 1H).P2 Example 7

[0204] ’H NMR (400 MHz, CD3OD) 5 7.98-7.80 (m, 1H), 7.28 (dd, J = 8.8, 5.0 Hz, 1H), 7.22 - 7.05 (m, 2H), 6.99 (td, J= 8.4, 3.0 Hz, 1H), 6.91 (s, 1H), 6.65 (br, 1H), 6.30 - 6.10 (m, 3H), 3.90 (d, J = 11 .4 Hz, 1 H), 3.69 - 3.72 (m, 1 H)P3 Example 8

[0205] 'HNMR (400 MHz, CD3OD) 6 7.82 (dd, J= 9.0, 4.5 Hz, 1H), 7.28 (dd, J= 9.0, 5.0 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 7.15-7.05 (m, 1H), 7.02 - 6.89 (m, 2H), 6.65 (br, 1H), 6.30 - 6.10 (m, 3H), 4.20 (d, J= 11.8 Hz, 1H), 3.60-3.40 (m, 1H).P4 Example 9

[0206] ’H NMR (400 MHz, CD3OD) 5 7.98-7.80 (m, 1H), 7.28 (dd, J = 8.8, 5.0 Hz, 1H), 7.22 - 7.05 (m, 2H), 6.99 (td, J= 8.4, 3.0 Hz, 1H), 6.91 (s, 1H), 6.65 (br, 1H), 6.30 - 6.10 (m, 3H), 3.90 (d, J = 11 .4 Hz, 1 H), 3.69 - 3.72 (m, 1 H)Example 5 N~(6~(2-ehiGro-5~fluoropheHy!)-8-oxo~7,8-dihydro-6H-[I,3]diGxoIo[4,5- e]isoindol-5-yI)benzo|d]isothiazole-3-carboxamide was synthesized via general route II from intermediate 5-amino~6”(2-ehlorc-5~fluoropheiiyI)-6,7"dihydro-8H-[l,3]dioxolo[4,5- eJisoindol-S-one:

[0207] Step A: To a solution of 5-amino-6~(2-chloro-5-fluorophenyl)~6,7~dihydro-8H- [l,3]dioxolo[4,5-e]isoindol-8-one (50 mg, 0 16 mmol, 1.0 eq) in DCM (2 mL) was added benzo[d]isothiazole~3 -carbonyl chloride (62 mg, crude) and DIEA (101 mg, 0.780 mmol, 5.0 eq) drop wise at 0 °C. Then the reaction mixture was stirred at room temperature for 2 h. The mixture was added water (2 mL) and extracted with DCM (2 mL x 3). The combined organic phases were washed with brine (2 mL), dried over NaaSCh and concentrated to give a residue. The residue was purified by Prep-HPLC to give N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro- 6H-[L3]dioxolo[4,5-e]isoindol-5-y1)benzo[d]isothiazole-3-carboxamide (5.2 mg, 3.5%). LCMS: m / z 482.0 ([M+H]+).1HNMR (300 MHz, DMSO-tfc): S 10.17 (s, 1H), 8.99 (s, 1H), 8.60 (d, J = 8.1 Hz, 1H), 8.30 (d, J= 8.4 Hz, 1H), 7.70-7.56 (m, 2H), 7.21-7.17 (m, 2H), 7.00-6.93 (m, 1H), 6.26 (d, J= 9.0 Hz, 2H), 6.07 (s, 1H).Example 11 (S)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[l,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-[l,3]dioxolo[4,5-e]isoindol-5-yl)benzo[d]isothiazole-3-carboxamide were separated from Example 5 with the prep-SFC method below:P1 Example 11 P2 Example 12Instrument: MG II preparative SFC(SFC-14) Column: ChiralCel OD, 250><30mm I.D. ,10pm Mobile phase: A for CO2 and B for EthanolGradient: B 30%Flow rate: 80 mL / minBack pressure: 100 barColumn temperature: 38°CWavelength: 220nmCycle time: ~5.5minSample preparation: Compound was dissolved in -120 ml methanol / DCMInjection: 4 ml per injection.Work up: After separation, the fractions were dried off via rotary evaporator at bath temperature 40°C to get the desired isomers.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 via General Synthesis route II from intermediate 5-amino-6-(2-chloro-5-fluorophenyl)-6,7-dihydro-8H-[1.3] dioxolo [4,5-e] isoindol-8-one

[0208] Step A: To a solution of 5-amino-6-(2-chloro-5-f1uorophenyl)-6,7-dihydro-8H-[1.3]dioxolo[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. Then the mixture was stirred for 2 h at the same temperature. The mixture was added water (2 mL) and extracted with DCM (2 mL x 3) The combined organic phases were washed with brine (2 mL), dried over NaaSOt and concentrated to give a residue. The residue was purified by Prep-HPLC (acetonitrile with 0.1% FA in water 35% to 47%) to afford 2.2 mg, 5% as a white solid. LCMS: m / z 476.9 ([M+H]+). ’H NMR (400 MHz, DMSO- d6y. 3 ppm 10.08 (s, 1H), 9.10 (brs, 1H), 7.73 - 7.60 (m, 1H), 7.55 - 7.28 (m, 3H), 7.20 - 7.09 (m, 1H), 7.04 (s, 1H), 6.90 - 6.50 (m, 1H), 6.36 - 6.15 (m, 2H), 6.05 - 5.80 (m, 1H).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-[l,4]dioxino[2,3-e]isoindol-6- yl)benzo[d]isothiazole-3-carboxamide were synthesized via General Synthesis route TT from intermediate 6-amino-7-(2-chloro-5-fluorophenyl)-2,3,7,8-tetrahydro-9H-[l,4]dioxino[2,3- e]isoindol-9-one

[0209] 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][l,2]thiazole-3 -carbonyl chloride (60 mg, 0.304 mmol). The mixture was stirred at rt for 2h. The solvent was removed and the residue was purified by prep-HPLC to afforded 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][l,2]thiazole-3-carboxamide (25 mg, 50 pmol, 16.6%) as a white solid. The solid was separated by prep-SFC to afforded Pl Example 13 (S)-N-((S)-7- (2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H-[l,4]dioxino[2,3-e]isoindol-6-yl)-5- fluoro-3 -hydroxy-3 -(trifluoromethyl)indoline- 1 -carboxamide (2.2 mg) as a pale solid. LCMS: ESI m / z 496 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 8 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-[l,4]dioxino[2,3-e]isoindol-6-yl)benzo[d]isothiazole- 3-carboxamide (2.0 mg) as a pale solid. LCMS: ESI m / z 496 [M+H]+’H NMR (400 MHz, DMSO-d6) 8 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).

[0210] Preparative SFC separation method:Instrument: Waters Thar 80 preparative SFC Column: ChiralPak IB, 250x21.2 mm I.D., 5 pm Mobile phase: A for CO2 and B for ETOH + 0.1%NH3H2O Gradient: B 40 %Flow rate: 40 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nm Cycle-time: 20 min Eluted time: 2 HExample 15 (R*)-N-((S)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H- [l,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-l- carboxamide and Example 16 (R*)-N-((R)-7-(2-chloro-5-fluorophenyl)-9-oxo-2, 3,8,9- tetr ahydro-7H- [1,4] dioxino [2,3-e] isoindol-6-yl)-5-fluoro-3-hydroxy-3- (trifluoromethyl)indoline-l-carboxamide

[0211] Step A: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-2,3,7,8-tetrahydro-9H-[l,4]dioxino[2,3-e]isoindol-9-one (25 mg, 0.075 mmol, 1.0 eq) in anhydrous THF (0.5 mL) wasadded 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 for 0.5 h at 0 °C. Then the solution was 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 aqueous NH4CI (10 mL) and extracted with DCM (10 mL x 3). The organic layers were washed with brine (5 mL x 3), dried over NaiSCL, filtered, and concentrated to give the crude, which was purified by Prep-HPLC (acetonitrile with 0.1% FA in water) to afford a mixture (13 mg). Then the mixture was separated by chiral separation to afford Pl Example 15 (R*)-N-((S)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9- tetrahydro-7H-[l,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline- 1-carboxamide (2.9 mg, white solid, yield for 7%). LCMS: m / z 582.0 ([M+H]+). 'H NMR (400 MHz, DMSO-fifc): d ppm 8.77 (brs, 1H), 8.36 (s, 1H), 7.78 (dd, J= 8.8, 4.4 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J= 8.8, 5.2 Hz, 1H), 7.27 - 7 14 (m, 2H), 7.14 - 7.02 (m, 1H), 6.94 (s, 1H), 5.91 (brs, 1H), 4.60 - 4.22 (m, 4H), 4.11 (d, J= 12.0 Hz, 1H), 3.51 (d, J= 11.6 Hz, 1H). And P2 Example 16 (R*)-N-((R)-7-(2-chloro-5-fluorophenyl)-9-oxo-2,3,8,9-tetrahydro-7H- [l,4]dioxino[2,3-e]isoindol-6-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-l -carboxamide (3.5 mg, white solid, yield for 8%). LCMS: m / z 582.0 ([M+H]'). 'H NMR (400 MHz, DMSO- d6. 3 ppm 8.75 (brs, 1H), 8.42 (s, 1H), 8.00 - 7.80 (m, 1H), 7.35 (s, 1H), 7.34 - 7.00 (m, 5H), 6.86 (s, 1H), 5.86 (brs, 1H), 4.60 - 4.24 (m, 4H), 3.91 (d, J= 12.0 Hz, 1H), 3.54 (d, J= 11.6 Hz, 1H).Example 17 N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H- [l,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized with the General Synthetic Route I

[0212] Step A: To a solution of 2,2-difluorobenz.o[d][l,3]dioxole-5-carbaldehyde (10 0 g, 53.7 mmol, 1.0 eq) in H2SO4 (50 mL) was added dropwise HNO3 (5 mL) at 0 °C. Then the reaction mixture was warm 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 NazSOr and concentrated to give 2,2-difluoro-6~ nitrobenzo[d][l,3]dioxole-5-carbaldehyde (11.0 g, 89%) as a yellow liquidNMR (300 MHz, CDCh): <5 ppm 10.35 (s, 1H), 7.87 (s, 3H), 7.67 (s, 1H).

[0213] Step B: To a solution of 2,2-difluoro-6-mtrobenzo[d][l,3]dioxole-5-carbaldehyde (5.0 g, 21.6 mmol, 1.0 eq) in H2SO4 (50 mL) was added portion wise NBS (5.8 g, 32.4 mmol, 1.5 eq) at 0 °C. Then the mixture was stirred for 12 h at room temperature. 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 NajSCL and concentrated to give a residue. The residue was purified by Prep-HPLC (acetonitrile with 0.1% FA in water 55% to 60%) to afford 4-bromo-2>2-difluoro-6-nitrobenzo[d][1 ,3]dioxole-5-carbaldehyde (1 .0 g, 14.9%) as a yellow solid. ‘H NMR (300 MHz, CDCh): <5 ppm 10.17 (s, 1H), 7.84 (s, 1H).

[0214] Step C: To a solution of 4"bromo-2,2-difluoro-6’nitrobenzo[d][l,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) at -78 °C under Na atmosphere Then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture quenched by the addition of the saturated aqueous NH4CI (20 mL). and the mixture was extracted with EtOAc (20 mL). The combined organic phases were washed with brine (10 ml,), dried over NazSO4 and concentrated to give (4-bromo-2,2-difluoro-6-nitrobenzo[d][l,3]dioxol-5- yl)(2-chloro-5-fluorophenyl)methanol (1 .6 g, crude) as a yellow liquid. LCMS: m / z 437.9 ([M- H] ).

[0215] ’H NMR (400 MHz, CDCh): 3 ppm 7.38 (s, 1H), 7.34 - 7.22 (m, 2H), 7.12 - 6.90 (m, 1H), 6.42 (s, 1H), 3.37 (brs, 1H).

[0216] Step D: To a solution of (4-bromo-2,2-diiIuoro-6-nitrobenzo[d][l,3]dioxol~5-yl)(2- cMoro-5-fluoropheny1)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). Then the reaction mixture was stirred at room temperature for 2 h. The mixture was added with water (50 mL) and extracted with DCM (50 ml, x 3 ). The combined organic phases were washed with brine (50 mL), dried over NA2SO4 andconcentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5:1) to afford (4-bromo-2,2-difluoro-6-nitrobenzo[d][l,3]dioxol-5-yl)(2-chloro- 5-fluorophenyl)methanone (1.0 g, 70 7% yield for 2 steps) as a yellow solid(400 MHz, CDCh): 3 ppm 7.99 (s, 1H), 7.75 (dd, J= 8.8, 3.2 Hz, 1H), 7.52 - 7.40 (m, 1H), 7.35 - 7.22 (m, 1H).

[0217] Step E: To a solution of (44>romo-2,2-difluorofomitrobenzo[d][1,3]dioxolfo~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 the reaction mixture was heated to 65 °C, a solution of NHiCl (15 mg, 0.9 mmol, 0.5 eq) in H2O (1.5 mL) was added. Then the reaction mixture was heated to reflux and stirred for 2 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give the crude product. ’Hie residue was purified by Prep-TLC (petroleum ether / EtOAc::::3:1 ) to give (6-amino-4-bromo-2,2-difluorobenzo[d][L3]dioxol-5-yl)(2-cbloro- 5-fluorophenyl)methanone (230 mg, 98.7%) as a yellow7solid. LCMS: m / z 407.9, 409.9 ([M+H]+).

[0218] Step F: To a solution of (6-amino-4-bromo-2,2-ditluorobenzo[d][l,3]dioxol-5-yr)(2- chloro-5-fluorophenyl)methanone (230 mg, 0.56 mmol, 1.0 eq) in DMAc (5 mL) was added Zn(CN)a (79 mg, 0.67 mmol, 1.2 eq) and Pd(PPh-j)4 (195 mg, 0.17 mmol, 0.3 eq). Then the reaction mixture was stirred at 160 °C for 30 min in the microwave. The mixture was added with water (20 mL) and extracted with EtOAc (10 mL x 3). ’Hie combined organic phases were washed with brine (10 mL), dried over Na2SC.l1 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][l ,3]dioxoie-4-carbonitrile (110 mg, 55.0%) as a yellow solid.

[0219] 'HNMR (400 MHz, DMSO-c / y): 3 ppm 8.17 (s, 2H), 7.65 - 7.57 (m, 1H), 7.52 - 7.38 (m, 2H), 7.18 (s, 1H).

[0220] Step G: To a solution of 6-amino-5-(2-chloro-5-fluorobenzoyl)-2,2- difluorobenzo[d][l,3]dioxole-'Lcarbonitrile (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. Then the reaction mixture was stirred at same temperature for 2 h. The mixture was dried over Na?SO 4 and concentrated to give a residue. The residue was purified by Prep-TLC (petroleum ether / EtOAc = 2:1) to give 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difIuoro-6-hydroxy-6,7-dihydro-8H-[1,3]dioxolo[4,5-e]isoindol-8-one (80 mg, 69,2%) as a yellow solid. LCMS: m / z 371.0 ([M- H]-).

[0221] Step H: To a solution of 5-araino-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). Then the reaction mixture was stirred at 50 °C for 12 h. The mixture was added with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over NazSCL and concentrated to give N-(6-(2-chloro-5-fluorophenyl)- 2,2~difluoro~6-hydroxy'-8-oxo-7,8~dihydro-6H~[l,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyllbenzamide (160 mg, crude) as a yellow solid. LCMS: m / z 560.9 ([M-H]-)

[0222] Step I: To a solution of N-(6-(2~chloro-5“fluorophenyI)-2,2-difluorO"6-hydroxy-8- oxo-7, 8-dihydro-6H-[L3]dioxolo[4,5-e]isoindol-5-yl)-3-f1uoro-5-(trifluoromethyl)benz.amide (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) Then the reaction mixture was stirred at room temperature for 2 h The mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (acetonitrile with 0.1% FA in water 45% to 64%) to give N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8- dihydro-6H-[l,3]dioxolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(fcrifluoromethyl)benzamide (18 mg, 15.3% yield for 2 steps) as a white solid. LCMS: m / z 547.0 ([M+H]+). ’H NMR (300 MHz, DMSO-t / e): d ppm 10.48 (brs, 1H), 9.38 (s, 1H), 7.95 (d, J= 7.8 Hz, 1H), 7.83 - 7.50 (m, 3H), 7.40 - 7.20 (m, 1H), 7.20 - 7.00 (m, 2H), 6.03 (s, 1H).Example 18 N-(6-(2-chloro-5-fluorophenyl)-2,8-dioxo-l,6,7,8-tetrahydro-2H-oxazolo[4,5- e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide was synthesized via General Synthetic Route I from intermediate 6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5- carbaldehyde

[0223] 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) at 25 °C. The reaction mixture was heated to reflux for 16 h. The mixture was concentrated, added with water (300 mL) and extracted with EtOAc (200 mL x 2). The combined organic phase was washed with brine (200 mL), dried over Na2SO4 and concentrated to give a residue. The residue was purified by silica gel chromatography (eluted with petroleum ether : EtOAc = 5:1) to give 4-(l,3-dioxan-2-yl)-2-nitrophenol (42 g, 69.3%) as a yellow solid.1H NMR (400 MHz, CDCh): 8 10.58 (s, 1H), 8.22 (d, J= 2.0 Hz, 1H), 7.69 (dd, J= 8.8, 2.0 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 5.46 (s, 1H), 4.37 - 4.10 (m, 2H), 4.09 - 3.70 (m, 2H), 2.30 - 2.10 (m, 1H), 1.57 - 1.40 (m, 1H). LCMS: m / z 224.1 ([M-H]').

[0224] Step B: To a solution of 4-(l,3-dioxan-2-yl)-2-nitrophenol (40.0 g, 177.6 mmol, 1.0 eq) in THF (500 mL) was added dropwise a solution of Nickel (15 g) at 25 °C under H2 atmosphere. The reaction mixture was stirred at 40 °C for 48 h. Then the mixture was filtered and concentrated to give 2-amino-4-(l,3-dioxan-2-yl)phenol (33 g, 95.2%) as a black solid. LCMS: m / z 196.1 ([M+H]+).

[0225] Step C: A solution of 2-amino-4-(l,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) was added protion-wise Triphosgene (51.4 g, 173.1 mmol, 1.3 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then the mixture was stirred at room temperature for 1 h. The mixture was added with water (300 mL) and extracted with DCM (200 mL x 2). The combined organic phase was washed with brine (300 mL), dried over Na2SOr and concentrated to give a residue. The residue was purified by silica gel chromatography (eluted with petroleum ether : EtOAc = 2 :1) to give2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (11.2 g, 51.5%) as a white solid. LCMS: m / z 162.1 ([M-H]').

[0226] 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 H2SO4 (98%, 120 mL) was added dropwise HNO3 (5.2 g, 82.4 mmol, 1.2 eq) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The product was then precipitated by pouring the solution over ice-water (600 mL) and collected by vacuum filtration to give 6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (10.0 g, 70.0%) as a red solid.1H NMR (300 MHz, DMSO-t^): 8 12.83 (brs, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 7.76 (s, 1H). LCMS: m / z 207.1 ([M-H]').

[0227] 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 product was then precipitated by pouring the solution over ice-water (400 mL) and collected by vacuum filtration to give 4- bromo-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (8.6 g, 62.4%) as a yellow solid. ’H NMR (300 MHz, DMSO-ofc): S 10.17 (s, 1H), 8.24 (s, 1H). LCMS: m / z 284.9, 286.9 ([M-H]').

[0228] 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. Then the mixture was added water (200 mL), extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with brine (200 mL), dried over Na2SO and concentrated to give a residue. The residue was purified by 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 ([M-H]'). ’H NMR (300 MHz, DMSO-fi ): 3 12.61 (brs, 1H), 7.92 (s, 1H), 7.50 (dd, J= 8.8, 5.2 Hz, 1H), 7.42 -7.00 (m, 2H), 6.73 (d, J= 6.0 Hz, 1H), 6.27 (d, J= 5.4 Hz, 1H).

[0229] 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 NH4CI (192.1 mg, 3.6 mmol, 0.5 eq) in H2O (10 mL) dropwise at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Then the mixture was addedwater (80 mL) and ethyl acetate (30 mL), filtered, then 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 ([M-H]').

[0230] 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) were 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 product was then precipitated by pouring the solution over ice-water (30 mL) and collected by vacuum filtration to give N-(4-bromo-5-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (600 mg, 57.7%) as a yellow solid. LCMS: m / z 574.9, 576.8 ([M-H] ).

[0231] Step T: 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) was added DMP (440 mg, 1.05 mmol, 3.0 eq) at 25 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was added with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic phase was washed with NaHCOs (10 mL x 2), Na2S20s (10 mL x 2) and brine (20 mL), dried over Na2SC>4 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 ([M-H]').

[0232] 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 the microwave at 160 °C for 0.5 h. The mixture was added water (3 mL) 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 by silica gel (eluted with petroleum ether / EtOAc = 2: 1) togive N-(5-(2-chloro-5-fluorobenzoyl)-4-cyano-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-fluoro- 5-(trifluoromethyl)benzamide (40 mg, crude) as a yellow oil. LCMS: m / z 520.0 ([M-H]').

[0233] 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) / H2O (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. The mixture was added water (3 mL) 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-l,6,7,8-tetrahydro-2H-oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, crude) as a yellow oil. LCMS: m / z 537.9 ([M-H]').

[0234] Step L: To a solution of N-(6-(2-chloro-5-fhiorophenyl)-6-hydroxy-2,8-dioxo- l,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 EtsSiH (104.7 mg, 0.9 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for 4 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(6-(2-chloro-5-fluorophenyl)-2,8-dioxo-l,6,7,8-tetrahydro-2H- oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.8 mg, three steps yield 5.9%) as a white solid. LCMS: m / z 522.0 ([M-H]'). 'HNMR (400 MHz, DMSO-t76): 6 12.59 (brs, 1H), 10.35 (s, 1H), 9.18 (brs, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.86 - 7.60 (m, 2H), 7.43 (s, 1H), 7.36 - 7.22 (m, 1H), 7.15 - 7.00 (m, 1H), 6.90 - 5.80 (m, 1H).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

[0235] 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.

[0236] Step B: 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 K2CO3 (764.3 mg, 5.5 mmol, 10.0 eq) in DMF (10 mb) was added CH3I (392.5 mg, 2.9 mmol, 5.0 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The mixture was added water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2SC>4 and concentrated to give 4-bromo-5-(2-chloro-5-fluorobenzoyl)-3-methyl-6-nitrobenzo[d]oxazol- 2(3H)-one (120 mg, crude) as a yellow oil.

[0237] 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 NH4CI (7.5 mg, 0.14 mmol, 0.5 eq) in H2O (0.3 mL) dropwise at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Then the mixture was added water (3 mL) and ethyl acetate (5 mL), filtered, then the filtrate was extracted with ethyl acetate (5 mL). The combined organic phases were washed with brine (5 mL), dried over Na2SC>4 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]+).

[0238] 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) were 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 the mixture was added water (3 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with brine (5 mL), dried over Na2SC>4 and concentrated to give a residue. The residue was purified by Pre-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, four steps yield 56.5%) as a yellow solid. LCMS: m / z 586.8, 588.9 ([M-H]’).

[0239] 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, 0.3eq) and DMAc (1.8 mL). The sealed vial was irradiated in the microwave at 160 °C for 0.5 h. The mixture was added water (3 mL) and extracted with EtOAc (2 mL x 2). The combined organic phases were washed with brine (3 mL x 2), dried over NaiSCL and concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether / EtOAc = 3 1) to give N-(5-(2-chloro-5-fluorobenzoyl)-4-cyano-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6- yl)-3-fluoro-5-(trifluoromethyl)benzamide (18.7 mg, 34.9%) as a yellow solid. LCMS: m / z 534.0 ([M-H]’).

[0240] 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) / H2O (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. The mixture was added water (2 mL) 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-l -methyl-2, 8-di oxo-1 , 6,7, 8-tetrahydro-2H-oxazolo[4, 5-e]isoindol-5- yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, crude) as a yellow oil. LCMS: m / z 551.9 ([M-H]’).

[0241] Step G: To a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-2,8- dioxo-l,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 TEA. (2 mL) was added EtiSiH (23.2 mg, 0.2 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(6-(2-chloro-5-fluorophenyl)-l-methyl-2,8-dioxo-l,6,7,8-tetrahydro-2H- oxazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (4.4 mg, two steps yield 16.4%) as a white solid. LCMS: m / z 535.9 ([M-H] ). 'HNMR (400 MHz, DMSO-t / e): 8 10.37 (s, 1H), 9.30 (brs, 1H), 7.93 (d, J= 8.8 Hz, 1H), 7.84 - 7.62 (m, 2H), 7.52 (s, 1H), 7.40 - 7.22 (m, 1H), 7.18 - 7.00 (m, 1H), 6.90 - 5.80 (m, 1H), 3.86 (s, 3H).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

[0242] 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), which was mixed with EtOAc (500 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give 3-methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (82.0 g, crude) as a yellow solid. LCMS: m / z 262.1 ([M-H]').

[0243] Step B: To a solution of 3-methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (82.0 g, crude, 0.31 mol, 1.0 eq) in H2SO4 (98%, 4100 mL) was added dropwise a solution ofHNCh (27.1 g) and H2SO4 (98%, 197 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Then the mixture was slowly poured into ice water (7.0 L) and fdtered to give 5-methoxy-2-nitro-4- (2,2,2-trifluoroacetamido)benzoic acid (64.0 g, 69.5% yield for 2 steps) as a brown solid. LCMS: m / z 307.0 ([M-H]’).XH NMR (300 MHz, DMSO-t / e): <5 ppm 11.13 (s, 1H), 8.27 (s, 1H), 7.46 (s, 1H), 3.99 (s, 3H).

[0244] Step C: To the 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 potion-wise BH3-Me2S (2M) (155.8 mL, 311.5 mmol, 3.0 eq) 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. The mixture was added water (300 mL) and extracted with EtOAc (200 mL x 2). The combined organic phase was washed with brine (300 mL), dried over Na2SO4 and concentrated to give 2,2,2-trifluoro-N-(4- (hydroxymethyl)-2-methoxy-5-nitrophenyl)acetamide (25.0 g, crude) as a yellow solid. LCMS: m / z 293.0 ([M-H]’).

[0245] 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 Themixture was added water (300 mL) and extracted with EtOAc (200 mL x 2). The combined organic phase was washed with brine (300 mL), dried over Na2SC>4 and concentrated to give residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give 2,2,2-trifluoro-N-(4-formyl-2-methoxy-5-nitrophenyl)acetamide (11.0 g, 60.4% yield for 2 steps) as a yellow solid. LCMS: m / z 291.0 ([M-H]').

[0246] 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 the 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-trifhioroacetamide (12.1 g, 86.6%) as a yellow solid. LCMS: m / z 368.9, 370.9 ([M-H]’). ‘H NMR (300 MHz, DMSO-^): <5 ppm 11.62 (s, 1H), 10.18 (s, 1H), 8.47 (s, 1H), 3.86 (s, 3H).

[0247] Step F: To a solution of N-(3-bromo-4-formyl-2-methoxy-5-nitrophenyl)-2,2,2- trifluoroacetamide (12.1 g, 32.6 mmol, 1.0 eq) in THF (121 mL) was added Int-A (2-chloro-5- fluorophenyl)magnesium bromide (326.0 mL, 0.5 M in THF, 163.0 mmol, 5.0 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Then the mixture was added water (200 mL) 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 ([M-H]'). ’H NMR (400 MHz, DMSO ): 3 ppm 11.46 (s, 1H), 8.06 (s, 1H), 7.60 - 7.51 (m, 1H), 7.32 - 7.20 (m, 1H), 7.04 (dd, J= 9.6, 3.2 Hz, 1H), 6.82 (d, J= 6.0 Hz, 1H), 6.29 (d, J= 5.2 Hz, 1H), 3.76 (s, 3H).

[0248] 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. The mixture was added water (200 mL) and extracted with DCM (200 mL x 2). The combined organic phase was washed with aqueous solution NaHCOi (200 mL x 2), aqueous solution NazS2O3 (100 mL x 2) and brine (200 mL), dried over NazSCf andconcentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give N-(3-bromo-4-(2-chloro-5-fluorobenzoyl)-2-methoxy-5- nitrophenyl)-2,2,2-trifluoroacetamide (6.6 g, 59.9%) as a yellow solid. LCMS: m / z 496.8, 498.8 ([M-H]-).

[0249] Step H: To a solution of N-(3-bromo-4-(2-chloro-5-fluorobenzoyl)-2-methoxy-5- nitrophenyl)-2,2,2-trifhioroacetamide (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 NH4CI (107.0 mg, 2.0 mmol, 0.5 eq) in H2O (20 mL) dropwise at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Then the mixture was added water (80 mL), EtOAc (30 mL) and filtered, then 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 ([M-H]').

[0250] 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). 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-trifluoroacetamido)phenyl)-3-fluoro-5- (trifluoromethyl)benzamide (800 mg, 57.7%) as a yellow solid. LCMS: m / z 656.8, 658.9 ([M- H]').

[0251] 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 the microwave at 160 °C for 0.5 h. The mixture was added water (9 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were 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- trifluoroacetamido)phenyl)-3-fluoro-5-(trifluoromethyl)benzamide (47 mg, 51.2%) as a yellow solid. LCMS: m / z 603.9 ([M-H]').

[0252] 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) / H2O (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. The mixture was added water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried overNa2SO4 and concentrated to give N-(6-amino-3-(2-chloro-5- fluorophenyl)-3 -hydroxy-7-m ethoxy- 1-oxoi soindolin-4-yl)-3 -fluoro-5- (trifluoromethyl)benzamide (144 mg, 86.5%) as a brown solid. LCMS: m / z 526.0 ([M-H]').

[0253] Step L: To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-7- methoxy-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (160 mg, 0.30 mmol, 1.0 eq) in TFA (2 mL) was added EtaSiH (174 mg, 1.5 mmol, 5.0 eq). The reaction mixture was stirred at 50 °C for 12 h. Then the reaction mixture was concentrated to give a residue, which was purified by Prep-TLC (EtOAc) to obtain N-(6-amino-3-(2-chloro-5-fluorophenyl)-7- methoxy-l -oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 52.1%) as a white solid. LCMS: m / z 512.0 ([M+H]+).

[0254] Step M: To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-methoxy-l- oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.02 mmol, 1.0 eq) in DCM (1 mL) was added BBn (7.5 mg, 0.03 mmol, 1.5 eq) dropwise at under N2 at 0 °C. The reaction mixture was stirred at room temperature for 2.5 h. Then the reaction mixture was quenched by MeOH (0.5 mL) and concentrated to obtain the N-(6-amino-3-(2-chloro-5-fluorophenyl)-7- hydroxy-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, crude) as yellow oil. LCMS: m / z 498.0 ([M+H]+).

[0255] Step N: To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-hydroxy-l- 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). Then the mixture was added Triphosgene (71 mg, 0.24 mmol, 1.2 eq) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1.5 h. Then the reaction mixture was concentrated to give a residue, which was purified by prep-HPLC (acetonitrile with 0.1% FA in water 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% yield for 2 steps) as a white solid. LCMS: m / z 522.0 ([M-H]'). ’H NMR (300 MHz, DMSO-6k): 3 ppm 10.22 (s, 1H), 9.00 (s, 1H), 8.35 - 8.20 (m, 1H), 7.91 (d, J= 8.4 Hz,1H), 7.78 - 7.55 (m, 2H), 7.38 - 7.22 (m, 1H), 7.15 - 6.93 (m, 2H), 6.80 - 6.50 (m, 1H), 6.10 - 5.80 (m, 1H).Example 21 (R*)-N-((R)-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H- [l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-l- carboxamideExample 22 (R*)-N-((S)-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H- [l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-l- carboxamide

[0256] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-6,7- dihydro-8H-[l,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. Then the reaction mixture was stirred at 0 °C for 30 min. A solution of rel- (R)-5-fhjoro-3-(trifluoromethyl)indolin-3-ol (248 mg, 1.12 mmol, 2.0 eq) in Pyridine (1.0 mL) was added. The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched by the addition of the saturated aqueous NH4CI (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 Prep-HPLC (acetonitrile with 0.1% FA in water 40% to 57%) to give rel-(3R)-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo- 7,8-dihydro-6H-[l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3-hydroxy-3- (trifluoromethyl)indoline-l -carboxamide (170 mg, 50.3%) as a white solid. LCMS: m / z 602.0 ([M-H]'). It (170 mg) was separated through chiral SFC separation to provide Pl (R*)-N-((R)-6- (2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5-e]isoindol-5-yl)- 5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-l-carboxamide (50.0 mg, 29.4%) as a white solid LCMS: m / z 602.0 ([M-H]'). ‘HNMR (300 MHz, DMSO-dk): <5 ppm 9.32 (s, 1H), 8.79 (s, 1H), 7.99 - 7.80 (m, 1H), 7.60 - 7.37 (m, 2H), 7.37 - 7.07 (m, 4H), 6.82 (brs, 1H), 6.06 (s, 1H), 3.91 (d, J=12.0 Hz, 1H), 3.55 (d, J= 12.0 Hz, 1H). And P2 (R*)-N-((S)-6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluoro-3- hydroxy-3 -(trifluoromethyl)indoline-l -carboxamide (41.6 mg, 24.5%) as a white solid. LCMS: m / z 601.9 ([M-H]-). ’H NMR (400 MHz, DMSO-tfc): S ppm 9.33 (s, 1H), 8.70 (s, 1H), 7.80 (dd, J = 8.8, 4.4 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.8, 4.2 Hz, 1H), 7.30 - 7.16 (m, 2H), 7.15 - 7.04 (m, 1H), 6.77 (brs, 1H), 6.12 (s, 1H), 4.20 - 4.00 (m, 1H), 3.51 (d, J = 12.0 Hz, 1H).

[0257] The prep-SFC separation is below:Chiral purity by SFC (area normalization)Principle NP HPLC with UV detection, Assessment in area %MeOH: HPLC grade, J&KCO2: 99.999% Solvent: ACN Equipment: apparatus Waters SFC Column: CHIRALCEL OD-H 20 mm*250 mm, 5 urn Chromatographic conditions: Mobile phase A: CO2 Mobile phase B: MeOH Gradient: B 20%Flow rate: 30 ml / minInjection volume: 0.5 mlInjection concentration: 20 mg / mlColumn temperature: 35°CPrep SFC Cycle time 11 minExample 23 (S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro- 6H-[l,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-[l,3]dioxolo[4,5-e]isoindol-5- yl)-5-fluorobenzamide

[0258] Step A: To a solution of 3-ch1oro-5-fluorobeozoic acid (5.0 g, 28.6 mmol, 1.0 eq) in THF (50 ml) was added dropwise (COC1)2 (10.9 g, 85.8 mmol, 3.0 eq) and DMF (0.1 mL) at room temperature. Then the reaction mixture was stirred for 2 h at the same temperature. The mixture was concentrated to give 3-chloro-5-fluorobenzoyl chloride (5.5 g, crude) as a yellow solid and was used directly.

[0259] Step B: To a sol ution of 5 -ami no-6-(2-chloro-5-fl uoropheny l)-2, 2-di fl uoro-6, 7 - dihydro-8H-[l,3]dioxolo[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. Then the mixture was stirred for 2 h at the same temperature. The mixture w;as added water (2 ml.) and extracted with E1O Ac (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 Prep-HPLC (acetonitrile with 0.1% FA in water 35% to 47%) to afford 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H- [l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (100.0 mg, 34.8%) as a white solid. LCMS: m / z 510.9 ([M-H] ). It was separated via chiral SFC with the condition below to provide Pl (S)- 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5- e]isoindol-5-yl)-5-fluorobenzamide (20.0 mg, 20.0%) as a white solid. LCMS: m / z 510.9 ([M- H]-). 'HNMR (300 MHz, DMSO-r / y): d ppm 10.33 (s, 1H), 9.37 (s, 1H), 7.77 - 7.63 (m, 1H), 7.60 (s, 1H), 7.48 - 7.23 (m, 3H), 7.23 - 7.05 (m, 1H), 6.85 (brs, 1H), 6.04 (s, 1H). And P2 CAN- 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5- e]isoindol-5-yl)-5-fluorobenzamide (30.0 mg, 30.0%), as a white solid. LCMS: m / z 510.9 ([M- H]’). ’H NMR (300 MHz, DMSO-^): 3 ppm 10.33 (s, 1H), 9.37 (s, 1H), 7.77 - 7.63 (m, 1H), 7.60 (s, 1H), 7.45 - 7.25 (m, 3H), 7.24 - 7.05 (m, 1H), 6.86 (brs, 1H), 6.04 (s, 1H).

[0260] Chiral SFC Separation Method:Chiral purity by SFC (area normalization)Principle NP HPLC with UV detection, Assessment in area %Reagents:MeOH: HPLC grade, J&KCO2: 99.999%Solvent: MeOH+CANEquipment: apparatus Waters SFCColumn: CHIRALCEL AS-H 20 mm*250 mm, 5 umChromatographic conditions:Mobile phase A: CO2Mobile phase B: MeOHGradient: B 30%Flow rate: 30 ml / minInj ection volume : 1.0 mlInjection concentration: 20 mg / mlColumn temperature: 35°CExample 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-carboxamideExample 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

[0261] Step A: To a solution of 3~chloro~5-fluorobenzoic acid (200 nig, 1.12 mmol, 1.0 eq) in TFIF (2.0 mL) was added dropwise (COCI)?. (0.425 g, 3 35 mmoL 3.0 eq) and DMF (0 1 mL) at room temperature. Then the reaction mixture was stirred for 2 h at the same temperature. The mixture was concentrated to give 3-ch1oro-5-fluorobenzoyl chloride (250 mg, crude) as a yellow solid and it was used as crude directly for next step.

[0262] Step B: To a sol ution of 5 -ami no-6-(2-chloro-5-fl uoropheny l)-2, 2-di fl uoro-6, 7 - dihydro-8H-[l,3]dioxolo[4,5-e]isoindol-8-one (200 mg, 0.56 mmol, 1.0 eq) in ACN (2 mL) was added 3-chloro-5-fluorobenz0yl chloride (133 mg, 0.67 mmol, 1.2 eq) and Pyridine (89 mg, 1 12 mmol, 2.0 eq) at room temperature. Then the mixture w7as stirred for 2 h at the same temperature. The mixture was added water (2 mL) and extracted with EtOAc (2 ml, x 3). The combined organic phases were washed with brine (2 mL), dried over NasSOi and concentrated to give a residue. The residue was purified by Prep-HPLC (acetonitrile with 0.1% FA in water 35% to 47%) to afford 3-chloro-N-(6-(2-chloro-5-fiuorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (~ 60 mg, 20.7%) as a white solid. LCMS: m / z 515.9 ([M-H]'). It was separated via chiral prep-SFC separation with the method below to provide Pl (S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-2,2-difluoro-8-oxo-7,8-dihydro-6H-[l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (15.7 mg, 39.3%) as a white solid. LCMS: m / z 515.9 ([M-H] ). ’H NMR (400 MHz, DMSO-t / e): 3 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-[l,3]dioxolo[4,5-e]isoindol-5-yl)-5-fluorobenzamide (17.9 mg, 44.8%), as a white solid. LCMS: m / z 515.9 ([M-H]’). ’H NMR (400 MHz, DMSO-fifc): 3 ppm 10.43 (s, 1H), 9.37 (s, 1H), 8.61 (d, J= 8.4 Hz, 1H), 8.31 (d, J= 8.4 Hz, 1H), 7.90 - 7.52 (m, 3H), 7.50 - 6.70 (m, 3H), 6.22 (brs, 1H).

[0263] Chiral prep-SFC Separation Method:Chiral purity by UPCC (area normalization)Principle NP HPLC with UV detection, Assessment in area % Reagents:MeOH: HPLC grade, MREDA CO2: 99.999% Solvent: MeOHEquipment: apparatus Waters UPCC Column: CHIRALPAK AS-3, 4.6mm* 150mm, 3um Chromatographic conditions Mobile phase A: CO2 Mobile phase B: MeOHGradient: B 30%Flow rate: 2.0ml / minDetection UV: 210nmColumn temperature: 35 °CInjection volume: 2.0ulExample 27 N-(3-(2-chloro-5-fluorophenyl)-7-methyl-l,6-dioxo-l,2,3,6,7,8- hexahydropyirolo[3,4-e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0264] Step A: To a stirred mixture of methyl 3-bromo-5-fluoro-2-methylbenzoate (5 g, 20.2 mmol) in dry THF (30 mL) cooled to -78 °C was added dropwise a solution of LDA (20.2 mL, 40.5 mmol, 2M) for 0.5 h. The reaction mixture was stirred at -78 °C for 20 min. A solution of 2- chloro-5-fluorobenzene-l-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 addition of aqueous saturated NH4CI solution. The following mixture was extracted with EA. The organic layer was washed with brine, dried over Na2 SO4 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 yellow oil.

[0265] 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) at 0 °C under N2 was added l,l,l-triacetoxy-l,3-dihydro-lX5-benzo[d][l,2]iodoxol-3-one (4.6 g, 10.8 mmol). The reaction mixture was stirred at rt for 1 hour. The mixture was treated with H2O (100 mL) and extracted with EA (3 x 300 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated. The crude product was purified by column chromatography (0-30% EA in PE) followed 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]+.

[0266] 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 CCU (1 mL) was added NBS (572 mg, 3.23 mmol) and 2-[(lE)-(2-cyanoprop-2-yl)diazenyl]-2-methylpropanenitrile (110 mg, 0.74 mmol). The reaction mixture was stirred at reflux for 2 h. The cooled reaction mixture diluted with water and extracted with DCM. The organic phase was washed with brine, dried over Na2SC>4 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.

[0267] Step D: A stirred solution of methyl 3-bromo-2-(bromomethyl)-4-[(2-chloro-5- fluorophenyl)carbonyl]-5-fluorobenzoate (1.1 g, 2.28 mmol) in methanamine (10 mL) was stirred for 0.5 h. The reaction was concentrated under reduced pressure give 4-bromo-5-[(2- chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-2,3-dihydro-lH-isoindol-l-one (650 mg, 1.62 mmol, 71.2%). LCMS: ESI m / z 400 / 402 [M + H]+.

[0268] Step E: To a solution of 4-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2- methyl-2,3-dihydro-lH-isoindol-l-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 phase was washed with brine, dried over anhydrous JSfeSCL and concentrated. The crude product was purified by column chromatography (PE: EA=2: 1) followed to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-l-oxo-2,3-dihydro- lH-isoindole-4-carbonitrile (350 mg, 1.01 mmol, 89.9%) as a yellow oil. LCMS: ESI m / z 347 [M + H]+.

[0269] Step F: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-l- oxo-2, 3-dihydro-lH-isoindole-4-carbonitrile (300 mg, 0.87 mmol) in DMSO (4 mL) was added DIEA (112 mg, 0.87 mmol) in sealed tube. The mixture was refluxed under N2 for 30 minutes until the starting material was consumed completely. 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 MgSCL, filtered and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EA = 3: 1 to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-2-methyl-l-oxo-2,3-dihydro-lH-isoindole-4- carbonitrile (80 mg, 0.16 mmol, 18.7%) as a yellow solid.

[0270] Step G: To a stirred mixture of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-2-methyl-l -oxo-2, 3-dihydro-lH-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 H2O (1 mL). The solution was stirred at room temperature for an additional 2 h. The reaction was then extracted with DCM (3 * 5.0 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with a solvent mixture composed of PE: EA=3: 1 to afford 3-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3- hydroxy-7-methyl-l,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindole-l,6-dione (40 mg, 0.08 mmol, 48.2%) as a yellow oil. LCMS: ESI m / z 512 [M + H]+.

[0271] Step H: To a solution of 3-(2-chloro-5-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-hydroxy-7-methyl-l ,2,3,6,7,8-hexahydropyrrolo[4,3- e]isoindole-l, 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 H2O (50 ml), adjusted pH=8 with saturated aqueous Nal ICO; and extracted with EA. The organic layer was washed with brine (50 mL), dried over Na2SC>4 and concentrated. The residue was purified by column (PE: EA=1 : 1) to give 4-amino-3- (2-chloro-5-fluorophenyl)-7-methyl-l,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindole-l,6-dione (30 mg, 0.09 mmol, 100%) as a yellow solid. LCMS: ESI m / z 346 [M + H]+.

[0272] Step I: To a stirred mixture of 4-amino-3-(2-chloro-5-fluorophenyl)-7-methyl- l,2,3,6,7,8-hexahydropyrrolo[4,3-e]isoindole-l,6-dione (20 mg, 0.06 mmol) and 5-fluoro-3- (trifluoromethyl)benzoic acid (12 mg, 0.06 mmol) in dry pyridine (1 mL) was added dropwise POCh (8.87 mg, 0.06 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for o.5 h. The reaction mixture was extracted with EA (15 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give N-[3-(2- chloro-5-fluorophenyl)-7-methyl-l,6-di oxo-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]+. ’H NMR (400 MHz, CD3OD) 5 7.82 (s, 1H), 7.66 (dd, J= 16.2, 8.7 Hz, 3H),7.27 (dd, J= 9.0, 5.0 Hz, 1H), 7.00 (td, J= 8.4, 3.0 Hz, 1H), 6.28 (s, 2H), 4.88 (d, J= 2.6 Hz, 2H), 3.27 (s, 3H).Example 28 N-[3-(2-chloro-5-fluorophenyl)-7-methyl-l-oxo-l,2,396,7,8- hexahydropyirolo[4,3-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[0273] Step A: To a solution of methyl 3-bromo-5-fluoro-2-methylbenzoate (1 g, 4.05 mmol) in CCh (10 mL) was added 1 -bromotetrahydropyrrole-2, 5-dione (1.08 g, 6.071 mmol) and benzoic peroxyanhydride (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 Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate in petroleum ether (0~5% gradient) to give methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (1.2 g, 3.68 mmol, 90.95%) as a colorless oil.

[0274] Step B: To a solution of methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (1 g, 3.07 mmol) in THF (10 mL) was added methanamine (7.7 mL, 15.3 mmol, 2M in THF). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water, 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 eluted with ethyl acetate in petroleum ether (35% gradient) to give 4-bromo-6-fluoro-2-methyl-2,3- dihydro-lH-isoindol-l-one (500 mg, 2.049 mmol, 66.78%) as a white solid. LCMS: ESI m / z 244 [M + H]+.

[0275] Step C: To a solution of 4-bromo-6-fluoro-2-methyl-2,3-dihydro-lH-isoindol-l-one (1 g, 4.09 mmol) in THF (7.5 mL) was added borane dimethylsulfane (5 mL, 50.0 mmol) at 25 °C, and the reaction mixture was stirred at 60 °C for 4 h. The cooled reaction solution was quenched with methanol and 6 M HC1 was added to adjusted pH to 1-2. Then the mixture washeated to 80 °C and stirred for 1 h. The reaction was cooled to room temperature and adjusted pH to 7-8 with 6 M NaOH. The reaction solution was extracted with EA. The organic layer was separated, washed with brine, dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with MeOH in DCM (0~5% gradient) to afford compound 4-bromo-6-fluoro-2-methyl-2,3-dihydro-lH-isoindole (650 mg, 2.825 mmol, 68.95%) as a colorless oil. LCMS: ESI m / z 230 [M + H]+.

[0276] Step D: To a solution of 4-bromo-6-fluoro-2-methyl-2,3-dihydro-lH-isoindole (1.5 g, 6.519 mmol) in dry THF (15 mL) was added dropwise lithium di(prop-2-yl)azanide (4.890 mL, 9.779 mmol) at -65 °C. The reaction mixture was stirred at -65 °C under N2 atmosphere for 0.5 h. A solution of 2-chloro-5-fluorobenzene-l-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 sat. aq. NH4CI solution, extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with MeOH in DCM (0— >4%, V / V) to give diethyl (4-bromo-6-fluoro-2-methyl-2,3-dihydro-lH-isoindol-5-yl)(2-chloro-5- fluorophenyljmethanol (1 g, 2.573 mmol, 39.47%) as a white solid. LCMS: ESI m / z 388 [M + H]+.

[0277] Step E: To a solution of (4-bromo-6-fluoro-2-methyl-2,3-dihydro-lH-isoindol-5- yl)(2-chloro-5-fluorophenyl)methanol (800 mg, 2.058 mmol) in propan-2-one (10 mL) was added 65272-70-0 (0.5 mL, 2.058 mmol) at 0 °C. The reaction mixture was stirred 0 °C for 2 hr. After 2 h, the reaction mixture was quenched with isopropyl alcohol (10 mL). The isopropyl alcohol was removed under vacuum then was extracted with EA, combined all organic phases, washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel with MeOH in DCM (0— >5%, V / V) to give (4- bromo-6-fluoro-2-methyl-2,3-dihydro-lH-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]+.

[0278] Step F: To a solution of (4-bromo-6-fluoro-2-methyl-2,3-dihydro-lH-isoindol-5- yl)(2-chloro-5-fluorophenyl)methanone (600 mg, 1.55 mmol) in l-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 miuture was diluted water, extracted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2SC>4 andconcentrated. The residue was purified by flash chromatography eluted with MeOH in DCM (0~3% gradient) to afford 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl-2,3-dihydro- lH-isoindole-4-carbonitrile (250 mg, 0.751 mmol, 48.4%) as a yellow solid. LCMS: ESI m / z 333 [M + H]".

[0279] Step G: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-methyl- 2,3-dihydro-lH-isoindole-4-carbonitrile (250 mg, 0.751 mmol) in DMSO (6 mL) was added (2,4-dimethoxyphenyl)methanamine (125 mg, 0.751 mmol) and ethyl[di(prop-2-yl)]amine (194 mg, 1.503 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 1 hr. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by flash chromatography eluted 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-lH-isoindole-4-carbonitrile (160 mg, 0.333 mmol, 44.37%) as a yellow solid. LCMS: ESI m / z 480 [M + H]+.

[0280] Step FT: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-2-methyl-2,3-dihydro-lH-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, washed with water and brine, dried over anhydrous Na SCf and concentrated. The residue was purified by flash chromatography eluted with MeOH in DCM (0~8% gradient) to afford 3-(2-chloro-5-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-hydroxy-7-methyl-l,2,3,6,7,8-hexahydropyrrolo[4,3- e]isoindol-l-one (114 mg, 0.229 mmol, 78.5%) as a yellow solid. LCMS: ESI m / z 498 [M + H]+.

[0281] Step I: To a solution of 3-(2-chloro-5-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-7-methyl-l,2,3,6,7,8-hexahydropyrrolo[4,3- e]isoindol-l-one (100 mg, 0.201 mmol) in 2,2,2-trifluoroacetic acid (3 mL) was added triethylsilane (0.3 mL) at rt. The reaction mixture was stirred at rt for 0.5 h. After 0.5 h, the reaction mixture was diluted with H2O. The aqueous layer was extracted with EA. Combined the EA layer and washed with brine, dried by Na2SOi, filtered and concentrated in vacuo to afford 4-amino-3-(2-chloro-5-fluorophenyl)-7-methyl-l,2,3,6,7,8-hexahydropyrrolo[4,3- e]isoindol-l-one (85 mg, 0.154 mmol, 76.54%) as a yellow oil. LCMS: ESI m / z 332 [M + H]+.

[0282] Step J: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-7-methyl-l,2,3,6,7,8- hexahydropyrrolo[4,3-e]isoindol-l-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 eluted with EA and further purified by prep-HPLC to afford N-[3-(2-chloro-5-fluorophenyl)-7-methyl-l-oxo- l,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]+. ’H NMR (400 MHz, DMSO-tL) 8 10.58 (s, 1H), 9.26 (s, 1H), 7.96 (d, J= 7.6 Hz, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.67 (s, 1H), 7.51 (s, 1H), 7.36 - 7.28 (m, 1H), 7.10 (s, 1H), 6.05 (s, 1H), 4.74 (s, 2H), 4.51 (s, 2H), 2.97 (s, 3H).Example 29 N-(6-(2-chloro-5-fluorophenyl)-3,8-dioxo-l,2,3?6,7,8-hexahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 29

[0283] Step A: A solution of N-[6-(2-chloro-5-fluorophenyl)-3-methoxy-8-oxo-l, 6,7,8- tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.056 mmol) in HBr (3 mL, 30% HBr in H2O) was stirred at 50 °C overnight. The cooled reaction mixture was diluted with H2O, extracted with EA, washed with brine, dried over Na2SC>4 and concentrated. The residue purified by prep-HPLC to afford compound N-(6-(2-chloro-5- fluorophenyl)-3,8-dioxo-l,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]+. 'HNMR (400 MHz, DMSO-tL) 8 12.43 (s, 1H), 10.82 (s, 1H), 10.28 (s, 1H), 9.07 (s, 1H), 7.93 (d, J= 8.2 Hz, 1H), 7.70 (d, J= 14.8 Hz, 4H), 7.29 (dd, J= 8.8, 5.1 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.13 (s, 1H).Example 30 N-[6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3,6,7,8-tetrahydro-lH-imidazo[4,5- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0284] Step A: To a stirred solution of 3-bromo-5-fluorobenzene-l,2-diamine (18 g, 87.8 mmol) in DMF (180 mL) under argon atmosphere was added CDI (10.9 mL, 87.8 mmol) at 0 °C. The reaction mixture was stirred at rt 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 phase was washed with brine, dried over anhydrous NaiSCL and concentrated. The residue was triturated with DCM (100 mL) and filtered to afford 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.

[0285] Step B: To the suspension of NaH (8.31 g, 208 mmol, 60% in mineral) in dry THF (60 mL) was added batchwise 4-bromo-6-fluoro-2,3-dihydro-lH-benzo[d]imidazol-2-one (16 g, 69.3 mmol) at 0 °C. After the completion of addition, the reaction mixture was stirred for additional 1.5 hours at 0 °C. 4-Methoxybenzylchloride (28.3 mL, 208 mmol) was added slowly, the mixture was stirred at 0 °C for 0.5 hr and stirred at rt for 2 hrs. The reaction mixture was quenched by addition of aqueous saturated NH4CI solution. The following mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by flash column chromatography on silica gel (0-30% EAin PE) to give 7- bromo-5-fluoro-l-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-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]+.

[0286] Step C: To a stirred mixture of 7-bromo-5-fluoro-l-[(4-methoxyphenyl)methyl]-2,3- dihydro-lH-benzo[d]imidazol-2-one (7 g, 19.9 mmol) in dry THF (70 mL) cooled to -78 °C was added dropwise a solution of LDA (39.9 mL, 79.7 mmol, 2M) for 0.5 h. The reaction mixture was stirred at -78 °C for 20 min. A solution of 2-chloro-5-fluorobenzene-l-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 addition of aqueous saturated NH4CI solution. The following mixture was extracted with EA. The organic layer was washedwith brine, dried over Na2SC>4 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-l-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH- benzo[d]imidazol-2-one (3.2 g, 6.28 mmol, 31.5%) as a yellow oil.

[0287] Step D: To a solution of 7-bromo-6-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-5- fluoro-l-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-benzo[d]imidazol-2-one (3.2 g, 6.28 mmol) in DCM (40 mb) at 0 °C under N2 was added l,l,l-triacetoxy-l,3-dihydro-lX5- benzo[d][l,2]iodoxol-3-one (832 mg, 1.96 mmol). The reaction mixture was stirred at rt for 1 hour. The mixture was treated with H2O (100 mL) and extracted with EA (3 x 300 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (0-30% EAin PE) followed to give 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-5-fluoro-l-[(4- methoxyphenyl)methyl]-2, 3 -dihydro- lH-benzo[d]imidazol -2-one (1.9 g, 3.74 mmol, 59.6%) as a yellow oil. LCMS: EST m / z 507 / 509 [M + H]+.

[0288] Step E: To a solution of 4-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-l- [(4-methoxyphenyl)methyl]-2,3-dihydro-lH-benzo[d]imidazol-2-one (1.7 g, 3.35 mmol) and Zn(CN)2 (0.47 g, 4.02 mmol) in DMA (20 mL) was added Zn (0.04 g, 0.67 mmol) followed by Pd2(dba)3 (0.31 g, 0.34 mmol), bis(cyclopentyldiphenylphosphane) iron(0) (0.38 g, 0.67 mmol) under N2 with stirred. The mixture was refluxed for 3 hours until the starting material was consumed completely. The cooled reaction mixture was treated with H2O (100 mL) and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (0-30% EAin PE) followed to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-l-[(4- methoxyphenyl)methyl]-2-oxo-3H-benzo[d]imidazole-4-carbonitrile (1.2 g, 2.64 mmol, 78.9%) as a yellow oil.

[0289] Step F: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-3-[(4- methoxyphenyl)methyl]-2-oxo-lH-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 eluted with ACN in H2O (0-65% gradient) to afford 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-I l ldimethoxyphenyl)methyl]amino}-3-[(4-methoxyphenyl)methyl]-2-oxo-lH-benzo[d]imidazole-4- carbonitrile (60 mg, 0.100 mmol, 32.4%) as a yellow solid. LCMS: ESI m / z 601 [M + H]+.

[0290] Step G: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-3-[(4-methoxyphenyl)methyl]-2-oxo-lH-benzo[d]imidazole-4- carbonitrile (60 mg, 0.100 mmol) in ACN (5 mL) and H2O (l mL) was added KOH (28.0 mg, 0.499 mmol) at 25 °C. The reaction mixture was stirred at 30 °C for overnight. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SO4, concentrated. The residue was purified by flash chromatography eluted with MeOH in DCM (0~8% gradient) to afford 6-(2-chloro-5-fluorophenyl)-5-{[(2,4- dimethoxyphenyl)methyl]amino}-6-hydroxy-l-[(4-methoxyphenyl)methyl]-l,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]+.

[0291] Step H: To a solution of 6-(2-chloro-5-fluorophenyl)-5-{[(2,4- dimethoxyphenyl)methyl]amino}-6-hydroxy-l -[(4-methoxyphenyl)methyl]-l ,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. The TFE and TfOH were removed under vacuum. Then the mixture was adjusted pH to 8 by NaHCO3(aqueous), extracted with EA. The organic layer was separated, washed with brine, dried over Na2 SO4, filtered and concentrated in vacuo to afford 5-amino-6-(2-chloro-5- fluorophenyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (10 mg, 0.021 mmol, 86.85%) as a yellow solid and used into next step without further purification. LCMS: ESI m / z 333 [M + H]“.

[0292] Step I: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindole-2, 8-dione (10 mg, 0.021 mmol) in acetonitrile (1 mL) was added Py (0.005 mL, 0.063 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (9.52 mg, 0.042 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 10 min. The ACN and pyridine were removed under vacuum to give a crude product which was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3,6,7,8-tetrahydro-lH- 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]+. 'H NMR (400 MHz, DMSO4) 8 11.38(s, 1H), 11.00 (s, 1H), 10.21 (s, 1H), 8.99 (s, 1H), 7.92 (d, J= 8.2 Hz, 1H), 7.71 (d, J= 9.4 Hz, 1H), 7.66 (s, 1H), 7.29 (dd, J= 8.8, 5.2 Hz, 1H), 7.07 (t, J= 6.8 Hz, 1H), 7.03 (s, 1H), 5.98 (s, 1H).Example 32 N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,3,7,8,9-hexahydro- [l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0293] 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) were added NaOEI (770 mg, 19.25 mmol, 4.0 eq) in H2O (20 mL). The reaction mixture was refluxed for 12 h. The reaction mixture was concentrated and added with DCM: MeOH=10: 1 (50 mL). Then the mixture was fdtered and the fdtrate was concentrated to give (3-amino-2-bromo-4-hydroxy-6- nitrophenyl)(2-chloro-5-fluorophenyl)methanone (2.3 g, crude) as a brown solid. LCMS: m / z 387.0, 388.9([M-H]-).

[0294] Step B: To a solution of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5- fluorophenyl)methanone (1.0 g, 2.57 mmol, 1.0 eq) in DCM (8.5 mL) were added TEA (546 mg, 5.39 mmol, 2.1 eq) and DMAP (63 mg, 0.51mmol, 0.2 eq) at 0 °C under N2 atmosphere. Then the chloroacetyl chloride (304 mg, 2.70 mmol, 1.05 eq) was added to the system. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to 25 °C and the 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 aqueous solution NaHSCU (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SC>4 and concentrated to give 5-bromo-6-(2-chloro-5- fluorobenzoyl)-7-nitro-2H-benzo[b][l,4]oxazin-3(4H)-one (1.1 g, crude) as a brown solid. LCMS: m / z 426.9, 428.8 ([M-H]’).

[0295] Step C: To a solution of 5-bromo-6-(2-chloro-5-fluorobenzoyl)-7-nitro-2H- benzo[b][l,4]oxazin-3(4H)-one (1.1 g, 2.45 mmol, 1.0 eq) in EtOH (10 mL) was added NH4CI (520 mg, 9.77 mmol, 4 eq) in H2O (3.5 mL). Then Fe (410 mg, 7.33 mmol, 3.0 eq) was added to the system at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Then water (15 mL) and ethyl acetate (5 mL) were added, filtered, the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried overNaiSCh and concentrated to give a curde. The residue was purified by Pre-TLC (eluted with petroleum ether / EtO Ac = 3 : 1) to give 7-amino-5-bromo-6-(2-chloro-5-fluorobenzoyl)-2H- benzo[b][l,4]oxazin-3(4H)-one (110 mg) as a yellow solid. LCMS: m / z 398.9, 400.9 ([M+H]+).

[0296] Step D: A sealed vial was charged with7-amino-5-bromo-6-(2-chloro-5- fluorobenzoyl)-2H-benzo[b][l,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(PPli3)4 (44 mg, 0.04 mmol, 0.3 eq) and DMAc (0.5 mL). The sealed vial was irradiated in the microwave at 160 °C for 30 min. The mixture was added water (3 mL) and extracted with EtOAc (3 mL x 2). The combined organic phases were washed with brine (5 mL x 2), dried over Na2 SO4 and concentrated to give a residue. The residue was purified by Pre- TLC (eluted with petroleum ether / EtOAc = 1: 1) to give 7-amino-6-(2-chloro-5-fluorobenzoyl)- 3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-5-carbonitrile (18 mg, 41.5 %) as a yellow solid. LCMS: m / z 344.1 ([M-H]’).

[0297] Step E: To a solution of 7-amino-6-(2-chloro-5-fluorobenzoyl)-3-oxo-3,4-dihydro- 2H-benzo[b][l,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. The mixture was added water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine (5 mL), dried over Na2SO4 and concentrated to give 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-7,8-dihydro- [l,4]oxazino[3,2-e]isoindole-2,9(lH,3H)-dione (150 mg, crude) as a yellow oil. LCMS: m / z 362.0 ([M-H]’).

[0298] Step F: To a solution of 6-amino-7-(2-chloro-5-fhiorophenyl)-7-hydroxy-7,8- dihydro-[l,4]oxazino[3,2-e]isoindole-2,9(lH,3H)-dione (150 mg, 0.41 mmol, 1.0 eq) in ACN (5 mL) were 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. Then the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mLx 2). The combined organic phases were washed with brine (5 mL) and aqueous solution Na2CC>3 (5 mL), dried over Na2SC>4 and concentrated to give N-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-2.9-dioxo-l,2,3,7,8,9-hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5- (trifluoromethyl)benzamide (240 mg, crude) as a yellow oil. LCMS: m / z 551.9 ([M-H]').

[0299] Step G: To a solution of N-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,9-dioxo-1.2.3.7.8.9-hexahydro-[l,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 EtsSiH (238 mg, 2.05 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,3,7,8,9-hexahydro-[1.4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (19 mg, three steps yield ~ 8.2%) as a white solid. LCMS: m / z 535.9 ([M-H]'). ‘HNMR (400 MHz, DMSO-dk): 5 10.34 (brs, 1H), 9.51 (brs, 1H), 9.28 (s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.63 (s, 1H), 7.33 - 7.30 (m, 1H), 7.12 - 7.07 (m, 2H), 6.90 - 6.76 (m, 1H), 5.95 (s, 1H), 4.81 (s, 2H).Example 35 N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,3,7,8,9-hexahydro-[1.4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide Example 48 (S)-N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,3,7,8,9-hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide Example 49 (R)-N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,3,7,8,9-hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide

[0300] Step A: To a solution of N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,3,7,8,9- hexahydro[l,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. To the cooled mixture was added IN HC1 and the pH wasadjusted to about 7. The reaction mixture was pre-purified by prep-HPLC purification to give N- [7-(2-chloro-5-fluorophenyl)-3,3-dideuterio-2,9-dioxo-l,2,3,7,8,9-hexahydro[l,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]+. ‘HNMR (400 MHz, CD3OD) 7.67 - 7.58 (m, 3H), 7.25 (dd, J= 8.8, 5.0 Hz, 1H), 7.08 (s, 1H), 7.02 - 6.94 (m, 1H), 6.68 (s, 1H). Another batch of 200 mg of N-[7-(2-chloro-5-fluorophenyl)-3,3-dideuterio-2,9-dioxo-l,2,3,7,8,9- hexahydro[l,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide was then subjected to chiral prep-SFC separation with the method below to afford Pl Example 48 (S)-N- (7-(2-chl oro-5-fluorophenyl)-2,9-di oxo- 1,2, 3,7,8, 9-hexahydro-[l, 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]+. 'H NMR (400 MHz, DMSO-fi) 8 10.40 (s, 1H), 9.52 (s, 1H), 9.26 (s, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.31 (dd, J= 8.8, 5.2 Hz, 1H), 7.11 (d, J= 6.4 Hz, 1H), 7.08 (dd, .7 = 8.6, 2.9 Hz, 1H), 6.86 (brs, 1H). And P2 Example 49 (R)- N-(7-(2-chloro-5-fluorophenyl)-2,9-di oxo- 1 ,2, 3,7,8, 9-hexahydro-[l , 4]oxazino[3, 2-e]isoindol-6- yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide (62.7 mg, 0.116 mmol, 62%) as a white solid (R)-N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,3,7,8,9-hexahydro-[l,4]oxazino[3,2- e]isoindol-6-yl-3,3,7-d3)-3-fluoro-5-(trifluoromethyl)benzamide. LCMS: ESI m / z 541 [M + H]+. 'HNMR (400 MHz, DMSO- L) 8 10.40 (s, 1H), 9.52 (s, 1H), 9.26 (s, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.31 (dd, J= 8.8, 5.2 Hz, 1H), 7.11 (d, J= 6.4 Hz, 1H), 7.08 (dd, J= 8.6, 2.9 Hz, 1H), 6.86 (brs, 1H).

[0301] Preparative separation method:Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IH, 250><20mm I.D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 20% Flow rate:40mL / min Back pressure: 100 bar Column temperature: 35°C Wavelength: 220 nm Cycle-time: 6min Eluted time: 2 hExample 36 N-[7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-l,2,3,7,8,9- hexahydro[l,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamideExample 37 N-((3R*,7R)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-l,2,357,8,9- hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 38 N-((3R*,7R)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-l,2,3,7,8,9- hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 39 N-((3R*,7S)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-l,2,3,7,8,9- hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 40 N-((3R*,7S)-7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-l,2,3,7,8,9- hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0302] Step A: To a stirred mixture of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2- chloro-5-fluorophenyl)methanone (500 mg, 1.28 mmol) in DCM (5 mL) was added dropwise TEA (0.357 mL, 2.56 mmol), DMAP (31 mg, 0.257 mmol) and 2-chloropropanoyl chloride (325 mg, 2.57 mmol) at RT. The reaction mixture was stirred at 50 °C for additional 2h. The cooled reaction was quenched with aqueous solution NaHSCU (10 mL), extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NaiSCL and concentrated. The residue was purified using 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[l,4]oxazin-3-one (450 mg, 1.014 mmol, 78.9%) as a white solid. LCMS: ESI m / z 442 [M+H]’.

[0303] Step B: To a stirred mixture of 5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2- methyl-7-nitro-3,4-dihydro-2H-benzo[l,4]oxazin-3-one (420 mg, 0.947 mmol) in EtOH / HzO (20 mL) was added dropwise NH4CI (152 mg, 2.84 mmol) and Fe (158 mg, 2.84 mmol). Thereaction mixture was stirred at 75 °C for an additional Ih. Water and ethyl acetate were added, filtered, the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NasSCX and concentrated. The residue was purified using 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[l,4]oxazin-3-one (380 mg, 0.919 mmol, 97.4%) as a white solid. LCMS: ESI m / z 412[M+H]’. ’H NMR (400 MHz, DMSO-cA) 8 9.79 (s, IH), 7.60 (dd, J= 8.8, 4.9 Hz, IH), 7.44 (dd, J = 8.2, 3.0 Hz, IH), 7.24 (dd, J= 8.6, 3.0 Hz, IH), 6.54 (s, IH), 6.25 (s, 2H), 4.69 (d, J= 6.8 Hz, IH), 1.42 (d, J = 6.8 Hz, 3H)..

[0304] Step C: To a stirred mixture of 7-amino-5-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-3-one (700 mg, 1.69 mmol) in NMP (8 mL) was added dropwise CuCN (303 mg, 3.38 mmol). The reaction mixture was stirred at 150 °C for Ih with microwave. The cooled resulting mixture was filtered, the filtrate was washed with EA. The combined organic layers were washed with brine, dried over anhydrous NaiSCE and concentrated under reduced pressure. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to afford compound 7-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3-oxo-3,4-dihydro-2H- benzo[l,4]oxazine-5-carbonitrile (480 mg, 1.33mmol, 78.8%) as a white solid. LCMS: ESI m / z 360 [M+H]’.

[0305] Step D: To a solution of 7-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3- oxo-3, 4-dihydro-2H-benzo[l,4]oxazine-5-carbonitrile (350 mg, 0.973 mmol) in CH3CN / H2O (8 mL) were 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 H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to afford 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-3-methyl-l,2,3,7,8,9- hexahydro[l,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]’

[0306] Step E: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-3-methyl- l,2,3,7,8,9-hexahydro[l,4]oxazino[3,2-e]isoindole-2,9-dione (200 mg, 0.529 mmol) in ACN (5 mL) were added pyridine (0.086 mL, 1.06 mmol) and 3-fluoro-5-(trifluoromethyl)benzoylchloride (144 mg, 0.635 mmol). The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4 and concentrated. The residue was purified using 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-di oxo-1, 2, 3,7,8, 9-hexahydro[l, 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]’

[0307] Step F: To a solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-3-methyl-2,9- di oxo- 1,2, 3,7,8, 9-hexahydro[l, 4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3- (trifluoromethyl)benzamide (200 mg, 0.352 mmol) in TFA (4 mb) were added EtsSiH (204 mg, 1.76 mmol). The reaction mixture was stirred at 50 °C for Ih. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with aqueous NaHCCh, extracted with EA. The organic phase was washed with brine, dried by Na2SO4 and concentrated. The residue was purified by prep-HPLC afford Example 36: N-[7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo- l,2,3,7,8,9-hexahydro[l,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 (400 MHz, DMSO-fifc) 5 10.34 (s, IH), 9.52 (s, 0.5H), 9.48 (s, 0.5H), 9.27 (s, IH), 7.93 (d, J= 8.4 Hz, IH), 7.70 - 7.66 (m, 2H), 7.41 - 7.25 (m, IH), 7.17 - 7.00 (m, 2H), 6.78 (s, IH), 5.88 (brs, IH), 5.02 - 4.84 (m, IH), 1.52 (d, J= 6.8 Hz, 3H).

[0308] Step G: Example 36 (100 mg, 0.181 mmol) was separated by chiral prep-SFC (Waters Thar 80 preparative SFC-Chiral Cel OD, 250x21.2mm I.D., 5pm, 20%, phase A: CO2, 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]+. ‘H NMR (400 MHz, DMSO-tL) 8 10.34 (s, IH), 9.52 (s, IH), 9.27 (s, IH), 7.93 (d, J= 8.4 Hz, IH), 7.70 - 7.66 (m, 2H), 7.41 - 7.25 (m, IH), 7.17 - 7.00 (m, 2H), 6.78 (s, IH), 5.88 (brs, IH), 4.96 (q, J= 6.8 Hz, IH), 1.51 (d, J= 6.8 Hz, 3H).

[0309] P-2 Example 38 (15.8 mg, 0.028 mmol, 10.8%) as a white solid. LCMS: ESI m / z 552[M + H]+. 'HNMR (400 MHz, DMSO-tfc) 8 10.34 (s, IH), 9.48 (s, 0.5H), 9.27 (s, IH), 7.93 (d, J = 8.4 Hz, IH), 7.69 - 7.66 (m, 2H), 7.41 - 7.25 (m, IH), 7.17 - 7.00 (m, 2H), 6.78 (s, IH), 5.88 (brs, IH), 4.94 (q, J= 6.8 Hz, IH), 1.52 (d, J= 6.8 Hz, 3H).

[0310] P-3 Example 39 (16.9 mg, 0.031 mmol, 11.6%) as a white solid LCMS: ESI m / z 552[M + H]+. ‘HNMR (400 MHz, DMSO-t / c) 8 10.34 (s, IH), 9.52 (s, 1H)„ 9.27 (s, IH), 7.93 (d, J= 8.4 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.00 (m, 2H), 6.78 (s, 1H), 5.88 (brs, 1H), 4.96 (q, J= 6.8 Hz, 1H), 1.51 (d, J = 6.8 Hz, 3H).

[0311] P-4 Example 40 (12.2 mg, 0.021 mmol, 8.34%) as a white solid. LCMS: ESI m / z 552[M + H]+. ‘HNMR (400 MHz, DMSO-^) 5 10.34 (s, 1H), 9.48 (s, 0.5H), 9.27 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.69 - 7.66 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.00 (m, 2H), 6.78 (s, 1H), 5.88 (brs, 1H), 4.94 (q, J= 6.8 Hz, 1H), 1.52 (d, J= 6.8 Hz, 3H).

[0312] Preparative separation method:Instrument: Waters Thar 80 preparative SFCColumn: ChiralPak IH, 250x21.2 mm I.D., 5 pmMobile phase: A for CO2 and B for MEOHGradient: B 20 %Flow rate: 40 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 6 minEluted time: 2 HExample 41 N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-l,2,3,7,8,9-hexahydro- [l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 42 (S)-N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-l,2,3,7,8,9- hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 43 (R)-N-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-l,2,3?7,8,9- hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0313] 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 dropwise 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) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 50 °C for an additional 2h. The cooled reaction was quenched with aqueous solution NaHSCU (10 mL), extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NazSCU and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 35%] to afford compound 2-bromo-N- (2-bromo-3-(2-chloro-5-fluorobenzoyl)-6-hydroxy-4-nitrophenyl)-2,2-difluoroacetamide (650 mg, 1.19 mmol, 58%) as a white solid. LCMS: ESI m / z 545 [M+H]’. ’H NMR (400 MHz, DMSO-tL) 8 11.86 (s, 1H), 11.10 (s, 1H), 7.82 (s, 1H), 7.75 - 7.65 (m, 2H), 7.65 - 7.55 (m, 1H).

[0314] 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) were added potassium carbonate (493 mg, 3.57 mmol), (2-methylprop-2-yl)oxidanecarboxylic anhydride (51 mg, 0.237 mmol) and DMAP (1.45 mg, 0.012 mmol). The reaction mixture was stirred at 50 °C under N2 overnight. The cooled reaction mixture was diluted with H2O, extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EAin PE [Gradient: 25%] to afford compound 5-bromo-6-(2-chloro-5-fluorobenzoyl)-2,2- difluoro-7-nitro-2H-benzo[b][l,4]oxazin-3(4H)-one (500 mg, 1.07 mmol, 90%) as a white solid. LCMS: ESI m / z 465 [M+H]+

[0315] Step C: To a stirred mixture of 5-bromo-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-7- nitro-2H-benzo[b][l,4]oxazin-3(4H)-one (500 mg, 1.074 mmol) in EtOHTEO (20 mL) was added dropwise NH4CI (172 mg, 3.222 mmol) and iron(0) (179 mg, 3.22 mmol) at rt under N2 atmosphere. The reaction mixture was stirred at 80 °C for Ih. The cooled reaction mixture was quenched with water at rt. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography eluting with EAin PE [Gradient: 30%] to afford compound 7-amino-5-bromo- 6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-2H-benzo[b][l,4]oxazin-3(4H)-one (410 mg, 0.941 mmol, 88%) as a white solid. LCMS: ESI m / z 436 [M+H]+. ’H NMR (400 MHz, DMSO-tL) 811.21 (s, 1H), 7.64 (dd, J= 8.8, 4.8 Hz, 1H), 7.49 (td, J= 8.4, 3.2 Hz, 1H), 7.35 (dd, J= 8.8, 3.0 Hz, 1H), 6.77 (s, 1H), 6.09 (s, 2H).

[0316] Step D: To a stirred mixture of 7-amino-5-bromo-6-(2-chloro-5-fluorobenzoyl)-2,2- difluoro-2H-benzo[b][l,4]oxazin-3(4H)-one (400 mg, 0.918 mmol) in NMP (6 mb) was added dropwise CuCN (164 mg, 1.837 mmol). The reaction mixture was stirred at 150 °C under N2 in microwave for Ih. The cooled reaction mixture was diluted with water, extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NazSCE and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 35%] to afford compound 7-amino-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro- 3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-5-carbonitrile (220 mg, 0.576 mmol, 63%) as a white solid. LCMS: ESI m / z 380 [M+H]'

[0317] Step E: To a solution of 7-amino-6-(2-chloro-5-fluorobenzoyl)-2,2-difluoro-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazine-5-carbonitrile (220 mg, 0.552 mmol) in CH3CN / H2O (8 mb) were added potassium hydroxide (97 mg, 1 .73 mmol). The reaction mixture was stirred at 50 °C for 30min. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by NazSCU, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 40%] to afford compound 6-amino-7-(2-chloro-5-fluorophenyl)-3,3-difluoro-7-hydroxy-7,8-dihydro-[1.4]oxazino[3,2-e]isoindole-2,9(lH,3H)-dione (120 mg, 0.30 mmol, 52%) as a white solid. LCMS: ESI m / z 398 [M+H]'

[0318] Step F: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-3,3-difluoro-7- hydroxy-7,8-dihydro-[l,4]oxazino[3,2-e]isoindole-2,9(lH,3H)-dione (100 mg, 0.25 mmol) in CAN (5 mb) were added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (68 mg, 0.300 mmol) and pyridine (0.04 mb, 0.500 mmol). The reaction mixture was stirred at RT for Ih.The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by NazSCL, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 35%] to afford compound N-(7-(2- chloro-5-fluorophenyl)-3,3-difluoro-7-hydroxy-2,9-dioxo-l,2,3,7,8,94iexahydro-[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]'

[0319] Step G: To a solution ofN-(7-(2-chloro-5-fluorophenyl)-3,3-difluoro-7-hydroxy-2,9- dioxo-l,2,3,7,8,9-hexahydro-[l,4]oxazino[3,2-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.153 mmol) in TFA (4 mL) were added EtsSiH (88 mg, 0.763 mmol). The reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was diluted with aqueous NaHCCh, extracted with EA. The organic phase was washed with brine, dried by NaiSCU and concentrated. The residue was purified by prep-HPLC afford N-(7-(2- chloro-5-fluorophenyl)-3,3-difluoro-2,9-dioxo-l,2,3,7,8,9-hexahydro-[l,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]+. ’H NMR (400 MHz, DMSO-tL) 8 10.81 (s, 1H), 10.50 (s, 1H), 9.44 (s, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 (td, J= 8.4, 2.8 Hz, 1H), 6.96 (s, 1H), 6.10 - 6.00 (brs, 1H).

[0320] Step H: N-[7-(2-chloro-5-fhiorophenyl)-3,3-difluoro-2,9-dioxo-l,2,3,7,8,9- hexahydro[l,4]oxazino[3,2-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25.5 mg) was purified by prep-SFC (Waters Thar 80 preparative SFC-Chiral Cel OD, 250x21 ,2mm I D., 5 pm, 20%, A :CC>2, phase B : IPA) to afford compound:

[0321] P-1 Example 42 (9.3 mg, 0.016 mmol, 73%) as a white solid LCMS: ESI m / z 574 [M+ H]+.XH NMR (400 MHz, DMSO-fifc) 8 10.81 (s, 1H), 10.50 (s, 1H), 9.44 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 (td, J= 8.4, 2.8 Hz, 1H), 6.96 (s, 1H), 6.10 - 6.00 (brs, 1H).

[0322] P-2 Example 43 (7.2 mg, 0.012 mmol, 56%) as a white solid. LCMS: ESI m / z 574 [M+ H]+.XH NMR (400 MHz, DMSO-flfe) 6 10.81 (s, 1H), 10.50 (s, 1H), 9.44 (s, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 (td, J= 8.4, 2.8 Hz, 1H), 6.96 (s, 1H), 6.10 - 6.00 (brs, 1H).Example 44 N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,2,4,7,8,9-hexahydro- [l,3]oxazino[4,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0323] Step A: A mixture of 2-bromo-l-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 CCI4 (15 m ) was stirred at 80 °C under N2 atmosphere for 18h. The reaction was cooled to room temperature and fdtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluted with EA / PE = 0-20%) to give a crude product 2-bromo-3 -(bromomethyl)- l-fluoro-4- nitrobenzene (1.0 g, 3.2 mmol, 75%) as a colorless oil.

[0324] Step B: A solution of 2-bromo-3-(bromomethyl)-l -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 over. The reaction was cooled and poured into ice-water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA / PE = 0 ~ 40%) to give the desired product 2-bromo-3-fluoro-6-nitrobenzene-l-carbaldehyde (800 mg, 3.2 mmol, 100%) as a yellow solid. ’H NMR (400 MHz, DMSO-tL) 5 10.20 (s, 1H), 8.33 (dd, J = 9.2, 4.4 Hz, 1H), 7.89 - 7.77 (m, 1H).

[0325] Step C: A solution of 2-bromo-3-fluoro-6-nitrobenzene-l-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 fori h. TLC and LCMS indicated the reaction was over. The reaction was cooled and poured into ice-water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was dissolved in THF (10 mL) and 6N HCI (10 mL). The solution was stirred at 60 °C for 1 h. The reaction was cooled to 0 °C, adjust pH to 7~8 with NaHCCh, extracted with EA. The organic layer was washed withbrine, dried over Na2SC>4, 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-l-carbaldehyde (500 mg, 2.0 mmol, 68%) as a yellow solid. LCMS: ESI m / z 246 / 248 [M+H]+. 'H NMR (400 MHz, DMSO-tL) 8 10.23 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.24 (s, 2H), 6.97 (d, J = 9.2 Hz, 1H).

[0326] Step D: To a mixture of 2-bromo-3-methyl-4-nitroaniline (800 mg, 3.2 mmol) and Ag2SC>4 (1.4 g, 4.5 mmol) in MeOH (20 mL) was added I2 (1 07g, 4.2 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC indicated the reaction was over. The mixture was poured into H2O. The mixture was filtered, and the filtrate was extracted with EA. The organic layer was concentrated and washed with brine, dried over Na SCf, 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-l- carbaldehyde (700 mg, 1.9 mmol, 58%) as a yellow solid. LCMS: ESI m / z 371.9 [M+H]+. ’H NMR (400 MHz, DMSO-rL) 8 10.13 (s, 1H), 8.47 (s, 1H), 6.87 (s, 2H).

[0327] Step E: To a solution of 3-amino-2-bromo-4-iodo-6-nitrobenzene-l-carbaldehyde (1.6 g, 4.31 mmol) in THF (30 mL) was added 2-chloro-5-fluorophenyl)magnesium chloride (0.5M, 30 mL) at 0 °C. The mixture was stirred at rt for Ih, then diluted with EA and aqueous NH4CI. The organic was seperated and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA / PE = 0-30%) to afford (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]+.

[0328] 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 rt 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]+.

[0329] 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), potassium trifluoro(vinyl)-V-boranuide (161 mg, 1.21 mmol), pd(dppf)C12 (73.3 mg, 100 pmol), K2CO3 (414 mg, 3.01 mmol), dioxane(10 mL) and H2O (2 mL). The mixture was stirred at 85 °C under N2 for 2h. 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 N 828 )4 and concentrated to give a residue. The residue was purified by column (eluted with (EA: PE=30%) to give (3-amino-2-bromo-6-nitro-4- vinylphenyl)(2-chloro-4-fhiorophenyl)methanone (270 mg, 0.676 mmol, 67%) as a yellow solid. LCMS: ESI m / z 401 [M+H]+.

[0330] 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 3h. The mixture was diluted with water (~10mL) 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 (eluted with (EA: PE=30%) to give 6-amino-2-[(2-chloro-4-fluorophenyl)carbonyl]-3-nitro-5-vinylbenzene-l -carbonitrile (170 mg, 0.492 mmol, 41%) as a brown solid. LCMS: EST m / z 346 [M+H]+.

[0331] 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 give 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-4-nitro-6-vinyl-2,3-dihydro-lH-isoindol-l-one (170 mg, 0.467 mmol, 95%) as a brown solid. LCMS: ESI m / z 364 [M+H]+.

[0332] Step J: To a solution of 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-4-nitro-6- vinyl-2,3-dihydro-lH-isoindol-l-one (70 mg, 0.192 mmol) in dioxane (2 mL) and H2O (0.2 mL) were added NalCh (123 mg, 0.577 mmol) and potassium citrate (7.09 mg, 19 pmol). The mixture was stirred at rt for 3 h. The mixture was quenched with saturated NaHCCh 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- IH-i soindole-5 - carbaldehyde (60 mg, 0.164 mmol, 85%) as a brown solid. LCMS: ESI m / z 366 [M+H]+.

[0333] Step K: To a solution of 4-amino-l-(2-chloro-4-fluorophenyl)-l-hydroxy-7-nitro-3- oxo-2, 3-dihydro-lH-isoindole-5-carbaldehyde (50 mg, 0.137 mmol) in THF (2 mL) was added NaBHi (10.3 mg, 0.273 mmol). The mixture was stirred at rt for Ih. The mixture wasdiluted with water (~10mL) and extracted with EtOAc (~20 mL x 2). The combined organic phases were washed with brine, dried over Na2SC>4 and concentrated to give a residue. The residue was purified by column (eluted with (MeOH: DCM=10%) to give 7-amino-3-(2-chloro- 4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-4-nitro-2,3-dihydro-lH-isoindol-l-one (40 mg, 0.109 mmol, 80%) as a brown solid. LCMS: ESI m / z 368 [M+H]+.

[0334] Step L: To a solution of 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6- (hydroxymethyl)-4-nitro-2,3-dihydro-lH-isoindol-l-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 diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SC>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-lH-isoindol-l-one (20 mg, 54 pmol, 29%) as a brown solid. LCMS: ESI m / z 394 [M+H]+.

[0335] Step M: To a solution of 7-amino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6- (hydroxymethyl)-4-nitro-2,3-dihydro-lH-isoindol-l-one (30 mg, 82 pmol) and Fe (21.3 mg, 0.381 mmol) in EtOH (1 mL) was added NH4CI (20.4 mg, 0.381 mmol) in H2O (0.3 mL). The reaction mixture was heated to 85 °C for 2 h. Then the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (MeOH: DCM = 1 : 10) to give 4,7-diamino-3-(2-chloro-4-fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-2,3- dihydro-lH-isoindol-l-one (20 mg, 59 pmol, 73%) as a brown solid. LCMS: ESI m / z 364 [M+H]+.

[0336] Step N: To a solution of 6-amino-7-(2-chloro-4-fluorophenyl)-7-hydroxy-l,2,4,7,8,9- hexahydro[l,3]oxazino[4,5-e]isoindole-2, 9-dione (20 mg, 55 pmol) in ACN (3 mL) was added py (21.7 mg, 0.275 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (16.2 mg, 71 pmol). The reaction mixture was stirred at rt for 30min. Then the mixture was diluted with water (~20 mL) and extracted with ethyl acetate (~20mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated to give N-[5-(5-chloro-2- fluorophenyl)-3-cyano-5-hydroxy-2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]indazol-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (25 mg, 45 pmol, 82%) as a brown solid. LCMS: ESI m / z 554 [M+H]+.

[0337] Step O: To a solution of N-[7-(2-chloro-4-fluorophenyl)-7-hydroxy-2,9-dioxo- l,2,4,7,8,9-hexahydro[l,3]oxazino[4,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 18 pmol) in TFA (1 mL) was added EtaSiH (0.2 mL, 18 pmol). The reaction mixture was stirred at 60 °C for 30min. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give N-[7-(2-chloro-4-fluorophenyl)-2,9-dioxo-l,2,4,7,8,9- hexahydro[l,3]oxazino[4,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3.5 mg, 7 pmol, 36%) as a white solid. LCMS: ESI m / z 538 [M+H]+. ‘HNMR (400 MHz, DMSO-cL) 5 10.40 (s, 1H), 9.31 (s, 1H), 8.91 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.65 (s, 1H), 7.34 (d, J= 4.4 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.10 (dd, J= 8.4, 5.2 Hz, 1H), 6.70 - 6.50 (s, 0.5H), 6.00 (brs, 1H), 5.52 (s, 2H).Example 45 N- [7-(2-chloro-5-fluorophenyl)-3-methyl-2,9-dioxo-2,394,7,8,9- h exahydro [1 ,3] oxazino [6,5-e] isoindol-6-yl] -5-fluoro-3-(trifluoromethyl)benzamide

[0338] Step A. To a solution of 2,6-dibromo-3-methyl-4-nitrophenol (10 g, 32.1 mmol) in CH3CN (100 mL) were added K2CO3 (8.89 g, 64.3 mmol) and CH3I (3.9 mL, 48.2 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-15%] to afford l,3-dibromo-2-methoxy-4-methyl-5-nitrobenzene (10 g, 30.7 mmol, 96%) as a white solid. ‘H NMR (400 MHz, DMSO-fifc) 8 8.31 (s, 1H), 3.87 (s, 3H), 2.46 (s, 3H).

[0339] Step B. To a solution of l,3-dibromo-2-methoxy-4-methyl-5-nitrobenzene (10 g, 30.7 mmol) in CCI4 (120 mL) were added NBS (6.30 g, 36.9 mmol) and AIBN (0.25 g, 1.53mmol). The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was diluted with H2O, extracted with DCM. The organic phase was washed with brine, dried over Na2 SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-20%] to afford l,3-dibromo-4-(bromomethyl)-2-methoxy- 5-nitrobenzene (10, 24.7 mmol, 80%) as a white solid. ’H NMR (400 MHz, DMSO-cL) 5 8.43 (s, 1H), 4.80 (s, 2H), 3.90 (s, 3H).

[0340] Step C. To a solution of l,3-dibromo-4-(bromomethyl)-2-methoxy-5-nitrobenzene (10g, 24.7 mmol) in CH3CN (60 mL) was added NMO (5.80 g, 49.3 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-30%] to afford compound 2,4-dibromo-3-methoxy-6-nitrobenzene-l-carbaldehyde (8.1 g, 24.0 mmol, 97%) as a white solid. ‘H NMR (400 MHz, DMSO- r,) 5 10.16 (s, 1H), 8.56 (s, 1H), 3.93 (s, 3H).

[0341] Ste D. To a solution of 2,4-dibromo-3-methoxy-6-nitrobenzene-l -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 rt for 2 h. The reaction mixture was quenched with NH4CI, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-40%] to afford compound (2-chloro-5-fluorophenyl)(2,4- dibromo-3-methoxy-6-nitrophenyl)methanol (7.1 g, 14.9 mmol, 59%) as a white solid. ’H NMR (400 MHz, DMSO-tL) 8 8.30 (s, 1H), 7.54 (dd, J= 8.8, 5.2 Hz, 1H), 7.25 (td, J= 8.4, 3.2 Hz, 1H), 7.06 (dd, J = 9.6, 3.2 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), 6.24 (d, J = 5.6 Hz, 1H), 3.84 (s, 4H).

[0342] 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) was added Dess-MARTIN (9.1 g, 21.3 mmol) slowly at 0 °C. After stirred at rt for 3h, the mixture was poured into ice-water (20 mL) and extracted with DCM (10 mL*3). The combined organic phase was washed with brine, dried with Na2 SO4, filtered and concentrated. The combined organic phase was washed with brine, dried with Na2SC>4, 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] .NMR (400 MHz, DMSO-c / ) 5 8.68 (s, 1H), 7.81 (dd, J= 9.2, 3.2 Hz, 1H), 7.74 (dd, J= 8.8, 4.8 Hz, 1H), 7.65 - 7.58 (m, 1H), 3.95 (s, 3H).

[0343] 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) / H20 (4 mL) was added (2,2- dimethyl-4-oxo-5-aza-3-oxahex-6-yl)trifluoro-X5-boranuide (2.6 g, 13.5 mmol), Pd(dppf)C12 (660 mg, 0.89 mmol) and K2CO3 (3.7 g, 26.9 mmol) at rt. After stirred at 70 °C under N2 overnight, the cooled mixture was poured into ice- water (20 mL) and extracted with DCM (10 mL*3). The combined organic phase was washed with brine, dried with Na2SCU, filtered and concentrated. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5- nitrophenyl}methyl)amino]methanoate (930 mg, 1.8 mmol, 20%) as a yellow solid. LCMS: m / z 517 [M+H]+.

[0344] Step G. To a stirred solution of2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]methanoate (900 mg, 1.7 mmol) in DMF (20 mL) was added NaH (125 mg, 5.2 mmol, 60% in mineral oil) slowly at - 20 °C. After stirred at -20 °C for Ih, CH3I (0.2 mL, 2.6 mmol) was added to the mixture. After stirred at rt for 2h, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The combined organic phase was washed with brine, dried with 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)(methyl)amino]methanoate (430 mg, 0.81 mmol, 46%) as a yellow solid. LCMS: m / z 531 [M+H]+.

[0345] Step H. To a stirred solution of 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(methyl)amino]methanoate (400 mg, 0.752 mmol) in EtOH (12 mL) / H2O (3 mL) was added NH4CI (161 mg, 3.1 mmol) and Fe (420 mg, 7.5 mmol) at rt. After stirred at 80 °C for 2h, the mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50 %, EtOAc in PE) to give 2- methylpropan-2-yl [({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl}methyl)(methyl)amino]methanoate (300 mg, 0.59 mmol, 79%) as a yellow solid. LCMS: m / z 502 [M+H]+.

[0346] Step I. To a stirred solution of 2-methylpropan-2-yl [({5-amino-3-bromo-4-[(2- chloro-5-fluorophenyl)carbonyl]-2-methoxyphenyl } methyl)(methyl)amino]methanoate (280 mg, 0.56 mmol) in NMP (3 mb) was added CuCN (150 mg, 1.7 mmol) at rt. After stirred at 130 °C under N2 for 2h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with NaiSCU, filtered and concentrated until there was no more drops. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % FA) to give 2-methylpropan-2-yl [({5-amino-4-[(2-chloro-5- fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(methyl)amino]methanoate (230 mg, 0.51 mmol, 92%) as a yellow solid. LCMS: m / z 448 [M+H]+.

[0347] Step J. To a stirred solution of 2-methylpropan-2-yl [({5-amino-4-[(2-chloro-5- fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl}methyl)(methyl)amino]methanoate (230 mg, 0.51 mmol) in ACN (2 mL) / H2O (1 mL) was added KOH (288 mg, 5.1 mmol) slowly at rt. After stirred at rt for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM to give 2-methylpropan-2-yl ({[7-amino-l-(2-chloro-5-fluorophenyl)-l-hydroxy-4-methoxy-3-oxo- 2,3-dihydro-lH-isoindol-5-yl]methyl}(methyl)amino)methanoate (170 mg, 0.36 mmol, 71%) as a white solid. LCMS: m / z 466 [M+H]+. 'HNMR (400 MHz, DMSO-cL) 8 8.81 (s, IH), 7.96 (dd, J= 10.4, 3.2 Hz, IH), 7.35 (d, J= 5.2 Hz, IH), 7.29 - 7.18 (m, IH), 6.99 (s, IH), 6.53 (s, IH), 4.47 (s, 2H), 4.34 (d, J= 6.0 Hz, 2H), 3.80 (s, 3H), 2.75 (s, 3H), 1.41 (d, J= 19.4 Hz, 10H).

[0348] Step K. To a stirred solution of 2-methylpropan-2-yl ({[7-amino-l-(2-chloro-5- fluorophenyl)-l-hydroxy-4-methoxy-3-oxo-2,3-dihydro-lH-isoindol-5- yl]methyl}(methyl)amino)methanoate (150 mg, 0.32 mmol) in ACN (2 mL) was added pyridine (76 mg, 0.97 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (145 mg, 0.64 mmol) slowly at rt. After stirred at rt for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography(silica gel, 0-10%, MeOH in DCM) to give 2-methylpropan-2-yl ({[l-(2-chloro-5-fluorophenyl)- 7-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-l-hydroxy-4-methoxy-3-oxo-2,3-dihydro-lH-isoindol-5-yl]methyl}(methyl)amino)methanoate (180 mg, 0.27 mmol, 85%) as a brown solid. LCMS: m / z 656 [M+H]+.

[0349] Step L. To a stirred solution of 2-methylpropan-2-yl ({[l-(2-chloro-5-fluorophenyl)- 7-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl] amino)-l -hydroxy -4-methoxy-3-oxo-2, 3- dihydro-lH-isoindol-5-yl]methyl}(methyl)amino)methanoate (170 mg, 0.26 mmol) in TFA (5 mL) was added EtsSiH (1 mL) at rt . After stirred at 70 °C for 2h, the cooled mixture was concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-6-[(methylamino)methyl]-l- oxo-2, 3-dihydro-lH-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (120 mg, 0.22 mmol, 86%) as a white solid. LCMS: m / z 540 [M+H]+. 'HNMR (400 MHz, DMSO-t / y) 8 10.45 (s, 1H), 9.17 (s, 1H), 8.82 (s, 2H), 7.97 (d, J= 8.4 Hz, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.68-7.60 (m, 2H), 7.32 (dd, J= 8.8, 5.2 Hz, 1H), 7.11 (td, J= 8.4, 2.8 Hz, 1H), 5.96 (brs, 1H), 4.25 (d, J= 7.7 Hz, 2H), 4.19 (s, 3H), 2.62 (s, 3H).

[0350] Step M. To a stirred solution of N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-6- [(methylamino)methyl]-l -oxo-2, 3-dihy dro-lH-isoindol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (110 mg, 0.21 mmol) in ACN (6 mL) was added TMSC1 (110 mg, 1.1 mmol) and Nal (152 mg, 1.1 mmol) at rt. After stirred at 90 °C for 4h, the cooled mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-12%, MeOH in DCM) to give N-[3-(2-chloro-5- fluorophenyl)-7-hy droxy-6-[(methylamino)methyl]-l -oxo-2, 3-dihy dro-lH-isoindol -4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.17 mmol, 87%) as a white solid. LCMS: m / z 526 [M+H]+.

[0351] Step N. To a stirred solution of N-[3-(2-chloro-5-fhiorophenyl)-7-hydroxy-6- [(methylamino)methyl]-l -oxo-2, 3-dihy dro-lH-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 rt . After stirred at 50 °C for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give N-[7-(2-chloro-5-fluorophenyl)-3-methyl-2,9- dioxo-2,3,4,7,8,9-hexahydro[l,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]+. 'HNMR (400 MHz, DMSO-t / s) 6 10.37 (s, 1H), 9.05 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.37 - 7.27 (m, 2H), 7.09 (td, .7= 8.4, 2.8 Hz, 1H), 5.92 (brs, 1H), 4.68 - 4.55 (m, 2H), 3.03 (s, 3H).Example 46 N-(7-(2-chloro-5-fluorophenyl)-9-oxo-l,2,3,7,8,9-hexahydro-[l,4]oxazino[3,2- e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0352] Step A: To a solution of (3-amino-2-bromo-4-hydroxy-6-nitrophenyl)(2-chloro-5- fluorophenyl)methanone (450 mg, 1.15 mmol) in DMSO (5 mL) was added K2CO3 (319 mg, 2.31 mmol) and 1,2-dibromoethane (0.150 mL, 1.73 mmol). The reaction mixture was stirred at 80 °C under N2 for 1 hr. The reaction was completed and monitored by TLC. The cooled reaction mixture was dissolved in EA (20 mL), washed with H2O (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 afford (5-bromo-7-nitro-3,4-dihydro-2H-benzo[b][l,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]+.

[0353] Step B: To a solution of (5-bromo-7-nitro-3,4-dihydro-2H-benzo[b][l,4]oxazin-6- yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.481 mmol) in DMF (5 mL) was added K2CO3 (199 mg, 1.44 mmol) and 4-Methoxybenzylchloride (150 mg, 0.962 mmol). The reaction mixture was stirred at 60 °C under N2 for 3 hrs. The reaction was completed and monitored by TLC. The cooled reaction mixture was dissolved in EA (20 mL), washed with H2O (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 afford (5-bromo-4-(4-methoxybenzyl)-7-nitro-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.373 mmol, 78%) as a yellow oil.

[0354] Step C: To a solution of (5-bromo-4-(4-methoxybenzyl)-7-nitro-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)(2-chloro-5-fluorophenyl)methanone (100 mg, 0.187 mmol) in EtOH (3 mL) and H2O (1 mL) was added NH4CI (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 completed and monitored by TLC. The cooled reaction mixture was filtered and concentrated. 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 (eluting with 0-50% EA in PE) to afford (7-amino-5-bromo-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][l,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]+. 'H NMR (400 MHz, DMSO-<A) 5 7.56 (dd, J = 8.8, 4.8 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.38 (dd, J = 8.8, 3.2 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.37 (s, 1H), 5.97 (s, 2H), 4.23 - 4.16 (m, 2H), 3.92 (s, 2H), 3.73 (s, 3H), 2.83 - 2.77 (m, 2H).

[0355] Step D: To a solution of (7-amino-5-bromo-4-(4-methoxybenzyl)-3,4-dihydro-2H- benzo[b][l,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 completed and monitored by LCMS. The cooled reaction mixture was 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 (eluting with 0-20% EA in PE) to afford N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-4-(4-methoxybenzyl)-3,4-dihydro-2H- benzo[b][l,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]+. ’H NMR (400 MHz, DMSO- L) 8 10.42 (s, 1H), 8.04 - 7.98 (m, 3H), 7.93 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 11.6 Hz, 2H), 7.51 (t, J = 2.4 Hz, 1H), 7.49 (t, J = 2.4 Hz, 1H), 7.38 - 7.30 (m, 2H), 6.98 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 4.29 - 4.23 (m, 2H), 4.14 (s, 2H), 3.76 (s, 3H), 2.98 - 2.91 (m, 2H).

[0356] Step E: To a solution ofN-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-4-(4- methoxybenzyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)-3-fluoro-5- (trifhioromethyl)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 N2 for 3 hrs. The reaction wascompleted and monitored by LCMS. The cooled reaction mixture was dissolved in EA (20 mL), washed with H2O (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 afford N-(6-(2- chloro-5-fluorobenzoyl)-5-cyano-4-(4-methoxybenzyl)-3,4-dihydro-2EI-benzo[b][l,4]oxazin-7- yl)-3-fhioro-5-(trifhioromethyl)benzamide (80.0 mg, 0.125 mmol, 79%) as a yellow oil. LCMS: ESI m / z 642.98 [M + H]+.

[0357] Step F: To a solution ofN-(6-(2-chloro-5-fluorobenzoyl)-5-cyano-4-(4- methoxybenzyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)-3-fluoro-5- (trifluoromethyl)benzamide (80.0 mg, 0.125 mmol) in ACN (3 mL) and H2O (1 mL) was added KOH (34.9 mg, 0.623 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was completed 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 afford N-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-l-(4-methoxybenzyl)-9-oxo-l,2,3,7,8,9- hexahydro-[l ,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]+.

[0358] Step G: To a solution ofN-(7-(2-chloro-5-fluorophenyl)-7-hydroxy-l-(4- methoxybenzyl)-9-oxo- 1,2, 3,7,8, 9-hexahydro-[l, 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 EtaSiH (400 pL, 2.50 mmol) and TfOH (80 pL, 0.904 mmol). The reaction mixture was stirred at 70 °C for 1 hr. The reaction mixture was completed and monitored by LCMS. The reaction mixture was concentrated and purified by prep-HPLC (C18, 30 ~ 95 % ACN in H2O with 0.1 % TFA) to afford N-(7-(2-chloro-5-fluorophenyl)-9-oxo-l,2,3,7,8,9-hexahydro-[l,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]+. ’H NMR (400 MHz, DMSO-tL) 5 9.98 (s, 1H), 8.73 (s, 1H), 7.88 (d, I = 8.0 Hz, 1H), 7.67 (d, I = 9.2 Hz, 1H), 7.63 (s, 1H), 7.27 (dd, J = 8.8, 5.2 Hz, 1H), 7.06 (td, J = 8.4, 2.8 Hz, 1H), 6.73 (s, 1H), 6.64 (brs, 1H), 5.82 (brs, 1H), 4.23 (dd, J = 11.2, 4.6 Hz, 2H), 3.40 - 3.36 (m, 2H).Example 47 N- [7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-2,9-dioxo-2,3,4,7,8,9- hexahydro-lH-pyrrolo[3,4-f|quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0359] 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-l -amine (1 .5 mL, 22.0 mmol). The reaction was stirred at rt O / N. The reaction mixture was diluted with water, extracted with EtOAc (100 mL*3). The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 5-8%) to afford (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]+.

[0360] 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 sat. NH4CI (5 mL). The reaction was stirred at 80 °C for 3h. The cooled reaction mixture was filtrated and concentrated. The residue was diluted with water, extracted with EtOAc (100 mL*3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 20%) to afford {3-amino-2,6-dibromo-4-[(2,2- difluoroethyl) amino] phenyl} (2 -chi oro-5 -fluorophenyl) methanone (1.78 g, 3.66 mmol, 99%) as an orange solid. LCMS: m / z 487 [M+H]+

[0361] 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, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. Theresidue was purified by a silica gel column chromatography eluted 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]+.

[0362] 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 Nal (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 / EAto afford 6,8-dibromo-7-[(2- chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-l,2,3,4-tetrahydroquinoxalin-2-one (360 mg, 0.684 mmol, 43%) as a brown solid. LCMS: ESI m / z 527.2 [M + H]+.

[0363] Step E: To a solution of 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2- difluoroethyl)-l,2,3,4-tetrahydroquinoxalin-2-one (240 mg, 0.456 mmol) in THF (24 mL) was added NaH (54.7 mg, 1 .37 mmol, 60% in mineral oil). The mixture was stirred at 20 °C for 10 min. SEMC1 (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 Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0 - 30% EtOAc / hexane to afford 6,8-dibromo-7- [(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-l-(5,5-dimethyl-2-oxa-5-silahex-l- yl)-l,2,3,4-tetrahydroquinoxalin-2-one (180 mg, 0.274 mmol, 60%) as a brown oil. 'H NMR (400 MHz, DMSO ) 5 7.85 (dd, J = 8.9, 5.0 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.65 (s, 1H), 7.49 (dd, J = 8.8, 2.8 Hz, 1H), 6.25-6.42 (m, 1H), 5.64 (s, 2H), 4.12 - 4.00 (m, 4H), 3.37 - 3.32 (m, 2H), 0.80 - 0.73 (m, 2H), 0.00 (s, 9H).

[0364] Step F: To a solution of 6,8-dibromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2- difluoroethyl)-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-l,2,3,4-tetrahydroquinoxalin-2-one (180 mg, 0.274 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (85.1 mg, 0.411 mmol) in dioxane (9 mL) was added CS2CO3 (268 mg, 0.822 mmol), Xant-PHOS (31.7 mg, 0.055 mmol) and Pd2(dba)s (25.1 mg, 0.027 mmol). The mixture was stirred at 95 °C under N2 for 12 hours. The cooled mixture was concentrated and the residue was purified by silica gel chromatography (5 g column) using 0 - 30% EtOAc / hexane to afford N-{8-bromo-7-[(2-chloro- 5-fluorophenyl)carbonyl]-4-(2,2-difluoroethyl)-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-2-oxo-l,2,3,4-tetrahydroquinoxalin-6-yl}-5-fluoro-3-(trifluoromethyl)benzamide (75 mg, 0.096 mmol, 35%) as a brown solid. 'HNMR (400 MHz, DMSO- / rt) 6 10.61 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 14.4 Hz, 2H), 7.61 (dd, J = 8.8, 4.8 Hz, 1H), 7.49 - 7.39 (m, 2H), 7.27 (s, 1H), 6.51 - 6.20 (m, 1H), 5.62 (s, 2H), 4.08 (s, 2H), 4.02 - 3.91 (m, 2H), 3.34 (d, J = 8.4 Hz, 2H), 0.81 - 0.73 (m, 2H), 0.02 - 0.02 (m, 9H).

[0365] Step G: To a solution ofN-{8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-4-(2,2- difluoroethyl)-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-2-oxo-l,2,3,4-tetrahydroquinoxalin-6-yl}- 5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.128 mmol) in DMA (4 mL) was added Zn(CN)2 (22.5 mg, 0.192 mmol) and Pd(PPh3)4 (14.8 mg, 0.013 mmol). The mixture was stirred at 150 °C under N2 for 1 hour in microwave. The mixture was purified by prep-TLC (PE / EA=7: 3) to give N-{7-[(2-chloro-5-fluorophenyl)carbonyl]-8-cyano-4-(2,2-difluoroethyl)- l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-2-oxo-l,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 [M - H]-.

[0366] Step H: To a solution ofN-{7-[(2-chloro-5-fluorophenyl)carbonyl]-8-cyano-4-(2,2- difluoroethyl)-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-2-oxo-l,2,3,4-tetrahydroquinoxalin-6-yl}- 5-fluoro-3-(trifluoromethyl)benzamide (35 mg, 0.048 mmol) in CH3CN (3 mL) and H2O (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, 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)-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-7-hydroxy-2,9-dioxo- 2,3,4,7,8,9-hexahydro-lH-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 [M - H]’.

[0367] Step I: A solution ofN-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-l-(5,5- dimethyl-2-oxa-5-silahex-l-yl)-7-hydroxy-2,9-dioxo-2,3,4,7,8,9-hexahydro-lH-pyrrolo[4,3- f]quinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.040 mmol) in HCl / dioxane (3 mL) 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-lH-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 [M - H]’.

[0368] Step J: To a solution ofN-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-7- hydroxy-2,9-dioxo-2,3,4,7,8,9-hexahydro-lH-pyrrolo[4,3-f]quinoxalin-6-yl]-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.049 mmol) in TFA (2 mL) was added EtsSiH (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 prep-HPLC to give N-[7-(2-chloro-5- fluorophenyl)-4-(2,2-difluoroethyl)-2, 9-dioxo-2, 3 ,4, 7, 8, 9-hexahy dro- 1 H-pyrrolo[3 ,4- fjquinoxalin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2 mg, 0.003 mmol, 7%) as a white solid. LCMS: ESI m / z 601 [M + H]+. 'HNMR (400 MHz, DMSO-tfc) 5 10.30 (s, 1H), 9.62 (s, 1H), 9.22 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.66 (s, 1H), 7.30 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (td, J = 8.4, 3.2 Hz, 1H), 6.91 (s, 1H), 6.76 (brs, 1H), 6.52-6.20 (m, 1H), 5.89 (brs, 1H), 4.16 (s, 2H), 3.87 - 3.71 (m, 2H).Example 50 N-(7'-(2-chloro-5-fluorophenyl)-2',9'-dioxo-l',7',8',9'-tetrahydro-2'H- spiro[cyclopropane-l,3'-[l,4]oxazino[3,2-e]isoindol]-6'-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[0369] Step A: To a solution of ethyl 1-hydroxycyclopropane-l -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 completed and monitored by TLC. The cooled reaction mixture was quenched with water, extracted with EA (80 mL). The organic phase was washed with H2O (50 mL) and brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (eluting with 0-30% EA in PE) to afford ethyl l-({3,5-dibromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-nitrophenyl}oxy)cyclopropane-l -carboxylate (5.50 g, 9.72 mmol, 73%) as a yellow solid. LCMS: ESI m / z 564.57 / 566.57 / 568.57 [M + H]+.

[0370] Step B: To a solution of ethyl l-({3,5-dibromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-nitrophenyl}oxy)cyclopropane-l -carboxylate (3.00 g, 5.30 mmol) in EtOH (30 mL) and H2O (30 mL) was added NH4CI (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 Ihr. The reaction was completed and monitored by TLC. The cooled reaction mixture was filtered, concentrated, diluted with water, extracted with EA (80 mL). The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EAin PE) to afford ethyl l-({2-amino-3,5-dibromo-4-[(2-chloro-5- fluorophenyl)carbonyl]phenyl}oxy)cyclopropane-l -carboxylate (1.90 g, 3.54 mmol, 66%) as a yellow solid. LCMS: ESI m / z 534.59 / 536.59 / 538.59 [M + H]+.

[0371] Step C: To a solution of ethyl l-({2-amino-3,5-dibromo-4-[(2-chloro-5- fluorophenyl)carbonyl]phenyl}oxy)cyclopropane-l -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 Ihr. The reaction was completed and monitored by TLC. The reaction mixture was quenched with water, extracted with EA (80 mL). The organic phase was washed with brine, dried over J feSCU and concentrated. The residue was purified by silica gel chromatography (eluting with 0-10% EA in PE) to afford 5,7-dibromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-3,4-dihydrospiro[benzo[l,4]oxazine-2,l'-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]+. ‘H NMR (400 MHz, DMSO-tL) 5 10.64 (s, 1H), 7.72 (dd, J = 8.8, 4.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 1.36 (s, 2H), 1.28 (s, 2H).

[0372] Step D: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3,4- dihydrospiro[benzo[l,4]oxazine-2,l'-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-C1 (0.922 mL, 5.20 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 1 hr. The reaction was completed and monitored by TLC. The reaction mixture was quenched with water, 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 0-30% EA in PE) to afford 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-3,4- dihydrospiro[benzo[l,4]oxazine-2,l'-cyclopropane]-3-one (700 mg, 1.12 mmol, 64%) as a yellow oil. ’H NMR (400 MHz, DMSO-ok) 5 7.76 (dd, J = 8.8, 4.8 Hz, 1H), 7.64 (dd, J =8.0, 3.2 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 6.0 Hz, 1H), 5.60 (s, 2H), 3.40 (t, J = 8.0 Hz, 2H), 0.90 - 0.84 (m, 2H), 0.84 - 0.76 (m, 2H), 0.74 (t, J = 8.0 Hz, 2H), 0.00 - -0.02 (m, 9H).

[0373] Step E: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-{[2- (trimethylsilyl)ethyl]oxy}-3,4-dihydrospiro[benzo[l,4]oxazine-2,T-cyclopropane]-3-one (150 mg, 0.248 mmol) in dioxane (20 m ) was added 5-fluoro-3-(trifluoromethyl)benzene-l- carboxamide (0.430 g, 2.09 mmol), CS2CO3 (2.05 g, 6.29 mmol), Pd2(dba)s (0.190 g, 0.210 mmol) and Xantphos (0.240 g, 0.420 mmol). The reaction mixture was stirred at 100 °C under N2 for 1 hr. The reaction was completed and monitored by TLC. The cooled reaction mixture was diluted with water, extracted with EA (80 mL). The organic phase was washed with brine, dried over NaiSCU and concentrated. The residue was purified by silica gel chromatography (eluting with 20-100% EAin PE) to afford N-{5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-4-(5,5- dimethyl-2-oxa-5-silahex-l-yl)-3-oxo-3,4-dihydrospiro[benzo[l,4]oxazine-2,l'-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]+.

[0374] Step F: To a solution ofN-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-3-oxo-4-((2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydrospiro[benzo[l,4]oxazine-2,l'-cyclopropan]-7-yl)-3- fluoro-5-(trifluoromethyl)benzamide (435 mg, 0.583 mmol) in dioxane (5 mL) was added HCl / dioxane (5 mL). The reaction mixture was stirred at 60 °C overnight. The reaction was completed 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[l,4]oxazine-2,T- cyclopropan]-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.162 mmol, 27%) as a yellow solid. LCMS: ESI m / z 615.74 / 617.74 [M + H]+.

[0375] Step G: To a solution of N-(5-bromo-6-(2-chloro-5-fluorobenzoyl)-3-oxo-3,4- dihydrospiro[benzo[l,4]oxazine-2,l'-cyclopropan]-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.162 mmol) in NMP (3 mL) was added CuCN (21.8 mg, 0.244 mmol). The reaction mixture was stirred at 130 °C under N2 for 3 hrs. The reaction was completed and monitored by LCMS. The cooled reaction mixture was diluted with water, extracted with EA. The organicphase was washed with brine, dried over NazSCU and concentrated. The residue was purified by silica gel chromatography (eluting with 0-100% EA in PE) to afford N-{6-[(2-chloro-5- fluorophenyl)carbonyl]-5-cyano-3-oxo-3,4-dihydrospiro[benzo[l,4]oxazine-2,l'-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]+.

[0376] Step H: To a solution ofN-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-3-oxo- 3,4-dihydrospiro[benzo[l,4]oxazine-2,l'-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 completed and monitored by LCMS. The reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,9-dioxo-2,7,8,9-tetrahydro- lH-spiro[[l,4]oxazino[3,2-e]isoindole-3,l'-cyclopropane]-6-yl]-3-fluoro-5-(tri fl uorom ethyl )benzam ide (90.0 mg, 0.155 mmol, 96%) as a yellow oil. LCMS: EST m / z580.86 [M + H]+.

[0377] Step I: To a solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,9-dioxo-2,7,8,9- tetrahydro-lH-spiro[[l,4]oxazino[3,2-e]isoindole-3,T-cyclopropane]-6-yl]-3-fluoro-5- (trifluoromethyl)benzamide (90 mg, 0.155 mmol) in TFA (1 mL) was added EtaSiH (0.200 mL). The reaction mixture was stirred at 50 °C for 0.5 hr. The reaction mixture was completed and monitored by LCMS. The reaction mixture was concentrated and purified by prep-HPLC (Cl 8, 30 ~ 95 % ACN in H2O with 0.1 % TFA) to afford N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo- 2,7,8,9-tetrahydro-lH-spiro[[l,4]oxazino[3,2-e]isoindole-3,r-cyclopropane]-6-yl]-3-fluoro-5- (trifluoromethyl)benzamide (22.7 mg, 0.0402 mmol, 23%) as a yellow solid. LCMS: ESI m / z564.87 [M + H]+. ‘HNMR (400 MHz, DMSO ) 5 10.36 (s, 1H), 9.60 (s, 1H), 9.32 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.08 (td, J = 8.4, 3.2 Hz, 1H), 7.04 (s, 1H), 5.96 (brs, 1H), 1.41 - 1.31 (m, 4H).Example 51 N- [6-(2-chloro-5-fluorophenyl)-2,8-dioxo-3-(2,2,2-trifluoroethyl)-7,8-dihydro- 6H-[l,3]oxazolo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[0378] 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) at 0 °C under nitrogen atmosphere was added Borane-methyl sulfide complex (0.36 mL, 3.60 mmol). The reaction mixture was stirred at 70 °C for 2 hr. 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 NaiSCU and concentrated. The residue was purified by silica gel chromatography (PE / EA= 1 / 100-100 / 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 yellow oil. LCMS: m / z 486.2 [M+H]+.

[0379] 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 / FfO (5:1) (10 mL) were added Fe (190 mg, 3.40 mmol) and NH4CI (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 NaiSCU and concentrated to afford 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]+.

[0380] 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) were 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 rt for 1 hr. The reaction mixture was concentrated. The residue was diluted with water, extracted with EA. The organic layer was washed with brine, dried over ISfeSCL and concentrated to afford crudecompound 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]+.

[0381] Step D: To a solution ofN-{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)2 (39.3 mg, 0.335 mmol) and Pd(PPh3)4 (32.2 mg, 0.028 mmol). The reaction mixture was degassed with N2 and stirred at 130 °C under N2 atmosphere for 1 hr using microwave. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over JSfeSCU and concentrated. The residue was purified using silica gel column chromatography eluted with EA / PE (1 / 100-2 / 1 ) to afford compound N-{2-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-4- methoxy-5-[(2,2,2-trifluoroethyl)amino]phenyl}-3-fluoro-5-(trifluoromethyl)benzamide (130 mg, 0.22 mmol, 79%) as a yellow oil. LCMS: m / z 592.1 [M+H]+.

[0382] 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 rt for 2 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (l%~60%) to afford compound N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7- methoxy-l-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (140 mg, 0.23 mmol, 97%) as a white solid. LCMS: m / z 608.0 [M- H]-.

[0383] Step F: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-l- oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (140 mg, 0.230 mmol) in TFA (5 mL) was added EfSiH (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, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in DCM (0%~10%) to afford compound N-[3-(2- chloro-5-fluorophenyl)-7-methoxy-l-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-lH-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]+.

[0384] Step G: To a solution of N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-l-oxo-6-[(2,2,2- trifluoroethyl)amino] -2,3 -dihydro- 1 H-i soindol-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 at under N2 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 obtain crude the N-[3-(2-chloro- 5-fluorophenyl)-7-hydroxy-l-oxo-6-[(2,2,2-trifluoroethyl)amino]-2,3-dihydro-lH-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]+.

[0385] Step H: To a solution of N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-l-oxo-6-[(2,2,2- trifluoroethyl)amino]-2,3-dihydro-lH-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 prep-HPLC (acetonitrile with 0.1% FA in water 30% to 70%) to give N-[6-(2-chloro-5- fluorophenyl)-2,8-dioxo-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-[l,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]+. 'HNMR (400 MHz, DMSO ) 8 10.50 (s, 1H), 9.28 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.35 - 7.24 (m, 1H), 7.16 - 7.01 (m, 1H), 6.68 (brs, 1H), 6.05 (brs, 1H), 5.03 - 4.74 (m, 2H).Example 52 N- [6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2,8-dioxo-7,8-dihydro- 6H-[l,3]oxazolo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0386] 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 mb, 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 give 3- methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (40 g, 152 mmol, 100%) as a yellow solid. LCMS: m / z 262.1 [M-H]'.

[0387] Step B: To a solution of 3-methoxy-4-[(trifluoroacetyl)amino]benzoic acid (40 g, 152 mmol) in con.FESCE (98%, 1000 mL) was added dropwise a solution of con.HNCh (13.6 g) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then the mixture was slowly poured into ice water (2000 mL) and filtered to give 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (40 g, 129 mmol, 85%) as a brown solid. LCMS: m / z 307.0 [M-H]'.

[0388] Step C: To the solution of 5-methoxy-2-nitro-4-[(trifluoroacetyl)amino]benzoic acid (40 g, 129 mmol) in THF (400 mL) was added potion-wise BH3-Me2S (10M, 39.0 mL, 390 mmol, 3.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 20 h. The mixture was added water (100 mL) and extracted with EtOAc (300 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated to give 2,2,2-trifluoro-N-(4-(hydroxymethyl)-2-methoxy-5-nitrophenyl)acetamide (9.0 g, 30.6 mmol, 24%) as a yellow solid. LCMS: m / z 293.0 [M-H]'. ’H NMR (400 MHz, DMSO i 5 11.01 (s, 1H), 8.30 (s, 1H), 7.55 (s, 1H), 5.70 (t, J= 5.6 Hz, 1H), 4.90 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H).

[0389] 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 The mixture was added water (30 mL) and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give 2,2,2-trifluoro-N-(4-formyl-2- methoxy-5-nitrophenyl)acetamide (8.4 g, 28.8 mmol, 94%) as a yellow solid. LCMS: m / z 291 [M-H]'. ’H NMR (400 MHz, DMSO-tL) 5 11.22 (s, 1H), 10.30 (s, 1H), 8.45 (s, 1H), 7.49 (s, 1H), 4.04 (s, 3H).

[0390] 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 rt for 18 h. The mixture was poured into icewater (200 mL) and filtered to give the 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 [M-H]'.

[0391] 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) were added bromo(2-chloro-5- fluorophenyl)magnesium (O.5M,13OM1,13.6 g, 57.9 mmol). The reaction was stirred at rt under N2 for 2 hr. LCMS showed the reaction was completed and. The reaction mixture was quenched with aqueous NH4CI, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted 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]+.

[0392] 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 CH2CI2 (200 mL) were added Dess-Martin periodinane (10.1 g, 23.9 mmol). The mixture was stirred at rt for 2 hr. LCMS showed the reaction was completed and. The reaction was diluted with DCM and H2O. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 15-25%) toafford N-{3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}-2,2,2- trifluoroacetamide (5.9 g, 11.8 mmol, 98%) as a red solid. LCMS: ESI m / z 499 / 501 [M + H]+.

[0393] 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) were added KOH (3.37 g, 60.0 mmol). The reaction was stirred at 80 °C under N2 for 1 hr. LCMS showed the reaction was completed and. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether(gradient:20-30%) to afford (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]+.

[0394] 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) were added 2,2-difluoroacetic anhydride (0.172 mL, 1 .49 mmol). The reaction was stirred at room temperature under N2 for 18 hr. LCMS showed the reaction was completed and. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 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]+.

[0395] 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 THE (15 mL) were added borane dimethyl sulfane (10M, 0.125 mL, 1.24 mmol). The reaction was stirred at 70 °C under N2 for 2 hr. LCMS showed the reaction was completed and. The cooled reaction mixture was quenched MeOH, diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 30-40%) to afford {2- bromo-4-[(2,2-difluoroethyl)amino]-3-methoxy-6-nitrophenyl}(2-chl oro-5- fluorophenyl)methanone (250 mg, 0.535 mmol, 64%)as a yellow solid. LCMS: ESI m / z 467 / 469 [M + H]+.

[0396] 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 (15mL) and H2O (3 mL) were added Fe (119 mg, 2.13 mmol) and NH4CI (114 mg, 2.14 mmol) .The reaction was stirred at 80 °C under N2 for 2 hr. LCMS showed the reaction was completed and. The cooled reaction mixture was filtered, concentrated, diluted water, extracted with EA. The organic phase was washed with brine, dried over NaiSCE and concentrated. The residue was purified using 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]+.

[0397] 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) were added Zn(CN)i (56.3 mg, 0.480 mmol), and Pd(PPh3)4 (36.9 mg, 0.032 mmol). The reaction was stirred at 130 °C under N2 for 1.5 hr using M.W. LCMS showed the reaction was completed and. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in dichloroform(gradient: 10- 20%) to afford 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]+.

[0398] Step M: To a solution of 3-amino-2-[(2-chloro-5-fluorophenyl)carbonyl]-5-[(2,2- difluoroethyl)amino]-6-methoxybenzene-l -carbonitrile (100 mg, 0.261 mmol) in ACN (10 mL) were 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 N2 for 2 hr. LCMS showed the reaction was completed and. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether(gradient:30-40%) to afford 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]+.

[0399] 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) were added KOH (32.2 mg, 0.575 mmol). The reactionwas stirred at room temperature under N2 for 1 hr. LCMS showed the reaction was completed and. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The organic layer was separated and concentrated to afford N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl)amino]-3-hydroxy- 7-methoxy-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (110 mg, 0.186 mmol, 97%) as a yellow solid. LCMS: ESI m / z 590 [M - H]'.

[0400] Step O: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-6-[(2,2- difluoroethyl)amino]-3-hy droxy-7-methoxy-l-oxo-2, 3-dihy dro-lH-isoindol -4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (110 mg, 0.186 mmol) in TFA (5 mL) were added EtsSiH (21.6 mg, 0.186 mmol). The reaction was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed and. The cooled reaction mixture was concentrated, diluted aqueous NaHCCh and extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 30-40%) to afford N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2- difhioroethyl)amino]-7-methoxy-l -oxo-2, 3-dihy dro-lH-isoindol -4-yl]-5-fluoro-3- (trifhioromethyl)benzamide (80 mg, 0.139 mmol, 75%) as a yellow solid. LCMS: ESI m / z 576 [M + H]+.

[0401] Step P: To a solution of N-fS-^-chloro-S-fluoropheny^-d-f^^- difhioroethy^aminoJ^-methoxy-l -oxo-2, 3-dihy dro-lH-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). The reaction was stirred at rt for 18 hr. LCMS showed the reaction was completed and. The reaction was diluted with EA and NaHCCL. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-TLC ethyl acetate in petroleum ether (gradient: 40-50%) to afford compound N-[3-(2-chloro-5- fluorophenyl)-6-[(2,2-difluoroethyl)amino]-7-hydroxy-l -oxo-2, 3-dihy dro-lH-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]+.

[0402] Step Q: To a solution of N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2- difluoroethyl)amino]-7-hydroxy-l -oxo-2, 3-dihydro- lH-isoindol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (40 mg, 0.071 mmol) in dioxane (3 mL) were added CD1 (23 mg, 0.142 mmol). The reaction was stirred at 100 °C for 1 hr. LCMS showed the reaction wascompleted and. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2,8-dioxo-7,8- dihydro-6H-[l,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]+. 'HNMR (400 MHz, DMSO- d6) 8 10.48 (s, 1H), 9.26 (s, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.34 - 7.25 (m, 1H), 7.15 - 7.05 (m, 1H), 6.60 - 6.30 (m, 1H), 6.02 (brs, 1H), 4.54 - 4.27 (m, 2H).Example 53 N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-3,9-dioxo-l,3,4,7,8,9- hexahydro[l,3]oxazino[5,4-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl) benzamide

[0403] Step A: To a solution of 2,6-dibromo-4-fluorobenzene-l-carbaldehyde (10 g, 35.5 mmol) in 1,2-di chloroethane (80 mL) was added ethylene glycol (9.9 mL, 177.4 mmol), triethoxymethane (5.0 mL, 30.5 mmol), 4-methylbenzenesulfonic acid (0.06 g, 0.36 mmol) at 25 °C. The reaction mixture was stirred at 80 °C O / N. The reaction mixture was cooled to 20 °C, washed successively with saturated NaHCCh (100 mL), and brine (2 * 100 mL), dried over NaiSCL and concentrated under reduced pressure to give residue. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (0%~5%) to afford 2-(2,6-dibromo-4-fluorophenyl)-l,3-dioxolane (7.8 g, 23.9 mmol, 67%) as a white solid. 'HNMR (400 MHz, DMSO-tL) 6 7.75 (d, J = 8.0 Hz, 2H), 6.22 (s, 1H), 4.22 (m, 2H), 4.01 (m, 2H).

[0404] Step B: To a solution of 2-(2,6-dibromo-4-fluorophenyl)-l,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 was stirred at -78 °C for 30min. Hexahydropyridine- 1-carbaldehy de (5.9 g, 52.0 mmol) was then slowly added. The reaction mixture was stirred for an additional 30min at -78 °C. Then the mixture was added to sat. NH4CI (100 mL), extracted with ethyl acetate (80 mL * 3). The combined organic phases were washed with brine (100 mL), dried over NaiSCU and concentrated to give a residue. The residue was purified by silica gel (EtOAc in PE = 10%) to give 2,4- dibromo-3-(l,3-dioxolan-2-yl)-6-fluorobenzene-l-carbaldehyde (8 g, 22.6 mmol, 65%) as a yellow solid. ‘H NMR (400 MHz, DMSO-tL) 8 10.19 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 6.35 (s, 1H), 4.27 - 4.21 (m, 2H), 4.07 - 4.01 (m, 2H).

[0405] Step C: To a solution of 2,4-dibromo-3-(l,3-dioxolan-2-yl)-6-fluorobenzene-l- carbaldehyde (3.9 g, 11.0 mmol) in dioxane (40 mL) was added DIEA (1.9 mL, 11.0 mmol) and 2,2-difluoroethan-l -amine (3.11 mL, 44.1 mmol) and was sealed and stirred at 80 °C O / N. The reaction mixture was quenched with IN HC1 (50mL) and was extracted with EtOAc (70 mL*3). The organic layer was separated, 4-methyl-benzenesulfonic acid (2.28 g, 13.2 mmol) was added. The reaction mixture was stirred at rt for 30 min (monitored by LCMS). Brine was added, the organic layer was separated and dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 5-10%) to afford 2,4-dibromo-6-[(2,2-difluoroethyl) amino]-3-(l,3-dioxolan-2-yl) benzene- 1-carbaldehy de (2.7 g, 6.5 mmol, 59%) as a yellow solid. LCMS: m / z 416 [M+H]+.

[0406] Step D: To a solution of 2,4-dibromo-6-[(2,2-difluoroethyl) amino]-3-(l,3-dioxolan- 2-yl) benzene- 1-carbaldehy de (760 mg, 1.83 mmol) in MeOH (7 mL) was added NaBHi (83.1 mg, 2.2 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and was stirred for Ih. The reaction mixture was quenched with water (10 mL) and was extracted with EtOAc (15 mL*3). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 10-15%) to afford {2,4-dibromo-6-[(2,2-difluoroethyl) amino]-3-(l,3- dioxolan-2-yl) phenyl} methanol (0.3 g, 0.72 mmol, 39 %) as a white solid. LCMS: m / z 418 [M+H]+. 1H NMR (400 MHz, DMSO-t / 6) 8 7.04 (s, IH), 6.34 - 5.97 (m, 3H), 5.38 (t, J = 5.2 Hz, IH), 4.73 (d, J = 5.2 Hz, 2H), 4.16 (t, J = 6.8 Hz, 2H), 3.94 (t, J = 6.8 Hz, 2H), 3.76 - 3.58 (m, 2H).

[0407] Step E: To a solution of {2,4-dibromo-6-[(2,2-difluoroethyl) amino]-3-(l,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 rt. The reaction mixture was stirred at 130°C until neat. The reaction mixture was quenched with water (10 mL) and was extracted with EtOAc (15 mL*3). The organic layer was separated, dried over NaiSCh and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-15%) to afford 5,7-dibromo-l-(2,2-difluoroethyl) -6-(l,3-dioxolan-2-yl)-2,4-dihydro-lH-benzo[d] [1,3] oxazin-2-one (1.2 g, 2.71 mmol, 38%) as a white solid. LCMS: m / z 444 [M+H]+.

[0408] Step F: To a solution of 5,7-dibromo-l-(2,2-difluoroethyl)-6-(l,3-dioxolan-2-yl)-2,4- dihydro-lH-benzo[d] [1,3] oxazin-2-one (700 mg, 1.58 mmol) in THF (7 mL) was added conc.HCl (0.3 mL, 3.20 mmol) at rt. The reaction mixture was stirred for 2h. The reaction mixture was quenched with water (10 mL) and was extracted with EtOAc (15 mL*3). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 20%) to afford 5,7-dibromo-l-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-lH- benzo[d] [1,3] oxazine-6-carbaldehyde (0.6 g, 1.5 mmol, 95%) as a yellow solid. LCMS: m / z 400 [M+H]+.

[0409] Step G: To a solution of 5,7-dibromo-l-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-lH- 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. Then the mixture was added to sat. NH4CI (15 mL), extracted with ethyl acetate (20 mL * 2). The combined organic phases were washed with brine (20 mL* 2), dried over Na2SC>4 and concentrated to give a residue. The residue was purified by silica gel (eluted with EtOAc in petroleum ether = 0 -15 %) to give 5,7- dibromo-6-[(2-chloro-5-fluorophenyl) carbonyl]-l-(2,2-difluoroethyl)-2,4-dihydro-lH-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]+.

[0410] Step H: A solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl) (hydroxy) methyl]- l-(2,2-difluoroethyl)-2,4-dihydro-lH-benzo[d] [1,3] oxazin-2-one (650 mg, 1.23 mmol) in DCM (7 mL) was added Dess-Martin periodinane (624.8 mg, 1.47 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The mixture was added to ice water (10 mL) and extracted with DCM(20 mL x 2). The combined organic phase was washed with brine (10 m x 2), dried over Na2SC>4 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]-l-(2,2-difluoroethyl)-2,4- dihydro-lH-benzo[d] [1,3] oxazin-2-one (540 mg, 1.0 mmol, 83%) as a white solid. LCMS(ESI): m / z 528 [M+H]+.

[0411] ’H NMR (400 MHz, DMSO-tL) 5 7.75 (m, 2H), 7.65 - 7.59 (m, 1H), 7.55 (m, 1H), 6.33 (m, 1H), 5.38 (d, J = 7.2 Hz, 2H), 4.49 (m, 2H).

[0412] Step I: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl) carbonyl]- 1 -(2,2- difluoroethyl)-2,4-dihydro-lH-benzo[d] [1,3] oxazin-2-one (50 mg, 0.1 mmol), CS2CO3 (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 Pd2(dba)3 (8.7 mg, 0.01 mmol). The mixture was stirred at 100 °C under N2 for 2h. The cooled mixture was diluted with water, extracted with EA (10 mL x 3). The combined organic phases were washed with brine, dried over NaiSCL and concentrated. The residue was purified by silica gel (PE / EtOAc = 10 %) to give N-{5-bromo-6-[(2-chloro-5-fluorophenyl) carbonyl]-l-(2,2-difluoroethyl)-2-oxo- 2,4-dihydro-lH-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[M-H]‘.

[0413] Step J: To a solution of N-{5-bromo-6-[(2-chloro-5-fluorophenyl) carbonyl]- 1 -(2,2- difluoroethyl)-2-oxo-2,4-dihydro-lH-benzo[d] [1,3] oxazin-7-yl} -5 -fluoro-3 -(trifluoromethyl) benzamide (100 mg, 0.15 mmol), Zn(CN)2 (26.9 mg, 0.23 mmol) in anhydrous DMA (2 mL) was added Pd(PPhs)4 (17.7 mg, 0.02 mmol). The mixture was stirred at 150 °C under N2 for 2h. The cooled mixture was diluted with water, extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (PE / EtOAc = 2:1) to give N-{6-[(2-chloro-5-fluorophenyl) carbonyl]-5- cyano-l-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-lH-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]+

[0414] Step K: To a stirred solution of N-{6-[(2-chloro-5-fluorophenyl) carbonyl]-5-cyano- l-(2,2-difluoroethyl)-2-oxo-2,4-dihydro-lH-benzo[d] [1,3] oxazin-7-yl}-5-fluoro-3- (trifluoromethyl) benzamide (20 mg, 0.03 mmol) in CH3CN (1 mL) was added KOH (2.86 mg, 0.05 mmol) and H2O (1 mL). The reaction mixture was stirred at rt for 1 h. The reaction wasmonitored by TLC. The mixture was treated with H2O (10 mL) and extracted with EA (3 * 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated to afford N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl) amino]-3 -hydroxy - 7-(hydroxymethyl)-l -oxo-2, 3-dihydro-lH-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl) benzamide (5 mg, 0.01 mmol, 25%) as a yellow oil, and was used without further purification. LCMS (ESI): m / z 590 [M-H]-

[0415] Step L: To a stirred solution of N-[3-(2-chloro-5-fluorophenyl)-6-[(2,2-difluoroethyl) amino]-3-hy droxy-7-(hydroxymethyl)-l -oxo-2, 3-dihy dro-lH-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 rt. The mixture was stirred O / N at 80 °C. The mixture was treated with H2O (5 mL) and extracted with EA (3 * 8 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated to afford N-[7-(2-chloro-5-fluorophenyl)-4-(2,2- difluoroethyl)-7-hydroxy-3,9-dioxo-l,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 yellow oil, and was used without further purification. LCMS(ESI): m / z 616 [M-H]'

[0416] Step M: To a stirred solution of N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl) -7-hydroxy-3,9-dioxo-l,3,4,7,8,9-hexa-hydro [1,3] oxazino[5,4-e] isoindol-6-yl]-5-fluoro-3- (trifluoromethyl) benzamide (10 mg, 0.02 mmol) in TFA (1 mL) was added triethylsilane (6 mg, 0.05 mmol) at rt. The mixture was stirred for Ih at 60 °C. The mixture was concentrated to give a residue. The residue was purified by prep-TLC (DCM / MeOH = 10: 1) and prep-HPLC to give N-[7-(2-chloro-5-fluorophenyl)-4-(2,2-difluoroethyl)-3,9-dioxo-l,3,4,7,8,9-hexa-hydro [1,3] oxazino[5,4-e] isoindol-6-yl]-5-fluoro-3-(trifluoromethyl) benzamide (1 mg, 0.002 mmol, 10%) as a white solid. LCMS(ESI): m / z 602 [M+H]+. 'H NMR (400 MHz, CD3OD) 8 7.76 - 7.53 (m, 3H), 7.37 (s, IH), 7.27 (dd, J = 8.8, 5.2 Hz, IH), 7.04 - 6.95 (m, IH), 6.41 - 6.07 (m, 2H), 5.92 (d, J = 2.4 Hz, 2H), 4.45 - 4.32 (m, 2H).Example 54 N-(7-(2-chloro-5-fluorophenyl)-2,2-dioxido-9-oxo-l,7,8,9-tetrahydro-3H- [l,3?4]oxathiazino[5,6-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0417] 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), TBSCI (2.71 g, 18 mmol) was added. The resulting mixture was stirred at 23 °C for 2h. The mixture was treated with H2O (100 mL) and extracted with EA (3x300 mL). The organic phase was washed with brine, dried over anhydrous NazSCL and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether and dried to afford compound (3-amino-2-bromo-4-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-6- nitrophenyl)(2-chloro-5-fluorophenyl)methanone (2 g, 3.97 mmol, 44%) as a yellow oil. LCMS: m / z 501 [M-H]'.

[0418] Step B: To a solution of (3 -amino-2-bromo-4-{ [dimethyl (2 -methylprop-2- yl)silyl]oxy}-6-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (2 g, 3.97 mmol) in Py (13 mL) and THF (13 mL) was added chloromethanesulfonyl chloride (0.9 mL, 9.92 mmol). The reaction mixture was refluxed for Ih. The reaction mixture was cooled to 25 °C. quenched with aqueous solution H2O (30 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over NazSCh and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether and dried to afford compound give N-{2-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[dimethyl(2- methylprop-2-yl)silyl]oxy}-4-nitrophenyl}-l -chloromethanesulfonamide (1.6 g, 2.6 mmol, 65%) as a yellow oil. LCMS: m / z 613 [M-H]'.

[0419] Step C: A solution of N-{2-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6- {[dimethyl(2-methylprop-2-yl)silyl]oxy}-4-nitrophenyl}-l-chloromethanesulfonamide (1.6 g, 2.6 mmol) in DMF (6 mL) were 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 phase was driedover anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EA=2: 1) followed to give 8-bromo-7-[(2-chloro-5- fluorophenyl)carbonyl]-6-nitro-lH-2X6-benzo[2, l-e][l, 3, 4] oxathiazine-2, 2-dione (700 mg, 1.5 mmol, 57.9%) as a yellow oil. LCMS: ESI m / z 465 [M + H]+.

[0420] Step D: To a solution of 8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-6-nitro-lH- 2X6-benzo[2, l-e][l, 3, 4] oxathiazine-2, 2-dione (700 mg, 1.5 mmol) in EtOH (28 mL) and HoO (7 mb) was added Fe (420 mg, 7.52 mmol) and NH4CI (402 mg, 7.52 mmol). The reaction mixture was stirred at 80 °C for 3 hrs. The cooled reaction mixture was filtered through Buchner funnel and washed with EA (200mL). The filtrate was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in di chloroform to afford compound 6-amino-8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-lH-2X6-benzo[2, 1- e][l, 3, 4]oxathiazine-2, 2-dione (500 mg, 1.15 mmol, 76%) as a yellow solid. ’H NMR (400 MHz, DMSO-t / e) 5 9.36 (s, 1H), 7.62 (dd, J= 8.0 Hz, 4.0 Hz, 1H), 7.46 (td, J= 8.0 Hz, 4.0 Hz, 1H), 7.23 (dd, J= 8.4, 3.2 Hz, 1H), 6.54 (s, 1H), 6.02 (s, 2H), 5.18 (s, 2H).

[0421] Step E: To a solution of 6-amino-8-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]- lH-2X6-benzo[2, l-e][l, 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 water, extracted with EA. The organic phase was washed with brine, dried over anhydrous NazSCU and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford compound 6-amino-7-[(2-chloro-5-fluorophenyl)carbonyl]-2,2-dioxo- lH-2X6-benzo[2,l-e][l,3,4]oxathiazine-8-carbonitrile (80 mg, 0.21 mmol, 91%) as a yellow solid. LCMS: ESI m / z 382 [M + H]+.

[0422] Step F: To a solution of 6-amino-7-[(2-chloro-5-fluorophenyl)carbonyl]-2,2-dioxo- lH-2X6-benzo[2,l-e][l,3,4]oxathiazine-8-carbonitrile (70 mg, 0.183 mmol) in CH3CN (3 mL) and H2O (0.3 mL) was added KOH (30.9 mg, 0.55 mmol). The mixture was stirred at 50 °C for 1 h. The cooled mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in di chloroform to afford compound 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-l,7,8,9-tetrahydro-2X6- [1, 3, 4]oxathiazino[5,6-e]isoindole-2, 2, 9-trione (40 mg, 0.1 mmol, 55%) as a yellow solid.

[0423] Step G: To a solution of 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-l,7,8,9- tetrahydro-26-[l, 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 rt for Ihr. Then the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20mL x 2). The combined organic phases were washed with brine (20 mL) dried over NaiSCh and concentrated to give N-[7-(2-chloro-5- fluorophenyl)-7-hydroxy-2,2,9-trioxo-l,7,8,9-tetrahydro-2X.6-[l,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 [M - H]’.

[0424] Step H: To a solution ofN-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-2,2,9-trioxo- l,7,8,9-tetrahydro-2X6-[l,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 under vacuum. The residue was purified by prep-HPLC to afford N-[7-(2-chloro-5-fluorophenyl)-2,2,9- trioxo- 1,7,8, 9-tetrahydro-2X6-[ 1,3, 4]oxathiazino[5,6-e]isoindol-6-yl]-5-fluoro-3- (trifluoromethyl)benzamide (1.1 mg, 0.002 mmol, 6%) as a white solid. LCMS: ESI m / z 574 [M + H]+. ‘H NMR (400 MHz, CD3OD) 8 7.68 - 7.60 (m, 3H), 7.38 - 7.16 (m, 2H), 6.99 (t, J= 8.0 Hz, 1H), 6.67 (brs, 1H), 6.10 (brs, 1H), 5.22 (s, 2H).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 Example 56 (S)-N-(7-(2-chloro-5-fluorophenyl)-3-(methyl-d3)-2,9-dioxo-2,3,4,7,8,9- hexahydro-[l,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide Example 57 (R)-N-(7-(2-chloro-5-fluorophenyl)-3-(methyl-d3)-2,9-dioxo-2,3?4,7,8,9- hexahydro-[l,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0425] 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 stirred at 65 °C for 3h, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-20%, EtOAc in PE) to give 2,6-dibromo-3-methyl-4-nitrophenol (45.1 g, 145 mmol, 71 %) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 8.21 (s, 1H), 2.51 (s, 3H).

[0426] Step B. To a solution of 2,6-dibromo-3-methyl-4-nitrophenol (44.2 g, 142 mmol) in CH3CN (450 mL) were added K2CO3 (29.5 g, 213 mmol) and CH3I (13.8 mL, 171 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-10%] to afford compound 3,5-dibromo-4-methoxy-2-methyl-l-nitrobenzene (41 g, 126 mmol, 89 %) as a white solid. ’H NMR (400 MHz, DMSO-tL) 6 8.30 (s, 1H), 3.87 (s, 3H), 2.47 (s, 3H).

[0427] Step C. To a solution of 3,5-dibromo-4-methoxy-2-methyl-l-nitrobenzene (41 g, 126 mmol) in CCh (300 mL) were 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 withH2O, extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EAin PE [Gradient : 0-15 %] to afford compound 3,5-dibromo-2-(bromomethyl)-4-methoxy-l- nitrobenzene (46.1 g, 89 mmol, 94 %) as a white solid.

[0428] Step D. To a solution of 3,5-dibromo-2-(bromomethyl)-4-methoxy-l-nitrobenzene (46.1 g, 89 mmol) in CH3CN (400 mL) was added NMO (20.9 g, 178 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na SC and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-30%] to afford compound 2,4-dibromo-3-methoxy-6-nitrobenzene-l-carbaldehyde (35.1 g, 74 mmol, 83 %) as a yellow solid.

[0429] Step E. To a solution of 2,4-dibromo-3-methoxy-6-nitrobenzene-l-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 RT for 2 h. The reaction mixture was quenched with NH4CI, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-40%] to afford compound (2-chloro-5-fluorophenyl)(2,4- dibromo-3-methoxy-6-nitrophenyl)methanol (40.2 g, 85.6 mmol, 95 %) as a white solid.

[0430] Step F. To a stirred solution of (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6- nitrophenyl)methanol (40.2 g, 85.6 mmol) in DCM (420 mL) was added DESS-MARTIN (40 g, 94.2 mmol) slowly at 0 °C. After stirred at rt for 3h, the mixture was poured into ice-water (500 mL) and extracted with DCM (200 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6- nitrophenyl)methanone (35.5 g, 75.9 mmol, 89 %) as a brown solid. 'H N R (400 MHz, DMSO-tL) 8 8.68 (s, 1H), 7.82 - 7.60 (m, 3H), 3.95 (s, 3H).

[0431] 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-oxahex-6-yl)trifluoro-X5-boranuide (5 g, 25.7 mmol), Pd(dppf)C12 (1.25 g, 1.71 mmol) and K2CO3 (5.91 g, 42.8 mmol) at rt . After stirred at 70 °C under N2 overnight, the cooled mixture was poured into ice-water (100 mL) and extracted with DCM (80 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered andconcentrated. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-methoxy-5- nitrophenyl}methyl)amino]methanoate (2.5 g, 4.83 mmol, 22 %) as a brown solid. LCMS: m / z 517 [M+H]+.

[0432] Step H. To a stirred solution of 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)amino]methanoate (1.6 g, 3.09 mmol) in DMF (20 mL) was added NaH (370 mg, 9.27 mmol, 60% in mineral oil) slowly at - 20 °C. After stirred at -20 °C for Ih, CD3I (2.24 g, 15.452 mmol) was added to the mixture. After stirred at rt for 2h, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give 2-m ethyl propan-2-yl [({3-bromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(trideuteriomethyl)amino]methanoate (1 g, 1.87 mmol, 61 %) as a yellow solid. LCMS: m / z 535 [M+H]+.

[0433] Step I. To a stirred solution of 2-methylpropan-2-yl [({3-bromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}methyl)(trideuteriomethyl)amino]methanoate (1 g, 1.87 mmol) in EtOH (16 mL) / H2O (4 mL) was added NH4CI (300 mg, 5.61 mmol) and Fe (835 mg, 14.9 mmol) at rt. After stirred at 80 °C for 2h, the mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50 %, EtOAc in PE) to give crude 2-methylpropan-2-yl [({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2- methoxyphenyl}methyl)(trideuteriomethyl)amino]methanoate (820 mg, 1.62 mmol, 87 %) as a yellow solid. LCMS: m / z 505 [M+H]+.

[0434] Step J. To a stirred solution of 2-methylpropan-2-yl [({5-amino-3-bromo-4-[(2- chloro-5-fluorophenyl)carbonyl]-2- methoxyphenyl}methyl)(trideuteriomethyl)amino]methanoate (820 mg, 1.62 mmol) in NMP (10 mL) was added CuCN (291 mg, 3.25 mmol) at rt . After stirred at 130 °C for 5h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50 %, EtOAc in PE) to give 2-methylpropan-2-yl[({5-amino-4-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyano-2- methoxyphenyl}methyl)(trideuteriomethyl)amino]methanoate (550 mg, 1.22 mmol, 75 %) as a yellow solid. LCMS: m / z 451 [M+H]+.

[0435] Step K. To a stirred solution of 2-methylpropan-2-yl [({5-amino-4-[(2-chloro-5- fluorophenyl)carbonyl]-3-cyano-2-methoxyphenyl]methyl)(trideuteriomethyl)amino]methanoate (500 mg, 1.1 mmol) in ACN (3 mb) / H2O (1 mL) was added KOH (622 mg, 11.1 mmol) slowly at rt. After stirred at rt for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM to give 2-methylpropan-2-yl ({[7-amino-l-(2-chloro-5-fluorophenyl)-l- hy droxy-4-methoxy-3 -oxo-2, 3 -dihydro- 1 H-i soindol-5 - yl]methyl] (trideuteri omethyl)amino)methanoate (480 mg, 1.02 mmol, 92 %) as a white solid. LCMS: m / z 469 [M+H]+.

[0436] Step L. To a stirred solution of 2-methylpropan-2-yl ({[7-amino-l -(2-chloro-5- fluorophenyl)-l-hydroxy-4-methoxy-3-oxo-2,3-dihydro-lH-isoindol-5- yl]methyl} (trideuteri omethyl)amino)methanoate (480 mg, 1.02 mmol) in ACN (10 mL) was added pyridine (0.3 mL, 3.1 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (348 mg, 1.54 mmol) slowly at rt. After stirred at rt for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 2-methylpropan-2-yl ({[l-(2-chloro-5-fluorophenyl)- 7-({ [5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-l -hydroxy -4-methoxy-3 -oxo-2, 3- dihydro-lH-isoindol-5-yl]methyl}(trideuteriomethyl)amino)methanoate (420 mg, 0.637 mmol, 62 %) as a brown solid. LCMS: m / z 659 [M+H]+.

[0437] Step M. To a stirred solution of 2-methylpropan-2-yl ({[l-(2-chloro-5-fluorophenyl)- 7-({ [5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-l -hydroxy -4-methoxy-3-oxo-2, 3- dihydro-lH-isoindol-5-yl]methyl}(trideuteriomethyl)amino)methanoate (420 mg, 0.637 mmol) in TFA (5 mL) was added EtsSiH (2 mL) at rt . After stirred at 70 °C for 2h, the cooled mixture was concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-l-oxo-6- { [(trideuteri omethyl)amino]methyl} -2, 3-dihydro-lH-isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (320 mg, 0.589 mmol, 92 %) as a white solid. LCMS: m / z 543 [M+H]+.

[0438] Step N. To a stirred solution of N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-l-oxo-6- { [(trideuteri omethyl)amino]methyl] -2, 3-dihy dro-lH-isoindol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (150 mg, 0.276 mmol) in ACN (6 mL) was added TMSC1 (150 mg, 1.38 mmol) and Nal (207 mg, 1.38 mmol) at rt . After stirred at 90 °C for 5h, the cooled mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with JXfeSCU, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-12%, MeOH in DCM) to give crude N-[3-(2- chloro-5-fluorophenyl)-7-hydroxy-l -oxo-6-{ [(trideuteri omethyl)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]+.

[0439] Step O. To a stirred solution ofN-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-l-oxo-6- { [(tri deuteri omethyl)amino]methyl}-2, 3-dihy dro-lH-i soindol-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 rt . After stirred at 50 °C for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-3- (trideuteriomethyl)-2,3,4,7,8,9-hexahydro[l,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]+. ’H NMR (400 MHz, DMSO- L) 5 10.40 (s, IH), 9.20 (s, IH), 8.00 (d, J= 8.4 Hz, IH), 7.68 (d, J= 8.8 Hz, IH), 7.64 (s, IH), 7.36 (s, IH), 7.32 (dd, J= 8.8, 5.2 Hz, IH), 7.12 - 7.06 (m, IH), 5.92 (brs, IH), 4.62 (t, 2H).

[0440] Step P. N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-3-(trideuteriomethyl)-2,3,4,7,8,9- hexahydro[l,3]oxazino[6,5-e]isoindol-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.090 mmol) was purified by SFC to give Pl Example 56: (R)-N-(7-(2-chloro-5-fluorophenyl)-3- (methyl-d3)-2,9-dioxo-2,3,4,7,8,9-hexahydro-[l,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5- (trifluoromethyl)benzamide (10.9 mg, 22%) as a white solid. ’H NMR (400 MHz, DMSO-tL) 8 10.36 (s, IH), 9.04 (s, IH), 7.96 (d, J= 7.2 Hz, IH), 7.72 (d, J= 7.6 Hz, IH), 7.64 (s, IH), 7.36 (s, IH), 7.32 (s, IH), 7.08 (s, IH), 6.64 (brm, IH), 5.96 (s, IH), 4.60 (s, 2H).

[0441] P2 Example 57: (S)-N-(7-(2-chloro-5-fluorophenyl)-3-(methyl-d3)-2,9-dioxo- 2,3,4,7,8,9-hexahydro-[l,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (19.5 mg, 39%) as a white solid.1H NMR (400 MHz, DMSO-t / ) 5 10.36 (s, 1H), 9.04 (s, 1H), 7.96 (d, J= 7.2 Hz, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 7.32 (s, 1H), 7.08 (s, 1H), 6.64 (brm, 1H), 5.96 (s, 1H), 4.60 (s, 2H).

[0442] Preparative separation method:Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IA, 250x30mm I.D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 45%Flow rate: 60mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220nmCycle-time: 12minEluted time: 2HExample 58 N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-2,3,4,7,8,9-hexahydro-[l,3]oxazino[6,5-e]isoindol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0443] 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]methanoate (800 mg, 1.54 mmol) in EtOH (12 mL) / H2O (3 mL) was added NH4CI (248 mg, 4.64 mmol) and Fe (690 mg, 12.3 mmol) at rt. After stirred at 80 °C for 2h, the cooled mixture was fdtered and concentrated. The residue was purified by chromatography (silica gel, 0-50 %, EtOAc in PE) togive crude 2-methylpropan-2-yl [({5-amino-3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2- methoxyphenyl}methyl)amino]methanoate (660 mg, 1.35 mmol, 87%) as a yellow solid. LCMS: m / z 488 [M+H]+.

[0444] 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]methanoate (650 mg, 1.33 mmol) in NMP (10 mL) was added CuCN (358 mg, 3.99 mmol) at rt. After stirred at 130 °C for 3h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated until there was no more drops. 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]methanoate (300 mg, 0.69 mmol, 52%) as a yellow solid. LCMS: m / z 434 [M+H]+.

[0445] 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]methanoate (300 mg, 0.69 mmol) in ACN (3 mL) / H2O (1 mL) was added KOH (194 mg, 3.45 mmol) slowly at rt. After stirred at rt for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, 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-l-(2-chloro-5-fluorophenyl)-l -hydroxy -4-methoxy- 3-oxo-2,3-dihydro-lH-isoindol-5-yl]methyl}amino)methanoate (300 mg, 0.66 mmol, 96%) as a yellow solid. LCMS: m / z 452 [M+H]+.

[0446] Step D. To a stirred solution of 2-methylpropan-2-yl ({[7-amino-l-(2-chloro-5- fluorophenyl)-l-hydroxy-4-methoxy-3-oxo-2,3-dihydro-lH-isoindol-5- yl]methyl}amino)methanoate (250 mg, 0.55 mmol) in ACN (5 mL) was added pyridine (0.2 mL, 1.67 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (188 mg, 0.83 mmol) slowly at rt. After stirred at rt for 2h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 2-methylpropan-2-yl ({[l-(2-chloro-5-fluorophenyl)-7-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)-l-hydroxy-4-m...

Claims

What is claimed is:CLAIMS1. A compound having the structural formula I:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered monocyclic non-aromatic ring, substituted with 0- 10 Ra’s;R1is ZB-RB;R2is Zc-Rc;X is N, CH or CRX;Rxis Zx-Rx; each of ZB, Zcand Zxis 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 a linking group selected from Ci-4 saturated or unsaturated bivalent hydrocarbon radicals, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S and O; each of RB, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, - S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, - C(O)N(R)OR, -OC(O)R, -OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, - N(R)C(NR)NRR’, -N(R)S(O)2NRR’, or -N(R)S(O)2R; or a Ci-6 aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatomsindependently selected from N, O and S, optionally substituted with one or more Rb, Rcor Rx, respectively; each of Ra, Rb, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)N(R)OR, -OC(O)R, -OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, - N(R)C(NR)NRR’, -N(R)S(O)2NRR’ or -N(R)S(O)2R; or a substituted or unsubstituted group selected from C1-6 alkyl or 4- to 6- membered carbocyclic ring; each of R and R’ is independently selected from H, unsubstituted or substituted C1-4 alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same C or N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; and7 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. The compound of claim 1, wherein Ring A is a 4- to 7-membered carbocyclic ring with no ring heteroatoms, substituted with 0-10 Ras. The compound of claim 1, wherein Ring A is a 4- to 7-membered heterocyclic ring with 1-4 ring heteroatoms selected from N, O and S, substituted with 0-10 Ras. The compound of any one of claims 1-3, wherein Ring A is a 4-membered non-aromatic ring, substituted with 0-4 Ras, having the structural formula Ia:wherein each of Y1and Y2is independently CH, CH2, N, NH, O or S, provided that at least one of Y1and Y2is C or CH. The compound of any one of claims 1-3, wherein Ring A is a 5-membered non-aromatic ring, substituted with 0-6 Ras, having the structural formula L:wherein each of Y1, Y2and Y3is independently CH, CH2, N, NH, 0, S or C(O), provided that at least one of Y1, Y2and Y3is not N or NH and at least one of Y1, Y2and Y3is C, CH or C(O).The compound of any one of claims 1-3, wherein Ring A is a 6-membered non-aromatic ring, substituted with 0-8 Ras, having the structural formula Ic:wherein each of Y1, Y2, Y3and Y4is independently CH, CH2, N, NH, O, S, S(O)2, orC('O), provided that at least two of Y1, Y2, Y3and Y4is not N or NH and at least two of Y1, Y2, Y3and Y4is C, CH or C(O).The compound of any one of claims 1-3, wherein Ring A is a 7-membered non-aromatic ring, substituted with 0-8 Ras, having the structural formula Id:Idwherein each of Y1, Y2, Y3, Y4and Y5is independently CH, CH2, N, NH, 0, S or C(O), provided that at least two of Y1, Y2, Y3, Y4and Y5is not N or NH and at least two of Y1, Y2, Y3, Y4and Y5is C, CH or C(O). The compound of any one of claims 1-7, whereinRBis Ring B, a 5- to 10-membered monocyclic or bicyclic carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, substituted with 0-6 Rbs; andRcis Ring C, a 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, substituted with 0-6 Rcs, having the structural formula Ie:wherein j is 0, 1, 2, 3, 4, 5 or 6; and& is 0, 1, 2, 3, 4, 5 or 6. The compound of claim 8, wherein ZBis NH-C(O) and Zcis a single bond, having the structural formula If:The compound of claim 8, wherein ZBis C(O)-NH and Zcis a single bond, having the structural formula Ig:The compound of any one of claims 1-4 and 8-10, wherein Ring A is selected from:The compound of any one of claims 1-4 and 8-10, wherein Ring A is selected from:The compound of any one of claims 1-4 and 8-10, wherein Ring A is:wherein Ra’ is CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN. The compound of claim 13, wherein Rais CH2CHF2. The compound of claim 13 or 14, wherein each Rais independently H, Cl, F, CN or CH3. The compound of any one of claims 1-3, 5 and 8-10, wherein Ring A is selected from:The compound of any one of claims 1-3, 5 and 8-10, wherein Ring A is selected from:The compound of any one of claims 1-3, 5 and 8-10, wherein Ring A is selected from:whereinRais CH2CHF2 or CH2CF3; and each Rais independently H, Cl, F, CN or CH3. The compound of any one of claims 1-3, 5 and 8-10, wherein Ring A iswherein one of Rais CH2CHF2 or CH2CF3, and the other Rais H, CH3 or CD3. The compound of any one of claims 1-3, 6 and 8-10, wherein Ring A is selected from:The compound of any one of claims 1-3, 6 and 8-10, wherein Ring A is selected from:wherein Rais CH2CHF2 or CH2CF3, and Rais H. The compound of any one of claims 1 -3, 6 and 8-10, wherein Ring A is selected from:wherein one of Raand Rais selected from H, CH3, CD3, CD2CD3, CH2CN and CH2CHF2, CH2CF3 and CH2CN; and the other Raand / or Ra’ is H. The compound of any one of claims 1-3, 6 and 8-10, wherein Ring A is selected from:wherein each Rais independently selected from H, CH3, CD3, CD2CD3, CH2CN and CH2CHF2, CH2CF3 and CH2CN The compound of 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. The compound of claim any one of 1-24, wherein X is N. The compound of claim any one of 1-24, wherein X is CH. The compound of claim any one of 1-24, wherein X is CRX, wherein Rxis C1-3 alkyl.The compound of any one of claims 1-27, wherein Ring B is selected from:The compound of claim 31, wherein Ring B is:The compound of any one of claims 1-27, wherein Ring B is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl. The compound of claim 33, wherein Ring B is a substituted or unsubstituted phenyl The compound of claim 33, wherein Ring B is a substituted or unsubstituted pyridyl. The compound of claim 33, wherein Ring B is a substituted or unsubstituted pyridazinyl. The compound of claim 33, wherein Ring B is a substituted or unsubstituted pyrazinyl. The compound of any one of claims 1-9 and 11-27, wherein ZBis NH-C(O). The compound of any one of claims 1-38, wherein Ring C is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl. The compound of claim 39, wherein Ring C is a substituted or unsubstituted phenyl. The compound of claim 39, wherein Ring C is a substituted or unsubstituted pyridyl. The compound of claim 39, wherein Ring C is a substituted or unsubstituted pyridazinyl. The compound of claim 39, wherein Ring C is a substituted or unsubstituted pyrazinyl. The compound of claim 34 or 40, wherein each of Ring B and Ring C is independently a substituted or unsubstituted phenyl. The compound of any one of claims 1-34, 40 and 44, wherein Ring C is selected from:

52. The compound of claim 1, having the structural formula II53. The compound of claim 1, having the structural formula Im54. The compound of claim 1, having the structural formula In:

55. A compound having a structural formula selected from:or a pharmaceutically acceptable form or an isotope derivative thereof.

56. A compound having a structural formula selected from:or a pharmaceutically acceptable form or an isotope derivative thereof.

57. A compound having a structural formula selected from:or a pharmaceutically acceptable form or an isotope derivative thereof.

58. A compound having a structural formula selected from:or a pharmaceutically acceptable form or an isotope derivative thereof. The compound of any one of claims 51-54, 57 and 58, having the following chirality in R1:The compound of any one of claims 51-54, 57 and 58, having the following chirality inR1:The compound of any one of claims 1-60, having the following chirality at the carbon to which R2is bond:The compound of any one of claims 1-60, having the following chirality at the carbon to which R2is bond:A compound selected from Table 1, or a pharmaceutically acceptable form or an isotope derivative thereof. The compound of any of claims 1-63, having one or more deuterium atoms in place of hydrogen. The compound of any of claims 1-64, having one deuterium atom in place of a hydrogen atom. A pharmaceutical composition comprising a compound according to any one of claims 1- 65 and a pharmaceutically acceptable excipient, carrier, or diluent.The pharmaceutical composition of claim 66, being suitable for oral administration. A unit dosage form comprising a pharmaceutical composition according to claim 66 or 67. The unit dosage form of claim 68, being in the form of a tablet or capsule. A method for inhibiting cellular proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of claims 1-65. A method for inhibiting phosphoinositide 3 -kinase a (PI3Ka) activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-65. A method for treating a disease or disorder mediated by phosphoinositide 3-kinase a (PI3Ka), comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1-65. The method of claim 72, wherein the disease or disorder is a cellular proliferative disease. A method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1-65. The method of claim 74, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma. 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, cholangiocarcinoma, bladder urothelial cancer, gastric cancer, bile duct cancer, and a hematologic malignancy. The method of any one of claims 74-76, wherein the subject has a mutated class IA PI3K pl 10a. The method of any one of claims 74-77, wherein the subject has at least one of the following PI3Ka mutations: H1047R, E542K, and E545K. The method of any one of claims 74-78, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy. Use of the compound according to any one of claims 1-65, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating adisease or disorder. The use of claim 80, wherein the disease or disorder is a cellular proliferative disease. The use of claim 81, wherein the disease or disorder is cancer. The use of claim 82, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma. 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 and non-small cell lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, gastric carcinomas, bile duct cancer, hepatocellular carcinoma, thyroid carcinoma, and a hematologic malignancy. The use of claim 82, wherein the cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas.

Images