Guanidino tricyclic compounds, and compositions and methods thereof

Abstract

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

Description

GUANIDINO TRICYCLIC COMPOUNDS, AND COMPOSITIONS AND METHODSTHEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 627,166, filed January 31, 2024, and 63 / 729,148, filed December 6, 2024, 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 guanidine derivatives of tricyclic compounds that are shown to be potent and selective phosphoinositide 3 -kinase a (PI3Kα) inhibitors. The invention also provides pharmaceutical compositions comprising compounds of the invention and methods for treating diseases and disorders associated with or related to PI3Kα 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 etal. 2009 Nature 458 (7239): 725-31; Leevers etal. (1999) Current Opinion in Cell Biology 11 (2): 219— 25.) Class I PI3Ks (p110α, p110β, p110δ and p110γ) are activated by tyrosine kinases or Gprotein-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 (PI3Kα) is mutated in many human cancers. Angiogenesis has been shown to selectively require the PI3Kα isoform in the control of endothelial cell migration. Mutations in the gene encoding PI3Kα (BIK3CA) or PI3Kα 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, PI3Kα mutations are often hotspot point mutations in the helical or kinase domain, such as H1047R, E542K, E545K and H1047X. (Graupera et al. 2008 Nature 453: 662-6; Campbell etal. 2004 Cancer Res 64, 7678-7681; Levine et al. 2005 Clin Cancer Res 11, 2875-2878; Wang et al. 2005 Hum Mutat 25, 322; Lee et al. 2005 Gynecol Oncol 97, 26-34; Bachman, etal. 2004 Cancer Biol Ther 3, 772-775; Li et al. 2006 Breast Cancer Res Treat 96, 91-95; Saal etal. 2005 Cancer Res 65, 2554-2559; Samuels and Velculescu 2004 Cell Cycle 3, 1221-1224; Samuels, et al. 2004 Science 304, 554; Velho et al. 2005 Eur J Cancer 41, 1649-1654; Oda et al. 2005 Cancer Res. 65, 10669-10673; Byun et al. 2003 Int J Cancer 104, 318-327; Lee et al. 2005 Oncogene 24, 1477-1480; Tang etal. 2006 Lung Cancer 51, 181-191; Massion et al. 2004 Am J Respir Grit Care Med 170, 1088-1094; Wu et al. 2005 J Clin Endocrinol 'Metah 90, 4688-4693; Sujobert et / . 1997 Blood 106, 1063-1066; Hickey and Cotter 2006 J Biol Chem 281, 2441-2450; Hartmann et al. 2005 Acta Neuropathol (BerT) 109, 639-642.)

[0006] There remains an urgent and unmet need for potent and selective PI3Kα inhibitors that are safe and effective in treating diseases and conditions associated with PI3Kα, 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 guanidine derivatives of tricyclic compounds as PI3Kα inhibitors, which are shown herein to exhibit favorable potency and selectivity profiles over known PI3Kα inhibitors. These novel compounds selectively target, bind to, inhibit and / or modulate the activity of PI3Kα. The compounds are also orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for treatingvarious diseases and disorders associated with or related to PI3Kα 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, wherein each of R1and R2is independently a CM alkyl substituted with0-8 RA, wherein each RAis independently D, halogen, CN, OR, SR, NRR’, or an unsubstituted or substituted C3-6 carbocyclic or heterocyclic group, or an unsubstituted or substituted 5- or 6-membered aryl or heteroaryl group;R3is L3-R3;L3is NH-C(O) or NH; each of R3and R4is independentlyH, D, oxo, halogen, CN, N02, OR, SR, NRR’, S(O)2R, S(0)2NRR’, S(O)R, S(0)NRR’, S(0)(NR)R, C(0)R, C(0)0R, C(0)NRR’, C(0)N(R)0R, 0C(0)R, 0C(0)NRR’, N(R)C(0)0R, N(R)C(0)R, N(R)C(0)NRR’, N(R)C(NR)NRR’, N(R)S(0)2NRR’, or N(R)S(0)2R; or a C1-6 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, 0 and S, optionally substituted with one or more Rbor Rc, respectively;R5is H, D, OR, or substituted or unsubstituted C1-4alkyl;R6is H, D, CN, C(0)R, C(O)OR, or substituted or unsubstituted C1-4alkyl; or R6and R1or R6and R2, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 Ras;each of Ra, Rband Rcis independently 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 C1-4alkyl, or unsubstituted or substituted 3- 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 m is 0 or 1.

[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 modulating (e.g, reducing) PI3Kα activity in a cell, comprising contacting the cell with a compound disclosed herein.

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

[0014] In yet another aspect, the 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 a prodrug 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 PI3Kα. 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 “PI3Kα” refers to a compound of the invention capable of negatively modulating or inhibiting all or a portion of the activity of PI3Kα.

[0028] As used herein, a “PI3Kα-associated” disease or disorder refers to diseases or disorders associated with or mediated by PI3Kα or having one or more PI3Kα mutations. Examples of PI3Kα-associated diseases or disorders include various cancer types. A PI3Kα- 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] As used herein, the term “contacting” refers to the bringing together of indicated moieties 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 cell in which inhibition of PI3Kα 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 PI3Kα. By negatively modulating the activity of PI3Kα, the methods disclosed herein are designed to inhibit undesired cellular proliferation resulting from enhanced PI3Kα 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 PI3Kα. The ability of compounds to bind PI3Kα 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 PI3Kα 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-C6alkyl, C1-C6alkyl, -OC1-C6alkenyl, -OC1-C6alkynyl, -C1-C6alkenyl, -C1-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6alkyl, -C(O)C1-C6alkyl, -OC(O)OC1- C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -NHC(O)CI-C6alkyl, -C(O)NHCI-C6alkyl, - S(O)2-C1-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, dodecyl sulfate, 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. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, 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+(C1-4alkyl)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, triethylamine, 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 intermolecular forces. 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 Pergam on 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 transporting the 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 PI3Kα mutations. In some embodiments, the subject has a cancer that is positive for a PI3Kα mutation. In some embodiments, the subject is suspected of having a PI3Kα 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 PI3Ku mutations using a sample (e.g., abiological 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 concentration than 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, “C1-4alkyl” 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 hydrocarbonthat 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 from one to ten carbon atoms (e.g., C1-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 C1-6 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)2 wherein 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-C1-C6alkyl, C1-C6alkyl, -C1-C6alkenyl, -OC1-C6alkynyl, -C1-C6alkenyl, -C1-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6alkyl, -C(O)C1-C6alkyl, -OC(O)OC1- C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -S(O)2-C1-C6alkyl, -S(O)NHC1-C6alkyl, and S(O)N(C1-C6alkyl)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, tetrahydronaphthal enyl, and tetrahydrobenzoannul enyl.

[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, azocinyl, 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, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothi azole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. “Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, 0, and S in which one ring system may be saturated or partially saturated.

[0054] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZiZ2)carbonyl. The term "NZ1Z2" as used herein, means two groups, Zi and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Zi and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0055] As used herein, the term “alkoxy” refers to an -O-alkyl 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 (C6), cyclohexenyl (C6), 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 (C7), cycloheptatrienyl (C7), 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., 0, 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- [1,4] 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 have at least one heteroatom (selected from the group consisting of N, 0, 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, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-lH,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H, 3 'H- spiro[cyclopropane-l,2'-pyrrolizine], hexahydro- IH-pyrrolizinyl, hexahydro- lH-pyrrolo[2,l- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, and tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- thi opy rany 1 1 , 1 -di oxi de .Detailed Description of the Invention

[0059] The invention is based in part on the discovery of novel guanidino tricyclic compounds and derivatives thereof as PI3Kα inhibitors. These compounds are shown herein to selectively target, bind to, inhibit and / or modulate the activity of PI3Kα. The compounds are orally available and can be used for treating various diseases and disorders associated with or related to PI3Kα 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, wherein each of R1and R2is independently a C1-6 (e.g., C1.3) alkyl substituted with0-8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7 or 8) RA, wherein each RAis independently D, halogen, CN, OR, SR, NRR’, or an unsubstituted or substituted C3-6 carbocyclic or heterocyclic group, or an unsubstituted or substituted 5- or 6-membered aryl or heteroaryl group;R3is L3-R3;L3is NH-C(O) or NH; each of R3and R4is independentlyH, D, 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 C1-6 aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 (e.g., 0, 1, 2, 3 or 4) ring heteroatoms independently selected from N, 0 and S, optionally substituted with one or more Rbor Rc, respectively;R5is H, D, OR, or substituted or unsubstituted alkyl; C1-4R6is H, D, CN, C(O)R, C(O)OR, or substituted or unsubstituted alkyl; or RC61a-n4d R1or R6and R2, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) Ras; each of Ra, Rband Rcis independentlydeuterium, 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 (e.g., C1-3) alkyl or 4-, 5- or 6-membered carbocyclic ring; each of R and R’ is independently selected from H, unsubstituted or substituted C1-4alkyl, or unsubstituted or substituted 3- to 6-membered (e.g., 3-, 4-, 5- or 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 (e.g., 4-, 5- or 6-membered) heterocyclic ring; and m is 0 or 1.

[0061] In certain embodiments of (I), m is 0, having the structural formula (II):

[0062] In certain embodiments of (I), m is 1, having the structural formula (III):

[0063] In certain embodiments of (I)-(III), R6is H.

[0064] In certain embodiments of (I)-(III), R6is CH3.

[0065] In certain embodiments of (I)-(III), R6is CD3.

[0066] In certain embodiments of (I)-(III), R6is CH2CH3.

[0067] In certain embodiments of (I)-(III), R6is CD2CD3.

[0068] In certain embodiments of (I)-(III), R6is CN, C(O)CH3 or C(O)OCH3.

[0069] In certain embodiments of (I)-(III), R6is characterized by the stereochemistry shown in formula (IVA):

[0070] In certain embodiments of (I)-(III), R6is characterized by the stereochemistry shown in formula (IVB):

[0071] In certain embodiments of (II), R1is CRlaRlbRlc, and R2is CR2aR2bR2c, having the structural formula (IIA):wherein each of Rlaand R2ais independently H, D or halogen; each of Rlband R2bis H, D or halogen; and each ofRlcand R2cisH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1.5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

[0072] In certain embodiments of (IIA), R2cis CR2dR2eR2f, having the structural formula (IIB):whereinR2dis H, D or halogen; and each of R2eand R2fis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’,S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1.5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

[0073] In certain embodiments of (IIA) and (IIB), each of Rlaand Rlbis H. In certain embodiments, Rlcis H.

[0074] In certain embodiments of (IIA) and (IIB), each of Rlaand Rlbis D. In certain embodiments, R1cis D.

[0075] In certain embodiments of (IIB), Rlcis CRldRleRlf, having the structural formula(IIC):whereinRldis H, D or halogen; and each of Rleand Rlfis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1.5 alkyl, C2.5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

[0076] In certain embodiments of (IIA)-(IIC), each of R2aand R2bis H.

[0077] In certain embodiments of (IIA)-(IIC), each of R2aand R2bis D.

[0078] In certain embodiments of (IIA)-(IIC), at least one of R2d, R2eand R2fis a halogen atom. In certain embodiments, one of R2d, R2eand R2fis F. In certain embodiments, two of R2d, R2eand R2fis F. In certain embodiments, each of R2d, R2eand R2fis F.

[0079] In certain embodiments of (IIA)-(IIC), at least one of R2d, R2eand R2fis a D. In certain embodiments, one of R2d, R2eand R2fis D. In certain embodiments, two of R2d, R2eand R2fis D. In certain embodiments, each of R2d, R2eand R2fis D.

[0080] In certain embodiments of (II), R6and R1, together with their respectively intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) Ras, having the structural formula (IID):wherein z is 0, 1, 2 or 3, and p is 0, 1 or 2.

[0081] In certain embodiments, p is 0.

[0082] In certain embodiments, p is 1.

[0083] In certain embodiments of (II), R6and R2, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) Ras, having the structural formula (IIE):wherein j is 0, 1, 2 or 3, and q is 0, 1 or 2.

[0084] In certain embodiments, q is 0.

[0085] In certain embodiments, q is 1.

[0086] In certain embodiments of (III), R1is CRlaRlbRlc, and R2is CR2aR:’R2c, having the structural formula (IIIA)wherein each of Rlaand R2ais independently H, D or halogen; each of Rlband R2bis H, D or halogen; and each of Rlcand R2cisH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C 1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

[0087] In certain embodiments of (IIIA), R2cis CR2dR2eR2f, having the structural formula(IIP):whereinR2dis H, D or halogen; and each of R2eand R2fis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1.5 alkyl, C2-5alkenyl, C2-5alkynyl, C3-6carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

[0088] In certain embodiments of (IIIA) and (IIIB), each of Rlaand Rlbis H. In certain embodiments, Rlcis H.

[0089] In certain embodiments of (IIIA) and (IIIB), each of Rlaand Rlbis D. In certain embodiments, R1Gis D.

[0090] In certain embodiments of (IIIB), Rlcis CRldRleRlf, having the structural formula(IIIC):whereinRldis H, D or halogen; and each of Rleand Rlfis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1.5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

[0091] In certain embodiments of (IIIA)-(IIIC), each of R2aand R2bis H.

[0092] In certain embodiments of (IIIA)-(IIIC), each of R2aand R2bis D.

[0093] In certain embodiments of (IIIA)-(IIIC), at least one of R2d, R2eand R2fis a halogen atom. In certain embodiments, one of R2d, R2eand R2fis F. In certain embodiments, two of R2d,R2eand R2fis F. In certain embodiments, each of R2d, R2eand R2fis F.

[0094] In certain embodiments of (IIIA)-(IIIC), at least one of R2d, R2eand R2fis a D. In certain embodiments, one of R2d, R2eand R2fis D. In certain embodiments, two of R2d, R2eand R2fis D. In certain embodiments, each of R2d, R2eand R2fis D.

[0095] In certain embodiments of (III)-(IIIC), R5is H.

[0096] In certain embodiments of (III)-(IIIC), R5is not H.

[0097] In certain embodiments of (IIA), (IIB), (IIC), (IIIA), (IIIB) and (IIIC), R6is characterized by a stereochemistry shown in formula (IVA).

[0098] In certain embodiments of (IIA), (IIB), (IIc), (IIIA), (IIIB) and (IIIC), R6is characterized by a stereochemistry shown in formula (IVB).

[0099] In certain embodiments of (III), R6and R2, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) Ras, having the structural formula (IIID):wherein k is 0, 1, 2 or 3, and r is 0, 1 or 2.

[0100] In certain embodiments, r is 0.

[0101] In certain embodiments, r is 1.

[0102] In certain embodiments of (III), R6and R1, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) Ras, having the structural formula (IIIE):wherein I is 0, 1, 2 or 3, and s is 0, 1 or 2.

[0103] In certain embodiments, s is 0.

[0104] In certain embodiments, 5 is 1.

[0105] In certain embodiments of (I), (II) or (III), R1and R2are independently selected from:R1: CH3, CH2D, CHD2, CD3, CH2F, CHF2, CD2F, CDF2, CF3, CH2CH3, CD2CH3, CH2CD3, CD2CD3, CH2CN, CH2CH2N(CH3)2,R2: CH3, CH2D, CHD2, CD3, CH2CH3, CH2CH2F, CD2CH2F, CH2CD2F, CD2CD3, CD2CD2F, CH2CHF2, CD2CHF2, CH2CDF2, CD2CDF2, CH2CF3, CD2CF3, CH2CN, CH2CH2N(CH3)2, CH2CH2OH, CH2CH2OCH3, CH2CH2CH2F, CH2CH2CHF2, CH2CH2CF3, propyl, isopropyl, n-butyl, isobutyl,

[0106] I

[0107] In certain embodiments of (IIID) and (IIIE), R5is not H.

[0108] In certain embodiments of (I)-(IIIE), R4is 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 (e.g., 0, 1, 2, 3, 4, 5 or 6) Rcs.

[0109] In certain embodiments of (I)-(IIIE), R4is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

[0110] In certain embodiments of (I)-(IIIE), R4is a substituted or unsubstituted phenyl.

[0111] In certain embodiments of (I)-(IIIE), R4is a substituted or unsubstituted pyridyl.

[0112] In certain embodiments of (I)-(IIIE), R4is a substituted or unsubstituted pyridazinyl.

[0113] In certain embodiments of (I)-(IIIE), R4is a substituted or unsubstituted pyrazinyl.

[0114] Non-limiting examples of R4include:

[0115] In certain embodiments, R4is:

[0116] In certain embodiments, R4is characterized by the following chirality:

[0117] In certain embodiments, R4is characterized by the following chirality:

[0118] In certain embodiments of (I)-(IIIE), L3is NH-C(O).

[0119] In certain embodiments of (I)-(IIIE), R3’ is a substituted or unsubstituted 5- or 6- membered monocyclic carbocyclyl or heterocyclic.

[0120] In certain embodiments of (I)-(IIIE), R3’ is a substituted or unsubstituted 5- or 6- membered monocyclic aryl or heteroaryl ring.

[0121] In certain embodiments of (I)-(IIIE), R3is a substituted or unsubstituted 8- to 10- membered bicyclic carbocyclyl or heterocyclic.

[0122] In certain embodiments of (I)-(IIIE), R3is a substituted or unsubstituted 8- to 10- membered bicyclic aryl or heteroaryl ring.

[0123] Non-limiting examples of R3include:

[0125] In certain embodiments of (I)-(IIIE), L3is NH.

[0126] In certain embodiments of (I)-(IIIE), R3is a 9- or 10-membered bicyclic aryl or heteroaryl with 0-4 e.g., 0, 1, 2, 3 or 4) ring heteroatoms independently selected from N, O and S, substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) Rbs.

[0127] In certain embodiments of (I)-(IIIE), R3’ is a 9-membered bicyclic heteroaryl comprising a 5-membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

[0128] In certain embodiments of (I)-(IIIE), R3’ has the structural formula (IV):wherein q is 0, 1, 2, 3 or 4;X1is N, O, S or CH;X2is N, O, S or CH;X3is N or C; andX4is N or C, with the proviso that when one of X3and X4is N, the other is CH.

[0129] Non-limiting examples of R3include:

[0130] In certain embodiments, each Rbis independently selected from CF3, CHF2, CH2F,CH3, F, Cl, Br, CN, OR, SF5, S(O)2R and C2-4alkynyl.

[0131] In certain embodiments, q is 1.

[0132] In certain embodiments, q is 2.

[0133] Non-limiting examples of R3include:

[0134] In certain embodiments of (I)-(IIIE), R3is a 10-membered bicyclic heteroaryl comprising a 6-membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

[0135] In certain embodiments R3’ has the structural formula (V):wherein p is 0, 1, 2, 3 or 4; each of Y1, Y2and Y3is independently selected from N and CH; each of Y4and Y5is independently selected from N and CH with the proviso that, when one of Y4and Y5is N, the other is C, and when each of Y2and Y3is N, Y1is CH and Y4is C.

[0136] In certain embodiments, R3is selected from:

[0137] In certain embodiments, each Rbis independently selected from CF3, CHF2, CH2F, CH3, F, Cl, Br, CN, OR, SF5, S(O)2R and C2-4 alkynyl.

[0138] In certain embodiments, p is 1.

[0139] In certain embodiments, p is 2.

[0140] Non-limiting examples of R3include:

[0141] Non-limiting exemplary compounds of the invention can also be found in Table 1 in the Examples section.

[0142] 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.

[0143] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0144] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0145] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0146] In certain embodiments, the unit dosage form is in the form of a tablet or capsule.

[0147] 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.

[0148] 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).

[0149] 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.

[0150] 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.

[0151] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In 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.

[0152] 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.

[0153] In yet another aspect, the invention generally relates to a method for modulating (e.g., reducing) PI3Kα activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0154] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Kα, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0155] In certain embodiments, the disease or disorder is a cellular proliferative disease.

[0156] 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.

[0157] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0158] 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.

[0159] 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.

[0160] In certain embodiments, the cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas.

[0161] In certain embodiments, the subject has a mutated class IA PI3K pl 10a.

[0162] In certain embodiments, the subject has at least one of the following PI3Kα mutations: H1047R, E542K, E545K and H1047X.

[0163] In certain embodiments, the subject does not have a PI3Kα mutant protein.

[0164] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0165] 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.

[0166] In yet another aspect, the invention generally relates to use of a compound disclosed herein for treating a disease or disorder.

[0167] The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the route of administration, the disposition of the compound and the discretion of the prescribing physician. In some 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.

[0168] 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.

[0169] 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.

[0170] 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. Coatingscan 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.

[0171] In the case of tablets for oral use, carriers that are commonly used include lactose and com 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.

[0172] 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.

[0173] 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.

[0174] 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 di glycerides. 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds, e.g., 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0185] In certain embodiments, the method further comprises administering a radiotherapy to the subject. In 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.

[0186] 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; pancrati statin; 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, ADRIAMYCIN® (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; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0187] 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).

[0188] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cisand trans-i 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.

[0189] 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.

[0190] 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.

[0191] 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,180,170,31P,32P,35S,18F, and36C1, respectively.

[0192] 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.

[0193] 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.)

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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 agents such 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.

[0200] 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.

[0201] 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.

[0202] 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 each such combination or subset of combinations is specifically contemplated and should be considered disclosed.Examples

[0203] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0204] 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 CompoundsList of AbbreviationsExemplary Synthetic Procedures

[0205] General LCMS Method:Shimadzu LCMS2020, Reverse-phase column (Shim-Pack Scepter C18, 33 x 3.0 mm, 3um), elution with A: H2O / MeCN / FA = 90 / 10 / 0.05; B: MeCN; Detection: MS, ELS, UV (100 μL splitto MS with in-line UV detector); MS ionization method: Electrospray (positive and negative ion).ES-API = electrospray-atmospheric pressure ionization.

[0206] General HPLC Purification Method:Instrument: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; 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.Exemplary chiral prep-SFC conditions and methods for racemic compounds separation:

[0207] Preparative separation method 1Instrument: SHIMADZUPREP SOLUTIONLCColumn: ChiralPAK IC, 250x20mm I.D., 5μmMobile phase: A for n-Hexane and B for IPA (0.1% 2 mol / L NH3 in MeOH)Gradient: B 40%Flow rate: 17 mL / minColumn temperature: 25 °CWavelength: 220 nmCycle-time: 22minRun time: 22 minInjection volume: 0.7 mLEluted time: 4 H

[0208] Preparative separation method 2Instrument: SHIMADZU PREP SOLUTION SFCColumn: (R,R)-WHELK, 250x20 mm I.D., 5 μmMobile phase: A for CO2 and B for MeOH (0.1% 2mol / L NH3 in MeOH)Gradient: B 50%Flow rate: 35 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 7 minInjection volume: 3.4 mLNumber of injection needles: 8Eluted time: 2 H

[0209] Preparative separation method 3Instrument: SHIMADZU PREP SOLUTION SFCColumn: (R,R)-WHELK, 250x20 mm ID., 5 μmMobile phase: A for CO2 and B for MeOH (0.1% 2mol / L NH3 in MeOH)Gradient: B 50%Flow rate: 40 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 7 minInjection volume: 2 mLNumber of injection needles: 4Eluted time: 2 H

[0210] Preparative separation method 4Instrument: SHIMADZUPREP SOLUTIONLCColumn: Chiral CEL OX, 250x20mm I.D., 5μmMobile phase: A for n-Hexane and B for EtOH (0.1% 2mol / L NH3 in MeOH)Gradient: B 50%Flow rate: 20 mL / minColumn temperature: 25 °CWavelength: 220 nmCycle-time: 40 minRun time: 40 minInjection volume: 2 mLNumber of injection needles: 5Eluted time: 4 H

[0211] Preparative separation method 5Instrument: SHIMADZU PREP SOLUTION SFCColumn: (R,R)-WHELK, 250x20 mm ID., 5 μmMobile phase: A for CO2 and B for MeOH (0.1% 2mol / L NH3 in MeOH)Gradient: B 50%Flow rate: 40 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 10 minInjection volume: 3.4 mLNumber of injection needles: 3Eluted time: 2 H

[0212] Preparative separation method 6Instrument: SHIMADZU PREP SOLUTION SFCColumn: (R,R)-WHELK, 250x20 mm I.D., 5 μmMobile phase: A for CO2 and B for MeOH (0.1% 2 mol / L NH3 in MeOH)Gradient: B 50%Flow rate: 40 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 10 minInjection volume: 3.4 mLNumber of injection needles: 3Eluted time: 2H

[0213] Preparative separation method 7Instrument: Waters Thar 80 preparative SFCColumn: ChiralPak IH, 250x30mm I D., 5μmMobile phase: A for CO2 and B for MEOHGradient: B 30%Flow rate: 60 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmRun time: 9 minCycle-time: 9 minInjection volume: 2 mLNumber of injection needles: 6Eluted time: 2HGeneral synthetic route I (m = 0):

[0214] From this general route I, R4were installed with nucleophilic addition such as Grignard reaction to the aldehyde at step B. R2was introduced at step D via an SNAr reaction with different amines. R1was installed at step G via N-nucleophilic reaction such as alkylation, while R6was installed via another N-nucleophilic reaction at step H. Then, R3was introduced at step J to replace the Br, for example, via metal -catalyzed C-N bond formation.General synthetic route II (R3’ installation):

[0215] This is an alternative route for installation of different R3s by introducing N first with a protected N source. Then, deprotection followed with a R3-N formation at last step.General synthetic route III (cyclized Rx-R6):LG = Leaving group: Br, I, Cl, OMs, OTf, OTs ...

[0216] Cyclized R'-R6was achieved in one-step or in a stepwise sequence. General synthetic route II was applied to this strategy for alternative R3variations in the scheme below in General synthetic routes IV.General synthetic route IV (R3’ installation with cyclized R’-R6):General synthetic route V (cyclized R2-R6):LG = Leaving group: Br, I, Cl, OMs, OTf, OTs ...General synthetic route VI (R3’ installation with cyclized R2-R6):Exemplary Synthetic Procedures for intermediates:[2-azanylidene-4,6-dibromo-l-(pentadeuterioethyl)-3H-benzo[d]imidazol-5-yl](2-chloro-5- fluorophenyl)methanone

[0217] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (10 g, 21.9 mmol) in dioxane (100 mL) was added DIEA (5.68 g, 43.9 mmol) and (2,4-dimethoxyphenyl)methanamine (3.67 g, 21.9 mmol). The mixture was stirred at 100 °C for 2 hours. The cooled mixture was concentrated and the residue was purified by silica gel chromatography (20 g column) using 0 - 10% EtOAc / hexane to afford (2-chloro-5- fluorophenyl)(2,6-dibromo-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-nitrophenyl)methanone (4.8 g, 7.96 mmol, 36 %) as a yellow solid. LCMS: m / z 601.1 [M-H]' .

[0218] Step B: A solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-nitrophenyl)methanone (4.7 g, 7.80 mmol) in TFA (50 mL) was stirred at 20 °C for 1 hour. The mixture was concentrated under vacuum to give a crude, which was poured into saturated NaHCCL and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated to give (4- amino-2,6-dibromo-3-nitrophenyl)(2-chloro-5-fluorophenyl)methanone (3.5 g, 7.73 mmol, 99 %) as an orange solid. LCMS: m / z 453.2 [M+H]+.

[0219] Step C: To a solution of (4-amino-2,6-dibromo-3-nitrophenyl)(2-chloro-5- fluorophenyl)methanone (3.5 g, 7.74 mmol) in DMF (50 mL) was added NaH (0.46 g, 11.6 mmol, 60% dispersion in mineral oil). The mixture was stirred at 0 °C for 10 min.Then 1,1,2,2,2-pentadeuterio-l -iodoethane (1.25 g, 7.74 mmol) was added and the mixture was stirred at 10 °C for 1 hour. The mixture was quenched with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, EtOAc in PE) to give (2-chloro- 5-fluorophenyl){2,6-dibromo-3-nitro-4-[(pentadeuterioethyl)amino]phenyl}methanone (2.7 g, 5.56 mmol, 72 %) as a yellow solid. LCMS: m / z 486.1 [M+H]+.

[0220] Step D: To a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-3-nitro-4- [(pentadeuterioethyl)amino]phenyl}methanone (2.7 g, 5.56 mmol) in EtOH (50 mL) and H2O (10 mL) was added Fe (1.86 g, 33.4 mmol) and NH4CI (1.49 g, 27.8 mmol). The mixture was stirred at 75 °C for 2 hours. The mixture was filtered and concentrated to give a crude, which was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated to give {3-amino-2,6-dibromo-4- [(pentadeuterioethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (2.27 g, 4.98 mmol, 89 %) as a yellow solid. LCMS: ESI m / z 456.1 [M + H]+.

[0221] Step E: To a solution of {3-amino-2,6-dibromo-4- [(pentadeuterioethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (2.27 g, 4.98 mmol) in MeOH (30 mL) and H2O (10 mL) was added cyanogen bromide (3.69 g, 34.9 mmol). The mixture was stirred at 75 °C for 12 hours. The cooled mixture was concentrated. The residue was triturated with EA and filtrated. The filter cake was dried under vacuum to give [2- azanylidene-4,6-dibromo-l-(pentadeuterioethyl)-3H-benzo[d]imidazol-5-yl](2-chloro-5- fhrorophenyl)methanone (2.39 g, 4.97 mmol, 99 %) as a white solid. LCMS: ESI m / z 481.1 [M + H]+.[2-azanylidene-4,6-dibromo-l-(2-fluoroethyl)-3H-benzo [d] imidazol-5-yl] (2-chloro-5- fluorophenyl)methanone

[0222] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (5 g, 10.9 mmol) and 2-fluoroethan-l -amine hydrochloride (1.09 g, 10.9 mmol) in dioxane (70 mL) was added DIEA (2.84 g, 21.9 mmol). The reaction mixture was stirred at 100 °C for 2 hours in sealed tube. The mixture was concentrated and the residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 15%) to afford (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2-fluoroethyl)amino]-3- nitrophenyl] methanone (4.16 g, 8.35 mmol, 76 %) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ 7.72 (dd, J = 9.6, 4.8 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.39 (s, 1H), 7.02 - 6.98 (m, 1H), 4.64 - 4.60 (m, 1H), 4.53 - 4.49 (m, 1H), 3.65 - 3.53 (m, 2H).

[0223] Step B: To a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2- fluoroethyl)amino]-3-nitrophenyl}methanone (4.16 g, 8.35 mmol) in ethanol (50 mL) and H2O (15 mL) was added NH4CI (2.23 g, 41.7 mmol) and Fe (2.8 g, 50.1 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was filtrated to remove Fe and concentrated under vacuum to give crude, which was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give {3-amino-2,6-dibromo-4- [(2-fluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (3.4 g, 7.26 mmol, 87 %) as an orange solid. LCMS: ESI m / z 469.1 [M + H]+.

[0224] Step C: To a solution of {3-amino-2,6-dibromo-4-[(2-fluoroethyl)amino]phenyl}(2- chloro-5-fluorophenyl)methanone (3.4 g, 7.26 mmol) in MeOH (50 mL) and H2O (15 mL) was added cyanogen bromide (5.38 g, 50.8 mmol) and the mixture was stirred at 75 °C for 12 hours. The mixture was concentrated under vacuum to give a crude, which was added EA and stirred for 20 min. The mixture was filtrated and the cake was dried under vacuum to give [2- azanylidene-4,6-dibromo-l-(2-fluoroethyl)-3H-benzo[d]imidazol-5-yl](2-chloro-5- fluorophenyl)methanone (3 g, 6.08 mmol, 84 %) as a gray solid. LCMS: ESI m / z 494.2 [M + H]+.[2-amino-4,6-dibromo-l-(l,1 2,2-tetradeuterio-2-fluoroethyl)benzo[d]imidazol-5-yl](2- chloro-4-fluorophenyl)methanone

[0225] Step A: To a solution of ethyl carbamoylmethanoate (2 g, 17.1 mmol) in anhydrous tetrahydrofuran (30 mL) was added LiAlD4 (1.43 g, 34.2 mmol) slowly maintaining thetemperature below 10 °C. Then reaction mixture was heated to 70 °C and stirred for 16 hrs. The mixture was cooled to 0 °C and quenched with sodium sulfate decahydrate. The mixture was fdtered through a pad of celite. The fdter cake was washed with a mixture of tetrahydrofuran: methanol (1 :3, 20 ml). The filtrate was concentrated to give a crude residue. The filter cake was suspended in ethylacetate: methanol (2:1, 50 ml), stirred for 15min, filtered and the filtrate concentrated to give a further crop of crude residue. The two residues were combined to give the desired product 2-amino- 1,1, 2, 2-tetradeuterioethan-l-ol (1.1 g, 16.9 mmol, 99%) as a crude.

[0226] Step B: To a solution of (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (4 g, 8.78 mmol) in dioxane (40 mL) was added DIPEA (2.27 g, 17.6 mmol) and 2-amino- 1,1, 2, 2-tetradeuterioethan-l-ol (570 mg, 8.78 mmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water, extracted with EA. The organic layer was separated, washed with brine, dried over Na SO4 and concentrated with rotovap. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-50%) to afford (2-chloro-4-fluorophenyl){2,6-dibromo-3- nitro-4-[(l,l,2,2-tetradeuterio-2-hydroxyethyl)amino]phenyl}methanone (2 g, 4.00 mmol, 45%) as a yellow solid. LCMS: ESI m / z 501 [M + H]+.

[0227] Step C: To a solution of (2-chloro-4-fluorophenyl){2,6-dibromo-3-nitro-4-[(l, 1,2,2- tetradeuterio-2-hydroxyethyl)amino]phenyl}methanone (1.94 g, 3.88 mmol) in DCM (20 mL) was added DAST (1.25 g, 7.75 mmol) at 0 °C. The mixture was stirred at rt for 16h, then diluted with DCM and aqueous NaHCCL. The organic layer was separated and concentrated. The residue was purified using silica gel column chromatography eluting with 0-70% ethyl acetate in petroleum ether to afford (2-chloro-4-fluorophenyl){2,6-dibromo-3-nitro-4-[(l, 1,2,2- tetradeuterio-2-fluoroethyl)amino]phenyl}methanone (800 mg, 1.59 mmol, 41%) as a brown solid. LCMS: ESI m / z 503 [M + H]+.

[0228] Step D: To a solution of (2-chloro-4-fluorophenyl){2,6-dibromo-3-nitro-4-[(l, 1,2,2- tetradeuterio-2-fluoroethyl)amino]phenyl}methanone (800 mg, 1.59 mmol) in EtOH (16 mL) and H2O (4 mL) was added Fe (446 mg, 7.96 mmol) and NH4CI (430 mg, 7.96 mmol)). The reaction was stirred at 85 °C for 2 h. The reaction mixture was filtrated, concentrated, diluted with water and extracted with EtOAc (50 mL*3). The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was triturated with PE / EA=7 / 10 to afford {3-amino- 2,6-dibromo-4-[(l,l,2,2-tetradeuterio-2-fluoroethyl)amino]phenyl}(2-chloro-4-fluorophenyl)methanone (650 mg, 1.38 mmol, 86%) as an orange solid. LCMS: ESI m / z 473 [M + H]+.

[0229] Step E: To a solution of {3-amino-2,6-dibromo-4-[(l,l,2,2-tetradeuterio-2- fluoroethyl)amino]phenyl}(2-chloro-4-fluorophenyl)methanone (650 mg, 1.38 mmol) in MeOH (9 mL) and H2O (3 mL) was added BrCN (1.17 g, 11.0 mmol). The reaction mixture was stirred at 80 °C for 16 h. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was triturated with EA to afford [2-amino-4,6-dibromo-l-(l,l,2,2-tetradeuterio-2- fluoroethyl)benzo[d]imidazol-5-yl](2-chloro-4-fluorophenyl)methanone (600 mg, 1.21 mmol, 88%) as a brown solid. LCMS: ESI m / z 498 [M + H]+.[2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3H-benzo[d]imidazol-5-yl](2-chloro-5- fluorophenyl)methanone

[0230] Step A: To a solution of 2,6-dibromo-4-fluorobenzene-l-carbaldehyde (110 g, 390 mmol) in conEESCU (550 mL) was added dropwise con. HNO3 (43.4 g, 468 mmol) at 0 °C. The reaction mixture was stirred at rt for 4 hr. The reaction mixture was poured into ice water and filtrated. The resulting solid was dissolved in EtOAc, and washed with water to remove theremaining acid, dried over Na2SC>4 and concentrated in vacuo to afford 2,6-dibromo-4-fluoro-3- nitrobenzene-1 -carb aldehyde (115 g, 352 mmol, 90%) as a black solid. LCMS: ESI m / z 328 [M + H]+.

[0231] Step B: To a solution of 2,6-dibromo-4-fluoro-3-nitrobenzene-l-carbaldehyde (40 g, 122 mmol) in THF (400 mL) was added 2-chloro-5-fluorophenyl)magnesium chloride (734 mL, freshly made, 0.5 M in THF) at 0 °C. The mixture was stirred at rt for Ih. The reaction mixture was quenched with aqueous solution of NH4CI, extracted with EA. The organic phase was washed with brine, dried over ISfeSCL and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA / PE = 0-20%) to afford (2-chloro-4- fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl)methanol (50 g, 109mmol, 89%) as a brown oil. (crude). LCMS: ESI m / z 458 [M + H]+.

[0232] Step C: To a solution of (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanol (122 g, 267 mmol) in DCM (1500 mL) was added DMP (170 g, 400 mmol) at 0 °C. The reaction was stirred at rt for Ih. The reaction mixture was diluted with water, extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-20%) to afford crude (2-chloro-4- fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl)methanone as a brown solid. The crude was triturated with 500 ml (EA: PE=1 : 10). The suspension was filtered to get (2-chloro-4- fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl)methanone (88 g, 193 mmol, 72%) as a white solid. LCMS: ESI m / z 456 [M + H]+.

[0233] Step C: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (18.0 g, 39.5 mmol) in 1,4-dioxane (200 mL) was added ethyl [di(prop-2- yl)]amine (13.7 mL, 79.0 mmol) and 2,2-difluoroethan-l -amine hydrochloride (3.95 g, 33.6 mmol). The mixture was stirred at r.t. for 72 h. The reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography eluted withPE / EA / DCM= 100 / 5 / 5 to give the starting material (2-chloro-5-fluorophenyl)(2,6-dibromo-4- fluoro-3-nitrophenyl)m ethanone (3.8 g), then eluted with DCM / EA=50 / 50 to afford (2-chloro-5- fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}methanone (14.0 g, 27.1 mmol, 69%) as a yellow solid. LCMS: ESI m / z 517 [M + H]+. ' H NMR (400 MHz, DMSO-d6) 871 (dd, J= 9.6, 4.8 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.51 (s, 1H), 7.02 (s, 1H), 6.15 (tt, 55.6, 3.6 Hz, 1H), 3.74 (t, J= 15.4 Hz, 2H).

[0234] Step D: To a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2- difluoroethyl)amino]-3-nitrophenyl}methanone (17.5 g x 2, 33.9 mmol x 2, parallel) in EtOH (170 mL) and H2O (34 mL) was added Fe (9.46 g, 169.4 mmol) and NH4C1 (9.1 g, 169.4 mmol). The reaction was stirred at 80 °C for 2h. The cooled reaction mixture was filtrated, concentrated, diluted with water and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was triturated with (PE / EA=4 / 1) to afford {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl)amino]phenyl}(2- chloro-5-fluorophenyl)methanone (26.0 g, 53.4 mmol, 79%) as an orange solid. LCMS: ESI m / z 487 [M + H]+.

[0235] Step F: To a solution of {3-amino-2,6-dibromo-4-[(2,2- difluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (4.3 g, 8.84 mmol) in mixture of MeOH and H2O (40 mL, VMeon:VH2o=3: 1) was added BrCN (5.62 g, 53.0 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried on Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EA in PE [Gradient: 42%] to afford [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (4 g, 7.820 mmol, 88%) as a white solid. LCMS: ESI m / z 512 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 6 7.70 (dd, J= 8.0, 4.0 Hz, 1H), 7.67 (s, 1H), 7.62 - 7.51 (m, 1H), 7.36 - 7.30 (m, 1H), 7.28 - 7.23 (m, 2H), 6.52 - 6.25 (m, 1H), 4.60 - 4.54 (m, 2H).[2-azanylidene-4,6-dibromo-l-(2,2,2-trifluoroethyl)-3H-benzo[d]iinidazol-5-yl](2-chloro-5- fluorophenyl)methanone

[0236] Step A. To a stirred solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (2 g, 4.39 mmol) in THF (20 mL) was added DIEA (2.3 mL, 13.1 mmol) and 2,2,2-trifluoroethan-l -amine (0.87 g, 8.78 mmol) at rt. After stirred at 60 °C for 72h, the mixture was poured into ice-water (50 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 30 %, EtOAc in PE) to give (2-chloro-5-fluorophenyl){2,6-dibromo-3-nitro-4-[(2,2,2- trifluoroethyl)amino]phenyl (methanone (2.2 g, 4.11 mmol, 94%) as a yellow solid. LCMS: m / z 531 [M+H]-.

[0237] Step B. To a stirred solution of (2-chloro-5-fluorophenyl){2,6-dibromo-3-nitro-4- [ (2, 2, 2-trifluoroethyl)amino]phenyl (methanone (2.2 g, 4.11 mmol) in EtOH (20 mL) / H2O (4 mL) was added Fe (2.3 g, 41.1 mmol) and NH4CI (0.66 g, 12.3 mmol) at rt. After stirred at 80 °C for 2h under N2 atmosphere, the mixture was filtered, concentrated. The residue was poured into ice-water (200 mL) and extracted with EtOAc (100 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, EtOAc in PE, 0-25%) to give {3-amino-2,6-dibromo-4-[(2,2,2- trifluoroethyl)amino]phenyl((2-chloro-5-fluorophenyl)methanone (2 g, 3.96 mmol, 96%) as a yellow solid. LCMS: ESI m / z 505 [M + H]+. 'H NMR (400 MHz, DMSO-d6) 5 7.68 (dd, J = 8.8, 5.0 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.30 (dd, J= 8.8, 3.2 Hz, 1H), 6.98 (s, 1H), 6.14 - 6.05 (m, 1H), 5.27 (s, 2H), 4.16 - 4.11 (m, 2H).

[0238] Step C. To a stirred solution of {3-amino-2,6-dibromo-4-[(2,2,2- trifluoroethyl)amino]phenyl((2-chloro-5-fluorophenyl)methanone (1.6 g, 3.17 mmol) in MeOH (15 mL) / H2O (5 mL) was added BrCN (2.7 g, 25.4 mmol) at rt. After stirred at 80 °C overnight, 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 residue was purified by chromatography (silica gel, EtOAc in PE, 0- 50%) to give [2-azanylidene-4,6-dibromo-l-(2,2,2-trifluoroethyl)-3H-benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1.2 g, 2.26 mmol, 71%) as a brown solid. LCMS: ESI m / z 528 [M+H]+.Intermediate l,3-dibromo-l,L2,2,393-hexadeuteriopropane

[0239] Step A: LiAlD4 (3 g, 71.6 mmol) was added portion-wise to anhydrous THF (90 mL) under argon and cooled to 0 °C. 2, 2-dideuterio-l,3-bis(deuteriooxidanyl)propane-l, 3-dione (4.66 g, 43.1 mmol) in anhydrous tetrahydrofuran (20 mL) was added slowly maintaining the temperature below 35 °C. The reaction mixture was stirred at 70 °C for 2h, then the mixture was cooled to 0 °C and quenched with sodium sulfate decahydrate. The mixture was fdtered through celite washing with THF : MeOH (1 :3, 50 mL) and the filtrate was concentrated to give a crude residue. The aluminium salts were suspended in EA: MeOH (2: 1, 50 ml), stirred for 15min, filtered and the filtrate concentrated to give a further crop of crude residue. The two residues were combined to give the desired product l,l,2,2,3,3-hexadeuterio-l,3- bis(deuteriooxidanyl)propane (1 g, 11.9 mmol, 28%) as a crude.

[0240] Step B: NBS (6.35 g, 35.7 mmol) was added portionwise to a solution of 1, 1,2, 2,3,3- hexadeuterio-l,3-bis(deuteriooxidanyl)propane (1g, 11.9 mmol) and PPhs (9.35 g, 35.7 mmol) in ACN (20 mL) and DCM (20 mL). Keeping the temperature below 35 °C. The reaction mixture was stirred at rt overnight. Hexane (40 mL) was added and the layers separated and re-extracted with hexane (20 mL). The combined hexane layers were washed with sodium hydroxide (10 mL, 2 M), then saturated aqueous sodium sulfite (10 mL), brine (20 mL), dried over magnesium sulfate and concentrated. The residue was triturated with heptane and the solid removed by filtration The filtrate was concentrated and the residue triturated a second time with heptane. The solid was removed by filtration and the filtrates was concentrated to give crude product 1,3- dibromo-l,l,2,2,3,3-hexadeuteriopropane (230 mg, 1.12 mmol, 9%) as an oil.Synthetic Procedures for examples:Example 1: N-[3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-l-oxo-l,2,3?6,8,9- hexahydroimidazo[l',2':l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0241] Step A: To a stirred solution of [2-amino-4,6-dibromo-l-(2,2- difluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (300 mg, 0.586 mmol) in DMF (0.5 mL) was added 1,2-dibromoethane (1 mL, 11.73 mmol). The reaction mixture was stirred at 130 °C using a sealed tube overnight. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by ISfeSCU, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with MeOH in DCM [Gradient: 6%] to give (2-chloro-5-fluorophenyl)[5,7-dibromo-9-(2,2- difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (100 mg, 0.186 mmol, 31%) as a yellow solid. LCMS: ESI m / z 538 [M+H]+

[0242] Step B: To a solution of (2-chloro-5-fluorophenyl)[5,7-dibromo-9-(2,2- difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (60 mg, 0.112mmol) in NMP (5 mL) was added CuCN (10 mg, 0.112 mmol). The reaction mixture was stirred at 140 °C for 2h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified by prep-HPLC to afford 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-9-(2,2- difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazole-5-carbonitrile (20 mg, 0.041 mmol, 37%) as a white solid. LCMS: ESI m / z 485 [M+H]+

[0243] Step C: To a solution of 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-9-(2,2- difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazole-5-carbonitrile (20 mg, 0.041 mmol) in dioxane (4 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (12 mg, 0.062 mmol), CS2CO3 (27 mg, 0.083 mmol), Xant-phos (5 mg, 0.008 mmol)and Pd2(dba)3 (4 mg, 0.004 mmol). The reaction mixture was stirred at 100 °C under N2 for Ih. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 12%] to afford N-{6-[(2-chloro-5- fluorophenyl)carbonyl]-5-cyano-9-(2,2-difluoroethyl)-3,9-dihydro-2TLbenzo[4,5]imidazo[l,2- a]imidazol-7-yl}-5-fluoro-3-(trifluoromethyl)benzamide (19 mg, 0,031 mmol, 75%) as a white solid. LCMS: ESI m / z 610 [M+H]+

[0244] Step D: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-9-(2,2- difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-7-yl]-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.049 mmol) in CH3CN / H2O (3 mL) was added potassium hydroxide (14 mg, 0.246 mmol). The reaction mixture was stirred at 100 °C for Ih. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MEOH in DCM [Gradient: 15%] to afford N-[3-(2-chloro- 5-fluorophenyl)-6-(2,2-difluoroethyl)-3-hydroxy-l-oxo-l,2,3,6,8,9- hexahydroimidazo[T,2': l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.032 mmol, 64%) as a white solid. LCMS: ESI m / z 628 [M+H]+

[0245] Step E: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-3- hydroxy-l-oxo-l,2,3,6,8,9-hexahydroimidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (15 mg, 0.024 mmol) in TFA (5 mL) was added triethylsilane (6 mg, 0.048 mmol). The reaction mixture was stirred at 50 °C forlh. The cooled reaction mixturewas diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC afford the title compound N-[3-(2-chloro-5-fhiorophenyl)-6-(2,2-difhioroethyl)-l-oxo-l,2,3,6,8,9- hexahydroimidazo[T,2': l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2 mg, 0.003 mmol, 14%) as a white solid. LCMS: ESI m / z 612 [M+H]+. NMR (400 MHz, DMSO-d6) 5 10.25 (s, 1H), 8.96 (s, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.81 - 7.62 (m, 2H), 7.33 - 7.17 (m, 1H), 7.10 - 7.08 (m, 2H), 6.65 (brs, 1H), 6.45 - 6.35 (m, 1H), 5.94 (brs, 1H), 4.35 - 4.12 (m, 6H).Example 2: N-[2-azanylidene-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8- oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamideExample 2

[0246] Step A: To a solution of [2-amino-4,6-dibromo-l-(2,2- difluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (800 mg, 1.564 mmol) in DMA (10 mL) was added iodomethane (0.381 mL, 4.692 mmol). The reaction mixture was stirred at 100 °C using a sealed tube for 2h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 6%] to afford [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- methylbenzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (800 mg, 1.522 mmol, 97%) as a white solid. LCMS: ESI m / z 526 [M+H]+

[0247] Step B: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- methylbenzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (60 mg, 0.114 mmol) in NMP (5 mL) was added CuCN (20 mg, 0.228 mmol). The reaction mixture was stirred at 130 °C for 2h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified by prep- HPLC to afford 2-azanylidene-6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (20 mg, 0.042 mmol, 37%) as a white solid. LCMS: ESI m / z 473 [M+H]+

[0248] Step C: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (20 mg, 0.042 mmol) in dioxane (4 mL) was added 3-fhioro-5-(trifluoromethyl)benzene-l-carboxamide (13 mg, 0.064 mmol), CS2CO3 (27 mg, 0.085 mmol), Xant-phos (5 mg, 0.008 mmol) and Pd2(dba)3 (4 mg, 0.004 mmol). The reaction mixture was stirred at 100 °C under N2 for Ih. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 10%] to afford N-{2- azanylidene-6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-l- methylbenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.025 mmol, 59%) as a white solid. LCMS: ESI m / z 598 [M+H]+

[0249] Step D: To a solution ofN-{2-azanylidene-6-[(2-chloro-5-fluorophenyl)carbonyl]-7- cyano-3-(2,2-difluoroethyl)-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.050 mmol) in CH3CN / H2O (5 mL) was added potassiumhydroxide (14 mg, 0.251 mmol). The reaction mixture was stirred at RT forlh. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by ISfeSCU, fdtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 15%] to afford N-[2-azanylidene-6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H- imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.032 mmol, 64%) as a white solid. LCMS: ESI m / z 616 [M+H]+

[0250] Step E: To a solution of N-[2-azanylidene-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro- 3-(trifluoromethyl)benzamide (20 mg, 0.032 mmol) in TFA (6 mL) was added triethylsilane (8 mg, 0.065 mmol). The reaction mixture was stirred at 50 °C for Ih. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC afford N-[2- azanylidene-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H- imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7 mg, 0.012 mmol, 36%) as a white solid. LCMS: ESI m / z 600 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 10.26 (s, IH), 9.11 (s, IH), 7.92 (d, J= 8.0 Hz, IH), 7.73 (d, 8.0 Hz, IH), 7.69 (s, IH), 7.29-7.25 (m, IH),7.21 (s, IH), 7.10-7.06 (m, IH), 6.66 (brs, IH), 6.45-6.25 (m, IH), 5.94 (brs, IH), 4.55 - 4.30 (m, 2H), 3.97 (s, 3H).Example 3: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-imino-l-(methyl-d3)-8- oxo-1, 2, 3,6,7, 8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamideExample 3

[0251] Step A: To a solution of (2-amino-4,6-dibromo-l-(2,2-difluoroethyl)-lH- benzo[d]imidazol-5-yl)(2-chloro-5-fluorophenyl)methanone (400 mg, 0.786 mmol) in DMA (5 mL) were added CD3I (0.098 mL, 1.57 mmol). The reaction was stirred at 100 °C under N2 for 3 hr in a sealed system. LCMS showed the reaction was completed. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give a crude (2-chloro-5-fluorophenyl)(4,6-dibromo-l-(2,2- difluoroethyl)-2-imino-3-(methyl-d3)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methanone (200 mg, 0.380 mmol, 48%) as a white solid. LCMS: ESI m / z 527 / 529 [M-H]'.

[0252] Step B: To a solution of (2-chloro-5-fluorophenyl)(4,6-dibromo-l-(2,2- difhioroethyl)-2-imino-3-(methyl-d3)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methanone (100 mg, 0.190 mmol) in NMP (4 mL) were added CuCN (51 mg, 0,570 mmol). The reaction was stirred at 130 °C under N2 for 8 hr. 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 using silica gel column chromatography eluted with ethyl acetate in DCM (gradient: 20-30%) to afford 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2,2-difluoroethyl)-2-imino-3- (methyl-d3)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (40 mg, 0.085 mmol, 44%) as a yellow solid. LCMS: ESI m / z 474 / 476 [M-H]'.

[0253] Step C: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2,2-difluoroethyl)- 2-imino-3-(methyl-d3)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (30 mg, 0.063 mmol) in dioxane (3 mL) were added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (19.6 mg, 0.094 mmol), Pd2(dba)s (5.77 mg, 0.006 mmol), and XANT PHOS (7.29 mg, 0.013 mmol), CS2CO3 (41 mg, 0.126 mmol). The reaction was stirred at 100 °C under IShfor 2 hr. 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 petroleum ether (gradient: 10-20%) to afford N-(6- (2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2-difluoroethyl)-2-imino-l-(methyl-d3)-2,3-dihydro- lH-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.033 mmol, 53%) as a yellow oil. LCMS: ESI m / z 601 / 603 [M+H]+.

[0254] Step D: To a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2- difluoroethyl)-2-imino- 1 -(methyl-d3 )-2, 3 -dihydro- 1 H-benzo[d]imidazol-5 -yl)-3 -fluoro-5 - (trifluoromethyl)benzamide (20 mg, 0.033 mmol) in H2O (1 mL) and ACN (3 mL) were added KOH (3.70 mg, 0.066 mmol). The reaction was stirred at room temperature under N2 for 1 hr. LCMS showed the reaction was completed. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The organic layer was separated and concentrated to afford N-(6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2-imino-l-(methyl-d3)-8-oxo-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 0.024 mmol, 73%) as a yellow solid. LCMS: ESI m / z 619 / 621 [M + H]+.

[0255] Step E: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-imino-l-(methyl-d3)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.032 mmol) in TFA (3 mL) were added EtsSiH (37 mg, 0.320 mmol). The reaction was stirred at 70 °C for 1 hr. 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 by prep- HPLC to afford N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-imino-l-(methyl-d3)-8- oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.6 mg, 0.004 mmol, 13%) as a white solid. LCMS: ESI m / z 603 / 605 [M + H]". 'H NMR (400MHz, CD3OD) 5 7.75 - 7.72 (m, 1H), 7.69 (d, 7.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.28 -7.25 (m, 1H), 7.03 - 7.00 (m, 1H), 6.53 - 6.20 (m, 1H), 4.74 - 4.67 (m, 2H).Example 4: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamidePd2(dba)3, xantphos, Cs2CO3, dioxane, 100 °C, 2hStep CExample 4

[0256] Step A: To a solution of (2-chloro-5-fluorophenyl)(4,6-dibromo-l-(2,2- difluoroethyl)-2-imino-3-methyl-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methanone (700 mg, 1.33 mmol) in DMA (10 mL) was added K2CO3 (184 mg, 1.33 mmol) and CH3I (1.89 g, 13.3 mmol). The reaction mixture was stirred at 50 °C for 3 h. The cooled mixture was diluted withH2O, 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 0- 10% methanol in dichloroform to afford the title compound (2-chloro-5-fluorophenyl)(4,6- dibromo-l-(2,2-difhioroethyl)-3-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazol-5- yl)methanone (150 mg, 0.28 mmol, 21%) as a yellow solid. LCMS: ESI m / z 538 [M + H]+.

[0257] Step B: To a solution of (2-chloro-5-fluorophenyl)(4,6-dibromo-l-(2,2- difluoroethyl)-3-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methanone (150 mg, 0.28 mmol) in NMP (3 mL) was added CuCN (50 mg, 0.56 mmol). The reaction mixture was stirred at 130 °C for 1.5 h. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using pre-HPLC to afford 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2,2- difhioroethyl)-3-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (40 mg, 0.08 mmol, 30%) as a white solid. LCMS: ESI m / z 485 [M + H]+.

[0258] Step C: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2,2-difluoroethyl)- 3-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (40 mg, 0.082 mmol) in dioxane (3 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (26 mg, 0.124 mmol), Xantphos (9.53 mg, 0.016 mmol), CS2CO3 (54 mg, 0.165 mmol) and Pd2(dba)s (7.54 mg, 0.008 mmol). The reaction mixture was stirred at 100 °C under N2 for 2 h. The cooled mixture was diluted with EA and washed with H2O and brine. The organic layer was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in DCM to afford N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2- difluoroethyl)-l-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.082 mmol, 99%) as a yellow solid. LCMS: ESI m / z 612 [M + H]+.

[0259] Step D: To a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2- difluoroethyl)-l-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.082 mmol) in ACN (5 mL) and H2O (1 mL) was added KOH (23 mg, 0.41 mmol), and the mixture was stirred at 25 °C for 1 h. The mixture was diluted with EA and washed with H2O and brine. The organic layer was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-15% methanol in DCM to afford N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (30 mg, 0.048 mmol, 58%) as a white solid. LCMS: ESI m / z 630 [M + H]+.

[0260] Step E: To a solution of N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.048 mmol) in TFA (2 mL) was added EtsSiH (28 mg, 0.24 mmol). The reaction mixture was stirred at 50 °C for 1 h. The mixture was concentrated with rotavap. The residue was purified using pre-HPLC to afford N-(6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (12.8 mg, 0.021 mmol, 44%) as a white solid. LCMS: ESI m / z 614 [M + H]+.1H NMR (400 MHz, DMSO-d6) 5 10.55 (s, 1H), 9.53 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.38 - 7.27 (m, 1H), 7.18 - 7.07 (m, 1H), 6.74 - 5.83 (m, 3H), 4.97 - 4.76 (m, 2H), 4.41 (s, 3H), 3.33 (s, 3H).Example 5: N-(6-(2-chloro-5-fluorophenyl)-2-(cyanoimino)-3-(2,2-difluoroethyl)-l-(methyl- d3)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 6: N-(2-(carbamoylimino)-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-8-oxo-l,2,3)6,7,8-hexahydroimidazo[4,5- e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 5 Example 6

[0261] Step A: To a solution of {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl) amino] phenyl} (2-chloro-5-fluorophenyl) methanone (3 g, 6.166 mmol) in CAN (30 mL) was added DIEA (1.99 g, 15.416 mmol) and [bis(phenyloxidanyl)methylidene] azanecarbonitrile (2.2 g, 9.25 mmol). The mixture was stirred at 100 °C for 60 hours. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 50%] to afford [(2E)-4,6-dibromo-5-[(2- chloro-5-fluorophenyl) carbonyl]-l-(2,2-difluoroethyl)-2,3-dihydro-lH-benzo[d]imidazol-2- ylidene] azanecarbonitrile (1.5 g, 2.796 mmol, 45%) as a yellow solid. LCMS: ESI m / z 535 [M + H]+.

[0262] Step B: To a solution of [(2E)-4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- (2,2-difluoroethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-ylidene]azanecarbonitrile (300 mg, 0.559 mmol) in DMA (10 mL) was added iodomethane (0.5 mL, 4.692 mmol). The mixture was stirred at 100 °C for 4 hrs. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 50%] toafford [(2E)-4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-ylidene]azanecarbonitrile (110 mg, 0.199 mmol, 35%) as a white solid. LCMS: ESI m / z 554 [M+H]+

[0263] Step C: To a solution of [(2E)-4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- (2,2-difluoroethyl)-3-(trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2- ylidene]azanecarbonitrile (100 mg, 0.181 mmol) in NMP (5 mL) was added CuCN (29 mg, 0.325 mmol). The mixture was stirred at 130 °C for 4 hrs. The reaction mixture was cooled down to rt, diluted with ELO, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 60%] to afford 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-2-[cyanoazanylidene]-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (40 mg, 0.080 mmol, 44%) as a white solid. LCMS: ESI m / z 500 [M+H]+.

[0264] Step D: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2- [cyanoazanylidene]-l-(2,2-difluoroethyl)-3-(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (30 mg, 0.060 mmol) in dioxane (4 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l- carboxamide (15 mg, 0.072 mmol), CS2CO3 (39 mg, 0.120 mmol), Xant-phos (7 mg, 0.012 mmol)and Pd2(dba)s (6 mg, 0.006 mmol). The mixture was stirred at 100 °C under N2 for 1 hrs. The reaction mixture was cooled down to rt, diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 10%] to afford N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-[cyanoazanylidene]-3-(2,2- difluoroethyl)-l-(trideuteriomethyl)benzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.048 mmol, 79%) as a white solid. LCMS: ESI m / z 644 [M+H]+

[0265] Step E: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-2-[cyanoazanylidene]-3- (2,2-difluoroethyl)-6-hydroxy-8-oxo-l-(trideuteriomethyl)-7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.031 mmol) in TFA (5 mL) was added triethylsilane (10.8 mg, 0.093 mmol). The mixture was stirred at 50 °C for 5 min. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC toafford N-(6-(2-chloro-5-fluorophenyl)-2-(cyanoimino)-3-(2,2-difluoroethyl)-l-(methyl-d3)-8- oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1 mg, 0.002 mmol, 5%) as a white solid. LCMS: ESI m / z 628 [M+H]+NMR (400 MHz, CD3OD) 8 7.73 - 7.54 (m, 4H), 7.31 - 7.21 (m, 1H), 7.03 - 6.91 (m, 1H), 6.52 - 6.22 (m, 2H), 4.76 - 4.70 (m, 2H). And N-(2-(carbamoylimino)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-l-(methyl-d3)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro- 5-(trifluoromethyl)benzamide (2 mg, 0.004 mmol, 12%) LCMS: ESI m / z 646 [M+H]+'H NMR (400 MHz, DMSO-d6) 8 10.64 (s, 1H), 9.55 (s, 1H), 8.04 - 7.92 (m, 2H), 7.81 (d, J= 8.0 Hz, 1H), 7.77 (s, 1H), 7.37 - 7.32 (m, 1H), 7.19 - 7.13 (m, 1H), 6.99 - 6.39 (m, 4H), 6.19 (brs, 1H), 4.98 - 4.88 (m, 2H).Example 7 : N-(3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-l-oxo-2,3,6,8,9,10- hexahydro-lH-pyrimido[2',l':2,3]imidazo[4,5-e]isoindol-4-yl-8,8,9,9,10,10-d6)-3-fluoro-5- (trifluoromethyl)benzamide

[0266] Step A: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-4-fluorophenyl)methanone (200 mg, 0.391 mmol) in DMA (2 mL) was added l,3-dibromo-l,l,2,2,3,3-hexadeuteriopropane (163 mg, 0.782 mmol). The mixture was stirred at 130 °C for 16h. The cooled mixture was purified by pre-HPLC to afforded (2-chloro-4-fluorophenyl)[6,8-dibromo-2,2,3,3,4,4-hexadeuterio-10-(2,2-difluoroethyl)-2,3,4,10- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidin-7-yl]methanone (50 mg, 90 μmol, 23%) as a brown oil. LCMS: ESI m / z 558 [M + H]+.

[0267] Step B: To a solution of (2-chloro-4-fluorophenyl)[6,8-dibromo-2,2,3,3,4,4- hexadeuterio-10-(2,2-difluoroethyl)-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidin-7- yl]methanone (50 mg, 90 μmol) in NMP (1 mL) was added CuCN (8 mg, 90 μmol). The reaction mixture was stirred at 140 °C for 2h, cooled down to rt, then diluted with EA and H2O. The organic layer was washed with aqueous NaCl 5 times. The organic layer was separated, dried over Na2SC>4 and concentrated in rotovap. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0%~ 10%) to afforded 8-bromo-7-[(2- chloro-4-fluorophenyl)carbonyl]-2,2,3,3,4,4-hexadeuterio-10-(2,2-difluoroethyl)-2,3,4,10- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidine-6-carbonitrile (20 mg, 40 μmol, 44%) as a brown solid. LCMS: ESI m / z 503 [M + H]+.

[0268] Step C: A mixture of 8-bromo-7-[(2-chloro-4-fluorophenyl)carbonyl]-2,2,3,3,4,4- hexadeuterio-10-(2,2-difluoroethyl)-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidine-6- carbonitrile (30 mg, 60 μmol), 5-fluoro-3-(trifluoromethyl)benzene-l -carboxamide (12.3 mg, 60 μmol), Pd2(dba)s (5 mg, 6 μmol), xantphos (7 mg, 12 μmol), CS2CO3 (58.1 mg, 0.179 mmol) in dioxane (1.5 mL) was stirred at 100 °C under N2 for 2h. The reaction mixture wasconcentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0%~l 0%) to afforded N-{7-[(2-chloro-4-fluorophenyl)carbonyl]-6- cyano-2,2,3,3,4,4-hexadeuterio-10-(2,2-difluoroethyl)-2,3,4,10- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidin-8-yl}-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 32 μmol, 53%) as a brown solid. LCMS: ESI m / z 630 [M + H]+.

[0269] Step D: To a solution of N-{7-[(2-chloro-4-fluorophenyl)carbonyl]-6-cyano- 2,2,3,3,4,4-hexadeuterio-10-(2,2-difluoroethyl)-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2- a]pyrimidin-8-yl}-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 32 μmol) in ACN (1 mL) and H2O (0.1 mL) was added KOH (9 mg, 0.159 mmol) at rt. The reaction mixture was stirred at rt for 30 min. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2SO4 and concentrated to give N-[3-(2-chloro-4-fluorophenyl)-8,8,9,9,10,10-hexadeuterio-6- (2,2-difluoroethyl)-3-hydroxy-l-oxo-2,3,6,8,9,10-hexahydro-lH-pyrimido[2',l':2,3]imidazo[4,5- e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 23 μmol, 73%) as a brown solid. LCMS: ESI m / z 648 [M + H]+.

[0270] Step E: To a solution ofN-[3-(2-chloro-4-fluorophenyl)-8,8,9,9,10,10-hexadeuterio- 6-(2,2-difluoroethyl)-3-hydroxy-l-oxo-2,3,6,8,9,10-hexahydro-lH- pyrimido[2',l':2,3]imidazo[4,5-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 23 μmol) in TFA (1 mL) was added triethylsilane (0.1 mL). The reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was concentrated and then purified by pre-HPLC to give N-[3 -(2-chloro-4-fluorophenyl)-8,8,9,9, 10, 10-hexadeuterio-6-(2,2-difluoroethyl)- 1 -oxo- 2,3,6,8,9,10-hexahydro-lH-pyrimido[2',T:2,3]imidazo[4,5-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (1 mg, 2 μmol, 7%) as a white solid. LCMS: ESI m / z 632 [M + H]+. ^NMR (400 MHz, CD3OD) 5 7.74 -7.63 (m, 3H), 7.64 (d, J= 8.4 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.04 - 7.00 (m, 1H), 6.61 - 6.15 (m, 2H), 4.85 - 4.62 (m, 2H).Example 8: N-(3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-l-oxo-l,2,3,6- tetrahydroimidazo [2 * , 1 * : 2,3] imidazo [4,5-e] isoindol-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[0271] Step A: The mixture of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (500 mg, 0.98 mmol) and 2-bromo- 1,1 -dimethoxy ethane (826 mg, 4.89 mmol) in DMA (3 mL) was stirred at 140 °C under N2 for 2h. The cooled mixture was diluted with water and extracted with EA twice. The combined organic layer was washed with water, brine, dried and concentrated. The residue was purified by FCC, eluting with EA / PE (0-50%) to give (2-chloro-5-fluorophenyl)[5,7-dibromo-9-(2,2- difluoroethyl)benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (110 mg, 0.21 mmol, 21%) as a brown solid. LCMS: m / z 536[M+H]+.

[0272] Step B: The mixture of (2-chloro-5-fluorophenyl)[5,7-dibromo-9-(2,2- difluoroethyl)benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (177 mg, 0.33mmol) and CuCN (59 mg, 0.66 mmol) in NMP (5 mL) was stirred at 140 °C under N2 for 3h. The cooled mixture was purified by FCC to give a crude. The crude was purified by reversed phase column to give 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-9-(2,2- difhioroethyl)benzo[4,5]imidazo[l,2-a]imidazole-5-carbonitrile (23 mg, 0.036 mmol, 11%) as a yellow solid. LCMS: ESI m / z 483 [M+H]+.

[0273] Step C: The mixture of 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-9-(2,2- difluoroethyl)benzo[4,5]imidazo[l,2-a]imidazole-5-carbonitrile (25 mg, 0.05 mmol) and 3- fluoro-5-(trifluoromethyl)benzene-l-carboxamide (16 mg, 0.08 mmol), Pd2(dba)s (5 mg, 0.005 mmol), Xantphos (6 mg, 0.01 mmol) and CS2CO3 (34 mg, 0.10 mmol) in dioxane (3 mL) was stirred at 120 °C for 2h. The cooled mixture was diluted with water and extracted with EA. The organic layer was washed with brine and concentrated. The mixture was used directly in the next step. LCMS: ESI m / z 608 [M+H]+.

[0274] Step D: To the solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-9-(2,2- difluoroethyl)benzo[4,5]imidazo[l,2-a]imidazol-7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.033 mmol) in MeCN (5 mL) and H2O (2 mL) was added KOH (19 mg, 0.33 mmol). The mixture was stirred at room temperature for 20 min. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na SO4 and concentrated. The residue was purified by prep-TLC (EA: PE=5: 3) to give N-[3-(2-chloro-5- fluorophenyl)-6-(2,2-difluoroethyl)-3 -hydroxy- 1 -oxo-2,3 -dihydro- 1 H- imidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-3-fIuoro-5-(trifluoromethyl)benzamide (5 mg, 0.008 mmol, 24%) as a yellow solid. LCMS: ESI m / z 626 [M+H]+,

[0275] Step E: The mixture ofN-[3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-3- hydroxy-l-oxo-2,3-dihydro-lH-imidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (15 mg, 0.024 mmol) in 2,2,2-trifluoroacetaldehyde (5 mL) and EtsSiH (0.5 mL) was stirred at 50 °C for 20 min. The mixture was concentrated. The residue was purified by prep-HPLC to give N-[3-(2-chloro-5-fluorophenyl)-6-(2,2- difluoroethyl)-l-oxo-2,3-dihydro-lH-imidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (2.3 mg, 0.004 mmol, 16%) as a yellow solid. LCMS: ESI m / z 610 [M+H]+. ^NMR (400 MHz, DMSO-d6) 8 10.57 (s, 1H), 9.36 (s, 1H), 7.96 (d, 8.8 Hz, 1H),7.93 (d, J= 1.6 Hz, 1H), 7.79 - 7.71 (m, 3H), 7.33 - 7.30 (m, 1H), 7.17 (d, J= 1.6 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.76 - 6.27 (m, 2H), 6.14 (brs, 1H), 4.92 - 4.53 (m, 2H).Example 9: N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-l-oxo-6-(2,2,2- trifluoroethyl)-l,2,3,6,8,9-hexahydroimidazo[r,2':l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro- 5-(trifluoromethyl)benzamide

[0276] Step A: To a stirred solution of [2-azanylidene-4,6-dibromo-l-(2,2,2-trifluoroethyl)- 3H-benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1.2 g, 2.26 mmol) in DMA (5 mL) was added l,2-dibromo-l,l,2,2-tetradeuterioethane (1.5 mL, 22.6 mmol) at rt. After stirred at 140 °C for 3h, the cooled 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 Na2SC>4, fdtered and concentrated. The residue was purified by chromatography (silica gel, MeOH inDCM 0 - 5%) to give (2-chloro-5-fluorophenyl)[5,7-dibromo-2,2,3,3-tetradeuterio-9-(2,2,2- trifluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (520 mg, 0.93 mmol, 41%) as a brown solid. LCMS: ESI m / z 600 [M+H]+.

[0277] Step B: To a stirred solution of (2-chloro-5-fluorophenyl)[5,7-dibromo-2,2,3,3- tetradeuterio-9-(2,2,2-trifluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-6- yl]methanone (300 mg, 0.53 mmol) in NMP (5 mL) was added CuCN (53 mg, 0.59 mmol) at rt. After stirred at 140 °C for 3hrs under N2 atmosphere, the cooled mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2,2,3,3- tetradeuterio-9-(2,2,2-trifluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazole-5- carbonitrile (30 mg, 0.06 mmol, 11%) as a yellow solid. LCMS: ESI m / z 505 [M+H]+.

[0278] Step C: To a stirred solution of 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2.2.3.3-tetradeuterio-9-(2,2,2-trifluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2- a]imidazole-5-carbonitrile (30 mg, 0.06 mmol) in dioxane (5 mL) was added 3-fluoro-5- (trifluoromethyl)benzene-l -carboxamide (18 mg, 0.09 mmol), Pd2(dba)s (6 mg, 0.006 mmol), XANTPHOS (7 mg, 0,012 mmol) and CS2CO3 (48 mg, 0, 15 mmol) at rt. After stirred at 100 °C for 2h under N2 atmosphere, the cooled mixture was poured into ice-water (20 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried on Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, MeOH in DCM, 0-8%) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-2,2,3,3- tetradeuterio-9-(2,2,2-trifluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-7-yl}-3- fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.05 mmol, 80%) as a yellow solid. LCMS: ESI m / z 632 [M + H]+.

[0279] Step D: To a stirred solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-2.2.3.3-tetradeuterio-9-(2,2,2-trifluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol- 7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.04 mmol) in ACN (4 mL) / H2O (1 mL) was added KOH (22 mg, 0.4 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 to give crude N-[3- (2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-3-hydroxy-l-oxo-6-(2,2,2-trifluoroethyl)- l,2,3,6,8,9-hexahydroimidazo[T,2': l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.03 mmol, 77%) as a yellow solid. LCMS: ESI m / z 650 [M+H]+.

[0280] Step E: To a stirred solution of N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio- 3 -hydroxy- 1 -oxo-6-(2,2,2-trifluoroethyl)- 1 ,2,3 ,6,8,9-hexahydroimidazo[ 1 ',2' : 1 ,2]imidazo[5,4- e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.03 mmol) in TFA (2 mL) was added EtsSiH (0.5 mL) at rt. After stirred at 70 °C for Ih, the cooled mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-l-oxo-6- (2,2,2-trifhioroethyl)-l,2,3,6,8,9-hexahydroimidazo[l',2':l,2]imidazo[5,4-e]isoindol-4-yl]-3- fluoro-5-(trifluoromethyl)benzamide (8 mg, 0.013 mmol, 41%) as a white solid. LCMS: ESI m / z 634 [M+H]+. *H NMR (400 MHz, DMSO-d6) 5 10.57 (s, IH), 10.32 (s, IH), 9.40 (s, IH), 7.97 (d, .7= 8.4 Hz, IH), 7.84 (s, IH), 7.76 (d, J= 8.8 Hz, IH), 7.71 (s, IH), 7.34 - 7.31 (m, IH), 7.14 - 7.11 (m, IH), 6.10 (brs, IH), 5.40 - 5.12 (m, 2H).Example 10: N-(3-(2-chloro-5-fluorophenyl)-7,10-dimethyl-l-oxo-l, 2,3,7,8,10- hexahydroimidazo [1' ,2' : 1 ,2] imidazo [4,5-e] isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0281] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (4 g, 8.783 mmol) in dioxane (40 mL) was added DIEA (2.27 g, 17.5mmol) and 2-aminopropan-l-ol (100 mg, 1.331 mmol). The reaction mixture was stirred at100 °C for 2h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 30%] to afford (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(l-hydroxyprop-2-yl)amino]-3- nitrophenyl} methanone (2.2 g, 4.31 mmol, 49%) as a white solid. LCMS: ESI m / z 511 [M+H]+.

[0282] Step B: To a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(l-hydroxyprop- 2-yl)amino] -3 -nitrophenyl (methanone (2.2 g, 4.31 mmol) in EtOH / FEO (20 mL) was added Fe (1.20 g, 21.5 mmol) and NELCl (1.15 g, 21.5 mmol). The reaction mixture was stirred at 75 °C for 2h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to give {3-amino- 2,6-dibromo-4-[(l-hydroxyprop-2-yl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (2 g, 4.16 mmol, 96%) as a white solid. LCMS: ESI m / z 481 [M+H]+

[0283] Step C: To a solution of {3-amino-2,6-dibromo-4-[(l-hydroxyprop-2- yl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (2 g, 4.16 mmol) in MeOH / FEO (30 mL) was added BrCN (2.64 g, 24.9 mmol). The reaction mixture was stirred at 75 °C overnight. Thereaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 60%] to afford [2-azanylidene-4,6- dibromo-l-(l-hydroxyprop-2-yl)-3H-benzo[d]imidazol-5-yl](2-chloro-5- fhiorophenyl)methanone (1.7 g, 3.363 mmol, 80 %) as a white solid. LCMS: ESI m / z 506 [M+H]+

[0284] Step D: To a solution of [2-azanylidene-4,6-dibromo-l-(l-hydroxyprop-2-yl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1 g, 1.97 mmol) in toluene (10 mL) was added (tributyl-X5-phosphanylidene)acetonitrile (2 mL, 7.912 mmol). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 50 %] to afford (2-chloro-5-fluorophenyl)(6,8-dibromo-3-methyl-3,9-dihydro-2H- benzo[4,5]imidazo[2,3-b]imidazol-7-yl)methanone (700 mg, 1.436 mmol, 72%) as a white solid. LCMS: ESI m / z 488 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 7.70 - 7.66 (m, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.59 - 7.52 (m, 1H), 7.36 - 7.32 (m, 1H), 4.75 - 4.71 (m, 1H), 4.19 (t, J= 8.0 Hz, 1H), 3.64 - 3.57 (m, 1H), 1.51 (d. J = 8.0 Hz, 3H).

[0285] Step E: To a solution of (2-chloro-5-fluorophenyl)(6,8-dibromo-3-methyl-3,9- dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-7-yl)methanone (800 mg, 1.641 mmol) in DMA (10 mL) was added iodomethane (0.5 mL, 4.923 mmol). The reaction mixture was stirred at 100 °C for 2h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by ISfeSCL, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 8%] to afford (2- chloro-5-fluorophenyl)(6,8-dibromo-3,9-dimethyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3- b]imidazol-7-yl)methanone (700 mg, 1.396 mmol, 85%) as a white solid. LCMS: ESI m / z 502 [M+H]+

[0286] Step F: To a solution of (2-chloro-5-fluorophenyl)(6,8-dibromo-3,9-dimethyl-3,9- dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-7-yl)methanone (600 mg, 1.196 mmol) in NMP (8 mL) was added CuCN (214 mg, 2.39 mmol). The reaction mixture was stirred at 130 °C for 3h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified usingsilica gel column chromatography eluting with MeOH in DCM [Gradient: 5%] to afford 6- bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-3,9-dimethyl-3,9-dihydro-2H- benzo[4,5]imidazo[2,3-b]imidazole-8-carbonitrile (200 mg, 0.447 mmol, 37%) as a white solid. LCMS: ESI m / z 449 [M+H]+

[0287] Step G: To a solution of 6-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-3,9- dimethyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazole-8-carbonitrile (100 mg, 0.223 mmol) in dioxane (10 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (83 mg, 0.402 mmol), CS2CO3 (145 mg, 0.447mmol), Xant-phos (26 mg, 0.045 mmol) and Pd (dba)3 (20 mg, 0.022 mmol). The reaction mixture was stirred at 100 °C for Ih. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 12%] to afford N-{7-[(2-chloro-5- fluorophenyl)carbonyl]-8-cyano-3,9-dimethyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3- b]imidazol-6-yl}-3-fluoro-5-(trifluoromethyl)benzamide (70 mg, 0.122 mmol, 54%) as a white solid. LCMS: ESI m / z 574 [M+H]+

[0288] Step H: To a solution ofN-{7-[(2-chloro-5-fluorophenyl)carbonyl]-8-cyano-3,9- dimethyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-6-yl}-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.087 mmol) in CH3CN / H2O (5 mL) was added potassium hydroxide (25 mg, 0.436 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 Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 20%] to afford 6-bromo-5-(2-chloro-5- fluorobenzoyl)-l-(2,2-difluoroethyl)-2-imino-3-methyl-2,3-dihydro-lH-benzo[d]imidazole-4- carbonitrileN-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7,10-dimethyl-l-oxo-l,2,3,7,8,10- hexahydroimidazo[2',3':2,3]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.051 mmol) as a white solid. LCMS: ESI m / z 592 [M+H]+

[0289] Step I: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7,10-dimethyl-l- oxo-l,2,3,7,8,10-hexahydroimidazo[2',3':2,3]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.084 mmol) in TFA (5 mL) was added tri ethyl silane (20 mg, 0.169 mmol). The reaction mixture was stirred at 50 °C for Ih. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried byNa2SC>4, filtered and concentrated. The residue was purified by prep-HPLC to afford N-[3-(2- chloro-5-fluorophenyl)-7,10-dimethyl-l-oxo-l,2,3,7,8,10- hexahydroimidazo[2',3':2,3]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (2.7 mg, 0.005 mmol, 6%) as a white solid. LCMS: ESI m / z 576 [M+H]+. 'H NMR (400 MHz, CDCI3) 8 8.03 (s, 1H), 7.45 - 7.41 (m, 3H), 7.33 - 7.30 (m, 2H), 6.98 - 6.95 (m, 1H), 6.69 (brs, 1H), 6.30 (brs, 1H), 6.11 (brs, 1H), 4.46 - 4.41 (m, 2H), 3.91 (s, 3H), 3.84 - 3.80 (m, 1H), 1.47 - 1.44 (m, 3H).Example 11: N-[(6R)-2-azanylidene-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide and Example 12: N-[(6S)-2-azanylidene-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0290] N-[2-azanylidene-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo- 7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.067_mmol) was purified by prep-SFC method 1 to afford N-[(6R)-2-azanylidene-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5- yl]-5-fluoro-3-(trifluoromethyl)benzamide (9.1 mg, 0.015 mmol, 23%) as a white solid, TFA salt. LCMS: ESI m / z 6008 7.76 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.64 (d, J= 8.8 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.06 - 6.95 (m, 1H), 6.59 - 6.17 (m, 2H), 4.81 - 4.67 (m, 2H), 4.39 (s, 3H). And N-[(6S)-2-azanylidene-6-(2-chloro-5-fluorophenyl)- 3-(2,2-difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (12 mg, 0.020 mmol, 30%) as a white solid. LCMS: ESI m / z 600 [M + H]+.JH NMR (400 MHz, CD3OD) 8 7.77 (s, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 7.64 (d, J= 8.8Hz, 1H), 7.29 - 7.25 (m, 1H), 7.06 - 6.95 (m, 1H), 6.55 - 6.22 (m, 2H), 4.77 - 4.68 (m, 2H), 4.39 (s, 3H).Example 13: N-(3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-l-oxo-l,2,3,6,8,9- hexahydroimidazo [2' ,1 ' : 2,3] imidazo [4,5-e] isoindol-4-yl-8,8,9,9-d4)-3-fluoro-5-(trifluoromethyl)benzamide

[0291] Step A: To a solution of [2-amino-4,6-dibromo-l-(2,2- difluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (2.00 g, 3.910 mmol) in DMA (5 mL) was added 1,2-dibromoethane (2 mL, 35.2 mmol). The reaction mixture was stirred at 130 °C overnight. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM[Gradient: 8%] to afford (2-chloro-5-fluorophenyl)[5,7-dibromo-2,2,3,3-tetradeuterio-9-(2,2- difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (450 mg, 0.831 mmol, 21%) as a yellow solid. LCMS: ESI m / z 542 [M+H]+

[0292] Step B: To a solution of (2-chloro-5-fluorophenyl)[5,7-dibromo-2,2,3,3-tetradeuterio- 9-(2,2-difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (500 mg, 0.923 mmol) in NMP (5 mL) was added CuCN (165 mg, 1.846 mmol). The reaction mixture was stirred at 130 °C for 3h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using prep-HPLC to afford 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2,2,3,3- tetradeuterio-9-(2,2-difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazole-5- carbonitrile (120 mg, 0.246 mmol, 26%) as a white solid. LCMS: ESI m / z 485 [M+H]+

[0293] Step C: To a solution of 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2,2,3,3- tetradeuterio-9-(2,2-difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazole-5- carbonitrile (100 mg, 0.205 mmol) in dioxane (4 mL) was added 3-fluoro-5- (trifluoromethyl)benzene-l -carboxamide (63 mg, 0.308 mmol), CS2CO3 (133 mg, 0.410 mmol), Xant-phos (23 mg, 0.041 mmol) and Pd2(dba)s (18 mg, 0.021 mmol). The reaction mixture was stirred at 100 °C under N2 for 2h. The reaction mixture was cooled down, then diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 10%] to afford N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano- 2,2,3,3-tetradeuterio-9-(2,2-difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-7- yl}-5-fluoro-3-(trifhioromethyl)benzamide (100 mg, 0.163 mmol, 79%) as a white solid. LCMS: ESI m / z 614 [M+H]+

[0294] Step D: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-2,2,3,3- tetradeuterio-9-(2,2-difluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-7-yl}-5- fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.163 mmol) in CH3CN / H2O (6 mL) was added potassium hydroxide (46 mg, 0.814 mmol). The reaction mixture was stirred at rt forlh. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 15%] to afford N-[3-(2-chloro- 5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2-difluoroethyl)-3-hydroxy-l-oxo-l,2,3,6,8,9-hexahydroimidazo[T,2': l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.127 mmol, 77%) as a white solid. LCMS: ESI m / z 632 [M+H]+

[0295] Step E: To a solution of N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2- difluoroethyl)-3 -hydroxy- 1 -oxo- 1 ,2,3,6, 8,9-hexahydroimidazo[ 1 ',2' : 1 ,2]imidazo[5,4-e]isoindol- 4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.158 mmol) in TFA (5 mL) was added triethylsilane (55 mg, 0.475 mmol). The reaction mixture was stirred at 50 °C for Ih. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using prep-HPLC to afford N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2-difluoroethyl)-l-oxo- l,2,3,6,8,9-hexahydroimidazo[T,2': l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (42 mg, 0.068 mmol, 43%) as a white solid. LCMS: ESI m / z 616 [M+H]+. ^NMR (400 MHz, DMSO-d6) 6 10.55 (s, IH), 10.12 (s, IH), 9.38 (s, IH), 7.97 (d, J = 8.0 Hz, IH), 7.76 - 7.71 (m, 3H), 7.32 (dd, J= 8.0, 4.0 Hz, IH), 7.13 - 7.10 (m, IH), 6.66 - 6.45 (m, 2H), 6.09 (brs, IH), 4.88 - 4.62 (m, 2H).Example 14: 5-fluoro-N-{2-[acetylazanylidene]-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl}-3- (trifluoromethyl)benzamide

[0296] Step A: To a solution of N-[2-azanylidene-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.017 mmol) in DCM (3 mL) were added acetyl chloride (0.004 mL, 0.05 mmol) and TEA (0.014 mL, 0.100 mmol). The reaction was stirred at room temperature under N2 for 2 hr. The reaction mixture was diluted with brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The organiclayer was separated and concentrated to afford N-acetyl-N-{7-acetyl-2-[acetylazanylidene]-6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (8 mg, 0.011 mmol, 66%) as a yellow solid. LCMS: 726 / 728 [M-H]’.

[0297] Step B: To a solution of N-acetyl-N-{7-acetyl-2-[acetylazanylidene]-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5- yl}-5-fluoro-3-(trifluoromethyl)benzamide (8 mg, 0.011 mmol) in H2O (1 mL) and ACN (3 mL) were added KOH (6.18 mg, 0.110 mmol). The reaction was stirred at room temperature under N2 for 2 hr. The reaction mixture was diluted with brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The organic layer was separated and concentrated to afford 5-fluoro-N-{2-[acetylazanylidene]-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5- yl}-3-(trifluoromethyl)benzamide (1.8 mg, 0.003 mmol, 25%) as a white solid. LCMS: ESI m / z 642 [M-H]’. TlNMR (400 MHz, DMSO-d6) 8 10.58 (s, 1H), 9.49 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J= 9.2 Hz, 1H), 7.72 (s, 1H), 7.35 - 7.27 (m, 1H), 7.16 - 7.07 (m, 1H), 6.77 - 6.28 (m, 2H), 6.17 (brs, 1H), 4.86 - 4.80 (m, 2H), 4.17 (s, 3H), 2.20 (s, 3H).Example 15: N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2-fluoroethyl)-l-oxo- l,2,3,6,8,9-hexahydroimidazo[r,2':l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide

[0298] Step A: To a solution of [2-azanylidene-4,6-dibromo-l-(2-fluoroethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (2.4 g, 4.86 mmol) in DMF (25 mL) was added l,2-dibromo-l,l,2,2-tetradeuterioethane (4.19 mL, 48.6 mmol) and K2CO3 (1.34 g, 9.73 mmol). The mixture was stirred at 120 °C for 12 hours in sealed tube. The mixture was concentrated under vacuum to remove DMA. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 3 %) to afford (2-chloro-5- fluorophenyl)[5,7-dibromo-2,2,3,3-tetradeuterio-9-(2-fluoroethyl)-3,9-dihydro-2H- benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (650 mg, 1.24 mmol, 26 %) as a brown oil. LCMS: ESI m / z 524.2 [M + H]+.

[0299] Step B: To a solution of (2-chloro-5-fluorophenyl)[5,7-dibromo-2,2,3,3-tetradeuterio- 9-(2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-6-yl]methanone (200 mg, 0.382 mmol) in NMP (3 mL) was added CuCN (51.3 mg, 0.573 mmol) and the mixture was stirred at 140 °C under N2 for 2 hours. The mixture was purified using silica gel column chromatography eluted with MeOH in H2O (gradient: 60%) to afford a crude, which was purified by pre-TLC(DCM / MeOH=10: l) to afford 7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2,2,3,3-tetradeuterio-9-(2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazole-5-carbonitrile (25 mg, 0.053 mmol, 14 %) as a yellow solid. LCMS: ESI m / z 471.2 [M + H]+.

[0300] Step C: To a solution of 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2,2,3,3- tetradeuterio-9-(2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazole-5- carbonitrile (25 mg, 0.053 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-l -carboxamide (11.0 mg, 0.053 mmol) in dioxane (1 mL) was added Pd2(dba)s (4.87 mg, 0.005 mmol), XANT PHOS (6.16 mg, 0.011 mmol) and CS2CO3 (34.7 mg, 0.106 mmol). The mixture was stirred at 100 °C under N2 for 2 hours. The mixture was purified by pre-TLC(DCM / MeOH=10: 1) to give N-{6- [(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-2,2,3,3-tetradeuterio-9-(2-fluoroethyl)-3,9- dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.017 mmol, 31 %) as a yellow solid. LCMS: ESI m / z 596.4 [M + H]+.

[0301] Step D: To a solution ofN-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-2,2,3,3- tetradeuterio-9-(2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[l,2-a]imidazol-7-yl}-3- fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.017 mmol) in CH3CN (2 mL) and H2O(0.5 mL) was added KOH (1.88 mg, 0.034 mmol) and the mixture was stirred at 20 °C for 30 min. The mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9- tetradeuterio-6-(2-fluoroethyl)-3-hydroxy-l-oxo-l,2,3,6,8,9- hexahydroimidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 97 %) as a yellow solid. LCMS: ESI m / z 614.4 [M + H]+.

[0302] Step E: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2- fluoroethyl)-3-hydroxy-l-oxo-l,2,3,6,8,9-hexahydroimidazo[l',2': l,2]imidazo[5,4-e]isoindol-4- yl]-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (1 mL) was added EtiSiH (0.25 mL) and the mixture was stirred at 70 °C for 30 min. The mixture was concentrated under vacuum to give a crude, which was purified by pre-HPLC to give N-[3-(2- chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2-fluoroethyl)-l-oxo-l,2,3,6,8,9- hexahydroimidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1 mg, 0.002 mmol, 10 %) as white solid. LCMS: ESI m / z 598.4 [M + H]+. 'H NMR (400 MHz, CD3OD) 8 7.72 - 7.62 (m, 4H), 7.29 - 7.26 (m, 1H), 7.04 - 6.97 (m, 1H), 6.63 (brs, 1H), 6.32 (brs, 1H), 4.80 - 4.77 (m, 2H), 4.59 - 4.43 (m, 2H).Example 16: N-(3-(2-chloro-5-fluorophenyl)-6-(2-fluoroethyl-l,l,2,2-d4)-l-oxo-l,2,3,6,8,9-hexahydroimidazo [2' ,1 ' : 2,3] imidazo [4,5-e] isoindol-4-yl-8,8,9,9-d4)-3-fluoro-5-(trifluoromethyl)benzamideExample 16

[0303] Step A: To a solution of [2-amino-4,6-dibromo-l-(l,l,2,2-tetradeuterio-2- fluoroethyl)benzo[d]imidazol-5-yl](2-chloro-4-fluorophenyl)methanone (700 mg, 1.41 mmol) in DMA (7 mL) was added l,2-dibromo-l,l,2,2-tetradeuterioethane (1.35 g, 7.03 mmol). The reaction mixture was stirred at 130 °C for 16 h, then diluted with EA and H2O. The organic layer was washed with aqueous NaCl for 5 times. The organic layer was dried over Na SCM and concentrated with rotovap. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0%~l 0%) to afford (2-chloro-4-fluorophenyl)[5,7- dibromo-2,2,3,3-tetradeuterio-9-(l,l,2,2-tetradeuterio-2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-6-yl]methanone (200 mg, 0.379 mmol, 27%) as a brown solid. LCMS: ESI m / z 528 [M + H]+.

[0304] Step B: To a solution of (2-chloro-4-fluorophenyl)[5,7-dibromo-2,2,3,3-tetradeuterio- 9-(l,l,2,2-tetradeuterio-2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-6- yl]methanone (200 mg, 0.379 mmol) in NMP (2 mL) was added CuCN (34 mg, 0.379 mmol). The reaction mixture was stirred at 140 °C for 2h. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with aqueous NaCl for 5 times, dried over Na2SO4 and concentrated with rotovap. The residue was purified by pre-HPLC to afford 7- bromo-6-[(2-chloro-4-fluorophenyl)carbonyl]-2,2,3,3-tetradeuterio-9-(l,l,2,2-tetradeuterio-2- fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazole-5-carbonitrile (50 mg, 0.106 mmol, 28%) as a brown solid. LCMS: ESI m / z 473 [M + H]+.

[0305] Step C: A solution of 7-bromo-6-[(2-chloro-4-fluorophenyl)carbonyl]-2,2,3,3- tetradeuterio-9-(l,l,2,2-tetradeuterio-2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[2,3- b]imidazole-5-carbonitrile (45 mg, 95 μmol), 5-fluoro-3-(trifluoromethyl)benzene-l- carboxamide (19.7 mg, 95 μmol), Pd2(dba)s (9 mg, 9 p mol), xantphos (11 mg, 19 μmol), CS2CO3 (92.6 mg, 0.285 mmol) in dioxane (2 mL) was stirred at 100 °C under N2 for 2h. The reaction mixture was concentrated with rotovap. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0% ~ 10%) to afforded N-{6-[(2- chloro-4-fluorophenyl)carbonyl]-5-cyano-2,2,3,3-tetradeuterio-9-(l,l,2,2-tetradeuterio-2- fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-7-yl}-3-fluoro-5- (trifluoromethyl)benzamide (30 mg, 50 μmol, 53%) as a brown solid. LCMS: ESI m / z 600 [M + H]+.

[0306] Step D: To a solution ofN-{6-[(2-chloro-4-fluorophenyl)carbonyl]-5-cyano-2,2,3,3- tetradeuterio-9-(l,l,2,2-tetradeuterio-2-fluoroethyl)-3,9-dihydro-2H-benzo[4,5]imidazo[2,3- b]imidazol-7-yl}-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 50 μmol) in ACN (1 mL) and H2O (0.2 mL) was added KOH (14 mg, 0.250 mmol) at it The reaction mixture was stirred at rt for 30min. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2SO4 and concentrated to give crude N-[3-(2-chloro-4-fluorophenyl)-8,8,9,9-tetradeuterio-3- hydroxy-l-oxo-6-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l,2,3,6,8,9-hexahydroimidazo[2',3':2,3]imidazo[4,5-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 40 μmol, 81%) as a brown solid. LCMS: ESI m / z 618 [M + H]+.

[0307] Step E: To a solution ofN-[3-(2-chloro-4-fluorophenyl)-8,8,9,9-tetradeuterio-3- hydroxy-l-oxo-6-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l,2,3,6,8,9- hexahydroimidazo[2',3':2,3]imidazo[4,5-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 40 gmol) in TFA (1 mL) was added EtsSiH (0.2 mL). The reaction mixture was stirred at 60 °C for 30min. The cooled reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give N-[3-(2-chloro-4-fluorophenyl)-8,8,9,9-tetradeuterio-l-oxo- 6-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l,2,3,6,8,9-hexahydroimidazo[2',3':2,3]imidazo[4,5- e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (3.2 mg, 5 μmol, 13%) as a white solid. LCMS: ESI m / z 602 [M + H]+.1H NMR (400 MHz, CD3OD) 6 7.72 - 7.63 (m, 4H), 7.29 - 7.26 (m, 1H), 7.03 - 6.98 (m, 1H), 6.60 (brs, 1H), 6.28 (brs, 1H).Example 17: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2-((methyl- d3)imino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamideI l lExample 17

[0308] Step A: To a solution of [2-amino-4,6-dibromo-l-(2,2- difluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (2 g, 3.91 mmol) in DMA (10 mL) was added trideuterio(iodo)methane (0.73 mL, 11.7 mmol). The mixture was stirred at 100 °C for 2 h. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was separated, 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: 0-8%) to afford [2-azanylidene-4,6-dibromo-l-(2,2- difluoroethyl)-3-(trideuteriomethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1.8 g, 3.40 mmol, 87%) as a yellow solid. LCMS: ESI m / z 529 [M + H]+.

[0309] Step B: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1.8 g, 3.40 mmol) in DMA (20 mL) was added K2CO3 (0.94 g, 6.81 mmol) and trideuterio(iodo)methane (2.2 mL, 34.2 mmol). The reaction was stirred at 40 °C for 3h. The reaction mixture was filtrated, diluted with water and extracted with EtOAc (20 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 MeOH in DCM (gradient: 0-5%) to afford (2-chloro-5- fluorophenyl)[4,6-dibromo-l-(2,2-difluoroethyl)-3-(trideuteriomethyl)-2- [(trideuteriomethyl)azanylidene]benzo[d]imidazol-5-yl]methanone (1.0 g, 1.83 mmol, 54%) as a yellow solid. LCMS: ESI m / z 546 [M + H]+.

[0310] Step C: To a solution of (2-chloro-5-fluorophenyl)[4,6-dibromo-l-(2,2- difluoroethyl)-3-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]benzo[d]imidazol-5- yl]methanone (1.0 g, 1.83 mmol) in NMP (10 mL) was added CuCN (173 mg, 1.93 mmol). The reaction mixture was stirred at 120 °C under N2 for 4h. The cooled reaction mixture was dilutedwith EA, filtered through a pad of celite. The filtrate was diluted with water, extracted with EtOAc (10 mL*3). The organic phase was washed with brine 3 times, dried over Na SO4 and concentrated. The crude was purified by prep-HPLC (C18, 10 ~ 50% MeCN in H2O with 0.1 % FA) to afford 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]benzo[d]imidazole-5-carbonitrile (150 mg, 0.31 mmol, 17%) as a yellow solid. LCMS: ESI m / z 491 / 493 [M + H]+.

[0311] Step D: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]benzo[d]imidazole-4- carbonitrile (150 mg, 0.31 mmol) in 1,4-dioxane (5 mL) was added 3-fluoro-5- (trifluoromethyl)benzene-l -carboxamide (95 mg, 0.46 mmol), Xantphos (35 mg, 0.06 mmol), CS2CO3 (199 mg, 0.61 mmol) and Pd2(dba)s (28 mg, 0.03 mmol). The reaction was stirred at 100 °C under N2 for 2h. The reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to afford N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]benzo[d]imidazol-5-yl -3-fluoro-5- (trifluoromethyl)benzamide (140 mg, 0,23 mmol, 74%) as a yellow solid. LCMS: ESI m / z 618 [M + H]+.

[0312] Step E: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- diftaoroethyl)-l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]benzo[d]imidazol-5-yl}- 3-fluoro-5-(trifluoromethyl)benzamide (140 mg, 0.23 mmol) in MeCN (5 mL) and H2O (1 mL) were added potassium hydroxide (56 mg, 0.91 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to afford crude N-[6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-8-oxo-l-(trideuteriomethyl)-2- [(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (130 mg, 0.204 mmol, 90%) as a yellow solid. LCMS: ESI m / z 636 [M +H]+.

[0313] Step F: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-8-oxo-l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-7,8-dihydro-6H- imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (130 mg, 0.204 mmol) in TFA (2 mL) was added triethylsilane (1 mL). The reaction was stirred at 70 °C for 20min. The reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to afford N-[6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-8-oxo-l-(trideuteriomethyl)-2- [(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (100 mg, 0.16 mmol, 79%) as a white solid. LCMS: ESI m / z 620 [M + H]+. 'H NMR (400 MHz, DMSO-d6) 5 10.22 (s, 1H), 9.06 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 - 7.64 (m, 2H), 7.29 - 7.25 (m, 1H), 7.14 - 7.01 (m, 2H), 6.82 - 5.80 (m, 3H), 4.52 - 4.06 (m, 2H).Example 18: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl)quinazolin-4-yl]amino}-l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[4,5-e]isoindol-8-oneExample 18

[0314] Step A: To a solution of [2-amino-4,6-dibromo-l-(2,2- difluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (6 g, 12 mmol) in DMA (10 mL) was added iodomethane (0.5 mL, 4.69 mmol). The reaction mixture was stirred at 100 °C for 2h with sealed tube. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to afford [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (6 g, 11.351 mmol, 96%) as a white solid. LCMS: ESI m / z 529 [M+H]+

[0315] Step B: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (5.5 g, 10.405 mmol) in DMA (50 mL) was added trideuterio(iodo)methane (5 mL, 83.243 mmol) and K2CO3 (1.434 g, 10.405 mmol). The reaction mixture was stirred at 40 °C for 2h with sealed tube. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 6%] to afford (2-chloro-5- fluorophenyl)[4,6-dibromo-l-(2,2-difluoroethyl)-3-(trideuteriomethyl)-2-[(Z)- (trideuteriomethyl)azanylidene]benzo[d]imidazol-5-yl]methanone (2.5 g, 4.582 mmol, 44%) as a white solid. LCMS: ESI m / z 546 [M+H]+

[0316] Step C: To a solution of (2-chloro-5-fluorophenyl)[4,6-dibromo-l-(2,2- difluoroethyl)-3-(trideuteriomethyl)-2-[(Z)-(trideuteriomethyl)azanylidene]benzo[d]imidazol-5- yl]methanone (2.5 g, 4.58 mmol) in NMP (40 mL) was added CuCN (0.62 g, 6.87 mmol). The reaction mixture was stirred at 130 °C under N2 forlh. The cooled reaction mixture was dilutedwith H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified using prep-HPLC [Gradient: 20-40%] to afford 6-bromo-5-[(2-chloro-5-fluorophenyl) carbonyl]-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)-2-[(Z)-(trideuteriomethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (750 mg, 1.52 mmol, 33 %) as a white solid. LCMS: ESI m / z 493 [M+H]+

[0317] Step D: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difhioroethyl)-3-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]benzo[d]imidazole-4- carbonitrile (750 mg, I.525mmol) in dioxane (10 mL) was added diphenylmethanimine (414 mg, 2.28 mmol), CS2CO3 (993 mg, 3.050 mmol), Xant-phos (176 mg, 0.305 mmol) and Pd2(dba)s (139 mg, 0.153 mmol). The reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 8%] to afford 5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-6-[(diphenylmethylidene)amino]-3- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (500 mg, 0.845 mmol, 55%) as a white solid. LCMS: ESI m / z 592 [M+H]+

[0318] Step E: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 6-[(diphenylmethylidene)amino]-3-(trideuteriomethyl)-2- [(trideuteriomethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (60 mg, 0.101 mmol) in CH3CN / H2O (4 mL) was added potassium hydroxide (56 mg, 1.013 mmol). The reaction mixture was stirred at 50 °C for Ih. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 16%] to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- [(diphenylmethylidene)amino]-6-hydroxy-l-(trideuteriomethyl)-2- [(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-one (50 mg, 0.082 mmol, 80%) as a white solid. LCMS: ESI m / z 610 [M+H]+

[0319] Step F: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- [(diphenylmethylidene)amino]-6-hydroxy-l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-one (450 mg, 0.738 mmol) in TFA (2 mL) was added triethylsilane (3 mL, 0.738 mmol). The reaction mixture wasstirred at 50 °C for 20min. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. The residue to afford 6-(2-chloro-5-fhrorophenyl)-3-(2,2-difluoroethyl)-5-[(diphenylmethylidene)amino]-l- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol- 8-one (450 mg crude, 0.757 mmol, 100%) as a white solid. LCMS: ESI m / z 594 [M+H]+

[0320] Step G: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- [(diphenylmethylidene)amino]-l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-7,8- dihydro-6H-imidazo[5,4-e]isoindol-8-one (450 mg, 0.757 mmol) in MeCN (4 mL) was added 1 N HC1 (4 mL). 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 Na2SO4, filtered and concentrated The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 20%] to afford 5-amino-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]- 7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-one (300 mg, 0.698 mmol, 92%) as a white solid. LCMS: ESI m / z 430 [M+H]+

[0321] Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4- e]isoindol-8-one (150 mg, 0.349 mmol) in l,l-dideuterio-l-(deuteriooxidanyl)-2,2,2- trifluoroethane (5 mL) was added 4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline (262 mg, 1.047 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 by Na2SO4, filtered and concentrated. The residue was purified using prep-HPLC to afford 6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl)quinazolin-4-yl]amino}-l- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[4,5-e]isoindol- 8-one (56 mg, 0.087 mmol, 24%) as a white solid. LCMS: ESI m / z 644 [M+H]".1H NMR (400 MHz, DMSO-d6) 8 10.04 (s, 1H), 9.47 (s, 1H), 8.40 (s, 1H), 8.28 - 8.22 (m, 2H), 7.89 (s, 1H), 6.79 - 7.08 (m, 2H), 6.35 - 6.75 (m, 2H), 6.04 (brs, 1H), 4.82 - 4.92 (m, 2H)Example 19: N-(3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-l,8-dioxo-l,2,3,6,8,9- hexahydroimidazo [2' ,1 ' : 2,3] imidazo [4,5-e] isoindol-4-yl)-3-fluoro-5- (trifluoromethyl)benzamideExample 19

[0322] Step A: To a solution of 2-amino-6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- (2,2-difluoroethyl)benzo[d]imidazole-4-carbonitrile (200 mg, 0.44 mmol) in DMA (2 mL) was added ethyl bromoacetate (0.5 mL) at it The mixture was stirred at 120 °C for 3h. The reaction mixture was cooled down to rt, then quenched with water, and the mixture was extracted with EtOAc (15 mL*3). The organic layer 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: 0-25%) afford ethyl {2-azanylidene-5-bromo-6-[(2-chloro- 5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)benzo[d]imidazol-l-yl}acetate (180 mg, 0.33 mmol, 76%) as an yellow solid. LCMS: ESI m / z 545 [M + H]+.

[0323] Step B: To a solution of ethyl {2-azanylidene-5-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)benzo[d]imidazol-l-yl}acetate (50 mg, 0.09 mmol) in 1,4-dioxane (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l- carboxamide (29 mg, 0.14 mmol), Xantphos (17 mg, 0.03 mmol), CS2CO3 (60 mg, 0.19 mmol) and Pd2(dba)3 (14 mg, 0.015 mmol). The reaction was stirred at 100 °C for 2h. The cooled reaction mixture was concentrated and purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) afford ethyl {2-azanylidene-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-5-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)benzo[d]imidazol-l-yl}acetate (15 mg, 0.022 mmol, 24%) as a yellow solid. LCMS: ESI m / z 670 [M + H]+.

[0324] Step C: To a solution of ethyl {2-azanylidene-6-[(2-chloro-5-fluorophenyl)carbonyl]- 7-cyano-3-(2,2-difluoroethyl)-5-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)benzo[d]imidazol-l-yl}acetate (15 mg, 0.022 mmol) in THF (3 mL) was added LiHMDS (1 M in THF, 0.1 mL, 0.1 mmol) at -68 °C. The mixture was stirred at -68 °C for Ih. After completion, the mixture was quenched with water at -68 °C. The mixture was extracted with EtOAc (10 mL*3). The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient:0-10%) to afford N-{6-[(2-chloro-5- fluorophenyl)carbonyl]-5-cyano-9-(2,2-difluoroethyl)-2-oxo-3,9-dihydro-2H- benzo[4,5]imidazo[2,3-b]imidazol-7-yl}-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 72%) as an yellow solid. LCMS: ESI m / z 624 [M + H]+,

[0325] Step D: To a solution ofN-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyano-9-(2,2- difluoroethyl)-2-oxo-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-7-yl}-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.016 mmol) in MeCN (3 mL) and H2O (0.6 mL) were added potassium hydroxide (7.20 mg, 0.13 mmol). The reaction was stirred at room temperature for 15 min. The reaction mixture was quenched with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to afford N-[3-(2- chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-3-hydroxy-l,8-dioxo-l,2,3,6,8,9- hexahydroimidazo[2',3':2,3]imidazo[4,5-e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 97%) as a yellow solid. LCMS: ESI m / z 642 [M +H]+.

[0326] Step E: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-3- hydroxy-l,8-dioxo-l,2,3,6,8,9-hexahydroimidazo[2',3':2,3]imidazo[4,5-e]isoindol-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (2 mL) was added triethylsilane (1 mL, 0.016 mmol) at rt. The mixture was stirred at 70 °C for 15 min. The reaction was concentrated and the residue was purified by prep-HPLC (Cl 8, 5 ~ 95 % MeCN in H2O with 0.1 % FA) to afford N-[3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-l,8-dioxo- 1,2, 3,6,8, 9-hexahydroimidazo[2',3':2,3]imidazo[4,5-e]isoindol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (1.2 mg, 0.002 mmol, 12%) as white solid. LCMS: ESI m / z 626 [M + H]+. 'H NMR (400 MHz, CD3OD) 8 7.75 - 7.60 (m, 4H), 7.27 (dd, J= 8.8, 4.8 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.55 - 6.16 (m, 2H), 4.92 - 4.89 (m, 2H), 4.73 - 4.55 (m, 2H).Example 20: Methyl {[(2E)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-l-methyl-8-oxo-l,2,3,6,7,8- hexahydroimidazo[5,4-e]isoindol-2-ylidene]amino}methanoateExample 20

[0327] Step A: To a solution of N-[2-azanylidene-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (15 mg, 0.025 mmol) in DCM (3 mL) were added methyl chloromethanoate (0.003 mL, 0.038 mmol) and lithium bis(trimethylsilyl)azanide (20.9 mg, 0.125 mmol). The reaction was stirred at 0°C under N2 for 2 hr. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford methyl {[(2E)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-({[5- fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-7-(methoxycarbonyl)-l-methyl-8-oxo- l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindol-2-ylidene]amino}methanoate (10 mg, 0.014 mmol, 56%) as a yellow solid. LCMS: ESI m / z 716 [M-H]'.

[0328] Step B: To a solution of methyl {[(2E)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difhroroethyl)-5-({[5-fhroro-3-(trifluoromethyl)phenyl]carbonyl}amino)-7-(methoxycarbonyl)-l- methyl-8-oxo-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindol-2-ylidene]amino}methanoate (10 mg, 0.014 mmol) in H2O (1 mL) and ACN (3 mL) were added KOH (2.36 mg, 0.042 mmol). The reaction was stirred at room temperature under N2 for 2 hr. 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 by prep-HPLC to afford methyl {[(2E)-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-l- methyl-8-oxo-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindol-2-ylidene]amino}methanoate (2.2 mg, 0.003 mmol, 24%) as a pink solid. LCMS: ESI m / z 658 [M-H]'. 'H NMR (400 MHz, DMSO-d6) 5 10.47 (s, 1H), 9.35 (s, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.32 - 7.28 (m, 1H), 7.14 - 7.06 (m, 1H), 6.74 - 6.25 (m, 2H), 6.07 (brs, 1H), 4.68 - 4.60 (m, 2H), 4.03 (s, 3H), 3.63 (s, 3H).Example 21: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-(ethylimino)-l-methyl-8-oxo-l,2,3?6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0329] Step A: A mixture of [2-amino-4,6-dibromo-l-(2,2-difluoroethyl)benzo[d]imidazol- 5-yl](2-chloro-5-fluorophenyl)methanone (2 g, 3.91 mmol) and iodomethane (1.90 mL, 23.5 mmol) in N,N-dimethylacetamide (20 mL) in a sealed tube was stirred at 100 °C for 2h. The cooled mixture was poured into cold water and filtered. The filter cake was washed with water and dried to give crude [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- methylbenzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1.6 g, 3.04 mmol, 78%) as a white solid. LCMS: ESI m / z 526 [M+H]+.

[0330] Step B: To a mixture of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- methylbenzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1.5 g, 2.85 mmol) and K2CO3 (0.79 g, 5.71 mmol) in DMA (25 mL) was added iodoethane (5.34 g, 34.2mmol). The mixture was stirred at 70 °C overnight. The cooled mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na SO4 and concentrated. The residue was purified by FCC, eluting with EA / PE (20%) to give (2-chloro-5- fluorophenyl)[4,6-dibromo-l-(2,2-difluoroethyl)-2-[(Z)-ethylazanylidene]-3- methylbenzo[d]imidazol-5-yl]methanone (850 mg, 1.53 mmol, 54%) as a yellow solid. LCMS: ESI m / z 554 [M+H]+.

[0331] Step C: The mixture of (2-chloro-5-fluorophenyl)[4,6-dibromo-l-(2,2-difluoroethyl)- 2-[(Z)-ethylazanylidene]-3-methylbenzo[d]imidazol-5-yl]methanone (680 mg, 1.23 mmol) and CuCN (220 mg, 2.46 mmol) in NMP (15 mL) was stirred at 130 °C for Ih. The cooled mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by FCC, eluting with EA / PE (0-20%) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2- [(Z)-ethylazanylidene]-3-methylbenzo[d]imidazole-4-carbonitrile (200 mg, 0.40 mmol, 33%) as a yellow solid and used directly for the next step.

[0332] Step D: A mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-[ethylazanylidene]-3-methylbenzo[d]imidazole-4-carbonitrile (50 mg, 0.10 mmol), 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (31.1 mg, 0.15 mmol), Pd (dba)3 (9.16 mg, 0.01 mmol), Xantphos (11.6 mg, 0.02 mmol) and CS2CO3 (65.2 mg, 0.20 mmol) in dioxane (2 mL) was stirred at 100 °C under N2 for 2h. The cooled mixture was filtered, and the filtrate was concentrated. The residue was used directly in the next step. LCMS: ESI m / z 626 [M+H]+.

[0333] Step E: To a mixture of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difluoroethyl)-2-[ethylazanylidene]-l-methylbenzo[d]imidazol-5-yl}-3-fluoro-5- (trifluoromethyl)benzamide (200 mg, 0.32 mmol) in acetonitrile (10 mL) and water (2 mL) was added potassium hydroxide (180 mg, 3.20 mmol). The mixture was stirred at room temperature for 30 min. The mixture was concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by FCC, eluting with MeOH / DCM (0-5% then -7%) to give N-[6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-2-[ethylazanylidene]-6-hydroxy-l-methyl-8-oxo-7,8- dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.23 mmol, 73%) as a yellow solid. LCMS: ESI m / z 644 [M+H]+.

[0334] Step F: A mixture ofN-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2- [ethylazanylidene]-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3- fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.078 mmol) in TFA (5 mL) and EfeSiH (0.5 mL) was stirred at 70 °C for 20 min. The cooled mixture was concentrated. The residue was purified by prep-HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2- [ethylazanylidene]-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (10.3 mg, 0.016 mmol, 21%) as a yellow solid. LCMS: ESI m / z 628 [M+H]+.XHNMR (400 MHz, DMSO-d6) 5 10.33 (s, 1H), 9.22 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.74 (d, J= 9.2 Hz, 1H), 7.70 (s, 1H), 7.35 (s, 1H), 7.29 - 7.25 (m, 1H), 7.13 - 7.05 (m, 1H), 6.83 - 6.19 (m, 2H), 5.97 (brs, 1H), 4.55 - 4.50 (s, 2H), 4.15 (s, 3H), 3.76 - 3.63 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H).Example 22: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2- ((methyl-d3)imino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamideExample 23: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2- ((methyl-d3)imino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0335] Step A: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2- ((methyl-d3)imino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (60 mg, 0.0969 mmol) was purified with prep-SFC to afford two fractions. Each fraction was acidified with HC1 (1 M in H2O) quickly to pH=5-6 and concentrated respectively, then purified with chiral prep-SFC method 2 (HC1 as additive) to afford (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2-((methyl-d3)imino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (15.1 mg, 0.024 mmol, 50%) as a white solid. LCMS: ESI m / z 620 [M + H]+. Tl NMR (400 MHz, DMSO-d6) 8 10.29 (s, 1H), 9.13 (s, 1H), 8.19 (s, 1H), 7.94 - 7.90 (m, 1H), 7.80 - 7.63 (m, 2H), 7.32 - 7.24 (m, 1H), 7.21 (s, 1H), 7.14 - 7.01 (m, 1H), 6.89 - 6.55 (m, 1H), 6.52 - 6.13 (m, 1H), 6.08 - 5.80 (m, 1H), 4.60 - 4.33 (m, 2H). And (S)-N-(6-(2-chloro- 5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2-((methyl-d3)imino)-8-oxo-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15.5 mg, 0.025 mmol, 52%) as a white solid. LCMS: ESI m / z 620 [M + H]+.1H NMR (400 MHz, DMSO-d6) 8 10.29 (s, 1H), 9.13 (s, 1H), 8.19 (s, 1H), 7.94 - 7.90 (m, 1H), 7.80 - 7.63 (m, 2H), 7.32 - 7.24 (m, 1H), 7.21 (s, 1H), 7.14 - 7.01 (m, 1H), 6.89 - 6.55 (m, 1H), 6.52 - 6.13 (m, 1H), 6.08 - 5.80 (m, 1H), 4.60 - 4.33 (m, 2H).Example 24: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2- (methylimino)-8-oxo-l,2,3?6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamideExample 25: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2- (methylimino)-8-oxo-l,2,3?6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[0336] Step A: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2- (methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.098 mmol) was purified with chiral prep-SFC method 3 to afford two fractions. Each fraction was acidified with HC1 (1 M in H2O) quickly to pH=5-6 and concentrated respectively. Each residue was purified with prep-HPLC (HC1 as additive) to afford (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20.4 mg, 0.033 mmol, 68%) as a white solid. LCMS: ESI m / z 614 [M + H]+.NMR (400 MHz, DMSO-d6) 5 10.61 (s, 1H), 9.51 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.87 - 7.69 (m, 3H), 7.35 - 7.26 (m, 1H), 7.16 - 7.04 (m, 1H), 6.75 - 5.91 (m, 3H), 5.10 - 4.80 (m, 2H), 4.41 (s, 3H), 3.33 - 3.31 (m, 3H). And (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2- (methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (19.1 mg, 0.031 mmol, 63%) as a white solid. LCMS: ESI m / z 614 [M + H]+. 'H NMR (400 MHz, DMSO-d6) 8 10.61 (s, 1H), 9.51 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.87 - 7.69 (m, 3H), 7.35 - 7.26 (m, 1H), 7.16 - 7.04 (m, 1H), 6.75 - 5.91 (m, 3H), 5.10 - 4.80 (m, 2H), 4.41 (s, 3H), 3.33 - 3.31 (m, 3H).Example 26: (S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-2-((methyl-d3)imino)-2,3,6,7- tetrahydroimidazo[4,5-e]isoindol-8(lH)-oneExample 27 : (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-2-((methyl-d3)imino)-2,3,6,7- tetrahydroimidazo[4,5-e]isoindol-8(lH)-one

[0337] Step A: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-2-((methyl-d3 )imino)-2, 3,6,7- tetrahydroimidazo[4,5-e]isoindol-8(lH)-one (50 mg, 0.078 mmol) was purified by chiral prep- SFC method 4. Each fraction was acidified with HCOOH quickly to pH=5-6 and concentrated respectively to afford (S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-2-((methyl-d3 )imino)-2, 3,6,7- tetrahydroimidazo[4,5-e]isoindol-8(lH)-one (16.5 mg, 0.026 mmol, 33%) as a white solidLCMS: ESI m / z 644 [M + H]+. 'H NMR (400 MHz, DMSO-d6) 5 9.79 (s, 1H), 9.04 (s, 1H), 8.26 (s, 1H), 8.20 (m, 2H), 7.17 (s, 1H), 6.85 - 6.97 (m, 2H), 6.60-6.57 (m, 1H), 6.25 - 6.48 (m, 1H), 5.87 (brs, 1H), 4.23 - 4.31 (m, 2H). And (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-2-((methyl- d3)imino)-2,3,6,7-tetrahydroimidazo[4,5-e]isoindol-8(lH)-one (15.1 mg, 0.023 mmol, 30%) LCMS: ESI m / z 644 [M + H]+. 'H NMR (400 MHz, DMSO-d6) 5 9.79 (s, 1H), 9.04 (s, 1H), 8.26 (s, 1H), 8.20 (m, 2H), 7.17 (s, 1H), 6.85 - 6.97 (m, 2H), 6.60-6.57 (m, 1H), 6.25 - 6.48 (m, 1H), 5.87 (brs, 1H), 4.23 - 4.31 (m, 2H).Example 28: N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-l-methyl-2-(methylimino)-8- oxo-l,2,3?6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0338] Step A: To a solution of [2-amino-4,6-dibromo-l-(2-fluoroethyl)benzo[d]imidazol-5- yl](2-chloro-5-fluorophenyl)methanone (6 g, 12.1 mmol) in DMA (60 mL) was addediodomethane (2.96 mL, 36.4 mmol). The reaction mixture was stirred at 100 °C for 2h with tube sealing. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 70%] to afford [2-azanylidene-4,6-dibromo-l-(2-fluoroethyl)-3-methylbenzo[d]imidazol-5-yl](2 -chloro- 5-fluorophenyl)methanone (6 g, 11.8 mmol, 97%) as a white solid. LCMS: ESI m / z 507 [M+H]+

[0339] Step B: To a solution of [2-amino-4,6-dibromo-l-(2-fluoroethyl)benzo[d]imidazol-5- yl](2-chloro-5-fluorophenyl)methanone (5.5g, 11.1 mmol) in N,N-dimethylacetamide (50 mL) was added K2CO3 (1.54 g, 11.1 mmol) and iodomethane (6 mL, 78.0 mmol). The reaction mixture was stirred at 40 °C for 2h with tube sealing. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to afford (2-chloro-5-fluorophenyl)(4,6-dibromo-l-(2- fluoroethyl)-3-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methanone (2 g, 3.8 mmol, 34%) as a white solid. LCMS: ESI m / z 522 [M+H]+

[0340] Step C: To a solution of (2-chloro-5-fluorophenyl)(4,6-dibromo-l-(2-fluoroethyl)-3- methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methanone (200 mg, 0.383 mmol) in NMP (4 mL) was added CuCN (51mg, 0.575 mmol). The reaction mixture was stirred at 130 °C for 2h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using prep-HPLC to afford 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2-fluoroethyl)-3- methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (30 mg, 0.064 mmol, 16 %) as a white solid. LCMS: ESI m / z 467 [M+H]+

[0341] Step D: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2-fluoroethyl)-3- methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (20 mg, 0.043 mmol) in dioxane (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (14 mg, 0.064 mmol), CS2CO3 (27 mg, 0.086 mmol), Xant-phos (4.95 mg, 0.009 mmol) and Pd2(dba)s (4 mg, 0.004 mmol). The reaction mixture was stirred at 100 °C under N2 for 2h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 10%] to N-(6-(2-chl oro-5-fluorobenzoyl)-7-cyano-3-(2-fluoroethyl)-l-methyl-2-(methylimino)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.017 mmol, 39%) as a white solid. LCMS: ESI m / z 594 [M+H]+

[0342] Step E: To a solution ofN-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2-fluoroethyl)- l-methyl-2-(methylimino)-2,3-dihydro-lH-benzo[d]imidazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (20 mg, 0.034 mmol) in CH3CN / H2O (5 mL) was added potassium hydroxide (18 mg, 0.337 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 Na2SO4, filtered and concentrated. The residue to afford N-(6-(2-chloro-5- fluorophenyl)-3-(2-fluoroethyl)-6-hydroxy-l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.032 mmol, 96%) as a white solid. LCMS: ESI m / z 612 [M+H]+

[0343] Step F: To a solution of N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-6-hydroxy- l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (120 mg, 0.196 mmol) in TFA (5 mL) was added triethylsilane (68 mg, 0.588 mmol). The reaction mixture was stirred at 70 °C for 0.5h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using prep-HPLC to afford N-(6-(2- chloro-5-fluorophenyl)-3-(2-fluoroethyl)-l-methyl-2-(methylimino)-8-oxo-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.101 mmol, 51 %) as a white solid. LCMS: ESI m / z 596 [M+H]+. NMR (400 MHz, DMSO-d6) 5 10.53 (s, IH), 9.51 (s, IH), 7.98 (d, .7= 8.4 Hz, IH), 7.65-7.79 (m, 3H), 7.31 (dd, J = 8.8, 5.2 Hz, IH), 7.05 - 7.14 (m, IH), 6.48 - 6.69 (m, IH), 6.13 (brs, IH), 4.91 - 4.59 (m, 4H), 4.40 (s, 3H), 1.24 (s, 3H).Example 29: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-2-methyl-8- (trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-2-((methyl-d3)imino)-2,3,6,7- tetrahydroimidazo[4,5-e]isoindol-8(lH)-oneC03Example 29

[0344] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-(methyl-d3)-2-((methyl-d3)imino)-2,3,6,7-tetrahydroimidazo[4,5-e]isoindol-8(lH)-one (150 mg, 0.349 mmol) in l,l-dideuterio-l-(deuteriooxidanyl)-2,2,2-trifluoroethane (5 mL) was added 4-chloro-6-fluoro-2-methyl-8-(trifluoromethyl)quinazoline (92 mg, 0.349 mmol). The reaction mixture was stirred at 80 °C for Ih. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na SO4, filtered and concentrated. The residue was purified using prep-HPLC to give 6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-2-methyl-8- (trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-2-((methyl-d3)imino)-2, 3,6,7- tetrahydroimidazo[4,5-e]isoindol-8(lH)-one (45 mg, 0.068 mmol, 19%) as a white solid. LCMS: ESI m / z 658 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 9.79 (s, IH), 9.19 (s, IH), 8.29 - 8.13 (m, 3H), 7.39 (s, IH), 6.89 - 7.02 (m, 2H), 6.65 (d, J= 8.4 Hz, IH), 6.25 - 6.51 (m, IH), 6.00 (brs, IH), 4.45 - 4.52 (m, 2H), 2.36 (s, 3H).Example 30: (l?)-N-[(3R)-3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2- difluoroethyl)-l-oxo-l,2,3,6,8,9-hexahydroimidazo[r,2':l,2]imidazo[5,4-e]isoindol-4-yl]-5- fluoro-3-(trifluoromethyl)benzamideExample 31: (S)-N-[(3R)-3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2- difluoroethyl)-l-oxo-l,2,3,6,8,9-hexahydroimidazo[l',2':l,2]imidazo[5,4-e]isoindol-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide

[0345] Step A: N-[3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2-difluoroethyl)-l- oxo-l,2,3,6,8,9-hexahydroimidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (20 mg, 0.032 mmol) was purified by prep-SFC (NH3 as additive). Each fraction was acidified with HC1 (1 M in H2O) quickly to pH=5-6 and concentrated respectively. Each residue was purified with prep-HPLC (HC1 as additive) to afford (2?)-N-[(3R)- 3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2-difluoroethyl)-l-oxo-l,2,3,6,8,9- hexahydroimidazo[l\2': l,2]imidazo[5,4-e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2 mg, 0.003 mmol, 10%) as a white solid. LCMS: ESI m / z 616 [M + H]+. ^NMR (400 MHz, DMSO-d6) 6 10.55 (s, 1H), 10.10 (s, 1H), 9.39 (s, 1H), 7.98 (d, J= 8.4 Hz, 1H), 7.79 - 7.64 (m, 3H), 7.38 - 7.29 (m, 1H), 7.21 - 7.09 (m, 2H), 6.63 - 6.45 (m, 2H), 6.07 (brs, 1H), 4.90 - 4.53 (m, 2H). And (5)-N-[(3S)-3-(2-chloro-5-fluorophenyl)-8,8,9,9-tetradeuterio-6-(2,2- difluoroethyl)-l-oxo-l,2,3,6,8,9-hexahydroimidazo[r,2': l,2]imidazo[5,4-e]isoindol-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (3 mg, 0.005 mmol, 15%) as a white solid. LCMS: ESI m / z 616 [M + H]+'H NMR (400 MHz, DMSO-d6) 5 10.55 (s, 1H), 10.10 (s, 1H), 9.39 (s, 1H), 7.98 (d, J= 8.4 Hz, 1H), 7.79 - 7.64 (m, 3H), 7.38 - 7.29 (m, 1H), 7.21 - 7.09 (m, 2H), 6.63 - 6.45 (m, 2H), 6.07 (brs, 1H), 4.90 - 4.53 (m, 2H).Example 32: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)benzo[d][l,2,3]triazin-4-yl)amino)-l-(methyl-d3)-2-((methyl-d3)imino)- 2,3,6,7-tetrahydroimidazo [4,5-e] isoindol-8(lH)-oneExample 32

[0346] Step A: To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazine (10 mg, 0.04 mmol) in l,l-dideuterio-l-(deuteriooxidanyl)-2,2,2-trifluoroethane (3 mL) were added (E)-5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2-((methyl- d3)imino)-2,3,6,7-tetrahydroimidazo[4,5-e]isoindol-8(lH)-one (17.2 mg, 0.04 mmol) and HC1 (30 mg, 0.82 mmol). The mixture was stirred at 100 °C overnight. The cooled mixture was concentrated under vacuum. The residue was purified using prep-HPLC to afford 6-(2-chloro-5- fluorophenyl)-3-(2,2-difhioroethyl)-5-((6-fluoro-8-(trifluoromethyl)benzo[d][l, 2, 3]tri azin-4- yl)amino)-l-(methyl-d3)-2-((methyl-d3)imino)-2,3,6,7-tetrahydroimidazo[4,5-e]isoindol-8(lH)- one (1 mg, 0.0015 mmol, 4%) as a yellow solid. LCMS: ESI m / z 645.2 [M + H]+. 'H NMR (400 MHz, CD3OD) 5 8.52 (s, 1H), 8.28 - 8.18 (m, 1H), 8.03 - 7.94 (m, 1H), 7.76 - 7.64 (m, 1H), 6.90 - 6.79 (m, 1H), 6.77 - 6.70 (m, 1H), 6.62 - 6.55 (m, 1H), 6.53 - 6.21 (m, 2H), 4.83 - 4.72 (m, 2H).Example 33: N-[6-(2-chloro-5-fluorophenyl)-2-[(Z)-(cyanomethyl)azanylidene]-3-(2,2- difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0347] Step A: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3H-benzo[d]imidazole-4-carbonitrile (1 g, 2.19 mmol) in DMA (10 mL) was added iodomethane (0.532 mL, 6.56 mmol). The reaction was stirred at 100 °C for 2 hr with a sealed tube. The cooled reaction was diluted with water, brine and EA. The following mixture was filtered. The filter cake was purified using silica gel column chromatography eluted with methanol in dichloroform (gradient: 0-10%) to afford 2- azanylidene-6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3- methylbenzo[d]imidazole-4-carbonitrile (900 mg, 1.91 mmol, 87%) as a white solid. LCMS: ESI m / z 473.0 [M + H]+.

[0348] Step B: To a mixture of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (200 mg, 0.424 mmol) in dioxane (15 mL) were added 3-fluoro-5-(trifluoromethyl)benzene-l- carboxamide (132 mg, 0.636 mmol), XANT PHOS (319 mg, 0.551 mmol), CS2CO3 (276 mg, 0.848 mmol) and Pd2(dba)s (38.8 mg, 0.042 mmol). The reaction was stirred at 100 °C under N2 for 2 hr. 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 using silica gel column chromatography eluted with methanol in di chloroform (gradient: 0-10%) to afford N-{2-azanylidene-6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difhioroethyl)-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (300 mg, 0.351 mmol, 83%) as a yellow solid. LCMS: ESI m / z 598.3 [M + H]+.

[0349] Step C: To a solution ofN-{2-azanylidene-6-[(2-chloro-5-fluorophenyl)carbonyl]-7- cyano-3-(2,2-difluoroethyl)-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (150 mg, 0.251 mmol) in DMA (5 mL) were added bromoacetonitrile (33.1 mg, 0.276 mmol) and K2CO3 (69.4 mg, 0.502 mmol). The reaction was stirred at 60 °C under N2 overnight. 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 methanol in dichloroform (gradient: 0-10%) to afford N-{6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-[(Z)-(cyanomethyl)azanylidene]-3-(2,2-difluoroethyl)-l- methylbenzo[d]imidazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.079 mmol, 31%) as a yellow solid. LCMS: ESI m / z 637.3 [M + H]".

[0350] Step D: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-[(Z)- (cyanomethyl)azanylidene]-3-(2,2-difluoroethyl)-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (50 mg, 0.079 mmol) in ACN (4 mL) and H2O (1 mL) was added KOH (22.0 mg, 0.393 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-2-[(Z)- (cyanomethyl)azanylidene]-3-(2,2-difluoroethyl)-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H- imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.046 mmol, 58%) as a yellow solid. LCMS: ESI m / z 655.3 [M + H] .

[0351] Step E: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-2-[(Z)- (cyanomethyl)azanylidene]-3-(2,2-difluoroethyl)-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H- imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.046 mmol) in TFA (2 mL) was added EtsSiH (0.5 mL). The reaction was stirred at 70 °C for 5 min. The reaction mixture was diluted saturated NaHCCh, 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)-2-[(Z)-(cyanomethyl)azanylidene]-3-(2,2- difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (2.4 mg, 0.004 mmol, 8%) as a white solid. LCMS: ESI m / z 639.5 [M + H]+. 'H NMR (400 MHz, DMSO-d6) 8 10.58 (s, 1H), 9.55 (s, 1H), 7.99 (d, J= 8.0 Hz, 1H), 7.95 - 7.82 (m, 1H), 7.78 (d, J= 9.2 Hz, 1H), 7.73 (s, 1H), 7.37 - 7.27 (m, 1H), 7.13 (s, 1H), 6.69 - 5.91 (m, 2H), 5.03 - 4.74 (m, 4H), 4.42 (s, 3H).Example 34: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2- (methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamideExample 34

[0352] Step A: To a solution of [2-amino-4,6-dibromo-l-(2,2- difluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (3.0 g, 5.9 mmol) in DMA (20 mL) was added trideuterio(iodo)methane (1.10 mL, 17.6 mmol). The mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water, extracted with EA. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford [2-azanylidene-4,6-dibromo-l-(2,2- difluoroethyl)-3-(trideuteriomethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (3.0 g, 5.7 mmol, 98%) as a yellow solid. LCMS: ESI m / z 529.1 [M + H]+.

[0353] Step B: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (3 g, 5.7 mmol) in DMA (20 mL) was added K2CO3 (1.57 g, 11.4 mmol) and iodomethane (2.8 mL, 45.4 mmol). The reaction was stirred at 50 °C for 3h. The reaction mixture was filtrated, concentrated, diluted with water and extracted with EtOAc (20 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 MeOH in DCM (gradient: 0-10%) to afford (2-chloro-5- fluorophenyl)[4,6-dibromo-l-(2,2-difluoroethyl)-2-[(E)-methylazanylidene]-3- (trideuteriomethyl)benzo[d]imidazol-5-yl]methanone (1.3 g, 2.40 mmol, 42%) as a yellow solid. LCMS: ESI m / z 543.1 [M + H]+.

[0354] Step C: To a solution of (2-chloro-5-fluorophenyl)[4,6-dibromo-l-(2,2- difluoroethyl)-2-[(E)-methylazanylidene]-3-(trideuteriomethyl)benzo[d]imidazol-5- yl]methanone (500 mg, 0.92 mmol) in NMP (5 mL) was added CuCN (87 mg, 0.97 mmol) at rt.The reaction was stirred at 120 °C for 3h. The cooled reaction mixture was diluted with EA, filtered through a pad of celite. The filtrate was extracted with EtOAc (10 mL*3). The organic phase was washed with brine for 3 times, dried over Na2SC>4 and concentrated. The crude was purified by prep-HPLC to afford 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difhroroethyl)-2-[(E)-methylazanylidene]-3-(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (70 mg, 0.14 mmol, 16%) as a yellow solid. LCMS: ESI m / z 490.2 [M + H]+.

[0355] Step D: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-[(E)-methylazanylidene]-3-(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (70 mg, 0.14 mmol) in 1,4-dioxane (5 mL) was added 5-fluoro-3-(trifluoromethyl)benzene-l- carboxamide (45 mg, 0.22 mmol), CS2CO3 (93 mg, 0.29 mmol), Xantphos (27 mg, 0.047 mmol) and Pd2(dba)s (21 mg, 0.024 mmol). The reaction was stirred at 100 °C under N2 for 2h. The reaction mixture was concentrated and purified using silica gel column chromatography eluting with MeOH in DCM (gradient: 0-10%) to give N-{6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-2-[(E)-methylazanylidene]-l- (trideuteriomethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.098 mmol, 68%) as a yellow solid. LCMS: ESI m / z 615.3 [M + H]+.

[0356] Step E: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difluoroethyl)-2-[(E)-methylazanylidene]-l-(trideuteriomethyl)benzo[d]imidazol-5-yl}-5-fluoro- 3-(trifluoromethyl)benzamide (60 mg, 0.098 mmol) in MeCN (5 mL) and H2O (1 mL) were added KOH (33 mg, 0.56 mmol). The reaction was stirred at rt for 4 h. The reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The organic layer was separated and concentrated to afford N-[6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2-[(E)-methylazanylidene]-8-oxo-l- (trideuteriomethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (50 mg, 0.079 mmol, 81%) as a yellow solid. LCMS: ESI m / z 633.0 [M +H]+.

[0357] Step F: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-3- hydroxy-l-oxo-2,3-dihydro-lH-imidazo[l',2': l,2]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.079 mmol) in TFA (2 mL) was added triethylsilane (1 mL) at rt. The mixture was stirred at 70 °C for 15 min. The reaction mixture was concentrated and purified by prep-HPLC to give N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-2-(methylimino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5- e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (5.9 mg, 0.010 mmol, 12%) as a white solid. LCMS: ESI m / z 617.3 [M + H]+. Tl NMR (400 MHz, DMSO-d6) 8 10.26 (s, 1H), 9.11 (s, 1H), 7.98 - 7.89 (m, 1H), 7.81- 7.63 (m, 2H), 7.36 - 7.22 (m, 1H), 7.17 (s, 1H), 7.12 - 7.02 (m, 1H), 6.91 - 6.57 (m, 1H), 6.49 - 6.14 (m, 1H), 6.06 - 5.78 (m, 1H), 4.54 - 4.27 (m, 2H), 3.40 (s, 1H).Example 35: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2-((methyl- d3)imino)-8-oxo-l,2,3?6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamideExample 35

[0358] Step A: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (5 g, 9.775 mmol) in DMA (60mL) was added trideuteriomethane (4.25 g, 29.3 mmol). The reaction mixture was stirred at 100 °C for 2h with tube sealing. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by NazSCU, filtered and concentrate. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to afford [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazol-5-yl](2- chloro-5-fluorophenyl)methanone (5 g, 9.51 mmol, 97%) as a white solid. LCMS: ESI m / z 525.9 [M+H]+

[0359] Step B: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1 g, 1.891 mmol) in DMA (10 mL) was added trideuterio(iodo)methane (2.2 g, 14.2 mmol) and K2CO3 (260 mg, 1.903 mmol). The reaction mixture was stirred at 40 °C for 2h with tube sealing. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 6%] to afford [2-azanylidene- 4,6-dibromo-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazol-5-yl](2-chloro-5- fluorophenyl)methanone (400 mg, 0.736 mmol, 38%) as a white solid. LCMS: ESI m / z 542.6 [M+H]+

[0360] Step C: To a solution of (2-chloro-5-fluorophenyl)[4,6-dibromo-l-(2,2- difluoroethyl)-3-methyl-2-[(Z)-(trideuteriomethyl)azanylidene]benzo[d]imidazol-5- yl]methanone (200 mg, 0.369 mmol) in NMP (6 mL) was added CuCN (99 mg, 1.107 mmol). The reaction mixture was stirred at 130 °C N2 forth. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to afford 16-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methyl-2-[(Z)- (trideuteriomethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (100 mg, 0.205 mmol, 55%) as a white solid. LCMS: ESI m / z 488.7 [M+H]+

[0361] Step D: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difhioroethyl)-3-methyl-2-[(E)-(trideuteriomethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (100 mg, 0.205 mmol) in dioxane (6 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l- carboxamide (64 mg, 0.307 mmol), CS2CO3 (134 mg, 0.409 mmol), Pd2(dba)3 (19 mg, 0.020mmol) and Xant-phos (12 mg, 0.020 mmol). The reaction mixture was stirred at 100 °C under N2 for 2h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 8%] to afford N- {6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-l-methyl-2-[(E)- (trideuteriomethyl)azanylidene]benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.130 mmol, 63%) as a white solid. LCMS: ESI m / z 614.9 [M+H]+

[0362] Step E: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-3-(2,2- difhioroethyl)-l-methyl-2-[(E)-(trideuteriomethyl)azanylidene]benzo[d]imidazol-5-yl}-5-fluoro- 3-(trifluoromethyl)benzamide (100 mg, 0.170 mmol) in CH3CN / H2O (5 mL) was added potassium hydroxide (190 mg, 3.390 mmol). The reaction mixture was stirred at RT forlh. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 16%] to afford N-[6- (2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-l-methyl-8-oxo-2-[(E)- (trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (60 mg, 0.095 mmol, 55%) as a white solid. LCMS: ESI m / z 632.9[M+H]+

[0363] Step F: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-l-methyl-8-oxo-2-[(E)-(trideuteriomethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.095 mmol) in TFA(2 mL) was added triethylsilane (55 mg, 0.475 mmol). The reaction mixture was stirred at 50 °C for 30 min. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated The residue was purified using prep-HPLC to afford t N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l -methyl-2- ((methyl-d3)imino)-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (9.2 mg, 0.015 mmol, 15%) as a white solid. LCMS: ESI m / z 616.9 [M+H]+. Ti NMR (400 MHz, DMSO-d6) 6 10.46 (s, 1H), 9.41 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.81 - 7.69 (m, 2H), 7.65 (s, 1H), 7.36 - 7.26 (m, 1H), 7.18 - 7.05 (m, 1H), 6.86 - 6.29 (m, 2H), 6.07 (brs, 1H), 4.88 - 4.63 (m, 2H), 4.33 (s, 3H).Example 36: N-[6-(2-chloro-5-fluorophenyl)-8-oxo-l-(trideuteriomethyl)-2-[(E)-(trideuteriomethyl)azanylidene]-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[0364] Step A: To a solution of [2-azanylidene-4,6-dibromo-l-(2,2,2-trifluoroethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (11.4 g, 21.5 mmol) in DMA (110 mL) was added trideuterio(iodo)methane (12.5 g, 86.1 mmol). The mixture was stirred at 100 °C for 2 hours in sealed tube. The cooled mixture was diluted with H2O and stirred for 10 min. The mixture was filtrated and the filter cake was washed with EA and dried under vacuum to give [2-azanylidene-4,6-dibromo-3-(trideuteriomethyl)-l-(2,2,2- trifluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (9.7 g, 17.7 mmol, 82 %) as a white solid. LCMS: ESI m / z 547.2 [M + H]+.

[0365] Step B: To a solution of [2-azanylidene-4,6-dibromo-3 -(trideuteri om ethyl)- 1 -(2,2,2- trifluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1 g, 1.83mmol) in DMA (10 mL) was added K2CO3 (0.51 g, 3.66 mmol) and trideuterio(iodo)methane (2.65 g, 18.3 mmol). The mixture was stirred at 40 °C for 1 hour in sealed tube. The mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to afford a residue, which was purified by silica gel chromatography (12 g column) using 0 - 100% DCM / hexane to afford (2-chloro-5-fluorophenyl)[4,6-dibromo-3- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-l-(2,2,2-trifluoroethyl)benzo[d]imidazol- 5-yl]methanone (510 mg, 0.905 mmol, 49 %) as a yellow solid. LCMS: ESI m / z 564.2 [M + H] .

[0366] Step C: To a solution of (2-chloro-5-fluorophenyl)[4,6-dibromo-3- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-l-(2,2,2-trifluoroethyl)benzo[d]imidazol- 5-yl]methanone (400 mg, 0.710 mmol) in NMP (4 mL) was added CuCN (95.3 mg, 1.06 mmol). The mixture was stirred at 130 °C under N2 for 2 hours. The mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (10 g column) using 0 - 1% MeOH / DCM to afford 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(trideuteriomethyl)-2- [(trideuteriomethyl)azanylidene]- 1 -(2,2,2-trifluoroethyl)benzo[d]imidazole-4-carbonitrile (200 mg, 0.392 mmol, 55 %) as a yellow solid. LCMS: ESI m / z 511.3 [M + H]+.

[0367] Step D: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-l-(2,2,2- trifluoroethyl)benzo[d]imidazole-4-carbonitrile (170 mg, 0.334 mmol) in dioxane (10 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (69.1 mg, 0.334 mmol), Pd2(dba)s (30.5 mg, 0.033 mmol), XANT PHOS (38.6 mg, 0.067 mmol) and CS2CO3 (217 mg, 0.667 mmol). The mixture was stirred at 100 °C under N2 for 2 hours. The mixture was concentrated and purified by silica gel chromatography (10 g column) using 0 - 70% EtOAc / hexane to afford N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-l-(trideuteriomethyl)-2- [(trideuteriomethyl)azanylidene]-3-(2,2,2-trifluoroethyl)benzo[d]imidazol-5-yl}-3-fluoro-5- (trifluoromethyl)benzamide (175 mg, 0.275 mmol, 82 %) as a brown oil. LCMS: ESI m / z 636.4 [M + H]+.

[0368] Step E: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-l- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-3-(2,2,2-trifluoroethyl)benzo[d]imidazol- 5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (175 mg, 0.275 mmol) in CH3CN (5 mL) and H2O (1 mL) was added KOH (46.3 mg, 0.826 mmol). The mixture was stirred at 20 °C for 1 hour.The mixture was poured into water and extracted with EA. The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated to give N-[6-(2-chloro-5- fluorophenyl)-6-hydroxy-8-oxo-l-(trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-3- (2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (175 mg, 0.268 mmol, 97 %) as a brown oil. LCMS: ESI m / z 654.4 [M + H]+.

[0369] Step F: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-l- (trideuteriomethyl)-2-[(trideuteriomethyl)azanylidene]-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H- imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (155 mg, 0.237 mmol) in TFA (4 mL) was added EtsSiH (1 mL). The mixture was stirred at 70 °C for 1 hour. The mixture was concentrated. The residue was purified by pre-HPLC to give N-[6-(2-chloro-5- fluorophenyl)-8-oxo-l -(trideuteri omethyl)-2-[(E)-(trideuteriomethyl)azanylidene]-3 -(2,2,2- trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (70 mg, 0.110 mmol, 46 %) as a white solid. LCMS: ESI m / z 638.4 [M + H]+. 'H NMR (400 MHz, DMSO-d6) 8 10.29 (s, 1H), 9.15 (s, 1H), 8.17 (s, 1H), 8.04 - 7.88 (m, 1H), 7.82 - 7.64 (m, 2H), 7.39 - 7.20 (m, 2H), 7.17 - 7.02 (m, 1H), 6.70 (s, 1H), 5.96 (s, 1H), 5.03 - 4.74 (m, 2H).Example 37: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)quinazolin-4-yl]amino}-l-methyl-2-[methylazanylidene]-7,8-dihydro-6H- imidazo[5,4-e]isoindol-8-oneExample 37

[0370] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-methyl-2-(methylazanylidene)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-one (30 mg, 0.07mmol) in 1,1 -di deuteri o-l -(deuteri ooxidanyl)-2, 2, 2-trifluoroethane (5 mL) were added 4-chloro- 6-fluoro-8-(trifluoromethyl)quinazoline (88.7 mg, 0.354 mmol). The reaction was stirred at 90 °C under N2 for 1 hr. LCMS showed the reaction was completed. The cooled reaction mixture was diluted brine, 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 6-(2-chloro-5- fluorophenyl)-3-(2,2-difhioroethyl)-5-{[6-fluoro-8-(trifluoromethyl)quinazolin-4-yl]amino}-l- methyl-2-[methylazanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-one (10.3 mg, 0.016 mmol, 23%) as a light green solid. LCMS: 638.0 [M-H]'. 'H NMR (400 MHz, CDCI3) 8 8.91 (brs, 1H), 8.25 (s, 1H), 7.80 (d, J= 5.6 Hz, 1H), 7.59 (d, J= 6.0 Hz, 2H), 6.96 - 6.93 (m, 1H), 6.81 - 6.72 (m, 1H), 6.64 (s, 1H), 6.52 (d, J= 8.8 Hz, 1H), 6.44 - 5.94 (m, 2H), 4.86 - 4.63 (m, 2H), 4.44 (s, 3H), 3.38 (s, 3H)Example 38: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)cinnolin-4-yl]amino}-l-methyl-2-[(Z)-methylazanylidene]-7,8-dihydro-6H- imidazo[4,5-e]isoindol-8-one

[0371] Step A: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5-fluorophenyl) carbonyl]-l-(2,2-difluoroethyl)-3H-benzo[d]imidazole-4-carbonitrile (5 g, 10.9 mmol) in DMA (50 mL) was added iodomethane (2.7 mL, 32.8 mmol). The reaction mixture was stirred at 100 °C in a sealed tube for 2h. The cooled reaction mixture was diluted with EtOAc and water. After filtration, the filter cake was triturated with EA (50 mL) to afford 2-azanylidene-6-bromo-5-[(2- chloro-5-fluorophenyl) carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d] imidazole-4- carbonitrile (5 g, 10.6 mmol, 97%) as a yellow solid. LCMS: 471.1, 473.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 10.46 (s, 2H), 8.42 (s, 1H), 7.80 - 7.74 (m, 1H), 7.70 - 7.62 (m, 1H), 7.60 - 7.55 (m, 1H), 6.72 - 6.30 (m, 1H), 5.24 - 4.93 (m, 2H), 3.98 (s, 3H).

[0372] Step B: To a mixture of 2-azanylidene-6-bromo-5-[(2-chloro-5-fluorophenyl) carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d] imidazole-4-carbonitrile (5 g, 10.6 mmol) and K2CO3 (1.47 g, 10.6 mmol) in DMA (50 mL) was added CH3I (8.6 mL, 106.0 mmol). The reaction mixture was stirred at 50 °C in a sealed tube for 1.5h. The cooled reaction mixture was quenched with water, extracted with EtOAc (50 mL*3). The organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was triturated with hot MeOH (15 mL*2) to afford 6-bromo-5-[(2-chloro-5-fluorophenyl) carbonyl]-l-(2,2- difhioroethyl)-3-methyl-2-methylazanylidene benzo[d]imidazole-4-carbonitrile (2.4 g, 4.9 mmol, 47%) as a yellow solid. LCMS: 485.1, 487.1 [M+H]+.

[0373] Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl) carbonyl]- 1 -(2,2- difluoroethyl)-3-methyl-2-methylazanylidene benzo[d] imidazole-4-carbonitrile (1.76 g, 3.6 mmol), diphenylmethanimine (0.91 mL, 5.4 mmol), CS2CO3 (3.54 g, 10.9 mmol), Xant-phos (0.21 g, 0.4 mmol) in 1,4-dioxane (110 mL) was added Pd2(dba)3 (0.33 g, 0.4 mmol). The reaction mixture was stirred at 90 °C under N2 for 3.5 h. The cooled reaction mixture was quenched with water, extracted with EtOAc (150 mL * 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (MeOH in DCM = 0 ~ 3%) to obtain 5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-6-[(diphenylmethylidene) amino]-3-methyl-2- methylazanylidene benzo[d] imidazole-4-carbonitrile (1.9 g, 2.9 mmol, 81%) as an orange solid. LC / MS (ESI) m / z: 586.4 [M+H]+

[0374] Step D: To a solution of 5-[(2-chloro-5-fluorophenyl) carbonyl]- 1 -(2,2- difluoroethyl)-6-[(diphenylmethylidene) amino]-3-methyl-2-methylazanylidene benzo[d] imidazole-4-carbonitrile (1.9 g, 2.9 mmol) in MeCN (16 mL) and H2O (4 mL) was added KOH (0.82 g, 14.6 mmol). The reaction mixture was stirred at 40 °C for 30min. The cooled reaction mixture was quenched with water, extracted with EtOAc (100 mL*3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with MeOH (50 mL) to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- [(diphenylmethylidene)amino]-6-hydroxy-l-methyl-2-methylazanylidene-7,8-dihydro-6H- imidazo[4,5-e] isoindol-8-one (1.9 g, 2.8 mmol, 97%) as a yellow solid. LCMS: 604.4 [M+H]+.

[0375] Step E: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- [(diphenylmethylidene)amino]-6-hydroxy-l-methyl-2-methylazanylidene-7,8-dihydro-6H-imidazo[4,5-e] isoindol-8-one (400 mg, 0.7 mmol) in MeCN (2 mL) was added cone. HC1 (1 mL, 12.0 mmol). The reaction mixture was stirred at rt for 30min. The reaction mixture was quenched with sat. NaHCCh, extracted with EtOAc (30 mL *3). The organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated to give the crude product 5- amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-l-methyl-2- methylazanylidene-7,8-dihydro-6H-imidazo[4,5-e] isoindol-8-one (400 mg, 0.6 mmol, 96%) as a yellow solid, which was used without further purification. LC / MS (ESI) m / z: 440.2 [M+H]+.

[0376] Step F: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 6-hydroxy-l-methyl-2-methylazanylidene-7,8-dihydro-6H-imidazo[4,5-e] isoindol-8-one (350 mg, 0.8 mmol) in tri ethyl silane (0.3 mL, 1.9 mmol) was added TFA (0.5 mL, 6.5 mmol). The reaction mixture was stirred at 50 °C for 5min. The reaction mixture was concentrated. The residue was triturated with EA (15 mL) then filtered to afford 5-amino-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-2-methylazanylidene -7,8-dihydro-6H- imidazo[4,5-e] isoindol-8-one (80 mg, 0.2 mmol, 22%) as a gray solid (purity 91%). And the remaining mother liquor was concentrated and was purified by column chromatography on silica gel (MeOH in DCM = 0 ~ 15%) to obtain 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difhioroethyl)-l-methyl-2-methylazanylidene-7,8-dihydro-6H-imidazo[4,5-e] isoindol-8-one (220 mg, 0.4 mmol, 46%) as a deep green oil (purity 70%). LCMS: 424.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 9.27 (s, 1H), 8.45 (s, 1H), 7.68 - 7.47 (m, 1H), 7.32 - 7.16 (m, 1H), 6.95 (s, 1H), 6.65 - 6.24 (m, 1H), 5.92 (s, 1H), 4.88 (s, 2H), 4.72 - 4.56 (m, 2H), 4.27 (s, 3H), 3.26 (s, 3H).

[0377] Step G: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-methyl-2-methylazanylidene-7,8-dihydro-6H-imidazo[4,5-e] isoindol-8-one (30 mg, 0.05 mmol) in 1,1 -di deuteri o-l -(deuteri ooxidanyl)-2, 2, 2-trifluoroethane (0.5 mL) was added conc.HCl (0.1 mL, 32.9 mmol). The reaction mixture was stirred at 90 °C O / N. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to obtain 6-(2- chloro-5-fluorophenyl)-3-(2,2-difhioroethyl)-5-{[6-fluoro-8-(trifluoromethyl) cinnolin-4- yl]amino}-l-methyl-2-methylazanylidene-7,8-dihydro-6H-imidazo [4,5-e] isoindol-8-one (1.1 mg, 0.002 mmol, 3%) as a yellow solid. LCMS: 638.0 [M+H]+.(400 MHz, DMSO-d6) 8 9.51 (s, 1H), 9.33 (s, 1H), 8.86 (s, 1H), 8.32 - 8.23 (m, 2H), 8.04 (s, 2H), 6.95 - 6.33 (m, 4H), 6.10 (s, 1H), 5.00 - 4.85 (m, 2H), 4.45 (s, 3H), 3.35 (s, 3H).Example 39: N-[3-(2-chloro-5-fluorophenyl)-10-methyl-l-oxo-l,2,3,7,8,10- hexahydroimidazo [1 \2' : 1 ,2] imidazo [4,5-e] isoindol-4-yl] -3-fhioro-5-(trifluoromethyl)benzamideExample 39

[0378] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (10 g, 21.9 mmol) in dioxane (100 mL) were added 2-aminoethan-l-ol(2.37 mL, 39.5 mmol) and DIEA (7.6 mL, 43.9 mmol). The reaction was stirred at 100 °C under N2 for 2 hr. 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 petroleum ether (gradient: 20- 30%) to afford (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2-hydroxyethyl)amino]-3- nitrophenyl] methanone (5 g, 10 mmol, 46%) as a yellow solid. LCMS: 497.0 [M-H]'.

[0379] Step B: To a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2- hydroxyethyl)amino] -3 -nitrophenyl [methanone (5 g, 10 mmol) in EtOH (100 mL) and H2O (20 mL) were added Fe (2.81 g, 50.3 mmol) and NH4CI (2.69 g, 50.3 mmol). The reaction was stirred at 80 °C under N2 for 1.5 hr. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated. The residue 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 eluting with ethyl acetate in petroleum ether (gradient: 65-75%) to afford {3-amino-2,6-dibromo-4-[(2-hydroxyethyl)amino]phenyl[(2- chloro-5-fluorophenyl)methanone (4 g, 8.57 mmol, 85%) as a yellow solid. LCMS: 467.0 [M- H]-.

[0380] Step C: To a solution of {3-amino-2,6-dibromo-4-[(2- hydroxyethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methanone (3.5 g, 7.5 mmol) in MeOH (60 mL) and H2O (15 mL) were added BrCN (3.97 g, 37.5 mmol). The reaction was stirred at 80 °C under N2 for 2 hr. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated. The residue was diluted water and EA. The following mixture was filtered. The filter cake was dried to give [2-azanylidene-4,6-dibromo-l -(2 -hydroxy ethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (3.5 g, 7.12 mmol, 95%) as an red solid. LCMS: 492.0 [M-H]'.

[0381] Step D: To a solution of [2-azanylidene-4,6-dibromo-l-(2-hydroxyethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (1 g, 2.03 mmol) in tol (20 mL) were added (tributyl-k5-phosphanylidene)acetonitrile (1.47 g, 6.10 mmol). The reaction was stirred at 100 °C under N2 for 18 hr. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluted with methanol in di chi oroform(gradi ent: 10-20%) to afford 6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-[(diphenylmethylidene)amino]-l-methyl-2-[(E)-methylazanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-one (100 mg, 0.170 mmol, 57%) as a yellow oil. LCMS: 474.0 [M-H]'.

[0382] Step E: To a solution of (2-chloro-5-fluorophenyl)(6,8-dibromo-3,9-dihydro-2H- benzo[4,5]imidazo[2,3-b]imidazol-7-yl)methanone (1 g, 2.11 mmol) in DMA (10 mL) were added CH3I (0.428 mL, 5.28 mmol). The reaction was stirred at 100 °C under N2 for 3 hr in a sealed system. LCMS showed the reaction was completed. 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 methanol in dichloroform (gradient: 5-15%) to afford compound (2-chloro-5- fluorophenyl)(6,8-dibromo-9-methyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-7- yl)methanone (200 mg, 0.410 mmol, 19%)as a yellow solid. LCMS: 486.0 [M-H]'.

[0383] Step F: To a solution of (2-chloro-5-fluorophenyl)(6,8-dibromo-9-methyl-3,9- dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-7-yl)methanone (1 g, 2.05 mmol) in NMP (40 mL) were added CuCN (0.28 g, 3.07 mmol). The reaction was stirred at 130 °C under N2 for 2.5 hr. LCMS showed the reaction was 60%DP. 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 MeOH in dichloroform (gradient: 20-30%) to afford 6-bromo-7-[(2-chloro-5- fluorophenyl)carbonyl]-9-methyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazole-8- carbonitrile (500 mg, 1.15 mmol, 56%) as a yellow solid. LCMS: ESI m / z 435.0 [M+H]+.

[0384] Step G: To a solution of 6-bromo-7-[(2-chloro-5-fluorophenyl)carbonyl]-9-methyl- 3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazole-8-carbonitrile (100 mg, 0.231 mmol) in dioxane (5 mL) were added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (71.6 mg, 0.346 mmol), XANTPHOS (26.6 mg, 0.046 mmol), and CS2CO3 (225 mg, 0.692 mmol), Pd2(dba)3 (21.1 mg, 0.023 mmol). The reaction was stirred at 100 °C under N2 for 2 hr. LCMS showed the reaction was 50% DP. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over ISfeSCU and concentrated. The residue was purified using silica gel column chromatography eluted with methanol in dichloroform(gradient:5-15%) to afford N-{7-[(2-chloro-5- fluorophenyl)carbonyl]-8-cyano-9-methyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-6-yl}-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.089 mmol, 39%)as a yellow solid. LCMS: ESI m / z 560 [M + H]+.

[0385] Step H: To a solution of N-{7-[(2-chloro-5-fluorophenyl)carbonyl]-8-cyano-9- methyl-3,9-dihydro-2H-benzo[4,5]imidazo[2,3-b]imidazol-6-yl}-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.089 mmol) in H2O (1 mL) and ACN (3 mL) were added KOH (25 mg, 0.447 mmol). The reaction was stirred at room temperature under N2 for 2 hr. LCMS showed the reaction was completed. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The organic layer was separated and concentrated to afford N-[3-(2-chloro-5-fluorophenyl)-3- hydroxy-10-methyl-l-oxo-l,2,3,7,8,10-hexahydroimidazo[2',3':2,3]imidazo[5,4-e]isoindol-4-yl]- 3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.043 mmol, 48%) as a yellow solid. LCMS: ESI m / z 578 [M + H]+.

[0386] Step I: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-10-methyl-l-oxo- 1,2, 3,7,8, 10-hexahydroimidazo[2',3':2,3]imidazo[5,4-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (20 mg, 0.035 mmol) in TFA (3 mL) were added EtaSiH (20 mg, 0.173 mmol). The reaction was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated, diluted aqueous NaHCOa and 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-[3-(2-chloro-5-fluorophenyl)- 10-methyl-l-oxo-l,2,3,7,8,10-hexahydroimidazo[T,2': l,2]imidazo[4,5-e]isoindol-4-yl]-3-fluoro- 5-(trifluoromethyl)benzamide (4.7 mg, 0.008 mmol, 24%) as a white solid. LCMS: ESI m / z 562 [M + H]+. Ti NMR (400 MHz, DMSO-d6) 5 10.46 (s, 1H), 9.90 (s, 1H), 9.46 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.34 - 7.28 (m, 1H), 7.15 - 7.06 (m, 1H), 6.48 (brs, 1H), 6.12 (brs, 1H), 4.43 (d, J= 8.8 Hz, 2H), 4.36 (d, J= 7.6 Hz, 2H), 4.17 (s, 3H).Example 40: N-(3-(2-chloro-5-fluorophenyl)-7,10-dimethyl-l-oxo-l,2,3,10- tetrahydroimidazo [1 * ,2 * : 1,2] imidazo [4,5-e] isoindol-4-yl)-3-fluoro-5- (trifluoromethyl)benzamideExample 40

[0387] Step A: To a solution of (2-chloro-5-fluorophenyl)(6,8-dibromo-3,9-dimethyl-2,9- dihydro-3H-benzo[d]imidazo[l,2-a]imidazol-7-yl)methanone (1 g, 1.99 mmol) in DCE (20 mL) was added MnO (3.47 g, 39.9 mmol). The reaction mixture was stirred at 80 °C for 2 h. The cooled mixture was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford (2-chloro- 5-fluorophenyl)(6,8-dibromo-3,9-dimethyl-9H-benzo[d]imidazo[l,2-a]imidazol-7-yl)methanone (280 mg, 0.56 mmol, 28%) as a yellow solid. LCMS: ESI m / z 498 [M + H]+.

[0388] Step B: To a solution of (2-chloro-5-fluorophenyl)(6,8-dibromo-3,9-dimethyl-9H- benzo[d]imidazo[l,2-a]imidazol-7-yl)methanone (250 mg, 0.5 mmol) in NMP (5 mL) was added CuCN (89.5 mg, 1 mmol). The reaction mixture was stirred at 130 °C for 3 h. The cooled mixture was diluted with EA and washed with H2O and brine. The organic layer was concentrated. The residue was purified using silica gel column chromatography eluting with 0- 50% ethyl acetate in petroleum ether to afford 6-bromo-7-(2-chloro-5-fluorobenzoyl)-3,9-dimethyl-9H-benzo[d]imidazo[l,2-a]imidazole-8-carbonitrile (100 mg, 0.22 mmol, 38%) as a yellow solid. LCMS: ESI m / z 445 [M + H]+.

[0389] Step C: To a solution of 6-bromo-7-(2-chloro-5-fluorobenzoyl)-3,9-dimethyl-9H- benzo[d]imidazo[l,2-a]imidazole-8-carbonitrile (100 mg, 0.18 mmol) in dioxane (8 mL) was added 3-fluoro-5-(trifluoromethyl)benzamide (70 mg, 0.639 mmol), Xantphos (26 mg, 0.045 mmol), CS2CO3 (146 mg, 0.45 mmol) and Pd2(dba)s (21 mg, 0.022 mmol). The mixture was stirred at 100 °C under N2 for 2 h. The cooled mixture was diluted with EA and washed with H2O and brine. The organic layer was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in DCM to afford N-(7-(2- chloro-5-fluorobenzoyl)-8-cyano-3,9-dimethyl-9H-benzo[d]imidazo[l,2-a]imidazol-6-yl)-3- fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.105 mmol, 46 %) as a yellow solid. LCMS: ESI m / z 572 [M + H]+.

[0390] Step D: To a solution of N-(7-(2-chloro-5-fluorobenzoyl)-8-cyano-3,9-dimethyl-9H- benzo[d]imidazo[l,2-a]imidazol-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.105 mmol) in ACN (5 mL) and H2O (1 mL) was added KOH (58 mg, 1.05 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with EA and washed with H2O and brine. The organic layer was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in DCM to afford N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-7,10-dimethyl-l-oxo-l,2,3,10-tetrahydroimidazo[l',2':l,2]imidazo[4,5-e]isoindol-4- yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.051 mmol, 48%) as a yellow solid. LCMS: ESI m / z 590 [M + H]+.

[0391] Step E: To a solution of N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-7,10-dimethyl-l- oxo- 1 ,2,3 , 10-tetrahydroimidazo[ 1 ' ,2' : 1 ,2]imidazo[4, 5-e]isoindol-4-yl)-3 -fluoro-5- (trifluoromethyl)benzamide (30 mg, 0.051 mmol) in TFA (3 mL) was added tri ethylsilane (60 mg, 0.51 mmol). The mixture was stirred at 75 °C for 1 h. The cooled mixture was concentrated under vacuum. The residue was purified using prep-HPLC to afford N-(3-(2-chloro-5- fluorophenyl)-7,10-dimethyl-l-oxo-l,2,3,10-tetrahydroimidazo[l',2': l,2]imidazo[4,5-e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (7 mg, 0.012 mmol, 23%) as a white solid. LCMS: ESI m / z 574 [M + H]+. ^NMR (400 MHz, DMSO-d6) 6 10.55 (s, 1H), 9.50 (s, 1H), 8.14 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 9.2 Hz, 1H), 7.73 (s, 1H), 7.39 - 7.28 (m, 2H), 7.16 - 7.05 (m, 1H), 6.81 - 5.80 (m, 2H), 4.40 (s, 3H), 2.64 (s, 3H).Example 41: N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(2,2- difluoroethyl)azanylidene]-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide

[0392] Step A: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3H-benzo[d]imidazole-4-carbonitrile (5 g, 10.93 mmol) in DMA (50 mL) was added CH3I (3.5 mL, 43.7 mmol). The reaction mixture was stirred at 100 °C for 2 h. The cooled mixture was diluted with H2O, brine and EA. The following mixture was filtered. The filter cake was dried to give 2-azanylidene-6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (4.5 g, 9.54 mmol, 87%) as a yellow solid. LCMS: 472.0, 470.0 [M+H]+.

[0393] Step B: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (500 mg, 1.06 mmol) in DMA (6 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (1134.8 mg, 5.30 mmol) and CS2CO3 (345 mg, 1.06 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 16 h. The cooled reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over ISfeSCL and concentrated to afford {6- bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2-[(2,2- difluoroethyl)azanylidene]-3-methylbenzo[d]imidazole-4-carbonitrile (100 mg, 0.14 mmol, 13%) as a yellow solid. LCMS: 536.0, 534.0 [M+H]+.

[0394] Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-[(2,2-difluoroethyl)azanylidene]-3-methylbenzo[d]imidazole-4-carbonitrile (100 mg, 0.14 mmol), 5-fhioro-3-(trifluoromethyl)benzene-l-carboxamide (34.8 mg, 0.17 mmol), CS2CO3 (91.2 mg, 0.28 mmol), XANT PHOS (16.2 mg, 0.028 mmol) in dioxane (3 mL) was added Pd2(dba)s (12.8 mg, 0,014 mmol). The reaction mixture was stirred at 100 °C under N2 for 2 h. The cooled reaction mixture was quenched with water, extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (MeOH in DCM = 0 ~ 3%) to obtain N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-2-[(2,2- difluoroethyl)azanylidene]-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.121 mmol, 86%) as an yellow solid. LCMS (ESI) m / z: 661.1 [M+H]+

[0395] Step D: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difluoroethyl)-2-[(E)-(2,2-difluoroethyl)azanylidene]-l-methylbenzo[d]imidazol-5-yl}-5-fluoro- 3-(trifluoromethyl)benzamide (80 mg, 0.12 mmol) in ACN (2 mL) and H2O (1 mL) was added KOH (33.91 mg, 0.604 mmol). The reaction was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford {N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 2-[(2,2-difluoroethyl)azanylidene]-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.12 mmol, 97%) as a yellow solid. LCMS: 679.1 [M+H]+.

[0396] Step E: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2- [(2,2-difluoroethyl)azanylidene]-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.059 mmol) in 2,2,2- trifluoroacetic acid (1 mL) was added triethylsilane (34.2 mg, 0.29 mmol). The reaction mixture was stirred at 70 °C for 10 min. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(2,2- difluoroethyl)azanylidene]-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (15.8 mg, 0.024 mmol, 40%) as a white solid. LCMS:663.1 [M+H]+.1H NMR (400 MHz, DMSO - d6) 5 10.59 (s, 1H), 9.56 (s, 1H), 8.88 (s, 1H), 8.01 - 7.96 (m, 1H), 7.91 (s, 1H), 7.79 - 7.75 (m, 1H), 7.72 (s, 1H), 7.34 - 7.28 (m, 1H), 7.16 - 7.08 (m, 1H), 6.65 - 6.01 (m, 3H), 5.09 - 4.79 (m, 2H), 4.39 (s, 3H), 4.15 (t, J= 14.8 Hz, 2H).Example 42: N-(l-acetyl-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-imino-8-oxo-

[0397] Step A: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3H-benzo[d]imidazole-4-carbonitrile (500 mg,1.093 mmol) in DMA (4 mL) was added acetyl chloride (257 mg, 3.28 mmol). The reaction mixture was stirred at 120 °C overnight with tube sealing. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 60%] to afford 3-acetyl-6-bromo-5-(2-chloro- 5-fluorobenzoyl)-l-(2,2-difluoroethyl)-2-imino-2,3-dihydro-lEI-benzo[d]imidazole-4- carbonitrile (120 mg, 0.240 mmol, 21%) as a white solid. LCMS: ESI m / z 501.6 [M+H]+

[0398] Step B: To a solution of 3-acetyl-6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2,2- difhioroethyl)-2-imino-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (100 mg, 0.205 mmol) in dioxane (6 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (64 mg, 0.307 mmol), CS2CO3 (134 mg, 0.409 mmol), Pd2(dba)s (19 mg, 0.020 mmol) and Xant- phos (12 mg, 0.020 mmol). The reaction mixture was stirred at 100 °C under N2 for2 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MEOH in DCM [Gradient: 8%] to afford N-(l-acetyl-6-(2- chloro-5-fluorobenzoyl)-7-cyano-3-(2,2-difluoroethyl)-2-imino-2,3-dihydro-lH- benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.130 mmol, 63%) as a white solid. LCMS: ESI m / z 625.9 [M+H]+

[0399] Step C: To a solution of N-(l-acetyl-6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2- difluoroethyl)-2-imino-2,3-dihydro-lH-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0,170 mmol) in CH3CN / H2O (5 mL) was added potassium hydroxide (190 mg, 3.390 mmol). The reaction mixture was stirred at 50 °C forlh. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 16%] to afford N-(l-acetyl-6-(2-chloro- 5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2-imino-8-oxo-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.095 mmol, 55%) as a white solid. LCMS: ESI m / z 643.9 [M+H]+

[0400] Step D: To a solution ofN-(l-acetyl-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-2-imino-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.095 mmol) in TFA(2 mL) was added triethylsilane (55 mg, 0.475 mmol). The reaction mixture was stirred at 50 °C forlh. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by IS^SCE, filtered and concentrated. The residue was purified using prep-HPLC to afford N-(l-acetyl-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-imino-8- oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (9.2 mg, 0.015 mmol, 15%) as a white solid. LCMS: ESI m / z 627.9 [M+H]+. NMR (400 MHz, DMSO-d6) 6 10.93 (s, 1H), 10.47 (s, 1H), 9.02 (s, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.81 - 7.63 (m, 3H), 7.33 - 7.24 (m, 1H), 7.17 - 7.00 (m, 1H), 6.68 - 6.21 (m, 2H), 6.07 (brs, 1H), 4.87 - 4.61 (m, 2H), 2.22 (s, 3H).Example 43: N-[6-(2-chloro-5-fluorophenyl)-2-cyclobutylazanylidene-3-(2,2-difluoroethyl)- l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e] isoindol-5-yl]-5-fluoro-3-(trifluoromethyl) benzamide

[0401] Step A. To the mixture of [2-azanylidene-4,6-dibromo-l-(2,2-difluoroethyl)-3- methylbenzo[d]imidazol-5-yl] (2-chloro-5-fluorophenyl) methanone (300 mg, 0.571 mmol) in DMA (5 mL) was added CS2CO3 (186 mg, 0.571 mmol) and iodocyclobutane (519 mg, 2.85 mmol) at rt. The mixture was stirred at 120 °C for 20h. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated. Then the crude was purified by prep-HPLC (Cl 8, 5 ~ 95% MeCN in H2O with 0.1 % TFA) to afford (2-chloro-5-fluorophenyl) {4,6-dibromo-2- cyclobutylazanylidene-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazol-5-yl} methanone (80 mg, 0.138 mmol, 24%) as a white solid. LCMS: ESI m / z 580.1 [M + H]+.

[0402] Step B. To a solution of (2-chloro-5-fluorophenyl) {4,6-dibromo-2- cyclobutylazanylidene-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazol-5-yl} methanone (80 mg, 0.138 mmol) in NMP (2 mL). was added CuCN (16 mg, 0.179 mmol). The reaction mixture was stirred at 130 °C under N2 for 3h. The cooled reaction mixture was quenched with water, extracted with EtOAc (20 mL x 3), washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was was purified by column chromatography on silica gel(EA in PE = 0 ~ 50%) to obtain 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2- cyclobutylazanylidene-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (15 mg, 0.029 mmol, 20%) as an orange solid. LC / MS (ESI) m / z: 525.1 [M+H]+

[0403] Step C. To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl) carbonyl]-2-[(E)- cyclobutylazanylidene]-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (15 mg, 0.029 mmol), 5 -fluoro-3 -(trifluoromethyl) benzene- 1 -carboxamide (8 mg, 0.037 mmol), CS2CO3 (18 mg, 0.057 mmol), XANT PHOS (3 mg, 0.006 mmol) in dioxane (3 mL) was added Pd(dba)s (2 mg, 0.003 mmol). The reaction mixture was stirred at 100 °C under N2 for 3h. The cooled reaction mixture was quenched with water, extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EA in PE = 0 ~ 50%) to obtain N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-cyclobutylazanylidene-3-(2,2- difhioroethyl)-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.015 mmol, 53%) as orange solid. LC / MS (ESI) m / z: 598.1 [M+H]+

[0404] Step D. To a solution of N-{6-[(2-chloro-5-fluorophenyl) carbonyl]-7-cyano-2-[(E)- cyclobutylazanylidene]-3-(2,2-difluoroethyl)-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3- (trifhioromethyl) benzamide (10 mg, 0.015 mmol) in ACN (1.5 mL) and H2O (0.3 mL) was added potassium hydroxide (4 mg, 0.077 mmol). The reaction mixture was stirred at RT for 30 min. The reaction mixture was quenched with water, extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product N-[6-(2-chloro-5-fluorophenyl)-2-cyclobutylazanylidene-3-(2,2- difluoroethyl)-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[4,5-e] isoindol-5-yl]-5- fluoro-3-(trifluorom ethyl) benzamide (8 mg, 0.012 mmol, 77%) which was used without further purification. LCMS (ESI) m / z: 670 [M+H]+

[0405] Step E. To a stirred solution of N-[6-(2-chloro-5-fluorophenyl)-2- cyclobutylazanylidene-3-(2,2-difluoroethyl)-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H- imidazo[5,4-e] isoindol-5-yl]-5-fluoro-3-(trifluoromethyl) benzamide (8 mg, 0.012 mmol) in TFA (1 mL) was added EtsSiH (7 mg, 0.060 mmol) at rt. The reaction mixture was stirred at 70 °C for 10 min. 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 prep-HPLC (Cl 8, 40 ~ 90 % MeCN inH2O with 0.1 % TFA) to give N-[6-(2-chloro-5-fluorophenyl)-2-cyclobutylazanylidene-3-(2,2- difluoroethyl)-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e] isoindol-5-yl]-5-fluoro-3- (trifluoromethyl) benzamide (1 mg, 0.002 mmol, 12%) as a white solid. LCMS: m / z 654.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 8 10.55 (s, 1H), 9.52 (s, 1H), 8.69 - 8.50 (m, 1H), 8.01- 7.94 (m, 1H), 7.84 (s, 1H), 7.79 - 7.69 (m, 2H), 7.33 - 7.28 (m, 1H), 7.16 - 7.07 (m, 1H), 6.72- 6.29 (m, 2H), 6.13 (brs, 1H), 5.02 - 4.78 (m, 2H), 4.36 (s, 3H), 3.58 - 3.56 (m, 1H), 2.09 - 1.89 (m, 2H), 0.64 - 0.53 (m, 2H), 0.44 - 0.36 (m, 2H).Example 44: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-((2- methoxyethyl)imino)-l-methyl-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide

[0406] Step A: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2,2-difluoroethyl)- 2-imino-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (2 g, 4.37 mmol) in DMA (20 mL) was added iodomethane (0.82 mL, 13.11 mmol) at rt. The mixture was stirred at 100 °C for 2h. The cold reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford 6-bromo-5-(2- chloro-5-fluorobenzoyl)-l-(2,2-difluoroethyl)-2-imino-3-methyl-2,3-dihydro-lH- benzo[d]imidazole-4-carbonitrile (1.1 g, 2.33 mmol, 53%) as a yellow solid. LCMS: ESI m / z 473.0 [M + H]+.

[0407] Step B: To a solution of 6-bromo-5-(2-chloro-5-fhiorobenzoyl)-l-(2,2-difluoroethyl)- 2-imino-3-methyl-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (100 mg, 0.21 mmol) in DMA (3 mL) was added l-iodo-2-methoxy ethane (87 mg, 0.47 mmol) at rt. The mixture was stirred at 100 °C for 16h. The cold reaction mixture was diluted with water, extracted with EA. The organic layer was separated, washed with brine, dried over ISfeSCL and concentrated. The residue was purified by prep-HPLC to afford 6-bromo-5-(2-chloro-5- fluorobenzoyl)-l -(2, 2-difluoroethyl)-2-((2 -methoxy ethyl)imino)-3-methyl-2, 3 -dihydro- 1H- benzo[d]imidazole-4-carbonitrile (15 mg, 0.028 mmol, 13%) as a yellow solid. LCMS: ESI m / z 531.2 [M + H]+.

[0408] Step C: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-l-(2,2-difluoroethyl)- 2-((2-methoxyethyl)imino)-3-methyl-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (15 mg, 0.028 mmol) in 1,4-dioxane (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l- carboxamide (10 mg, 0.05 mmol), Pd2(dba)s (10 mg, 0.011 mmol), Xantphos (13 mg, 0.023mmol), CS2CO3 (18 mg, 0.057 mmol). The reaction was stirred at 100 °C for 2h. The reaction mixture was concentrated and purified using silica gel column chromatography eluting with MeOH in DCM (gradient: 0-10%) to give N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2- difhioroethyl)-2-((2-methoxyethyl)imino)-l-methyl-2,3-dihydro-lH-benzo[d]imidazol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.015 mmol, 54 %) as a yellow solid. LCMS: ESI m / z 656.4 [M + H]+.

[0409] Step D: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difluoroethyl)-2-[(E)-(2 -methoxy ethyl)azanylidene]-l-methylbenzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.015 mmol) in MeCN (3 mL) and H2O (1 mL) were added potassium hydroxide (17 mg, 0.31 mmol). The reaction was stirred at room temperature for 2 hr. LCMS showed the reaction was completed. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The organic layer was separated and concentrated to afford N-(6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2-((2-methoxyethyl)imino)-l-methyl-8- oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (8 mg, 0,012 mmol, 78%) as a yellow solid. LCMS: ESI m / z 674.3 [M +H]+.

[0410] Step E: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-((2-methoxyethyl)imino)-l-methyl-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5- e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (8 mg, 0.012 mmol) in TFA (2 mL) was added triethylsilane (1 mL) at rt. The mixture was stirred at 70 °C for 15 min. The reaction mixture was concentrated and purified by prep-HPLC to give N-(6-(2-chloro-5-fluorophenyl)-3- (2,2-difluoroethyl)-2-((2-methoxyethyl)imino)-l-methyl-8-oxo-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.1 mg, 0.003 mmol, 27%) as a white solid. LCMS: ESI m / z 658.4 [M + H]+. NMR (400 MHz, DMSO-d6) 8 10.56 (s, 1H), 9.53 (s, 1H), 8.68 - 8.50 (m, 1H), 8.01 - 7.95 (m, 1H), 7.86 (s, 1H), 7.81 - 7.68 (m, 2H), 7.37 - 7.28 (m, 1H), 7.24 - 7.07 (m, 1H), 6.72 - 6.31 (m, 2H), 6.26 - 5.99 (m, 1H), 5.06 - 4.78 (m, 2H), 4.37 (s, 3H), 3.95 - 3.76 (m, 2H), 3.63 (t, J = 5.2 Hz, 2H), 3.31 (s, 3H).Example 45: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-((2-fluoroethyl)imino)- l-methyl-8-oxo-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[0411] Step A: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-4- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (200 mg, 0.424 mmol) in DMA (2 mL) was added l-fluoro-2-iodoethane (369 mg, 2.12 mmol) and CS2CO3 (276 mg, 0.848 mmol). The reaction mixture was stirred at 130 °C for 16 h. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep- HPLC to afforded 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2-[(2- fluoroethyl)azanylidene]-3-methylbenzo[d]imidazole-4-carbonitrile (70 mg, 0.135 mmol, 32%) as a brown solid. LCMS: 519.0 [M+2+H]+.

[0412] Step B: A solution of 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-[(2-fluoroethyl)azanylidene]-3-methylbenzo[d]imidazole-4-carbonitrile (20 mg, 33 μmol), 5-fluoro-3-(trifluoromethyl)benzene-l-carboxamide (8.00 mg, 39 μmol), Pd2(dba)s (3.53 mg, 4 μmol), xantphos (4.47 mg, 8 μmol), CS2CO3 (37.7 mg, 0.116 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0%~l 0%) to afford N-{6-[(2-chloro-4-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-2- [(2-fluoroethyl)azanylidene]-l-methylbenzo[d]imidazol-5-yl}-3-fluoro-5- (trifluoromethyl)benzamide (15 mg, 23 μmol, 60%) as a brown solid (crude). LCMS: 644.1 [M+H]+.

[0413] Step C: To a solution of N-{6-[(2-chloro-4-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difhioroethyl)-2-[(2-fluoroethyl)azanylidene]-l-methylbenzo[d]imidazol-5-yl}-3-fluoro-5- (trifluoromethyl)benzamide (20 mg, 31 μmol) in ACN (1 mL) and H2O (0.2 mL) was added KOH (8.70 mg, 0.155 mmol) at room temperature. The reaction mixture was stirred at rt for 30 min. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2SO4 and concentrated to give N-[6-(2-chloro-4-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(2- fluoroethyl)azanylidene]-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5- yl]-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 23 μmol, 73%) as a brown solid. LCMS: 662.1 [M+H]+.

[0414] Step D: To a solution ofN-[6-(2-chloro-4-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(2- fluoroethyl)azanylidene]-6-hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5- yl]-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 23 μmol) in TFA (1 mL) was added EtsSiH (0.2 mL). The reaction mixture was stirred at 60 °C for 30 min. Then the cooled reaction mixture was concentrated to give a residue. The residue was purified by pre-HPLC to give N-[6-(2- chloro-4-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(2-fluoroethyl)azanylidene]-l-methyl-8-oxo-7,8- dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1.2 mg, 2 μmol, 8%) as a white solid. LCMS: 646.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 10.57 (s, 1H), 9.54 (s, 1H), 8.77 (s, 1H), 7.99 - 7.97 (d, J= 8.4 Hz, 1H), 7.88 (s, 1H), 7.78 - 7.76 (d, J= 8.8 Hz, 1H), 7.72 (s, 1H), 7.33 - 7.30 (m, 1H), 7.14 - 7.10 (m, 1H), 6.63 - 6.10 (m, 2H), 4.99 - 4.87 (m, 2H), 4.69 - 4.67 (m, 2H), 4.37 (s, 3H), 4.08 - 4.00 (m, 2H).Example 46: N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-2-[(2,2,2- trifluoroethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0415] Step A: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methylbenzo[d]imidazole-4-carbonitrile (200 mg, 0.424 mmol) in DMA (8 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (196 mg, 0.848 mmol) and CS2CO3 (276 mg, 0.848 mmol). The reaction was stirred at 100 °C under N2 in a sealed system for 24h. The cooled reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methyl-2-[(2,2,2- trifluoroethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (23 mg, 0.042 mmol, 10%) as a yellow solid. LCMS: 553.0 [M-H]'.

[0416] Step B: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-methyl-2-[(2,2,2-trifluoroethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (23 mg, 0.042 mmol) in dioxane (5 mL) were added 5-fluoro-3-(trifluoromethyl)benzene-l- carboxamide (12.9 mg, 0.062 mmol), XANT PHOS (4.81 mg, 0.008 mmol), and CS2CO3 (33.8 mg, 0.104 mmol), Pd2(dba) (3.80 mg, 0.004 mmol). The reaction was stirred at 100 °C under N2 for 2 hr. LCMS showed the reaction was 80% DP. 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 petroleum ether(gradient:30-40%) to afford N-{6-[(2-chloro-5-fluorophenyl)carbonyl]- 7-cyano-3-(2,2-difluoroethyl)-l-methyl-2-[(2,2,2-trifluoroethyl)azanylidene]benzo[d]imidazol-5- yl}-5-fluoro-3-(trifhioromethyl)benzamide (17 mg, 0.025 mmol, 60%) as a yellow solid. LCMS: 680.0 [M-H]'.

[0417] Step C: To a solution ofN-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difhioroethyl)-l-methyl-2-[(2,2,2-trifluoroethyl)azanylidene]benzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (17 mg, 0.025 mmol) in H2O (1 mL) and ACN (5 mL) were added KOH (4.21 mg, 0.075 mmol). The reaction was stirred at room temperature under N2 for 2 hr. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The organic layer was separated and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-l- methyl-8-oxo-2-[(2,2,2-trifluoroethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5- yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.021 mmol, 86%) as a yellow solid. LCMS: 698.0 [M-H]’.

[0418] Step D: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-l-methyl-8-oxo-2-[(2,2,2-trifluoroethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.021 mmol) in TFA (5 mL) were added EtsSiH (2.5 mg, 0.021 mmol). The reaction was stirred at 70 °C for 1 hr. The cooled reaction mixture was concentrated, diluted aqueous NaHCCh and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue waspurified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl- 8-oxo-2-[(2,2,2-trifluoroethyl)azanylidene]-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (2.4 mg, 0.004 mmol, 16%) as a white solid. LCMS: 682.010.26 (s, 1H), 9.12 (s, 1H), 7.93 (d, J= 6.0 Hz, 1H),7.74 (d, J= 8.8 Hz, 1H), 7.70 (s, 1H), 7.34 - 7.25 (m, 1H), 7.20 (s, 1H), 7.14 - 7.04 (m, 1H),6.75 - 6.10 (m, 2H), 5.96 (brs, 1H), 4.53 - 4.30 (m, 4H), 4.13 (s, 3H).Example 47: N-[6-(2-chloro-5-fluorophenyl)-2-[(2,2-difluoroethyl)azanylidene]-l-methyl-8- oxo-3-(pentadeuterioethyl)-7,8-dihydr o-6H-imidazo [5,4-e] isoindol-5-yl] -5-fluoro-3- (trifluoromethyl)benzamideExample 47

[0419] Step F: To a solution of [2-azanylidene-4,6-dibromo-l-(pentadeuterioethyl)-3H- benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (2.39 g, 4.97 mmol) in DMA(30 mL) was added iodomethane (2.82 g, 19.9 mmol). The mixture was stirred at 100 °C for 2hours in sealed tube. The cooled mixture was diluted with H2O and stirred for 10 min. The mixture was filtered and the filter cake was washed with EA and dried under vacuum to give [2- azanylidene-4,6-dibromo-3-methyl-l-(pentadeuterioethyl)benzo[d]imidazol-5-yl](2-chloro-5- fluorophenyl)methanone (2.4 g, 4.85 mmol, 97 %) as a white solid. LCMS: ESI m / z 495.1 [M + H]+.

[0420] Step G: To a solution of [2-azanylidene-4,6-dibromo-3 -methyl- 1- (pentadeuterioethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluorophenyl)methanone (100 mg, 0.202 mmol) in DMA (2 mL) was added CS2CO3 (98.7 mg, 0.303 mmol) and l,l-difluoro-2- iodoethane (310 mg, 1.62 mmol). The mixture was stirred at 90 °C in sealed tube for 2 hours. The mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford a residue, which was purified by silica gel chromatography (12 g column) using 0 - 1% MeOH / DCM to afford (2-chloro-5- fluorophenyl){4,6-dibromo-2-[(2,2-difluoroethyl)azanylidene]-3-methyl-l- (pentadeuterioethyl)benzo[d]imidazol-5-yl}methanone (70 mg, 0.125 mmol, 62 %) as a brown solid. LCMS: ESI m / z 559.2 [M + H]+.

[0421] Step H: To a solution of (2-chloro-5-fluorophenyl){4,6-dibromo-2-[(2,2- difluoroethyl)azanylidene]-3-methyl- 1 -(pentadeuterioethyl)benzo[d]imidazol-5-yl Jmethanone (70 mg, 0.125 mmol) in NMP (2 mL) was added CuCN (16.8 mg, 0.188 mmol). The mixture was stirred at 130 °C under N2 for 2 hours. The mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over ISfeSCU and concentrated to give a crude, which was purified by pre-TLC(PE / EA=l: l) to give 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-2-[(E)-(2,2-difluoroethyl)azanylidene]-3-methyl-l- (pentadeuterioethyl)benzo[d]imidazole-4-carbonitrile (25 mg, 0.050 mmol, 39 %) as a yellow solid. LCMS: ESI m / z 506.2 [M + H]+.

[0422] Step I: To a mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-[(2,2- difluoroethyl)azanylidene]-3-methyl-l-(pentadeuterioethyl)benzo[d]imidazole-4-carbonitrile (25 mg, 0.050 mmol) and 5-fluoro-3-(trifluoromethyl)benzene-l -carboxamide (12.3 mg, 0.059 mmol) in dioxane (2 mL) was added Pd2(dba)s (4.54 mg, 0.005 mmol), XANT PHOS (5.73 mg, 0.010 mmol) and CS2CO3 (32.3 mg, 0.099 mmol). The mixture was stirred at 100 °C under N for 2 hours. The cooled mixture was concentrated and purified by pre-TLC(PE / EA=l : 1) to afford N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-[(2,2-difluoroethyl)azanylidene]-l-methyl-3-(pentadeuterioethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.024 mmol, 48 %) as a yellow oil. LCMS: ESI m / z 631.4 [M + H]+.

[0423] Step J: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-[(2,2- difhioroethyl)azanylidene]-l-methyl-3-(pentadeuterioethyl)benzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (15 mg, 0.024 mmol) in CH3CN (2 mL) and H2O (0.25 mL) was added KOH (4.00 mg, 0.071 mmol). The mixture was stirred at 20 °C for 30 min. The mixture was poured into water and extracted with EA. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated to give N-[6-(2-chloro-5- fluorophenyl)-2-[(2,2-difluoroethyl)azanylidene]-6-hydroxy-l-methyl-8-oxo-3- (pentadeuterioethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (15 mg, 0.023 mmol, 97 %) as a yellow oil. LCMS: ESI m / z 649.4 [M + H]+.

[0424] Step K: To a solution of N-[6-(2-chloro-5-fluorophenyl)-2-[(2,2- difluoroethyl)azanylidene]-6-hydroxy-l-methyl-8-oxo-3-(pentadeuterioethyl)-7,8-dihydro-6H- imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.023 mmol) in TFA (1 mL) was added EtsSiH (0.25 mL). The mixture was stirred at 70 °C for 30 min. The mixture was concentrated under vacuum to give a crude, which was purified by pre- HPLC to give N-[6-(2-chloro-5-fluorophenyl)-2-[(2,2-difluoroethyl)azanylidene]-l-methyl-8- oxo-3-(pentadeuterioethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (2 mg, 0.003 mmol, 14 %) as a white solid. LCMS: ESI m / z 633.4 [M + H]+.1H NMR (400 MHz, DMSO-d6) 5 10.21 (s, 1H), 9,05 (s, 1H), 8.18 (s, 1H), 7.95 - 7.90 (m, 1H), 7.77 - 7.68 (m, 2H), 7.31 - 7.23 (m, 1H), 7.14 - 7.03 (m, 2H), 6.65 (s, 1H), 6.25 - 5.75 (m, 2H), 4.12 - 4.03 (m, 2H), 3.97 (s, 3H).Example 48: N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-2- methylazanylidene-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamideExample 48

[0425] Step A: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3H-benzo[d]imidazole-4-carbonitrile (500 mg, 1.09 mmol) in DMA (10 mL) were added methyl 2-bromo-2,2-difluoroacetate (309 mg, 1.64 mmol) and K2CO3 (302 mg, 2.19 mmol). The reaction was stirred at 100 °C for 4 hr. The cooled reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford 2- azanylidene-6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3- (difluoromethyl)benzo[d]imidazole-4-carbonitrile (100 mg, 0.197 mmol, 18%) as a white solid.LCMS: 507.0 [M-H]’.

[0426] Step B: To a solution of 2-azanylidene-6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-(difluoromethyl)benzo[d]imidazole-4- carbonitrile (100 mg, 0.197 mmol) in DMA (5 mL) were added K2CO3 (27.2 mg, 0.197 mmol) and CH3I (0.123 mL, 1.97 mmol). The reaction was stirred at 50 °C for 18 hr in a sealed system. LCMS showed the reaction was 30%DP. The cooled reaction mixture was concentrated, extracted with EA. The residue was triturated with (MeOH) to afford 6-bromo-5- [(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-(difluoromethyl)-2-[methylazanylidene]benzo[d]imidazole-4-carbonitrile (30 mg, 0.058 mmol, 29%) as a yellow solid. LCMS: 521.0 [M-H]'.

[0427] Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-(difluoromethyl)-2-[methylazanylidene]benzo[d]imidazole-4-carbonitrile (30 mg, 0.058 mmol) in dioxane (5 mL) were added 5-fluoro-3-(trifluoromethyl)benzene-l- carboxamide (17.8 mg, 0.086 mmol), XANTPHOS (6.66 mg, 0.012 mmol), and CS2CO3 (56.1 mg, 0.173 mmol), Pd (dba)3 (5.27 mg, 0.006 mmol). The reaction was stirred at 100 °C under N2 for 2 hr. 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 using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 35- 45%) to afford compound N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difhioroethyl)-l-(difluoromethyl)-2-[methylazanylidene]benzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.046 mmol, 81%) as a yellow solid. LCMS: 648.0 [M-H]'.

[0428] Step D: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difluoroethyl)-l-(difluoromethyl)-2-[methylazanylidene]benzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.046 mmol) in H2O (1 mL) and ACN (3 mL) were added KOH (13 mg, 0.232 mmol). The reaction was stirred at room temperature under N2 for 2 hr. LCMS showed the reaction was completed. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na SO4 and concentrated. The organic layer was separated and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2- dif oroethyl)-l-(difluoromethyl)-6-hydroxy-2-methylazanylidene-8-oxo-7,8-dihydro-6H- imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.038 mmol, 81%) as a yellow solid. LCMS: 666.0 [M-H]'.

[0429] Step E: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (difluoromethyl)-6-hydroxy-2-methylazanylidene-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol- 5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.038 mmol) in TFA (3 mL) were added EtiSiH (21.8 mg, 0.188 mmol). The reaction was stirred at 70 °C for 0.5 hr. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated, diluted aqueous NaHCCL and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-2-methylazanylidene-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7 mg, 0.011 mmol, 29%) as a white solid. LCMS: 650.0 [M-H]’. NMR (400 MHz, DMSO-d6) 6 10.35 (s, 1H), 9.41 (s, 1H), 9.06 - 8.72 (m, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 9.2 Hz, 1H), 7.70 (s, 1H), 7.32 - 7.24 (m, 1H), 7.21 (s, 1H), 7.13 - 7.05 (m, 1H), 6.83 (brs, 1H), 6.48 - 5.81 (m, 2H), 4.39 - 4.15 (m, 2H), 3.20 (s, 3H).Example 49: N-(3-(2-chloro-5-fluorophenyl)-6-(2,2-difluoroethyl)-9-fluoro-l-oxo-2,3,6, 8,9, 10-hexahydro-lH-pyrimido[2',l':2,3]imidazo[4,5-e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0430] Step A: To a solution of 2-amino-6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-l- (2,2-difluoroethyl)benzo[d]imidazole-4-carbonitrile (100 mg, 0.219 mmol) in DMF (2 mL) was added CS2CO3 (142 mg, 0.437 mmol) and 2-(bromomethyl)oxirane (49.9 mg, 0.328 mmol). The reaction mixture was stirred at 120 °C for 16 h. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was wash with brine, dried over Na2SC>4 and concentratedin vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to afforded 8-bromo-7-[(2-chloro-4-fluorophenyl)carbonyl]-10-(2,2- difluoroethyl)-3-hydroxy-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidine-6-carbonitrile (50 mg, 97 μmol, 44%) as a brown solid. LCMS: 515.0 [M+2+H]+.

[0431] Step B: To a solution of 8-bromo-7-[(2-chloro-4-fluorophenyl)carbonyl]-10-(2,2- difluoroethyl)-3-hydroxy-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidine-6-carbonitrile (45 mg, 88 μmol) in DCM (2 mL) was added DAST (0.5 mL) at 0 °C. The reaction mixture was stirred at rt for 16 h. The mixture was diluted with H2O, extracted with EA. The organic layer was wash with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afforded 8- bromo-7-[(2-chloro-4-fluorophenyl)carbonyl]-10-(2,2-difluoroethyl)-3-fluoro-2,3,4,10- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidine-6-carbonitrile (15 mg, 29 μmol, 33%) as a brown solid. LCMS: 517.0 [M+H]+.

[0432] Step C: A solution of 8-bromo-7-[(2-chloro-4-fluorophenyl)carbonyl]-10-(2,2- difluoroethyl)-3-fluoro-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidine-6-carbonitrile (15 mg, 29 μmol), 5-fluoro-3-(trifluoromethyl)benzene-l-carboxamide (6,02 mg, 29 μmol), Pd2(dba)3 (2.66 mg, 3 μmol), xantphos (3.36 mg, 6 μmol), Cs2CO3 (28.3 mg, 87 μmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0%~10%) to afforded crude N-{7-[(2-chloro-4-fluorophenyl)carbonyl]-6- cyano-10-(2,2-difluoroethyl)-3-fluoro-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidin-8- yl}-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 23 μmol, 80%) as a brown solid. LCMS:642.1 [M+H]+.

[0433] Step D: To a solution of N-{7-[(2-chloro-4-fluorophenyl)carbonyl]-6-cyano-10-(2,2- difhioroethyl)-3-fluoro-2,3,4,10-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrimidin-8-yl}-3-fluoro-5- (trifluoromethyl)benzamide (15 mg, 23 μmol) in ACN (1 mL) and H2O (0.2 mL) was added KOH (6.55 mg, 0.117 mmol) at room temperature. The reaction mixture was stirred at rt for 30 min. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2SO4 and concentrated to give N-[3-(2-chloro-4-fluorophenyl)-6-(2,2-difluoroethyl)-9-fluoro-3-hydroxy-l-oxo-2,3,6,8,9,10-hexahydro-lH-pyrimido[2',r:2,3]imidazo[4,5-e]isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (12 mg, 18 μmol, 78%) as a brown solid. LCMS: 660.1 [M+H]+.

[0434] Step E: To a solution ofN-[3-(2-chloro-4-fluorophenyl)-6-(2,2-difluoroethyl)-9- fhioro-3-hydroxy-l-oxo-2,3,6,8,9,10-hexahydro-lH-pyrimido[2',l':2,3]imidazo[4,5-e]isoindol-4- yl]-3-fluoro-5-(trifluoromethyl)benzamide (12 mg, 18 μmol) in TFA (1 mL) was added EtsSiH (0.2 mL). The reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was concentrated to give a residue. The residue was purified by pre-HPLC to give_N-[3-(2- chloro-4-fluorophenyl)-6-(2,2-difluoroethyl)-9-fluoro-l-oxo-2,3,6,8,9,10-hexahydro-lH- pyrimido[2',r:2,3]imidazo[4,5-e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1.7 mg, 3 μmol, 14%) as a white solid. LCMS: 644.2 [M+H]+ 1H NMR (400 MHz, CD3OD) 5 7.79 (s, 1H), 7.73 - 7.63 (m, 3H), 7.29 - 7.26 (m, 1H), 7.03 - 6.99 (m, 1H), 6.54 - 6.27 (m, 2H), 5.88 - 5.55 (m, 2H), 4.85 - 4.66 (m, 2H), 4.62 - 4.53 (m, 1H), 4.07 - 3.78 (m, 2H).Example 50: N-[(6R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(2,2- difluoroethyl)azanylidene]-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamideExample 51: N-[(6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(2,2- difluoroethyl)azanylidene]-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide

[0435] Step A: N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-[(E)-(2,2- difluoroethyl)azanylidene]-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (29 mg, 0.044 mmol) was purified by chiral prep-SFC method 6 (NH3 as additive). Each fraction was acidified with HC1 (1 M in H2O) quickly to pH=5-6 and concentrated respectively. Each residue was purified with prep-HPLC (one fractionFA as additive, another fraction TFA as additive) to afford N-[(6R)-6-(2-chloro-5-fluorophenyl)- 3-(2,2-difluoroethyl)-2-[(2,2-difluoroethyl)azanylidene]-l-methyl-8-oxo-7,8-dihydro-6H- imidazo[5,4-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (6.1 mg, 0.009 mmol, 21%) as a white solid. LCMS: ESI m / z 663.1 [M + H]+. 1HNMR (400 MHz, DMSO-d6) 8 10.26 (s, 1H), 9.12 (s, 1H), 7.93 (d, J= 6.8 Hz, 1H), 7.72 (d, J= 20.1 Hz, 2H), 7.32 - 7.03 (m, 3H), 6.56 - 5.81 (m, 3H), 4.36 (s, 2H), 4.11 (s, 5H). And N-[(6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-2-[(2,2-difluoroethyl)azanylidene]-l-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (6.3 mg, 0.009 mmol, 21%) as a white solid. LCMS: ESI m / z 663.1 [M + H]+. 'HNMR (400 MHz, DMSO-d6) 6 10.59 (s, 1H), 9.56 (s, 1H), 8.88 (s, 1H), 8.02 - 7.86 (m, 2H), 7.82 - 7.67 (m, 2H), 7.35 - 7.27 (m, 1H), 7.12 (s, 1H), 6.70 - 6.04 (m, 3H), 5.07 - 4.80 (m, 2H), 4.39 (s, 3H), 4.21 - 4.07 (m, 2H).Example 52: N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl-8-oxo-2-(prop-2-ylazanylidene)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0436] Step A: To a solution of 6-bromo-2-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- (2,2-difluoroethyl)benzo[d]imidazole-4-carbonitrile (300 mg, 0.629 mmol) in DMA(5 mL) were added propan-2-amine (55.8 mg, 0.943 mmol) and TEA (191 mg, 1.89 mmol). The mixture was stirred at 100 °C for Ih. 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 petroleum ether (gradient: 0-30%) to afford 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2-(prop-2-ylamino)benzo[d]imidazole-4- carbonitrile (150 mg, 0.300 mmol, 48%) as a yellow solid. LCMS: ESI m / z 501.1 [M + H]+.

[0437] Step B: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-(prop-2-ylamino)benzo[d]imidazole-4-carbonitrile (150 mg, 0.299 mmol) in DMA (5 mL) were added iodomethane (127 mg, 0.896 mmol) and K2CO3 (124 mg, 0.896 mmol). The mixture was stirred at 100 °C for 2h with sealed tube. 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(gradi ent: 0-30%) to afford 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-methyl-2-(prop-2- ylazanylidene)benzo[d]imidazole-4-carbonitrile (more polar, 50 mg, 0.08 mmol, 33%) as a yellow oil. LCMS: ESI m / z 515.1 [M + H]T

[0438] Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-methyl-2-(prop-2-ylazanylidene)benzo[d]imidazole-4-carbonitrile (50 mg, 0.097 mmol) in dioxane (5 mL) were added 3-fhioro-5-(trifluoromethyl)benzene-l-carboxamide (30.2 mg, 0.146 mmol), Pd2(dba)3(8.91 mg, 0.010 mmol), XANT PHOS (11.26 mg, 0.019mmol) and CS2CO3 (63.4 mg, 0.195 mmol). The reaction was stirred at 100 °C under N2 for 3 hr. 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 using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-20%) to afford N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-l-methyl-2- (prop-2-ylazanylidene)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.078 mmol, 81%) as a yellow solid. LCMS: ESI m / z 640.4 [M + H]+.

[0439] Step D: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2- difhioroethyl)-l-methyl-2-(prop-2-ylazanylidene)benzo[d]imidazol-5-yl}-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.047 mmol) in ACN (2 mL) and H2O (0.5 mL) was added KOH (13.2 mg, 0.234 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-l-methyl-8-oxo-2-(prop-2-ylazanylidene)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]- 5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.046 mmol, 97%) as a yellow oil. LCMS: ESI m / z 658.3 [M + H]+.

[0440] Step E: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-l-methyl-8-oxo-2-(prop-2-ylazanylidene)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]- 5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.046 mmol) in TFA (2 mL) was added EtsSiH (0.5 mL). The reaction was stirred at 50 °C for 5 min. The reaction mixture was diluted Saturated NaHCCh, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)- 3-(2,2-difluoroethyl)-l-methyl-8-oxo-2-(prop-2-ylazanylidene)-7,8-dihydro-6H-imidazo[4,5- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (5.6 mg, 0.009 mmol, 19%) as a white solid. LCMS: ESI m / z 641.7 [M + H]+. Tl NMR (400 MHz, DMSO-d6) 8 10.53 (s, 1H), 9.48 (s, 1H), 8.25 (d, J= 8.8 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J= 9.2 Hz, 1H), 7.68 (s, 1H), 7.32 - 7.23 (m, 1H), 7.13 - 7.04 (m, 1H), 6.69 - 5.75 (m, 3H), 4.97 - 4.71 (m, 2H), 4.34 - 4.19 (m, 4H), 1.39 - 1.30 (m, 6H).Example 53: N-(6-(2-chloro-5-fluorophenyl)-2-((2-fluoroethyl)imino)-l-methyl-8-oxo-3- (2,2,2-trifluoroethyl)-l,2,396,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[0441] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (5 g, 10.9 mmol) in dioxane (50 mL) was added 2,2,2-trifluoroethan-l- amine (980 mg, 9.88 mmol), and DIEA (2 mL, 10.9 mmol). The reaction mixture was stirred at 100 °C for 5h with tube sealing. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 10%] to afford (2-chloro-5-fluorophenyl){2,6-dibromo-3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}methanone (3 g, 5.613 mmol, 51%) as a white solid. LCMS: ESI m / z 534.4 [M+H]’

[0442] Step B: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-methyl-2-[(E)-(trideuteriomethyl)azanylidene]benzo[d]imidazole-4-carbonitrile (3 g, 5.607 mmol) in EtOH / H2O (30 mL) was added NH4C1 (1.5 g, 28.0 mmol) and Fe (1.57 g, 28.0 mmol). The reaction mixture was stirred at 75 °C for 2h. The reaction mixture was filtered with diatomite and concentrated. Then the reaction mixture diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 15%] to afford (2-chloro-5-fluorophenyl){2,6-dibromo-3-nitro-4-[(2,2,2- trifluoroethyl)amino]phenyl}...

Claims

What is claimed is:CLAIMS1. A compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, wherein each of R1and R2is independently a C1-6 alkyl substituted with0-8 RA, wherein each RAis independently D, halogen, CN, OR, SR, NRR’, or an unsubstituted or substituted C3-6 carbocyclic or heterocyclic group, or an unsubstituted or substituted 5- or 6-membered aryl or heteroaryl group;R3is L3-R3;L3is NH-C(O) or NH; each of R3’ and R4is independentlyH, D, 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 C1-6 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, 0 and S, optionally substituted with one or more Rbor Rc, respectively;R5is H, D, OR, or substituted or unsubstituted alkyl; C1-4R6is H, D, CN, C(O)R, C(O)OR, or substituted or unsubstituted alkyl; or RC61-4and R1or R6and R2, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 Ras; each of Ra, Rband Rcis independently 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 substitutedC1-4alkyl, or unsubstituted or substituted 3- 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 m is 0 or 1.

2. The compound of claim 1, wherein m is 0, having the structural formula (II):

3. The compound of claim 1, wherein m is 1, having the structural formula (III):

4. The compound of any one of claims 2-3, wherein R6is H.

5. The compound of any one of claims 2-3, wherein R6is CH3, CD3, CH2CH3 or CD2CD3.

6. The compound of any one of claims 2-3, wherein R6is CN, C(O)CH3 or C(O)OCH3.

7. The compound of any one of claims 2 and 4-6, wherein R1is CRlaRlbRlc, and R2isCR2aR2bR2c, having the structural formula (IIA):wherein each of Rlaand R2ais independently H, D or halogen; each of Rlband R2bis H, D or halogen; and each of Rlcand R2cisH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

8. The compound of claim 7, wherein R2cis CR2dR2eR2f, having the structural formula (IIB):whereinR2dis H, D or halogen; and each of R2eand R2fis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R,S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1.5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

9. The compound of claim 7 or 8, wherein each of Rlaand Rlhis H.

10. The compound of claim 7 or 8, wherein each of Rlaand Rlbis D.

11. The compound of claim 9, wherein Rlcis H.

12. The compound of claim 10, wherein Rlcis D.

13. The compound of claim 8, wherein Rlcis CRldRleRlf, having the structural formula (IIC):whereinRldis H, D or halogen; and each of Rleand Rlfis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1-5 alkyl, C2.5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

14. The compound of any one of claims 7-13, wherein each of R2aand R2his H.

15. The compound of any one of claims 7-13, wherein each of R2aand R2his D.

16. The compound of any one of claims 7-15, wherein at least one of R2d, R2eand R2fis a halogen atom.

17. The compound of claim 16, wherein the halogen atom is F.

18. The compound of claim 17, wherein one of R2d, R2eand R2fis F.

19. The compound of claim 17, wherein two of R2d, R2eand R2fis F.

20. The compound of claim 17, wherein each of R2d, R2eand R2fis F.

21. The compound of any one of claims 7-15, wherein at least one of R2d, R2eand R2fis a D.

22. The compound of claim 21 , wherein one of R2d, R2eand R2fis D.

23. The compound of claim 21 , wherein two of R2d, R2eand R2fis D.

24. The compound of claim 21, wherein each of R2d, R2eand R2fis D.

25. The compound of claim 2, wherein R6and R1, together with their respectively intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 Ras, having the structural formula (IID):wherein z is 0, 1, 2 or 3, and p is 0, 1 or 2.

26. The compound of claim 25, wherein p is 0.

27. The compound of claim 25, wherein p is 1.

28. The compound of claim 2, wherein R6and R2, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 Ras, having the structural formula (IIE):wherein j is 0, 1, 2 or 3, and q is 0, 1 or 2.

29. The compound of claim 28, wherein q is 0.

30. The compound of claim 28, wherein q is 1.

31. The compound of any one of claims 3-6, wherein R1is CRlaRlbRlc, and R2is CR2aR2bR2c, having the structural formula (IIIA):wherein each of Rlaand R2ais independently H, D or halogen; each of Rlband R2bis H, D or halogen; and each of Rlcand R2cisH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1-5 alkyl, C2.5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

32. The compound of claim 31, wherein R2cis CR2dR2eR2f, having the structural formula(III8):whereinR2dis H, D or halogen; and each of R2eand R2fis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

33. The compound of claim 31 or 32, wherein each of Rlaand Rlbis H.

34. The compound of claim 31 or 32, wherein each of Rlaand Rlbis D.

35. The compound of claim 33, wherein Rlcis H.

36. The compound of claim 34, wherein Rlcis D.

37. The compound of claim 32, wherein Rlcis CRldRleRlf, having the structural formula(IIIC)whereinRldis H, D or halogen; and each of Rleand Rlfis independentlyH, D, halogen, CN, OR, SR, NRR’, S(O)2R, S(O)2NRR’, S(O)R, S(O)NRR’, S(O)(NR)R or C(O)NRR’; or an unsubstituted or substituted C1-5 alkyl, C2-5 alkenyl, C2.5 alkynyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

38. The compound of any one of claims 31-37, wherein each of R2aand R2bis H.

39. The compound of any one of claims 31-37, wherein each of R2aand R2bis D.

40. The compound of any one of claims 31-37, wherein at least one of R2d, R2eand R2fis a halogen atom.

41. The compound of claim 40, wherein one of R2d, R2eand R2fis F.

42. The compound of claim 40, wherein two of R2d, R2eand R2fis F.

43. The compound of claim 40, wherein each of R2d, R2eand R2fis F.

44. The compound of any one of claims 31-37, wherein at least one of R2d, R2eand R2fis a D.

45. The compound of claim 44, wherein one of R2d, R2eand R2fis D.

46. The compound of claim 44, wherein two of R2d, R2eand R2fis D.

47. The compound of claim 44, wherein each of R2d, R2eand R2fis D.

48. The compound of any one of claims 31-47, wherein R5is H.

49. The compound of claim 3, wherein R6and R2, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 Ras, having the structural formula (IIID):wherein is 0, 1, 2 or 3, and r is 0, 1 or 2.

50. The compound of claim 49, wherein r is 0.

51. The compound of claim 49, wherein r is 1.

52. The compound of claim 3, wherein R6and R1, together with their respective intervening carbon and nitrogen atoms, may form a 5- or 6-membered heterocyclic ring, optionally substituted with 0-3 Ras, having the structural formula (IIIE):wherein / is 0, 1, 2 or 3, and 5 is 0, 1 or 2.

53. The compound of claim 52, wherein 5 is 0.

54. The compound of claim 52, wherein s is 1.

55. The compound of claim 49-54, wherein R5is H.

56. The compound of claim 49-54, wherein R5is not H.

57. The compound of any one of claims 1-24 and 31-48, wherein R6is characterized by the stereochemistry shown in formula (IVA):

58. The compound of any one of claims 1-24 and 31-48, wherein R6is characterized by the stereochemistry shown in formula (IVB):

59. The compound of any one of claims 1-58, wherein R4is a 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, 0 and S, substituted with 0-6 Rcs,60. The compound of claim 59, wherein R4is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

61. The compound of claim 60, wherein R4is a substituted or unsubstituted phenyl.

62. The compound of claim 60, wherein R4is a substituted or unsubstituted pyridyl.

63. The compound of claim 60, wherein R4is a substituted or unsubstituted pyridazinyl.

64. The compound of claim 60, wherein R4is a substituted or unsubstituted pyrazinyl.

65. The compound of any one of claims 1-60, wherein R4is selected from:

66. The compound of claim 65, wherein R4is:

67. The compound of any one of claims 1-66, having the following chirality:

68. The compound of any one of claims 1-66, having the following chirality:

69. The compound of any one of claims 1-68, wherein L3is NH-C(O).

70. The compound of claim 69, wherein R3is a substituted or unsubstituted 5- or 6- membered monocyclic carbocyclyl or heterocyclic.

71. The compound of claim 69, wherein R3is a substituted or unsubstituted 5- or 6- membered monocyclic aryl or heteroaryl ring.

72. The compound of claim 69, wherein R3’ is a substituted or unsubstituted 8- to 10- membered bicyclic carbocyclyl or heterocyclic.

73. The compound of claim 69, wherein R3’ is a substituted or unsubstituted 8- to 10- membered bicyclic aryl or heteroaryl ring.

74. The compound of claim 69, wherein R3is selected from:

75. The compound of claim 69, wherein R3is selected from:

76. The compound of any one of claims 1-68, wherein L3is NH.

77. The compound of claim 76, wherein R3is a 9- or 10-membered bicyclic aryl or heteroaryl with 0-4 ring heteroatoms independently selected from N, 0 and S, substituted with 0-6 Rbs.

78. The compound of claim 77, wherein R3’ is a 9-membered bicyclic heteroaryl comprising a 5-membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

79. The compound of claim 77, wherein R3has the structural formula (IV):wherein q is 0, 1, 2, 3 or 4;X1is N, 0, S or CH;X2is N, O, S or CH;X3is N or C; andX4is N or C, with the proviso that when one of X3and X4is N, the other is CH.

80. The compound of claim 77, wherein R3is selected from:

81. The compound of claim 79 or 80, wherein each Rbis independently selected from CF3,CHF2, CH2F, CH3, F, Cl, Br, CN, OR, SF5, S(O)2R and C2-4 alkynyl.

82. The compound of any one of claims 79-81, wherein q is 1 or 2.

83. The compound of any one of claims 79-82, wherein R3is selected from:

84. The compound of claim 76, wherein R3is a 10-membered bicyclic heteroaryl comprising a 6-membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

85. The compound of claim 84, wherein R3has the structural formula (V):wherein p is 0, 1, 2, 3 or 4; each of Y1, Y2and Y3is independently selected from N and CH; each of Y4and Y5is independently selected from N and CH with the proviso that, when one of Y4and Y3is N, the other is C, and when each of Y2and Y3is N, Y1is CH and Y4is C.

86. The compound of claim 85, wherein R3is selected from:

87. The compound of claim 85 or 86, wherein each Rbis independently selected from CF3, CHF2, CH2F, CH3, F, Cl, Br, CN, OR, SF5, S(O)2R and C2-4alkynyl.

88. The compound of any one of claims 85-87, wherein p is 1 or 2.

89. The compound of any one of claims 84-88, wherein R3is selected from:

90. A compound selected from Table 1, or a pharmaceutically acceptable form or an isotope derivative thereof.

91. The compound of any of claims 1-90, having one or more deuterium atoms in place of hydrogen.

92. The compound of any of claims 1-91, having one deuterium atom in place of a hydrogen atom.

93. A pharmaceutical composition comprising a compound according to any one of claims 1- 90 and a pharmaceutically acceptable excipient, carrier, or diluent.

94. The pharmaceutical composition of claim 93, being suitable for oral administration.

95. A unit dosage form comprising a pharmaceutical composition according to claim 93 or 94.

96. The unit dosage form of claim 95, being in the form of a tablet or capsule.

97. 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 1-92.

98. A method for inhibiting phosphoinositide 3 -kinase a (PI3Kα) activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-92.

99. A method for treating a disease or disorder mediated by phosphoinositide 3-kinase a (PI3Kα), comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1-92.

100. The method of claim 99, wherein the disease or disorder is a cellular proliferative disease.

101. 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 1-92.

102. The method of claim 101, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

103. The method of claim 101 or 102, 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.

104. The method of any one of claims 101-103, wherein the subject has a mutated class IA PI3K pl l0a.

105. The method of any one of claims 101-104, wherein the subject has at least one of the following PI3Kα mutations: H1047R, E542K, E545K and H1047X.

106. The method of any one of claims 101-105, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

107. Use of the compound according to any one of claims 1-92, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

108. The use of claim 107, wherein the disease or disorder is a cellular proliferative disease.

109. The use of claim 108, wherein the disease or disorder is cancer.

110. The use of claim 109, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

111. The use of claim 109, 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.

112. The use of claim 109, wherein the cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas.

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