WO2025165835A1

WO2025165835A1 - Anilino tricyclic compounds, and compositions and methods thereof

Info

Publication number: WO2025165835A1
Application number: PCT/US2025/013539
Authority: WO
Inventors: Mingzong Li; Tao Liu; Hongbo Deng
Original assignee: Ensem Therapeutics Inc
Current assignee: Ensem Therapeutics Inc
Priority date: 2024-01-31
Filing date: 2025-01-29
Publication date: 2025-08-07
Anticipated expiration: 2026-07-31

Abstract

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

Description

ANILINO TRICYCLIC COMPOUNDS, AND COMPOSITIONS AND METHODS

THEREOF

Priority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63/627,147, 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 anilino derivatives of tricyclic compounds that are shown to be potent and selective phosphoinositide 3 -kinase a (PI3Ka) inhibitors. The invention also provides pharmaceutical compositions comprising compounds of the invention and methods for treating diseases and disorders associated with or related to PI3Ka activities, such as various types of cancer.

Background of the Invention

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

[0004] The PI3K family is divided into three different classes: Class I, Class II, and Class III, based on their primary structure, regulation, and lipid substrate specificity. (Kalaany et al. 2009 Nature 458 (7239): 725-31; Leevers et al. (1999) Current Opinion in Cell Biology/ 11 (2): 219— 25.) Class I PI3Ks (pl 10a, pl 100, pl 105 and pl lOy) are activated by tyrosine kinases or G protein-coupled receptors to produce phosphatidylinositol-3,4,5-triphosphate (PIP 3).

Association of effectors such as PDPK1/AKT with PIP3 activates downstream signaling pathways.

[0005] The class IA PI3K pl 10a (PI3Ka) is mutated in many human cancers. Angiogenesis has been shown to selectively require the PI3Ka isoform in the control of endothelial cell migration. Mutations in the gene encoding PI3Ka (PIK3CA) or PI3Ka up-regulation occurs in many human cancers such as ovarian cancer, cervical cancer, breast cancer, colorectal cancer, endometrial cancer, gastric carcinomas, hepatocellular carcinoma, small and non-small cell lung cancer, thyroid carcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas. In cancer, PI3Ka mutations are often hotspot point mutations in the helical or kinase domain, such as H1047R, E542K, E545K and H1047X. (Graupera et al. 2008 Nature 453: 662-6; Campbell el al. 2004 Cancer Res 64, 7678-7681 ; Levine et al. 2005 Clin Cancer Res 11, 2875-2878; Wang et al. 2005 Hum Mulat 25, 322; Lee el al. 2005 Gynecol Oncol 97, 26-34; Bachman, et al. 2004 Cancer Biol Ther 3, 772-775; Li et al. 2006 Breast Cancer Res Treat 96, 91-95; Saal et al. 2005 Cancer Res 65, 2554-2559; Samuels and Velculescu 2004 Cell Cycle 3, 1221-1224; Samuels, etal. 2004 Science 304, 554; Velho et al 2005 Eur J Cancer 41 , 1649-1654; Oda et al. 2005 Cancer Res. 65, 10669-10673, Byun el al. 2003 IntJ Cancer 104, 318-327; Lee et al. 2005 Oncogene 2.4, 1477-1480; Tang et al. 2006 Lung Cancer 51, 181-191, Massion et al. 2004 A/n .1 Respir Grit Care Med 170, 1088-1094; Wu et al. 2005 ,7 Clin Endocrinol Metab 90, 4688-4693; Suj obert et al. 1997 Blood 106, 1063-1066; Hickey and Cotter 2006 J Biol Chem 281 , 2441-2450; Hartmann el al. 2005 Ada Neuropalhol (BerLi 109, 639-642.)

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

Summary of the Invention

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

Z¹ is N-R²;

Z² is N or C=O;

Z³ is N-R¹ or C-R¹, wherein R¹ is H or R¹ ; each of R¹ and R² is independently a Ci-6 alkyl, C2-5 alkenyl or C2-5 alkynyl group, substituted with 0-8 R^A, wherein each R^A is independently D, halogen, CN, OR, SR, NRR’, an unsubstituted or substituted C3-6 carbocyclic or heterocyclic group, or an unsubstituted or substituted 5- or 6-membered aryl or heteroaryl group;

R³ is NH-R³ ; each of R³ and R⁴ is independently

H, 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, O and S, optionally substituted with one or more R^b or R^c, respectively; each of R^b and R^c is independently

D, oxo, halogen, CN, NO₂, OR, SR, NRR’, SF₅, 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 Ci-6 alkyl, C2-4 alkynyl or 4- to 6-membered carbocyclic ring;

[0009] each of R and R’ is independently selected from H, unsubstituted or substituted C1-4 alkyl, 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.

[0010] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0011] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0012] 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.

[0013] In yet another aspect, the invention generally relates to a method for modulating (e.g., reducing) PI3Ka activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0014] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Ka, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0015] 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.

[0016] 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

[0017] 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.

[0018] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0019] 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.

[0020] 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.

[0021] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0022] 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.

[0023] 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. [0024] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0025] 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.

[0026] In some embodiments, the amount is that is sufficient to negatively modulate or inhibit the activity of PI3Ka. In some embodiments, the amount is that effective for reduction or amelioration of a symptom to stop or reversion of progression of a disease or disorder such as cancer. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer.

[0027] 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.

[0028] As used herein, an “inhibitor” of “PI3Ka” refers to a compound of the invention capable of negatively modulating or inhibiting all or a portion of the activity of PI3Ka.

[0029] As used herein, a “PI3Ka-associated” disease or disorder refers to diseases or disorders associated with or mediated by PI3Ka or having one or more PI3Ka mutations. Examples of PI3Ka-associated diseases or disorders include various cancer types. A PI3Ka- associated disease or disorder may also refer allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diabetic complications, or acute coronary syndrome. [0030] As used herein, the term “contacting” refers to the bringing together of indicated rnoieties 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 PI3Ka activity is desired is contacted with an effective amount of a compound disclosed herein or pharmaceutically acceptable form thereof to negatively modulate the activity ofPI3Ka. By negatively modulating the activity of PI3Ko, the methods disclosed herein are designed to inhibit undesired cellular proliferation resulting from enhanced PI3Ka activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of PI3Ka. The ability of compounds to bind PI3Ka may be monitored in vitro using methods known in the art. The inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of PI3Ka activity using methods known in the art.

[0031] 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 (z.c. 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-CI-C₆ alkyl, Ci-C₆ alkyl, -OCi-C₆ alkenyl, -OCi-C₆ alkynyl, -Ci-C₆ alkenyl, -Ci-C₆ alkynyl, -OH, -OP(O)(OH)₂, -OC(O)Ci-C₆ alkyl, -C(O)Ci-C₆ alkyl, -OC(O)OCi- C₆ alkyl, NH₂, NH(CI-C₆ alkyl), N(CI-C₆ alkyl)₂, -NHC(O)CI-C₆ alkyl, -C(O)NHCI-C₆ alkyl, - S(O)₂-Ci-C₆ alkyl, -S(O)NHCI-C₆ alkyl, and S(O)N(CI-C₆ alkyl)₂.

[0032] 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.

[0033] 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. [0034] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0035] 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, sulfmic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0036] 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.

[0037] 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.

[0038] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0039] 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 fdler, 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.

[0040] 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.

[0041] In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated with a compound disclosed herein and/or according to a herein disclosed method. In some embodiments, the subject has been identified or diagnosed as having a cancer having one or more PI3Ka mutations. In some embodiments, the subject has a cancer that is positive for a PI3Ka mutation. In some embodiments, the subject is suspected of having a PI3Ka gene-associated cancer.

[0042] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the subject has one or more PI3Ka. mutations using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject. Various techniques may be employed, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis. Northern blotting, and PCR-based amplification (e g., RT-PCR and quantitative real-time RT-PCR).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.”

[0048] 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.

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-4 alkyl” is intended to encompass, Ci, C2, C3, C4, C1-3, Ci-2, C2-4, C3-4 and C2-3 alkyl groups.

[0050] As used herein, the term “aliphatic” or “aliphatic group” refers to a linear or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic.

[0051] 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., C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a Ci-6 alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, - ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3- methylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4- methylhexyl, 5-methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in 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(R^x)3 , -OR^X, -SR^X, -OC(O)-R^X, -N(R^X)2, - C(O)R^X, -C(O)OR^X, -OC(O)N(R^X)₂, -C(O)N(R^X)₂, -N(R^X)C(O)OR^X, -N(R^X)C(O)R^X, - N(R^X)C(O)N(R^X)₂, -N(R^X)C(NR^X)N(R^X)₂, -N(R^x)S(O)tN(R^x)₂ (where t is 1 or 2), -P(=O)(R^X)(R^X), or -O-P(=O)(OR^X)₂ wherein each R^x is 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.

[0052] Unless otherwise specifically defined, the term “aromatic” or “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, H, halogen, -O-Ci-Ce alkyl, Ci-Ce alkyl, -Ci-Ce alkenyl, -OCi-Ce alkynyl, -Ci-Ce alkenyl, -Ci-C₆ alkynyl, -OH, -OP(O)(OH)₂, -OC(O)Ci-C₆ alkyl, -C(O)Ci-C₆ alkyl, -OC(O)OCi- C₆alkyl, NH₂, NH(CI-C₆ alkyl), N(CI-C₆ alkyl)₂, -S(O)₂-Ci-C₆ alkyl, -S(O)NHCi-C₆alkyl, and S(O)N(Ci-Ce alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthal enyl, and tetrahydrobenzoannulenyl.

[0053] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0054] 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, benzoforanyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H~pyrrolo[l,2- ajirnidazole, furanyl, furazanyk imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedi oxy phenyl, naphthyridinyl, octabydroisoquinolinyl, 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, pyrazinyi, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, 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, thienotliiazolyl, 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 heieroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.

[0055] 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, alkyl carbonyl oxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ'.Z2)carbonyl. The term "NZjZ?" as used herein, means two groups, Zj and Z?, which are appended to the parent molecular moiety through a nitrogen atom. Z] and 7.2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of X/:/.;- include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0056] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0057] 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 moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 carbocyclyl groups include norbornyl (C7). Examples of C3-8 carbocyclyl groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (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 (R^ajh , -OR^a, - SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)Ra, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, - N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)tN(R^a)₂ (where t is 1 or 2), - P(=O)(R^a)(R^a), or -O-P(=O)(OR^a)₂ where each R^a is 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.

[0058] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., O, N, S, P or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl include 2-hydroxy-aziridin-l-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2-dimethyl- tetrahydrofuran-3-yl, 3 -carboxy -morpholin-4-yl, l-cyclopropyl-4-methyl-piperazin-2-yl. 2- pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H- [l,4]oxazine, etc.

[0059] 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, O, and S) in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. A heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, iinidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxoianyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1, 1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyi, azabic-yclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-lH,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 111, 3'H- spiro[cyclopropane-l,2’-pyrrolizine], hexahydro- IH-pyrrolizinyl, hexahydro-lH-pyrrolo[2,l- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl s, oxaazaspirooctanyl s, diazaspirononanyl s, oxaazabi ocycloheptanyl s, hexahydropyrrolizinyl 4(lH)-oxide, and tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- thi opyranyl 1 , J -dioxide

Detailed Description of the Invention

[0060] The invention is based in part on the discovery of novel anilino derivatives of tricyclic compounds as PI3Ka inhibitors. These compounds are shown herein to selectively target, bind to, inhibit and/or modulate the activity of PI3Ka. The compounds are orally available and can be used for treating various diseases and disorders associated with or related to PI3Ka activities, such as various types of cancer.

[0061] 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

Z¹ is N-R²; Z² is N or C=O;

Z³ is N-R¹ or C-R¹, wherein R¹ is H or R¹ ; each of R¹ and R² is independently a Ci-6 (e-g., C1-3) alkyl, C2-5 alkenyl or C2-5 alkynyl group, substituted with 0-8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7 or 8) R^A, wherein each R^A is independently D, halogen, CN, OR, SR, NRR’, an unsubstituted or substituted C3-6 carbocyclic or heterocyclic group, or an unsubstituted or substituted 5- or 6-membered aryl or heteroaryl group;

R³ is NH-R³ ; each of R³ and R⁴ is independently

H, 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, O and S, optionally substituted with one or more R^b or R^c, respectively; each of R^b and R^c is independently

D, oxo, halogen, CN, NO₂, OR, SR, NRR’, SF₅, 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, C2-4 alkynyl or 4-, 5- or 6-membered carbocyclic ring; each of R and R’ is independently selected from H, unsubstituted or substituted C1-4 alkyl, or unsubstituted or substituted 3- to 6-membered (c.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. [0062] In certain embodiments of (I), Z² is C=O and Z³ is N-R¹, having the structural formula (II):

[0063] In certain embodiments of (II), R² is CR^2aR^2bR^2c, having the structural formula (II⁴): wherein

R^2a is H, D or halogen;

R^2b is H, D or halogen; and

R^2e is

H, D, halogen, CN, OR, SR, or NRR’; or an unsubstituted or substituted C1-5 alkyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

[0064] In certain embodiments of (II^A), R¹ is CR^laR^lbR^lc, having the structural formula

(II^B): wherein

R^la is H, D or halogen;

R^lb is H, D or halogen; and

R^lc is

[0065] In certain embodiments of (II^B), R^2c is CR^2dR^2eR^2f, having the structural formula

(II^C): wherein

R^2d is H, D or halogen; and each of R^2e and R^2t is independently

H, D, halogen, CN, OR, SR, or NRR’; or an unsubstituted or substituted C1-5 alkyl, C3-6 carbocyclic or heterocyclic group, or a 5- or 6-membered aryl or heteroaryl group.

[0066] In certain embodiments of (II^B)-(II^C), one of R^la and R^lb is H.

[0067] In certain embodiments of (II^B)-(II^C), two of R^la and R^lb is H

[0068] In certain embodiments of (II^B)-(II^C), each of R^la, R^lb and R^lc is H.

[0069] In certain embodiments of (II^B)-(II^C), one of R^la and R^lb is D.

[0070] In certain embodiments of (II^B)-(II^C), two of R^la and R^lb is D.

[0071] In certain embodiments of (II^B)-(II^C), each of R^la, R^lb and R^lc is D.

[0072] In certain embodiments of (II^C), R^lc is CR^ldR^leR^lf, having the structural formula

(IP):

wherein

R^ld is H, D or halogen; each of R^le and R^lf is independently

[0073] In certain embodiments of (II^A)-(II^D), one of R^2a and R^2b is H.

[0074] In certain embodiments of (II^A)-(II^D), two of R^2a and R^2b is H.

[0075] In certain embodiments of (II^A)-(II^D), one of R^2a and R^2b is D.

[0076] In certain embodiments of (II^A)-(II^D), two of R^2a and R^2b is D.

[0077] In certain embodiments of (II^A)-(II^D), each of R^2a, R^2b and R^2c is H.

[0078] In certain embodiments of (II^A)-(II^D), each of R^2a, R^2b and R^2c is D. In certain embodiments of (II^C)-(II^D), at least one of R^2d, R^2e and R²¹ is a halogen atom. In certain embodiments of (II^C)-(II^D), one of R^2d, R^2e and R^2f is F. In certain embodiments of (II^C)-(II^D), two of R^2d, R^2e and R^2f is F. In certain embodiments of (II^C)-(II^D), each of R^2d, R^2e and R^2f is F. [0079] In certain embodiments of (II^A)-(II^D), at least one of R^2d, R^2e and R^2f is a D. In certain embodiments of (II^A)-(II^D), one of R^2d, R^2e and R^2f is D. In certain embodiments of (II^A)-(II^D), two of R^2d, R^2e and R^2f is D. In certain embodiments of (II^A)-(II^D), each of R^2d, R^2e and R^2f is D. [0080] In certain embodiments of (I), Z² is N and Z³ is C-R¹, having the structural formula (HI)

[0081] In certain embodiments of (III), R² is CR^2aR^2bR^2c, having the structural formula

(III^A): wherein

R^2a is H, D or halogen;

R^2b is H, D or halogen; and

R^2c is

[0082] In certain embodiments of (III)-(III^A), R¹ is H.

[0083] In certain embodiments of (III)-(III^A), R¹ is D.

[0084] In certain embodiments of (III)-(III^A), R^2e is CR^2dR^2eR^2f, having the structural formula (III^B) or (III^C):

(III^B) (III^C) wherein

R^2d is H, D or halogen; and each of R^2e and R^2f is independently

[0085] In certain embodiments of (III)-(III^A), R¹ is CR^laR^lbR^lc, having the structural formula (III^D): wherein

R^la is H, D or halogen;

R^lb is H, D or halogen; and

R^lc is

H, D, halogen, CN, OR, SR, or NRR’; or an unsubstituted or substituted C1-5 alkyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group. [0086] In certain embodiments of (III^D), R^2C is CR^2dR^2eR^2f, having the structural formula

(III^E) wherein

R^2d is H, D or halogen; and each of R^2e and R^2f is independently

[0087] In certain embodiments of (III^B)-(III^E), one of R^la and R^lb is H.

[0088] In certain embodiments of (III^B)-(III^E), two of R^la and R^lb is H.

[0089] In certain embodiments of (III^B)-(III^E), each of R^la, R^lb and R^lc is H.

[0090] In certain embodiments of (III^B)-(III^E), one of R^la and R^lb is D.

[0091] In certain embodiments of (III^B)-(III^E), two of R^la and R^lb is D.

[0092] In certain embodiments of (III^B)-(III^E), each of R^la, R^lb and R^lc is D.

[0093] In certain embodiments of (III^E), R^lc is CR^ldR^leRⁿ, having the structural formula

(III^F) (III^F) wherein

R^ld is H, D or halogen; and each of R^le and R^lf is independently

[0094] In certain embodiments of (III^A)-(III^F), one of R^2a and R^2b is H.

[0095] In certain embodiments of (III^A)-(III^F), two of R^2a and R^2b is H.

[0096] In certain embodiments of (III^A)-(III^F), one of R^2a and R^2b is D.

[0097] In certain embodiments of (III^A)-(III^F), two of R^2a and R^2b is D.

[0098] In certain embodiments of (III^A)-(III^F), each of R^2a, R^2b and R^2c is H.

[0099] In certain embodiments of (III^A)-(III^F), each of R^2a, R^2b and R^2c is D.

[00100] In certain embodiments of (III^B)-(III^F), at least one of R^2d, R^2e and R^2f is a halogen atom.

[00101] In certain embodiments of (III^B)-(III^F), one of R^2d, R^2e and R^2f is F.

[00102] In certain embodiments of (III^B)-(III^F), two of R^2d, R^2e and R^2f is F.

[00103] In certain embodiments of (III^B)-(III^F), each of R^2d, R^2e and R^2f is F

[00104] In certain embodiments of (I), (II) or (III), R¹ and R² are 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,

[00105] In certain embodiments, R⁴ is 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 R^es,

[00106] In certain embodiments, R⁴ is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

[00107] In certain embodiments, R⁴ is a substituted or unsubstituted phenyl.

[00108] In certain embodiments, R⁴ is a substituted or unsubstituted pyridyl.

[00109] In certain embodiments, R⁴ is a substituted or unsubstituted pyridazinyl.

[00110] In certain embodiments, R⁴ is a substituted or unsubstituted pyrazinyl.

[00111] Non-limiting examples of R⁴ include: [00113] In certain embodiments, R³ is a 9- or 10-membered bicyclic aryl or heteroaryl with 0- 4 ring heteroatoms independently selected from N, O and S, substituted with 0-6 R^bs.

[00114] In certain embodiments, R³ is a 9-membered bicyclic heteroaryl comprising a 5- membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

[00115] In certain embodiments, R³ has the structural formula (IV): wherein q is 0, 1, 2, 3 or 4;

X¹ is N, O, S or CH;

X² is N, O, S or CH;

X³ is N or C; and

X⁴ is N or C, with the proviso that when one of X³ and X⁴ is N, the other is CH.

[00116] In certain embodiments, R³ is selected from:

[00117] In certain embodiments of (IV), each R^b is independently selected from CF3, CHF2, CH₂F, CH₃, F, Cl, Br, CN, OR, SF₅, S(O)₂R and C_2.4 alkynyl.

[00118] In certain embodiments, q is 1.

[00119] In certain embodiments, q is 2.

[00120] Non-limiting examples of R³ include:

[00121] In certain embodiments, R³ is a 10-membered bicyclic heteroaryl comprising a 6- membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

[00122] In certain embodiments, R³ has the structural formula (V): wherein p is 0, 1, 2, 3 or 4; each of Y¹, Y² and Y³ is independently selected from N and CH; each of Y⁴ and Y⁵ is independently selected from N and CH with the proviso that, when one of Y⁴ and Y^? is N, the other is C, and when each of Y² and Y³ is N, Y¹ is CH and Y⁴ is C [00123] In certain embodiments, R³ is selected from:

[00124] In certain embodiments, each R^b is independently selected from CF₃, CHF₂, CH₂F,

CH₃, F, Cl, Br, CN, OR, SF₅, S(O)₂R and C₂-4 alkynyl.

[00125] In certain embodiments,/? is 1.

[00126] In certain embodiments,/? is 2.

[00127] Non-limiting examples of R³ include: [00128] In certain embodiments of (I), the compound has the structural formula (VT^A): wherein each of p and r is independently 0, 1, 2, 3 or 4; each of Y¹, Y² and Y³ is independently selected from N and CH; each of Y⁴ and Y⁵ is independently selected from N and CH with the proviso that, when one of Y⁴ and Y⁵ is N, the other is C, and when each of Y² and Y³ is N, Y¹ is CH and Y⁴ is C.

[00129] In certain embodiments of (I), the compound has the structural formula (VI^B): wherein each of p and r is independently 0, 1, 2, 3 or 4; each of Y¹, Y² and Y³ is independently selected from N and CH; each of Y⁴ and Y⁵ is independently selected from N and CH with the proviso that, when one of Y⁴ and Y⁵ is N, the other is C, and when each of Y² and Y³ is N, Y¹ is CH and Y⁴ is C. [00130] In certain embodiments of (I), the compound has the structural formula (VI¹ ): wherein each of q and r is independently 0, 1, 2, 3 or 4;

X¹ is N, O, S or CH;

X² is N, O, S or CH;

X³ is N or C; and

[00131] In certain embodiments of (I), the compound has the structural formula (VI^D): wherein each of q and r is independently 0, 1, 2, 3 or 4;

X¹ is N, O, S or CH;

X² is N, O, S or CH;

X³ is N or C; and X⁴ is N or C, with the proviso that when one of X³ and X⁴ is N, the other is CH

[00132] In certain embodiments, a compound disclosed herein has the chirality shown in formula (VII^A):

[00133] In certain embodiments, a compound disclosed herein has the chirality shown in formula (VII^B):

[00134] Non-limiting exemplary compounds of the invention can also be found in Table 1 in the Examples section.

[00135] 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.

[00136] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[00137] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[00138] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[00139] In certain embodiments, the unit dosage form is in the form of a tablet or capsule.

[00140] 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.

[00141] 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).

[00142] 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.

[00143] 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.

[00144] 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.

[00145] In yet another aspect, the invention generally relates to a method for modulating PI3Ka activity in a cell, comprising contacting the cell with a compound disclosed herein. [00146] In yet another aspect, the invention generally relates to a method for reducing PI3Ka activity in a cell, comprising contacting the cell with a compound disclosed herein.

[00147] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Ka, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[00148] In certain embodiments, the disease or disorder is a cellular proliferative disease. [00149] 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.

[00150] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma. [00151] 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.

[00152] 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.

[00153] In certain embodiments, the cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas. [00154] In certain embodiments, the subject has a mutated class IA PI3K pl 10a.

[00155] In certain embodiments, the subject has at least one of the following PI3Ka mutations: H1047R, E542K, E545K and H1047X.

[00156] In certain embodiments, the subject does not have a PI3Ka mutant protein.

[00157] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy. [00158] 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.

[00159] In yet another aspect, the invention generally relates to use of a compound disclosed herein for treating a disease or disorder.

[00160] 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. [00161] 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.

[00162] 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.

[00163] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[00164] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[00165] 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.

[00166] 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.

[00167] 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 parenteral ly-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[00168] 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.

[00169] 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.

[00170] 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. [00171] 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.

[00172] 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.

[00173] 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.

[00174] 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.

[00175] 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. [00176] 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.

[00177] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[00178] 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.

[00179] 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); cryptophycins (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; capeci tabine (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.

[00180] 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).

[00181] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cisand trcinsd 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.

[00182] 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. [00183] 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.

[00184] 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 as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³³S, ¹⁸F, and ³⁶C1, respectively.

[00185] 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.

[00186] 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 abundant ¹²C with ¹³C. (See, WO 2007/005643, WO 2007/005644, WO 2007/016361, and WO 2007/016431.) [00187] 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.

[00188] 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.

[00189] 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. [00190] 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.

[00191] 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.

[00192] 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. [00193] 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.

[00194] 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.

[00195] 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 [00196] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[00197] 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 Compounds List of Abbreviations aq: aqueous

Ac = Acetyl

AcO = Acetate

Ac2O = Acetic anhydride

AIBN = a,a'-Azoisobyronitrile

All = Allyl

Alloc = Allyloxycarbonyl

Am = Amyl (Pentyl)

Ar = Aryl

B2Pin2 = bis(pinacolato)diboron

9-BBN = 9-Borabicyclononane

BHT = tert-Butylhydroxytoluene

BINAP = 2,2'-Bis(diphenylphosphino)-l,r-binaphthyl

BMS = Borane-methylsulphide complex

Bn = Benzyl

Boc = tert-Butoxycarbonyl

BOP = Bis(2-oxo-3-oxazolidinyl)phosphine

Bu or n-Bu = n-Butyl s-Bu or sBu = sec-Butyl t-Bu or tBu = tert-Butyl

BuOH = Butanol

Bz = Benzoyl

Bzl = Benzyl

CAN = Ceric ammonium nitrate cataCXium A Pd G3 = mesylate [(di(l-adamantyl)-n-butylphosphine)-2-(2’-amino-

1, 1 ’biphenyl)]palladium(II)

CBS = Corey -Bashki-Shibat

Cbz = Benzyloxycarbonyl

CbzCl = Benzyl chloroformate ox Cod = Cyclooctadiene

Cp = Cyclopentadienyl

CSA = Camphorsulphonic acid

DABCO = 1,4-Diazabicyclo[2.2.2]octane, Triethylendiamine

DAST = Diethylaminosulphur trifluoride dba = Dibenzylideneacetone

DBU = l,8-Diazabyciclo[5.4.0]undec-7-ene

DCC = 1,3 -Dicyclohexylcarbodiimide

DCM = Dichloromethane

DDQ = 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone

DEAD = Diethyl azodi carb oxy late

DHP = Dihydropiran

DHQD = Dihydroquinidine

DIBAL = Diisobutylaluminium hydride

DIBAL-H = Diisobutylaluminium hydride

DIC = Diisopropylcarbodiimide

DIPEA = Diisopropylethylamine

DMA = N,N-Dimethylacetamide

DMAC = N,N-Dimethylacetamide

DMAP = 4-Dimethylaminopyridine

DME = 1,2-Dimethoxy ethane

DMF = N,N-Dimethylformamide

DMP = Dess-Martin periodinane

DMPU = l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pirimidone

DMS = Dimethylsulphide

DMSO = Dimethylsulphoxide

DPA = Diisopropylamine

DPPA = Diphenylphosphoryl azide

Ddpb = l,4-bis(diphenylphosphino)butane

Dppe = l,2-bis(diphenylphosphino)ethane

Dppf = 1 ,2-bi s(diphenylphosphino)ferrocene dppp = l,3-bis(diphenylphosphino)propane

Dtbbpy = 4, 4’-di-tert-butyl-2,2’-dipyridyl

EA = Ethyl acetate

EDC = l-Ethyl-3-(3-dimethylaminopropy)carbodiimide

EDCI = l-Ethyl-3-(3-dimethylaminopropy)carbodiimide hydrochloride

Eq = equivalent

ESI or ES = Electrospray ionization

Et = ethyl

Et2O = Diethyl ether

EtOAc = Ethyl acetate

FMOC = 9-Fluorenylmethoxycarbonyl

FCC = Flash column chromatography

HATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

HMDS = Hexamethyldisilazane

HMPA = Hexamethylphosphoramide

HOAt = 7-Aza-l-hydroxybenzotriazole

HOBt = 1 -Hydroxybenzotriazole

HPLC = high pressure liquid chromatography

IP A = Isopropyl alcohol

Im = Imidazole

KHMDS = Potassium bis(trimethylsilyl)amide

KO Ac = Potassium acetate

LAH = Lithium aluminium hydride

LDA = Lithium diisopropylamide

LHMDS = Lithium bis(trimethylsilyl)amide

MCPBA = meta-chloroperoxybenzoic acid

Me = Methyl

MeCN = Acetonitrile

MeOH = Methanol

MOM = Methoxymethyl Mg = magnesium

MS = Molecular sieves

Ms = Methanesulphonyl

MTBE = Methyl tert-butyl ether m/z = mass divided by charge Na2SO4 = Sodium Sulphate

NaHMDS = Sodium bis(trimethylsilyl)amide

NaCNBH3 = Sodium cyanoborohydride

NBS = N-Bromosuccinimide

NCS = N-Chlorosuccinimide

NIS = N-Iodosuccinimide

NMM = N-Methylmorpholine

NMO = N-Methylmorpholine-N-oxide

NMP = N-Methylpyrrolidone

NMR = Nuclear magnetic resonance

Ns = p-Nitrophenyl sulphonyl

Pd(dppf)C12 = [1 J’-bis(diphenylphosphino)ferrocene]dichloropalladium

Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium

PDC = Pyridinium dichlorochromate

PCC = Pyridinium chlorochromate

PE = Petroleum ether

Ph = Phenyl

Piv = Pivaloyl, 2,2-dimethylacetyl

PMB = p-Methoxybenzyl

PPA = Polyphosphoric acid

PPTS = Pyridinium p-toluensulphonate n-Pr = n-Propyl

Pr = Propyl i-Pr or iPr = iso-propilo

PTC = Phase transfer catalyst

PTS A = p-Toluenesulphonic acid Pv = Pivaloyl, 2,2-dimethylacetyl

Py = Pyridine

Red-Al® = Sodium bis(2-methoxyethoxy)aluminium hydride RT = room temperature

SFC = supercritical fluid chromatography

Prep-SFC = Preparative SFC

SEM = 2-(Trimethylsilyl)ethoxymethyl TBAF = Tetrabutylammonium fluoride TBDMS = tert-Butyl di methyl silyl

TBDPS = tert-Butyldiphenylsilyl TBHP = tert-Butylhydroperoxyde

TBS = tert-Butyldimethylsilyl

TEA = Tri ethylamine

TES = Tri ethyl silyl

Tf = Trifluoromethanesulfonyl

TfO = Trifluoromethanesulfonate

Tf2O = Trifluoromethanesulfonyl anhydride TfOH = Trifluoromethanesulfonic acid

TFA = Trifluoroacetic acid

TFAA = Trifluoroacetic anhydride

Thexyl = 2,3 -dimethyl-2 -butyl

THF = Tetrahydrofurane

THP = Tetrahydropyranyl

TIPS = Triisopropyl silyl

TMEDA = N,N,N',N'-Tetramethylethylendiamine

TMG = Tetramethylguanidine

TMS = Trimethyl silyl

Tol = p-Toluyl

TPAP = Tetra-n-propylammonium perruthenate TPS = Tripropyl silyl

Tr = Trityl, triphenylmethyl Troc = 2,2,2-Trichloroethoxycarbonyl

Trt = Trityl, triphenylmethyl

Ts = p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acid

UV = ultraviolet

Z = Benzyloxycarbony

UV: ultra violet

[00198] General LCMS Method:

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

[00199] General HPLC Purification Method:

Instrument: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8 A; GX-281.

Column: YMC-Triart Cl 8, 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:

[00200] Preparative separation method 1

Instrument: Waters Thar 80 preparative SFC

Column: ChiralPak IC, 250><30mm I.D., 5pm

Mobile phase: A for CO? and B for MEOH

Gradient: B 30%

Flow rate: 60 mL/min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm Run time: 10 min

Cycle-time: 6 min

Injection volume: 1.5 mL

Eluted time: 2 H

[00201] Preparative separation method 2

Instrument: SHIMADZU PREP SOLUTION SFC Column: (R,R)-WHELK, 250*20 mm I.D., 5 pm Mobile phase: A for CO2 and B for MeOH Gradient: B 50%

Flow rate: 40 mL/min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm

Cycle-time: 10 min

Eluted time: 5 H

[00202] Preparative separation method 3

Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IH, 150*20mm I.D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 20%

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220nm

Cycle-time: 15 min

Eluted time: 4 H

[00203] Preparative separation method 4

Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IC, 250*20mm I.D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 25% Flow rate: 40 mL/min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220nm

Cycle-time: 7 min

Injection volume: 3.4 mL

Eluted time: 2 H

[00204] Preparative separation method 5

Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralPak C-IC, 250><30mm I.D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 50%

Flow rate: 60 mL /min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220nm

Cycle-time: lOmin

Eluted time: 1H

[00205] Preparative separation method 6

Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralCel OZ, 250x20mm I.D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 40%

Flow rate: 40 mL /min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm

Cycle-time: 7.5 min

Injection volume: 2 mL

Number of injection needles: 10

Eluted time: 2 H [00206] Preparative separation method 7

Instrument: Waters Thar 80 preparative SFC Column: ChiralPak C-IC, 250><30mm I.D., 5pm Mobile phase: A for CO2 and B for MeOH Gradient: B 45%

Flow rate: 60 mL/min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm

Run time: 10 min

Cycle-time: 10 min

Injection volume: 4 mL

Number of injection needles: 5

Eluted time: 2 H

[00207] Preparative separation method 8

Instrument: SHIMADZU PREP SOLUTION SFC Column: (R,R)- WHELK, 250x30 mm I.D., 5 pm Mobile phase: A for CO2 and B for MeOH (0.05% TFA) Gradient: B 50%

Flow rate: 60 mL/min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm

Cycle-time: 15 min

Eluted time: 2 H

[00208] Preparative separation method 9

Instrument: SHIMADZU PREP SOLUTION SFC Column: (R,R)-WHELK, 250x30 mm I.D., 5 pm Mobile phase: A for CO2 and B for MeOH (0.05% TFA) Gradient: B 50%

Flow rate: 60 mL/min Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm

Cycle-time: 10 min

Eluted time: 2 H

[00209] Preparative separation method 10

Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IH, 150><20mm I D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 15%

Flow rate: 40 mL /min

Back pressure: 100 bar

Column temperature: 35°C

Wavelength: 220nm

Cycle-time: 15 min

Eluted time: 2 H

[00210] Preparative separation method 11

Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IC, 250x20mm I.D., 5pm Mobile phase: A for CO2 and B for MeOH Gradient: B 20%

Flow rate: 40 mL/min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220nm

Cycle-time: 8 min

Injection volume: 3.4 mL

Number of injection needles: 6

Eluted time: 2 H

[00211] Preparative separation method 12

Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IC, 250x30mm I D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 20%

Flow rate: 60 mL /min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm

Cycle-time: 15min

Eluted time: 2H

[00212] Preparative separation method 13

Instrument: Waters Thar 80 preparative SFC

Column: ChiralPak IH, 250 x 30 mm I D., 5pm

Mobile phase: A for CO2 and B for MeOH

Gradient: B 20%

Flow rate: 60 mL/min

Back pressure: 100 bar

Column temperature: 35 °C

Wavelength: 220 nm

Run time: 13 min

Cycle-time: 7 min

Injection volume: 2 mL

Number of injection needles: 12

Eluted time: 2H

Exemplary Synthetic Procedures

General synthetic routes:

[00213] Compounds of the invention were synthesized from the Int-I via a C-N bond formation below to install R³ .

General synthetic route I:

[00214] In some cases, C-N bond formation caused oxidation on the benzylic position. A reduction reaction step B was applied to make the desired compound.

Step A Step B

[00215] In cases of formula (II), Int-II were synthesized via the synthetic routes below:

General synthetic route II- 1:

Int-ll-A

CuCN C-N bond formation

NMP, 130 °C, 2h

Step H Step I

PG = Protecting Group

[00216] In some cases, step K reduction and step L were carried out in one-pot reaction if they both occurred under the same condition, i.e., acidic condition.

[00217] Alternatively, Int-II-A were synthesized vial a different sequence to install R¹ and R² with the synthetic route below:

General synthetic route II-2:

PG = protecting group, i.e., PMB, DMB...

[00218] In the case of formular (III), int-III was synthesized via the synthetic route below:

General synthetic route III:

[00219] In some cases, R¹ was carried from the beginning of the synthesis in the scheme above. In some other cases, R¹ was introduced at later steps in the scheme below via a sequence of bromination followed by a functionalization of Br to install R¹.

[00220] In this case, R² served as protecting group at early steps, then deprotected in a later step to install invention R².

Exemplary Synthetic procedure for intermediates:

5-amino-6-(2-chloro-5-fluorophenyl)-l-(methyl-d3)-3-(2,2,2-trifluoroethyl)-l,3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione Step A Step B

DMP

□ IEA, dioxane

Step C Step D

Step I

[00221] Step A: To a solution of 2,6-dibromo-4-fluorobenzene-l-carbaldehyde (110 g, 390 mmol) in con.lfcSCh (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 the remaining acid, dried over Na2SC>4 and concentrated in vacuo to afford 2,6-dibromo-4-fluoro-3- nitrobenzene-l-carbaldehyde (115 g, 352 mmol, 90%) as a black solid. LCMS: ESI m/z 328 [M + H]⁺.

[00222] Step B: To a solution of 2, 6-dibromo-4-fluoro-3 -nitrobenzene- 1-carbaldehy de (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 Na?SO4 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]⁺.

[00223] 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 NazSCU 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 fdtered 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]⁺.

[00224] Step D: To a solution of (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (45 g, 98.8 mmol) in tetrahydrofuran (450 mL) was added DIEA (38.3 g, 296 mmol) and 2,2,2-trifluoroethan-l -amine hydrochloride (26.8 g, 198 mmol). The mixture was stirred at 65 °C for 16 h. The reaction mixture was diluted with water, extracted with EA. The organic layer was separated, washed with brine, dried overlSfeSCE and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-10%, with 5% of DCM) to afford the title compound(2-chloro-4- fluorophenyl){2,6-dibromo-3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}methanone (22 g, 41.2 mmol, 41%) as a yellow solid.

[00225] Step E: To a solution of (2-chforo-4-fluorophenyl){2,6-dibromo-3-nitro-4-[(2,2,2- trifluoroethyl)amino]phenyl}methanone (30 g, 56.1 mmol) in EtOH (300 mL) and H2O (75 mL) was added Fe (15.7 g, 281 mmol) and NH4CI (15.2 g, 281 mmol)). The reaction was stirred at 80 °C for 2h. The cooled reaction mixture was filtered. The filtrate was concentrated, diluted with water and extracted with EtOAc (100 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: 0-20%) to afford {{3- amino-2,6-dibromo-4-[(2,2,2-trifluoroethyl)amino]phenyl}(2-chloro-4-fluorophenyl)methanone (26 g, 51.5 mmol, 92%) as an orange solid. LCMS: ESI m/z 505 [M + H]⁺.

[00226] Step F: To a solution of {3-amino-2,6-dibromo-4-[(2,2,2- trifluoroethyl)amino]phenyl }(2-chloro-4-fluorophenyl)methanone (5 g, 9.91 mmol), TEA (2.76 mL, 19.8 mmol) in THF (50 mL) was added triphosgene (1.47 g, 4.96 mmol) at 0 °C. The reaction was stirred at rt for 2h. Aqueous solution of NaHCCh was added, and the mixture was extracted with EtOAc (50 mL*3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford 4,6-dibromo-5-[(2- chloro-4-fluorophenyl)carbonyl]-l -(2,2,2-trifluoroethyl)-2,3-dihydro-lH-benzo[d]imidazol-2- one (5 g, 9.43 mmol, 95%) as a white solid. LCMS: m/z 531 [M+H]⁺.

[00227] Step G: To a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- (2,2,2-trifluoroethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (10 g, 18.9 mmol) in THF (150 mL) was added NaH (1.51 g, 37.7 mmol, 60% in mineral) at 0 °C. The mixture was stirred at 0 °C for lOmin, then CD3I (5.47 g, 37.7 mmol) was added. The following mixture was stirred at rt for 16 h. The reaction mixture was quenched by water, and the mixture was extracted with EtOAc (150 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%~20%) to afford 4,6-dibromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-3-(trideuteriomethyl)-l-(2,2,2-trifluoroethyl)-2,3-dihydro-lH- benzo[d]imidazol-2-one (8.1 g, 14.9 mmol, 78%) as a colorless oil. LCMS: m/z 548 [M+H]⁺. [00228] Step H: To a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3- (trideuteriomethyl)-l-(2,2,2-trifluoroethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (500 mg, 0.913 mmol) in NMP (10 mL) was added CuCN (85.9 mg, 0.959 mmol). The mixture was stirred at 130 °C under N2 for 3h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic layer was wash with brine for 5 times, dried over Na2SC>4 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]- 2-oxo-3-(trideuteriomethyl)-l-(2,2,2-trifluoroethyl)benzo[d]imidazole-4-carbonitrile (140 mg, 0.284 mmol, 31%) as a brown solid. LCMS: ESI m/z 493 [M + H]⁺.

[00229] Step I: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-3-(methyl-d3)-2-oxo- l-(2,2,2-trifluoroethyl)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (1 g, 2.03 mmol) in dioxane (50 mL) were added diphenylmethanimine (0.512 mL, 3.05 mmol), Pd2(dba)3 (0.19 g, 0.203 mmol), and xantphos (0.24 g, 0.407 mmol), CS2CO3 (1.99 g, 6.09 mmol)3-fluoro- 5-(trifluoromethyl)benzene-l -carboxamide (14.3 mg, 0.069 mmol). The reaction was stirred at 100 °C under IShfor 3 hr. 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 Na2SCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether(gradient:20-30%)to afford the title compound 5-(2- chloro-5-fluorobenzoyl)-6-((diphenylmethylene)amino)-3-(methyl-d3)-2-oxo-l-(2,2,2- trifluoroethyl)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (900 mg, 1.518 mmol, 75%)as a yellow oil. LCMS: 594 [M-H]⁺.

[00230] Step J: To a solution of 5-(2-chloro-5-fluorobenzoyl)-6-((diphenylmethylene)amino)- 3-(methyl-d3)-2-oxo-l-(2,2,2-trifluoroethyl)-2,3-dihydro-lH-benzo[d]imidazole-4-carbonitrile (100 mg, 0.169 mmol) in ACN (5 mL) and H2O (1 mL) were added KOH (18.9 mg, 0.338 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 6-(2-chloro-5-fluorophenyl)-5- ((diphenylmethylene)amino)-6-hydroxy-l-(methyl-d3)-3-(2,2,2-trifluoroethyl)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (100 mg, 0.164 mmol, 97%)as a yellow solid. LCMS: 612 [M-H]⁺.

[00231] Step K: To a solution of 6-(2-chloro-5-fluorophenyl)-5-((diphenylmethylene)amino)- l-(methyl-d3)-3-(2,2,2-trifhioroethyl)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (900 mg, 1.47 mmol) in TFA (5 mL) were added EtsSiH (0.235 mL, 6.26 mmol). The reaction was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated, diluted aqueous NaHCCL and extracted with EA. The organic phase was washed with brine, dried over ISfeSCL and concentrated. The organic layer was separated and concentrated to afford 6-(2-chloro-5-fluorophenyl)-5-((diphenylmethylene)amino)-6-hydroxy-l- (methyl-d3)-3-(2,2,2-trifluoroethyl)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (700 mg, 1.176 mmol, 80%) as a yellow solid. LCMS: 596 [M-H]⁺.

[00232] Step L: To a solution of 6-(2-chloro-5-fluorophenyl)-5-((diphenylmethylene)amino)- l-(methyl-d3)-3-(2,2,2-trifluoroethyl)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (200 mg, 0.336 mmol) in THF (3 mL) were added HC1 (0.5 mL, 1 mmol). The reaction was stirred at rt for 1 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated, diluted aqueous NaHCCL and 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 ethyl acetate in petroleum ether (gradient: 40-50%) to afford 5- amino-6-(2-chloro-5-fluorophenyl)-l-(methyl-d3)-3-(2,2,2-trifluoroethyl)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (70 mg, 0.162 mmol, 49%) as a yellow solid. LCMS: 432 [M-H]⁺. 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

[00233] Step A: 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 with

PE/EA/DCM= 100/5/5 to give the starting material (2-chloro-5-fluorophenyl)(2,6-dibromo-4- fluoro-3-nitrophenyl)methanone (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] ¹ . ^XH NMR (400 MHz, DMSO-t/6) 6 7.71 (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, J= 55.6,

3.6 Hz, 1H), 3.74 (t, J= 15.4 Hz, 2H).

[00234] Step B: To a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2- difhjoroethyl)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 NH4CI (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 Na2SO4 and 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]T

[00235] Step C: To a solution of{3-amino-2,6-dibromo-4-[(2,2- difluoroethyl)amino]phenyl}(2-chloro-4-fluorophenyl)methanone (26.0 g, 53.4 mmol), TEA (10.8 g, 106 mmol) in THF (260 mL L) was added triphosgene (7.93 g, 26.7 mmol) at 0 °C. The reaction was stirred at rt for 2h. Water was added, and the mixture was extracted with EtOAc (1000 mL*3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was triturated with DCM/EA=10/l to afford 4,6-dibromo-5-[(2-chloro- 4-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (21.3 g,

41.6 mmol, 78%) as a brown solid. LCMS: ESI m/z 513 [M + H]⁺.

[00236] Step D: To a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difhioroethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (10.1 g x 2, 19.8 mmol x 2, parallel) in THF (150 mL) was added NaH (1.58 g, 39.61 mmol, 60% purity in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 10 min, then CD3I (3.70 mL, 59.41 mmol) was added. The mixture was stirred at rt for 16h. The reaction mixture was quenched by ice-water, and the mixture was extracted with EtOAc (1000 mL*3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was triturated with (PE/EA=10/l) and fdtered to afford 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3- (trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (19.1 g, 36.0 mmol, 91%) as a white solid. LCMS: ESI m/z 530 [M + H]-. ’H NMR (400 MHz, DMSO-r/6) 5 7.77 (s, 1H), 7.73 (dd, J= 8.8, 4.8 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.48 (dd, J= 8.8, 2.8 Hz, 1H), 6.36 (tt, J= 54.8, 3.2 Hz, 1H), 4.42 (td, J= 15.6, 3.2 Hz, 2H).

[00237] Step E: To a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-(trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (10 g x 2 , 18.9 x 2 mmol, parallel) in NMP (150 mL) was added CuCN (1.77 g, 39.6 mmol). The reaction mixture was stirred at 120 °C under N2 for 3h. The cooled reaction mixture was diluted with EA, fdtered through a pad of celite. The filtrate was extracted with EtOAc (100 mL*3). The organic phase was washed with brine for 5 times, dried over Na2SO4 and concentrated. The residue was triturated with MeOH three times, then triturated with MeCN two times and filtered to afford 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2-oxo-3- (trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (5.5 g, 11.5 mmol, 31%) as a white solid. LCMS: ESI m/z 530 [M + H]⁺. ’HNMR (400 MHz, DMSO-t/6) 5 7.97 (s, 1H), 7.74 (dd, J = 8.8, 4.8 Hz, 1H), 7.65 - 7.45 (m, 2H), 6.63 - 6.14 (m, 1H), 4.46 (td, J= 15.6, 2.8 Hz, 2H). [00238] Step F: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-oxo-3-(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (800 mg, 1.68 mmol) in 1,4-dioxane (40 mL) was added diphenylmethanimine (0.42 mL, 2.52 mmol), Pd2(dba)a (154 mg, 0.17 mmol) , Xantphos (194 mg, 0.34 mmol), CS2CO3 (1.1 g, 3.36 mmol). The reaction was stirred at 100 °C under N2 for 2h. The cooled reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 0%~25%) to afforded 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difhioroethyl)-6-[(diphenylmethylidene)amino]-2-oxo-3-(trideuteriomethyl)benzo[d]imidazole- 4-carbonitrile (800 mg, 1.39 mmol, 83%) as a green solid. LCMS: ESI m/z 576 [M + H]⁺.

[00239] Step G: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 6-[(diphenylmethylidene)amino]-2-oxo-3-(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (800 mg, 1.39 mmol) in ACN (20 mL) and H2O (4 mL) were added KOH (156 mg, 2.78 mmol). The reaction was stirred at room temperature for 2 hr. LCMS showed the reaction was completed. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford 6-(2-chloro-5- fluorophenyl)-3-(2,2-difhioroethyl)-5-[(diphenylmethylidene)amino]-6-hydroxy-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (800 mg, 1.35 mmol, 97%) as a yellow solid. LCMS: ESI m/z 594 [M + H]⁺.

[00240] Step H: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- [(diphenylmethylidene)amino]-6-hydroxy-l -(trideuteri omethyl)- 1,2, 3, 6, 7, 8- hexahydroimidazo[5,4-e]isoindole-2, 8-dione (200 mg, 0.34 mmol) in TFA (4 mL) were added EtsSiH (2 mL). The reaction was stirred at 70 °C for 20 min. The cooled reaction mixture was concentrated. The residue was added MeCN (8 mL) and aqueous HC1 (2 mL, 1.0 M) at rt. The reaction was stirred at rt for 20 min. The reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over NazSCL and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 30-80%) afford 5-amino-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-l -(trideuteri omethyl)- 1,2, 3, 6, 7, 8- hexahydroimidazo[5,4-e]isoindole-2, 8-dione (80 mg, 0.19 mmol, 55%) as an yellow solid. LCMS: ESI m/z 414 [M + H]⁺.

5-amino-6-(2-chloro-5-fluorophenyl)-3-(pentadeuterioethyl)-l-(trideuteriomethyl)- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione

[00241] Step A: To a solution of 5,7-dibromo-6-(2-chloro-4-fluorobenzoyl)-l-(methyl-d3)- l,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 2.16 mmol) and 1 -bromo- 1,1, 2, 2, 2- pentadeuterioethane (0.49 g, 4.32 mmol) in N,N-dimethylacetamide (15 mL) was added CS2CO3 (2.11 g, 6.49 mmol). The mixture was stirred at 60 °C for 5h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by column (eluted with (EA: PE=30%) to give 4,6-dibromo-5-(2-chloro-4-fluorobenzoyl)-l-(ethyl-d5)-3-(methyl-d3)-l,3-dihydro-2H- benzo[d]imidazol-2-one (600 mg, 1.21 mmol, 56%) as a brown solid. LCMS: ESI m/z 496 [M + H]⁺.

[00242] Step B: To a solution of 4,6-dibromo-5-(2-chloro-4-fluorobenzoyl)-l-(ethyl-d5)-3- (methyl-d3)-l,3-dihydro-2H-benzo[d]imidazol-2-one (600 mg, 1.21 mmol) in NMP (6 mL) was added CuCN (108 mg, 1.21 mmol), and the mixture was stirred at 130 °C under N2 for 2h. The mixture was stirred at 60 °C for 5h. The cooled reaction mixture was diluted with H2O, 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 ethyl acetate in petroleum ether (gradient: 0%~30%) to afford 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]- 3-methyl-2-oxo-l-(pentadeuterioethyl)benzo[d]imidazole-4-carbonitrile (200 mg, 0.453 mmol, 37%) as a brown solid. LCMS: ESI m/z 441 [M + H]⁺.

[00243] Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-oxo-l- (pentadeuterioethyl)-3-(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (210 mg, 0.472 mmol) and diphenylmethanimine (128 mg, 0.708 mmol) in dioxane (10 mL) was added CS2CO3 (307 mg, 0.944 mmol), XANT PHOS (54.6 mg, 0.094 mmol) and Pd₂(dba)₃ (43.2 mg, 0.047 mmol). The mixture was stirred at 100 °C under N2 for 2 hours. The cooled mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (3 g column) using 0 - 50% EtOAc/hexane to afford 5-[(2-chloro-5-fluorophenyl)carbonyl]-6- [(diphenylmethylidene)amino]-2-oxo-l-(pentadeuterioethyl)-3- (trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (140 mg, 0.257 mmol, 54 %) as a yellow solid. LCMS: ESI m/z 545.4 [M + H]⁺.

[00244] Step D: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6- [(diphenylmethylidene)amino]-2-oxo-l-(pentadeuterioethyl)-3-

(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (130 mg, 0.239 mmol) in CH3CN

(5 mL) and H2O (l mL) was added KOH (26.8 mg, 0.477 mmol). The mixture was stirred at 20 °C for 1 hour. The cooled mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (3 g column) using 0 - 60% EtOAc/hexane to afford 6-(2-chloro-5-fluorophenyl)-5-[(diphenylmethylidene)amino]-6-hydroxy-3- (pentadeuterioethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8- dione (108 mg, 0.192 mmol, 80 %) as a yellow solid. LCMS: ESI m/z 563.5 [M + H]⁺.

[00245] Step E: To a solution of 6-(2-chloro-5-fluorophenyl)-5-

[(diphenylmethylidene)amino]-6-hydroxy-3-(pentadeuterioethyl)-l-(trideuteriomethyl)- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (103 mg, 0.183 mmol) in TFA

(3 mL) was added EtsSiH (0.7 mL) and the mixture was stirred at 70 °C for 1 hour. The cooled mixture was concentrated under vacuum to give a crude, which was diluted with saturated NaHCCh, 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: 80%) to afford 5-amino-6-(2-chloro-5-fluorophenyl)-3- (pentadeuterioethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8- dione (35 mg, 0.091 mmol, 50 %) as a yellow solid. LCMS: ESI m/z 383.3 [M + H]⁺.

5-amino-6-(2-chloro-5-fluorophenyl)-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l-

(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione

[00246] Step A: The mixture of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-l- (trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (460 mg, 0.988 mmol),2-bromo- 1,1,2,2-tetradeuterioethan-l-ol (255 mg, 1.98 mmol), CS2CO3 (870 mg, 2.67 mmol) and Nal (444 mg, 2.97 mmol) in DMF (10 mL) was stirred at 100 °C for 2h. 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 (0-50%) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(l,l,2,2-tetradeuterio-2- hydroxyethyl)-3-(trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (180 mg, 0.28 mmol, 28%). LCMS: ESI m/z 514 [M+H]⁺.

[00247] Step B: To a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- (l ,l ,2,2-tetradeuterio-2-hydroxyethyl)-3-(trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol- 2-one (840 mg, 1.64 mmol) in DCM (40 mL) was added diethyl(trifluoro-X4-sulfanyl)amine (527 mg, 3.27 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The mixture was quenched with cold water and extracted with DCM. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by FCC, eluting with EA/PE (0-20%) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(l,l,2,2- tetradeuterio-2-fluoroethyl)-3-(trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2-one (640 mg, 1.24 mmol, 76%) as a yellow solid. LCMS: ESI m/z 516[M+H]⁺. [00248] Step C: The mixture of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- (l,l,2,2-tetradeuterio-2-fluoroethyl)-3-(trideuteriomethyl)-2,3-dihydro-lH-benzo[d]imidazol-2- one (560 mg, 1.09 mmol) and cyanocopper(I) (292 mg, 3.26 mmol) in NMP (28 mL) was stirred at 140 °C for 2h. 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%, 10% DCM) to give 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-2-oxo-l -(1,1,2, 2-tetradeuterio-2 -fluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (170 mg, 0.37 mmol, 34%) as a pink solid. LCMS: ESI m/z 461[M+H]t

[00249] Step D: A mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-oxo-l- ( 1,1, 2, 2-tetradeuterio-2-fluoroethyl)-3 -(trideuteri omethyl)benzo[d]imidazole-4-carbonitrile (1.76 g, 3.81 mmol), diphenylmethanimine (1.04 g, 5.72 mmol), Pd2(dba)s (0.35 g, 0.38 mmol), Xantphos (0.44 g, 0.76 mmol) and CS2CO3 (2.48 g, 7.62 mmol) in dioxane (35 mL) was stirred at 100 °C under N2 for 2h. The cooled mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SCU and concentrated. The residue was purified by FCC, eluting with EA/PE (20%-30%) to afford 5-[(2-chloro-5- fluorophenyl)carbonyl]-6-[(diphenylmethylidene)amino]-2-oxo-l-(l,l,2,2-tetradeuterio-2- fluoroethyl)-3-(trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (1.2 g, 2.14 mmol, 56%) as a yellow solid. LCMS: m/z 562[M+H]⁺.

[00250] Step E: The mixture of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6- [(diphenylmethylidene)amino]-2-oxo-l -(1,1,2, 2-tetradeuterio-2-fluoroethyl)-3- (trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (900 mg, 1.60 mmol) and potassium hydroxide (899 mg, 16.01 mmol) in acetonitrile (20 mL) and H2O (5 mL) was stirred at room temperature for Ih. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was used directly in next step.

[00251] Step F: The mixture of 6-(2-chloro-5-fluorophenyl)-5- [(diphenylmethylidene)amino]-6-hydroxy-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (200 mg, 0.35 mmol) in TFA (3 mL) and EtsSiH (0.3 mL) was stirred at 50°C for 20 min. The cooled mixture was concentrated, and the residue was used directly in next step. LCMS: m/z 564 [M+H]⁺. [00252] Step G: To the mixture of 6-(2-chloro-5-fluorophenyl)-5- [(diphenylmethylidene)amino]-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l-(trideuteriomethyl)- l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (2.3 g, 4.08 mmol) in MeCN (30 mL) was added 1.0 M HC1 (3 mL). The mixture was stirred at room temperature for Ih. The mixture was concentrated and triturated with water. The mixture was filtered. The filter cake was dried to give 5-amino-6-(2-chloro-5-fluorophenyl)-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (1.0 g, 2.00 mmol, 49%) as a gray solid. LCMS: m/z 400[M+H]⁺.

5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-l,2,3,6,7,8- hexahydroimidazo [4, 5-e] isoindole-2, 8-dione

[00253] Step A: To a solution of 6-amino-3-bromo-2-[(2-chloro-5-fluorophenyl)carbonyl]-5- [ (2, 2-difluoroethyl)amino]benzene-l -carbonitrile (2 g, 4.62 mmol) in THF (20 mL) was added trichloromethyl [(trichloromethyl)oxy]methanoate (1.37 g, 4.62 mmol) and triethylamine (1.9 mL, 13.87 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was heated with PE: EA=5: 1 to afforded 6-bromo-5-[(2- chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2-oxo-3H-benzo[d]imidazole-4- carbonitrile (E8 g, 3.93 mmol, 85%) as a brown solid. LCMS: ESI m/z 458.1 [M - H] ¹ .

[00254] Step B: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-oxo-3H-benzo[d]imidazole-4-carbonitrile (1.8 g, 3.93 mmol) in DMF (18 mL) was added K2CO3 (1.1 g, 7.85 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.2 g, 5.89 mmol). The reaction mixture was stirred at 80 °C for 16 h. The mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was beated with EA: PE=1 : 5 to afforded 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-(difluoromethyl)-2-oxobenzo[d]imidazole-4- carbonitrile (1.3 g, 2.56 mmol, 65%) as a brown solid. LCMS: ESI m/z 510.1 [M + H]⁺.

[00255] Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-3-(difluoromethyl)-2-oxobenzo[d]imidazole-4-carbonitrile (1.3 g, 2.56 mmol) in 1,4-dioxane (40 mL) was added diphenylmethanimine (0.64 mL, 3.83 mmol), Pd2(dba)s (234 mg, 0.26 mmol), Xantphos (296 mg, 0.51 mmol), CS2CO3 (1.66 g, 5.11 mmol). The reaction was stirred at 100 °C for 2h. The reaction mixture was concentrated and purified using silica gel column chromatography eluting with EA in PE (gradient: 0-30%) to give 5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-3-(difluoromethyl)-6- [(diphenylmethylidene)amino]-2-oxobenzo[d]imidazole-4-carbonitrile (600 mg, 0.99 mmol, 39%) as a yellow solid. LCMS: ESI m/z 609.3 [M + H]⁺.

[00256] Step D: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 3-(difluoromethyl)-6-[(diphenylmethylidene)amino]-2-oxobenzo[d]imidazole-4-carbonitrile (600 mg, 0.99 mmol) in MeCN (8 mL) and H2O (2 mL) were added potassium hydroxide (1.1 g, 19.7 mmol). The reaction was stirred at room temperature for 2 hr. LCMS showed the reaction was completed. 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 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)- 5-[(diphenylmethylidene)amino]-6-hydroxy-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8- dione (600 mg, 0.96 mmol, 97%) as a yellow solid. LCMS: ESI m/z 627.3 [M +H]⁺.

[00257] Step E: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (difluoromethyl)-5-[(diphenylmethylidene)amino]-6-hydroxy-l,2,3,6,7,8-hexahydroimidazo[4,5- e]isoindole-2, 8-dione (600 mg, 0.96 mmol) in TFA (6 mL) was added triethylsilane (3 mL) at rt. The mixture was stirred at 70 °C for 15 min. The reaction mixture was concentrated to afford 6- (2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-5- [(diphenylmethylidene)amino]-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (520 mg, 0.85 mmol, 89%) as a yellow solid. LCMS: ESI m/z 611.4 [M + H]⁺.

[00258] Step F: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (difluoromethyl)-5-[(diphenylmethylidene)amino]-l,2,3,6,7,8-hexahydroimidazo[4,5- e]isoindole-2, 8-dione (520 mg, 0.85 mmol) in MeCN (8 mL) was added HC1 (4 mL, 1.0 M aqueous) at rt. The reaction was stirred at rt for 20 min. The reaction mixture was diluted with water, adjusted to pH=8 with aqueous NaHCCL, 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- 40%) afford 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (255 mg, 0.57 mmol, 67%) as an yellow solid. LCMS: ESI m/z 447.2 [M + H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 9.40 (s, 1H), 9.04 (t, J = 57.2 Hz, 1H), 7.69 - 7.49 (m, 1H), 7.41 - 7.20 (m, 1H), 7.11 - 6.94 (m, 1H), 6.85 (s, 1H), 6.70 - 6.24 (m, 1H), 5.97 (s, 1H), 4.79 (s, 2H), 4.50 - 4.25 (m, 2H).

5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6,7-dihydropyrrolo[3,4- e] indazol-8(3H)-one

[00259] Step A: To a solution of 4-bromo-6-fluoro-lH-indazole (1.03 g, 4.79 mmol) in N,N- dimethylmethanamide (10 mL) cooling in an ice bath was added NaH (0.25 g, 6.23 mmol, 60% in mineral). The mixture was stirred for 10 min. SEM-C1 (0.96 g, 5.75 mmol) was added dropwise. The reaction was stirred at 0 °C for 30 min. The reaction was diluted with water and extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified by FCC eluting with EA/PE(0-5%) to afford 4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6-fluoroindazole (1 g, 2.90 mmol, 60%) as a white solid. LCMS: m/z 345 [M + H]⁺, 347 [M + H]⁺.

[00260] Step B: To a -67 °C solution of 4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6- fluoroindazole (1 g, 2.90 mmol) in THF (15 mL) was added dropwise LDA (2.17 mL, 4.34 mmol) under N2. The mixture was stirred at this temperature for 30 min. A solution of 2-chloro- 5-fluorobenzene-l-carbaldehyde (0.69 g, 4.34 mmol) in THF (1 mL) was added dropwise at - 67 °C. The reaction was stirred at this temperature for 1 hour. The reaction was quenched with water and extracted with EA twice. The combined organic layer was washed with brine, dried over Na?SO4 and concentrated. The residue was purified by FCC eluting with EA/PE(0-9%- 15%) to afford [4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6-fluoroindazol-5-yl](2-chloro- 5 -fluorophenyl )methanol (540 mg, 1.07 mmol, 37%) as a white solid. 'H NMR (400 MHz, DMSO-d6) 8 8.17 (s, 1H), 7.71 (d, J= 10.2 Hz, 1H), 7.60 (d, J= 11.2 Hz, 1H), 7.37 (dd, J= 8.8, 5.2 Hz, 1H), 7.18 (td, J= 8.4, 3.2 Hz, 1H), 6.57 (d, J= 4.8 Hz, 1H), 6.26 (d, 4.8 Hz, 1H), 5.70 (s, 2H), 3.50 (t, J= 8.0 Hz, 2H), 0.77 (td, J= 7.6 Hz, 1.4, 2H), -0.13 (s, 9H).

[00261] Step C: To a solution of [4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6- fluoroindazol-5-yl](2-chloro-5-fluorophenyl)methanol (540 mg, 1.07 mmol) in DCM (10 mL) was added Dess-Martin periodinane (545 mg, 1 .29 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with a aqueous solution of ^2826)3 and extracted with DCM. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by FCC eluting with EA/PE(0-10%) to afford [4-bromo-l-(5,5-dimethyl-2- oxa-5-silahex-l-yl)-6-fluoroindazol-5-yl](2-chloro-5-fluorophenyl)methanone (370 mg, 0.737 mmol, 69%) as a white solid. LCMS: m/z 501 [M + H]⁺,503 [M + H]⁺.

[00262] Step D: To a solution of [4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6- fluoroindazol-5-yl](2-chloro-5-fluorophenyl)methanone (330 mg, 0.658 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give a residue. The residue was dissolved in MeCN (2 mL), followed by the addition of 0.4 mL aqueous ammonia. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, diluted with water and extracted with EA. The organic layer was washed with brine, dried over NfoSCL and concentrated to give (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5-fluorophenyl)methanone (240 mg, 0.646 mmol, 98%) as a white solid. LCMS: m/z 371 [M + H]⁺,373 [M + H]⁺.

[00263] Step E: To a solution of (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5- fhiorophenyl)methanone (1.4 g, 3.77 mmol) in DMF (20 mL) was added CS2CO3 (2.46 g, 7.54 mmol). The mixture was stirred at room temperature for 30min. l,l-difluoro-2-iodoethane (2.53 g, 13.2 mmol) was added and the mixture was stirred at 70 °C for 1-2 hours. The cooled mixture was diluted with water and extracted with EA twice. The combined organic layer was washed with brine, dired over Na2SO4 and concentrated. The residue was purified by FCC eluting with EA/PE(0-5%) to give [4-bromo-l-(2,2-difluoroethyl)-6-fluoroindazol-5-yl](2-chloro-5- fluorophenyl)methanone (850 mg, 1.951 mmol, 52%) as a white solid. LCMS: m/z 435 [M + H]⁺,437 [M + H]⁺.

[00264] Step F: The mixture of [4-bromo-l-(2,2-difluoroethyl)-6-fluoroindazol-5-yl](2- chforo-5-fluorophenyl)methanone (400 mg, 0.918 mmol)and CuCN (411 mg, 4.59 mmol) in NMP (10 mL) was stirred at 120 °C under N2 for 2 hours. The cooled mixture was diluted with water and extracted with EA. The organic layer was washed brine twice, dried over Na2SC>4 and concentrated. The residue was purified by FCC eluting with EA/PE(50%) to give 5- [(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-6-fluoroindazole-4-carbonitrile (200 mg, 0.524 mmol, 57%) as a white solid. LCMS: m/z 382 [M + H]⁺. [00265] Step G: The mixture of 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 6-fluoroindazole-4-carbonitrile (330 mg, 0.865 mmol) and DIEA (335 mg, 2.60 mmol) in DMSO-d6 (10 mL) was stirred at 120 °C. (4-methoxyphenyl)methanamine (237 mg, 1.73 mmol) was added and the mixture was stirred at 120 °C for 4 hours. The cooled reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-6-{[(4- methoxyphenyl)methyl]amino}indazole-4-carbonitrile (66 mg, 0.132 mmol, 15%) as a white solid. LCMS: m/z 499 [M + H]⁺.

[00266] Step H: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 6-{[(4-methoxyphenyl)methyl]amino}indazole-4-carbonitrile (62 mg, 0.124 mmol) in MeCN (6 mL) and H2O (4 mL) was added potassium hydroxide (69.7 mg, 1.24 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-5-{[(4-methoxyphenyl)methyl]amino}- 7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (48 mg, 0.093 mmol, 75%) as a white solid. LCMS: m/z 517 [M + H]⁺.

[00267] Step I: To the mixture of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-5-{[(4-methoxyphenyl)methyl]amino}-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (26 mg, 0.050 mmol) in TFA (4 mL) and tri ethyl silane (0.4 mL) was added TfOH (3 drops). The mixture was stirred at 80 °C for 30min. The cooled reaction mixture was concentrated. The residue was diluted with aqueous sodium bicarbonate and extracted with EA twice. The organic layer was washed with brine, dried over Na2SO i and concentrated to give a crude of 5-amino-6- (2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (19.2 mg, 0.050 mmol). l-chloro-7-fluoro-5-(trifluoromethyl)isoquinoline

[00268] Step A. To a solution of [4-fluoro-2-(trifluoromethyl)phenyl]acetonitrile (1.8 g, 8.8 mmol) in MeOH (20 mL) was added NH4OH (1.9 mL, 49.2 mmol) and Raney -Ni (2 g, 49.2 mmol). The reaction mixture was stirred at rt under H2 using a H2 balloon for 18h. After filtration via celite pad, the filtrate was diluted with water, extracted with EA (30 ml). The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated to give 2-[4- fluoro-2-(trifluoromethyl)phenyl]ethan-l -amine (1.4 g, 6.7 mmol, 76 %) as a yellow oil. LCMS: ESI m/z 208 [M + H]⁺.

[00269] Step B. To a solution of 2-[4-fluoro-2-(trifluoromethyl)phenyl]ethan-l -amine (1.4 g, 6.7 mmol) in DCM (15 mL) was added ethyl[di(prop-2-yl)]amine (2.6 mL, 14.9 mmol), followed by 2,2,2-trifluoroacetic anhydride (1.1 mL, 8.1 mmol) dropwise at 0 °C. The solution was stirred at rt for 2h. The reaction mixture was diluted with DCM (40 mL). The combined organic layer was washed with 10% aqueous NaHCCL, water and brine solution. The organic layer was dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography eluted with PE: EA=3: 1 to give 2,2,2-trifhioro-N-{2-[4-fluoro-2- (trifluoromethyl)phenyl]ethyl}acetamide (1.3 g, 4.2 mmol, 63%) as a white solid. LCMS: ESI m/z 304 [M + H]⁺.

[00270] Step C. To a solution of 2,2,2-trifluoro-N-{2-[4-fluoro-2- (trifluoromethyl)phenyl]ethyl} acetamide (1.2 g, 3.9 mmol) in [(dioxo-X5-phosphanyl)oxy]dioxo- X5-phosphane methanesulfonic acid (10 mL) was added paraformaldehyde (450 mg, 4.9 mmol) at rt. The solution was stirred at rt for 18h. The reaction mixture was diluted with EA (30 mL), the combined organic layer was washed with 10% aqueous NaHCCL, water and brine solution. The organic layer was dried over Na2SC>4 and concentrated to give 2,2,2-trifluoro-l-[7- fluoro-5-(trifluoromethyl)-l,2,3,4-tetrahydroisoquinolin-2-yl]ethan-l-one (1 g, 3.2 mmol, 80%) as a yellow oil. LCMS: ESI m/z 316 [M + H]⁺.

[00271] Step D. To a solution of 2,2,2-trifluoro-l-[7-fluoro-5-(trifluoromethyl)-l,2,3,4- tetrahydroisoquinolin-2-yl]ethan-l-one (900 mg, 2.8 mmol) in EtOH (8 mL) and H2O (2 mL) was added K2CO3 (1.9 g, 14.3 mmol) at rt. The reaction mixture was stirred at 80 °C for Ih. The reaction mixture was poured into 60 mL of water and extracted with 60 mL EA. The combined organic layer was washed with brine, dried over N^SCL and concentrated. The residue was purified by silica gel chromatography eluted with DCM: MeOH=10: 1 to give 7- fluoro-5-(trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline (500 mg, 2.28 mmol, 79 %) as a white solid. LCMS: ESI m/z 220 [M + H]⁺.

[00272] Step E. To a stirred solution of 7-fluoro-5-(trifluoromethyl)-l,2,3,4- tetrahydroisoquinoline (300 mg, 1.4 mmol) in ACN (8 mL) was added NaClCL (185 mg, 2.1 mmol) at rt. After stirred at 50 °C overnight under CO2 atmosphere, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SCU, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-60 %, EtOAc in PE) to give 7-fluoro-5-(trifluoromethyl)-l,2,3,4- tetrahydroisoquinolin-l-one (90 mg, 0.38 mmol, 28%) as a yellow oil. LCMS: ESI m/z 233 [M + H]⁺.

[00273] Step F. To a stirred solution of 7-fIuoro-5-(trifluoromethyl)-l,2,3,4- tetrahydroisoquinolin-l-one (80 mg, 0.34 mmol) in DCE (5 mL) was added MnO2 (447 mg, 5.2 mmol) at rt. After stirred at 120 °C for 3d, the mixture was filtered and concentrated. The residue was purified by prep-TLC (PE: EtOAc= 3: 1) to give 7-fluoro-5-(trifluoromethyl)-l,2- dihydroisoquinolin-l-one (40 mg, 0.17 mmol, 50 %) as a yellow solid. LCMS: ESI m/z 231 [M + H]⁺.

[00274] Step G. A mixture of 7-fluoro-5-(trifluoromethyl)-l,2-dihydroisoquinolin-l-one (30 mg, 0.13 mmol) in POCI3 (2 mL) was stirred at 110 °C for Ih, the mixture was concentrated. The reaction mixture was diluted with EA (8 mL), the combined organic layer was washed with 10% aqueous NaHCCh, water and brine solution. The organic layer was dried over Na2SO4 and concentrated to give l-chloro-7-fluoro-5-(trifluoromethyl)isoquinoline (25 mg, 0.1 mmol, 77 %) as a yellow oil. LCMS: ESI m/z 250 [M + H]⁺. l-chloro-5-(trifluoromethyl)isoquinoline

[00275] Step A: To a solution of 5-(trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline (900 mg, 4.47 mmol) in MeCN (10 mL) was added sodium oxohypochlorite (485 mg, 5.36 mmol). The reaction mixture was stirred at rt under CO2 (balloon) 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: 48%] to afford the title compound 5- (trifluoromethyl)-l,2,3,4-tetrahydroisoquinolin-l-one (400 mg, 1.85 mmol, 41%) as a white solid. LCMS: ESI m/z 216 [M+H]⁺

[00276] Step B: To a solution of 5-(trifhioromethyl)-l,2-dihydroisoquinolin-l-one (100 mg, 0.469 mmol) in DCE (8 mL) was added manganese dioxide (4 g, 46.47 mmol). The reaction mixture was stirred at 120 °C for 48 h using a sealed tube. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SCU, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 58%] to afford the title compound 5- (trifluoromethyl)-l,2-dihydroisoquinolin-l-one (100 mg, 0.469 mmol, 25%) as a white solid. LCMS: ESI m/z 214 [M+H]⁺

[00277] Step C: A solution of 5-(trifluoromethyl)-l,2-dihydroisoquinolin-l-one (100 mg, 0.469 mmol) in POCI3 (2 mL) was stirred 120 °C for 1 h. The cooled reaction mixture was concentrated. The residue 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: 28%] to afford the title compound l-chloro-5-(trifluoromethyl)isoquinoline (60 mg, 0.259 mmol, 55%) as a white solid. LCMS: ESI m/z 232 [M+H]⁺

1 ,5,7-trichloroisoquinoline

[00278] Step A. To a stirred solution of 5,7-dichloro-l,2,3,4-tetrahydroisoquinoline (200 mg, 1.4 mmol) in ACN (8 mL) was added NaClCE (185 mg, 2.1 mmol) at rt. After stirred at 50 °C overnight under CO2 atmosphere, the mixture was poured into ice- water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, fdtered and concentrated. The residue was purified by chromatography (silica gel, 0-60 %, EtOAc in PE) to give 5,7-dichloro-3,4-dihydroisoquinolin-l(2H)-one (70 mg, 0.38 mmol, 28%) as a yellow oil. LCMS: ESI m/z 215 [M + H]⁺.

[00279] Step B. To a stirred solution of 5,7-dichloro-3,4-dihydroisoquinolin-l(2H)-one (70 mg, 0.3 mmol) in DCE (5 mL) was added Mn02 (447 mg, 5.2 mmol) at rt. After stirred at 120 °C overnight, the mixture was filtered and concentrated. The residue was purified by prep-TLC (PE: EtOAc= 3: 1) to give 5,7-dichloroisoquinolin-l(2H)-one (40 mg, 0.17 mmol, 50%) as a yellow solid. LCMS: ESI m/z 213 [M + H]⁺.

[00280] Step C. A mixture of 5,7-dichloroisoquinolin-l(2H)-one (30 mg, 0.12 mmol) in POCI3 (2 mL) was stirred at 110 °C for Ih. The cooled mixture was concentrated. The residue was diluted with EA (8 mL), washed with 10% aqueous NaHCCh, water and brine. The organic layer was dried over IsfeSCU and concentrated to give 1,5,7-trichloroisoquinoline (25 mg, 0.1 mmol, 77 %) as a yellow oil. LCMS: ESI m/z 232 [M + H]⁺.

4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline Step A Step B Step C

[00281] Step A: To a solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (1 g, 3.88 mmol) in DMSO (8 mL) and MeOH (8 mL) was added TEA (1.08 mL, 7.75 mmol) and bis[5- (diphenylphosphanyl)cyclopenta-l,3-dienyl]-X2-iron(II) palladium chloride (0.28 g, 0.39 mmol). The reaction mixture was stirred at 80 °C under CO overnight. 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% ethyl acetate in petroleum ether to afford the title compound methyl 2-amino-5-fluoro-3- (trifluoromethyl)benzoate (900 mg, 3.8 mmol, 97%) as a yellow liquid. LCMS: ESI m/z 238 [M + H]⁺.

[00282] Step B: To a solution of methyl 2-amino-5-fluoro-3-(trifluoromethyl)benzoate (500 mg, 2.108 mmol) in EtOH (5 mL), THF (5 mL) and H2O (5 mL) was added NaOH (253 mg, 6.3 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH=5-6 with 4M HC1, extracted with EA. The organic layer was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in di chloroform to afford the title compound 2-amino-5-fluoro-3-(trifluoromethyl)benzoic acid (400 mg, 1.79 mmol, 85%) as a yellow solid. LCMS: ESI m/z 224 [M + H]⁺.

[00283] Step C: A solution of 2-amino-5-fluoro-3-(trifluoromethyl)benzoic acid (400 mg, 1.793 mmol) in formamide (5 mL, 125 mmol) was stirred at 150 °C overnight. 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 dichloroform to afford the title 6-fluoro-8- (trifluoromethyl)quinazolin-4(3H)-one (400 mg, 1.72 mmol, 96%) as a white solid. LCMS: ESI m/z 233 [M + H]⁺.

[00284] Step D: A solution of 6-fluoro-8-(trifluoromethyl)quinazolin-4(3H)-one (50 mg, 0.22 mmol) in dichlorophosphinyl chloride (1 mL, 10.7 mmol) was stirred at 140 °C for 3 h. The mixture was concentrated under vacuum to afford the title compound 4-chloro-6-fluoro-8- (trifluoromethyl)quinazoline (50 mg, 0.2 mmol, 92%) as a yellow solid, which was used to the next step without further purification. LCMS: ESI m/z 251 [M + H]⁺. l,5-dichloro-7-fluoroisoquinoline

[00285] Step A: To a solution of 3-chloro-5-fluoro-2-methylbenzoic acid (1.00 g, 5.30 mmol) in DMF (10 mL) was added HATU (3.02 g, 7.95 mmol), NH₄C1 (0.34 g, 6.36 mmol) and DIEA (2.8 mL, 15.91 mmol). The reaction was stirred at rt for 2h. The reaction mixture was quenched by water, and the mixture was extracted with EtOAc (30 mL*3). The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient:O- 60%) afford 3-chloro-5-fluoro-2-methylbenzene-l-carboxamide (1.0 g, 5.33 mmol, 101%) as a yellow solid. LCMS: ESI m/z 188 [M + H]⁺.

[00286] Step B: To a solution of 3-chloro-5-fluoro-2-methylbenzene-l-carboxamide (1.0 g, 5.33 mmol) in THF (10 mL) was added DMF-DMA (1.42 mL, 10.66 mmol). The reaction mixture was stirred at rt for 2h. The mixture was diluted with water. The aqueous layers were extracted with extracted with EtOAc (30 mL*3). The combined organic layers were then washed with brine, dried over Na2SO4, concentrated, and chromatographed (PE/EA =2/1) to afford (3- chloro-5-fluoro-2-methylphenyl){ [(E)-(dimethylamino)methylidene]amino}methanone (1.1 g, 4.53 mmol, 85%) as a white solid. LCMS: ESI m/z 243 [M + H]⁺.

[00287] Step C: To a solution of (3-chloro-5-fluoro-2-methylphenyl){[(E)- (dimethylamino)methylidene]amino}methanone (800 mg, 3.30 mmol) in THF (5 mL) was added potassium 2-methylpropan-2-olate (4.0 mL, 4.0 mmol, 1 M in THF) at 0 °C. The mixture was stirred at 65 °C for 10 h. The mixture was cooled down to room temperature, aqueous HC1 (1.0 M) was added until Ph = 5-6. The mixture was extracted with EtOAc (15 mL*3). The organic layer was washed with brine, dried over Na?SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0- 5%) afford 5-chloro-7-fluoro-l,2-dihydroisoquinolin-l-one (240 mg, 1.22 mmol, 37%) as a white solid. LCMS: ESI m/z 198 [M + H]-.

[00288] Step D: A solution of 5-chloro-7-fluoro-l,2-dihydroisoquinolin-l-one (210 mg, 1.06 mmol) in dichlorophosphinyl chloride (6 mL, 0.51 mmol) was heated 100 °C for 3h. The reaction mixture was concentrated and then quenched by saturated NaHCCh, extracted with EA (three times). The separated organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered, and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient:0-20%) afford l,5-dichloro-7-fluoroisoquinoline (160 mg, 0.74 mmol, 70%) as a white solid. LCMS: ESI m/z 216 [M + H]⁺.

5-fluoro-7-(trifluoromethyl)benzo[c]isoxazol-3-amine

[00289] Step A: To a solution of 6-bromo-4-fluoro-2-(trifluoromethyl)aniline (5 g, 19.3 mmol) in NMP (20 mL) was added CuCN (3.47 g, 38.7 mmol) and the mixture was stirred at 150 °C under N2 for 4h. TLC showed the reaction was completed. The cooled mixture was quenched with water (50 mL), diluted with EA, filtered and the filtrate was extracted with EtOAc (50 mL*2). The combined organic layers were dried over Na2SC>4, filtered concentrated. The residue was purified by flash silica gel column (5% EA in PE) to give 2-amino-5-fluoro-3- (trifluoromethyl)benzene-l-carbonitrile (1.6 g, 36%) as white solid. (400 MHz, DMSO-d6) 8 7.84 (dd, J = 8.2, 2.8 Hz, 1H), 7.69 (dd, J = 8.8, 2.8 Hz, 1H), 6.18 (s, 2H).

[00290] Step B: To a solution of 2-amino-5-fluoro-3-(trifluoromethyl)benzene-l-carbonitrile (200 mg, 0.980 mmol) in TFA (3 mL) was added H2O2 (0.067 mL, 1.96 mmol) and the mixture was stirred at 50 °C for 20min. TLC showed the reaction was completed. The cooled mixture was poured in water (10 mL), extracted with EtOAc (10 mL). The organic layer was quenched with Na2SOs (a.q), extracted with EtOAc (5 mL*2), dried over Na2SO4, filtered and the filtrate was concentrated and purified by flash silica gel column (EA 8% in PE) to give 5-fluoro-7- (trifluoromethyl)benzo[c]isoxazol-3-amine (50 mg, 21%) as yellow solid. 'H NMR (400 MHz, DMSO-d5) 8 8.55 (s, 2H), 7.68 (d, J = 8.8 Hz, IH), 7.63 - 7.59 (m, IH).

[00291] Step A: To the mixture of 4-fluoro-2-(trifluoromethyl)aniline (2 g, 11.2 mmol) in IPA (40 mL) was added 5-(methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4, 6-dione (2.29 g, 12.3 mmol). The mixture was stirred at 95 °C for 3h. The mixture was cooled and stirred at room temperature for Ih. The mixture was filtered. The filter cake was washed with cold EtOH and dried to give 5-({[4-fluoro-2-(trifluoromethyl)phenyl]amino}methylidene)-2,2- dimethyl- 1,3 -dioxane-4, 6-dione (2.85 g, 8.55 mmol, 77%) as a white solid. LCMS: ESI m/z 332[M-H]’. Tl NMR (400 MHz, DMSO-d6) 8 11.57 (d, J= 12.2 Hz, IH), 8.64 (d, J= 12.2 Hz, IH), 8.00 (dd, J= 9.1, 4.6 Hz, IH), 7.77 (dd, J = 8.6, 2.8 Hz, IH), 7.70 (td, J = 8.6, 2.8 Hz, IH), 1.69 (s, 6H).

[00292] Step B: The mixture of 5-({[4-fluoro-2-(trifluoromethyl)phenyl]amino}methylidene)- 2, 2-dimethyl-l,3-dioxane-4, 6-dione (870 mg, 2.61 mmol) in (phenyloxy)benzene (10 mL) was stirred at 200 °C for Ih. The cooled mixture was diluted with PE and purified by FCC, eluting with EA/PE (5%- 100%) to give 6-fluoro-8-(trifluoromethyl)quinolin-4-ol (560 mg, 2.42 mmol, 93%) as a yellow solid. LCMS: ESI m/z 232 [M+H]⁺.

[00293] Step C: The mixture of 6-fluoro-8-(trifluoromethyl)quinolin-4-ol (150 mg, 0.65 mmol) in POCI3 (2 mL) was stirred at 110 °C for an hour. The mixture was concentrated. The residue was diluted with NaHCCL solution and extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by FCC, eluting with EA/PE (0-10%) to give 4-chloro-6-fluoro-8-(trifluoromethyl)quinoline (100 mg, 0.40 mmol, 62%) as a white solid. LCMS: ESI m/z 250 [M+H]⁺.

5-bromo-l-chloro-7-fluoroisoquinoline

[00294] Step A: To a solution of 3-bromo-5-fluoro-2-methylbenzoic acid (2.0 g, 8.58 mmol) in DMF (20 mL) was added HATU (4.89 g, 12.8 mmol), NH₄C1 (0.55 g, 10.30 mmol) and DIEA (4.5 mb, 25.75 mmol). The reaction was stirred at rt for 2h. The reaction mixture was quenched by water, and the mixture was extracted with EtOAc (30 mL*3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient:0-50%) afford 3 -bromo-5-fluoro-2-methylbenzene-l -carboxamide (1.98 g, 8.53 mmol, 100%) as a yellow solid. LCMS: ESI m/z 232/234 [M + H]⁺.

[00295] Step B: To a solution of 3-bromo-5-fluoro-2-methylbenzene-l-carboxamide (1.98 g, 8.53 mmol) in THF (20 mL) was added DMF-DMA (2.4 mL, 17.24 mmol) at rt. The mixture was stirred at rt for 2h. The reaction mixture was concentrated and purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient:0-50%) afford (3- bromo-5-fluoro-2-methylphenyl){ [(E)-(dimethylamino)methylidene]amino}methanone (2 g, 6.97 mmol, 81%) as an yellow solid. LCMS: ESI m/z 287/289 [M + H]⁺.

[00296] Step C: To a solution of (3 -bromo-5-fluoro-2-m ethylphenyl) {[(E)- (dimethylamino)methylidene]amino}methanone (2.0 g, 6.965 mmol) in THF (5 mL) was added potassium 2-methylpropan-2-olate (10.5 mL, 10.45 mmol) at rt. The mixture was stirred at 70 °C for 5 h. The reaction mixture was quenched by water, and the mixture was extracted with EtOAc (30 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%) afford 5-bromo-7-fluoro-l,2-dihydroisoquinolin-l-one (1.3 g, 5.37 mmol, 77%) as a white solid. LCMS: ESI m/z 242/244 [M + H]⁺.

[00297] Step D: A solution of 5-bromo-7-fluoro-l,2-dihydroisoquinolin-l-one (1.3 g, 5.37 mmol) in dichlorophosphinyl chloride (13 mL) was heated 100 °C for 3h. The reaction mixture was concentrated and then quenched by saturated NaHCCL, extracted with EA (three times). The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient:0-20%) afford 5-bromo-l-chloro-7-fluoroisoquinoline (1.0 g, 3.84 mmol, 72%) as a white solid. LCMS: ESI m/z 260/262 [M + H]⁺. l-chloro-7-methyl-5-(trifluoromethyl)isoquinoline

[00298] Step A: 2-methyl-3-(trifluoromethyl)benzoic acid (5 g, 24.5 mmol) was dissolved in H2SO4 (50 mL). l,3-diiodo-5,5-dimethylimidazolidine-2, 4-dione (4.84 g, 12.7 mmol) was added at rt. The mixture was stirred at rt for 2 h. The reaction mixture was poured into ice-water. The resulting mixture was filtered. The filter cake was dried to obtain the desired product 5-iodo-2- methyl-3-(trifluoromethyl)benzoic acid (7 g, 21.2 mmol, 87%) as a light yellow solid. LCMS: ESI m/z 329 [M -H]⁺.

[00299] Step B: To a solution of 5-iodo-2-methyl-3-(trifluoromethyl)benzoic acid (3.5 g, 10.6 mmol) in DMF (55 mL) was added TEA (5.37 g, 53.0 mmol) and HATU (4.03 g, 10.6 mmol). The mixture was stirred at rt for lOmin, then ammonium chloride (1 .13 g, 21 .2 mmol) was added. The mixture was stirred at rt for 16h, then diluted with EA and H2O. The organic layer was wash with aqueous NaCl for 5 time. The organic layer was separated dried over Na2SC>4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0%~50%) to afford 5-iodo-2-methyl-3- (trifluoromethyl)benzene-l-carboxamide (2.3 g, 6.99 mmol, 66%) as a brown solid. LCMS: ESI m/z 330 [M + H] ¹.

[00300] Step C: A solution of 5-iodo-2-methyl-3-(trifluoromethyl)benzene-l-carboxamide (1.5 g, 4.56 mmol) in DMF-DMA (15 mL) was stirred at 100 °C for 2h. The mixture was concentrated to afforded { [(Z)-(dimethylamino)methylidene]amino}[5-iodo-2-methyl-3- (trifluoromethyl)phenyl]methanone (1.6 g, 4.16 mmol, 91%). The residue was used in the next step directly without further purification. LCMS: ESI m/z 385 [M + H]L

[00301] Step D: To a solution of {[(Z)-(dimethylamino)methylidene]amino}[5-iodo-2- methyl-3-(trifluoromethyl)phenyl]methanone (1.71 g, 4.45 mmol) in THF (20 mL) was added t- BuOK (0.60 g, 5.34 mmol). The mixture was stirred at 50 °C for Ih, then diluted with EA and H2O. The organic layer was separated dried over Na?SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl MeOH in DCM (gradient: 0%~10%) to afford 7-iodo-5-(trifluoromethyl)-l,2-dihydroisoquinolin-l-one (1.2 g, 3.54 mmol, 79%) as a brown solid. LCMS: ESI m/z 340 [M + H]⁺.

[00302] Step E: A solution of 7-iodo-5-(trifluoromethyl)-l,2-dihydroisoquinolin-l-one (500 mg, 1.48 mmol), 5-fhioro-3-(trifluoromethyl)benzene-l-carboxamide (108 mg, 0.523 mmol), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (278 mg, 2.21 mmol), Pd(dppf)C12 (108 mg, 0.147 mmol), K2CO3 (509 mg, 3.69 mmol), dioxane (5 mL) and H2O (1 mL) was stirred at 90 °C under N2 for 16h. 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 afford crude 7-methyl-5-(trifluoromethyl)-l,2-dihydroisoquinolin-l-one (250 mg, 1.10 mmol, 75%) as a brown solid. LCMS: ESI m/z 228 [M + H]⁺.

[00303] Step F: A solution of 7-methyl-5-(trifluoromethyl)-l,2-dihydroisoquinolin-l-one (200 mg, 0.880 mmol) in POCI3 (2 mL) was stirred at 100 °C for Ih. The cooled reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford l-chloro-7-methyl- 5-(trifluoromethyl)isoquinoline (120 mg, 0.489 mmol, 55%) as a brown solid. LCMS: ESI m/z 246 [M + H]-. l-chloro-5-(difluoromethyl)-7-fluoroisoquinoline

[00304] Step A: To a solution of 5-bromo-l-chloro-7-fluoroisoquinoline (600 mg, 2.30 mmol) in THF (8 mL) was added n-BuLi (2.5 M, 1.84 mL, 4.61 mmol) at -68 °C. The reaction was stirred at -68 °C for 20 min. Then DMF (0.278 mL, 3.455 mmol) was added at -68 °C. The reaction was stirred at -68 °C for 30 min. LCMS showed the reaction was completed. The reaction mixture was quenched by saturated NH4CI, and the mixture was extracted with EtOAc (30 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:0-30%) afford l-chloro-7-fluoroisoquinoline-5-carbaldehyde (250 mg, 1.19 mmol, 52%) as a yellow solid. LCMS: ESI m/z 210 [M + H]⁺. 'H NMR (400 MHz, DMSO- d6) 5 10.45 (s, 1H), 8.96 - 8.84 (m, 1H), 8.56 - 8.47 (m, 2H), 8.39 (dd, J = 9.2, 2.0 Hz, 1H).

[00305] Step B: To a solution of l-chloro-7-fluoroisoquinoline-5-carbaldehyde (250 mg, 1.19 mmol) in DCM (5 mL) was added DAST (0.47 mL, 3.58 mmol) at 0 °C. The reaction was stirred at rt for 3h. LCMS showed the reaction was completed. The reaction mixture was quenched by ice-water, and the mixture was extracted with DCM (20 mL*3). The organic layer was washed with brine, dried over Na2SCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford l-chloro-5-(difluoromethyl)-7-fluoroisoquinoline (180 mg, 0.78 mmol, 65%) as a yellow solid. LCMS: ESI m/z 232 [M + H]⁺.

4-bromo-6-fluoro-8-(trifluoromethyl) isoquinoline

[00306] Step A. To a solution of 4-fluoro-2-(trifluoromethyl) benzene-l-carbaldehyde (5 g,

26.0 mmol) in THF (250 mL) was added 2-amino- 1,1 -dimethoxy ethane (3.28 g, 31.2 mmol) at RT. The reaction mixture was stirred for 2h. Sodium cyanoborohydride (3.27 g, 52.1 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature under N2 for overnight. The reaction was complete detected by TLC. The reaction mixture was poured into 60 mL of water and extracted with 60 mL EA. The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography eluted with DCM: MeOH=10: 1 to afford 2-({ [4-fhioro-2-(trifluoromethyl) phenyl] methyl] amino)- 1,1 -dimethoxy ethane (4 g, 14.2 mmol, 54%) as a yellow oil. LCMS: ESI m/z 282 [M + H]⁺.

[00307] Step B. To a solution of sulfurochloridic acid (15 mL) was added 2-({[4-fluoro-2- (trifluoromethyl) phenyl] methyl] amino)- 1,1 -dimethoxy ethane (1.5 g, 5.33 mmol) slowly at 0 °C. The reaction mixture was stirred at 90 °C for 1 hr. On completion, the reaction mixture was added into ice water (100 mL), and extracted with DCM (40 mL). To the aqueous phase was add NaOH (I N) until the pH=8, then extracted with DCM (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-20%, EtOAc in PE) to give 6-fluoro-8-(trifluoromethyl) isoquinoline (360 mg, 1.67 mmol, 31%) as a brown solid. LCMS: ESI m/z 216 [M + H]⁺.

[00308] Step C. To a stirred solution of 6-fluoro-8-(trifluoromethyl) isoquinoline (300 mg, 1.020 mmol) in acetic acid (2 mL) was added NBS (236 mg, 1.33 mmol) at rt. After stirred at 80 °C for Ih, the mixture was poured into ice-water (lOmL) and extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-20%, EtOAc in PE) to give 4-bromo-6-fluoro-8-(trifluoromethyl) isoquinoline (250 mg, 0.850 mmol, 83 %) as a white solid. LCMS: m/z 294 [M+H]⁺. l-chloro-7-fluoro-5-(trifluoromethyl)phthalazine

Step A Step B Step C

[00309] Step A: To a solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (10 g, 38 mmol) in DMSO (60 mL) and MeOH (60 mL) was added TEA (11 mL, 78 mmol) and bis[5- (diphenylphosphanyl)cyclopenta-l,3-dienyl]-X2-iron(II) palladium chloride (2 g, 2.7 mmol), and the mixture was stirred at 80 °C under CO overnight. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na?SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0- 10% ethyl acetate in petroleum ether to afford the title compound methyl 2-amino-5-fluoro-3- (trifluoromethyl)benzoate (10 g, 38 mmol, 98%) as a light oil. LCMS: ESI m/z 238 [M + H]⁺.

[00310] Step B: To a solution of methyl 2-amino-5-fluoro-3-(trifluoromethyl)benzoate (10 g, 42 mmol) in CH3CN (150 mL) was added HBr (47%, 22 g, 127 mmol) and NaNCh (3.78 g, 54.8 mmol), and the mixture was stirred at 25 °C for 1 h. Then CuBr (9.07 g, 63.3 mmol) was added, and the mixture was stirred at 70 °C for 2 h. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with saturated NaHCCL, brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0- 10% ethyl acetate in petroleum ether to afford the title compound methyl 2-bromo-5-fluoro-3- (trifluoromethyl)benzoate (7 g, 23.3 mmol, 55%) as a light oil. ^XH NMR (400 MHz, DMSO-d6) 5 7.98-7.92 (m, 2H), 3.91 (s, 3H).

[00311] Step C: To a solution of 2-bromo-5-fluoro-3-(trifluoromethyl)benzoate (7 g, 23.3 mmol) in dioxane (10 mL) and H2O (1 mL) was added 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane (11.68 g, 46.507 mmol), Pd(dppf)Ch (1.70 g, 2.33mmol) and K^CCL (6.43 g, 46.5 mmol), and the mixture was stirred at 90 °C under N2 for 4 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 silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford the title compound methyl 5-fluoro- 2-methyl-3-(trifhioromethyl)benzoate (5.2 g, 22 mmol, 95%) as a light oil. ^JH NMR (400 MHz, DMSO-d6) 8 7.81 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 2.48 (s, 3H).

[00312] Step D: To a solution of methyl 5-fluoro-2-methyl-3-(trifluoromethyl)benzoate (5.2 g, 22 mmol) in CCU (50 mb) was added NBS (4.31 g, 24.2 mmol) and benzoic peroxyanhydride (0.53 g, 2.2 mmol), and the mixture was stirred at 90 °C for 4 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 silica gel column chromatography eluting with 0- 30% ethyl acetate in petroleum ether to afford the title compound methyl 2-(bromomethyl)-5- fluoro-3-(trifluoromethyl)benzoate (6 g, 19 mmol, 86%) as a light oil.

[00313] Step E: To a solution of methyl 2-(bromomethyl)-5-fluoro-3- (trifluoromethyl)benzoate (3 g, 9.5 mmol) in CH3CN (30 mL) was added NMO (2.23 g, 19 mmol), and the mixture was stirred at 50 °C for 3 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 0-30% ethyl acetate in petroleum ether to afford the title compound methyl 5-fluoro-2-formyl-3-(trifluoromethyl)benzoate (1.1 g, 4.4 mmol, 46%) as a light oil. LCMS: ESI m/z 251 [M + H]⁺.

[00314] Step F: To a solution of methyl 5-fluoro-2-formyl-3-(trifluoromethyl)benzoate (500 mg, 2 mmol) in DCE (15 mL) was added 2,2,2-trifluoroacetic acid (3 mL, 40 mmol) and aminoammonium hydroxide (0.15 mL, 2.2 mmol). The mixture was stirred at 70 °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 0-50% ethyl acetate in petroleum ether to afford the title compound 7-fluoro-5- (trifluoromethyl)phthalazin-l(2H)-one (100 mg, 0.43 mmol, 22%) as a yellow oil. LCMS: ESI m/z 233 [M + H]⁺.

[00315] Step G: A solution of 7-fluoro-5-(trifluoromethyl)phthalazin-l(2H)-one (100 mg, 0.43 mmol) in POCI3 (3 mL, 33 mmol) was stirred at 100 °C for 1 hour. The mixture was concentrated under vacuum to afford the title compound l-chloro-7-fluoro-5- (trifluoromethyl)phthalazine (80 mg, 0.32 mmol, 74%) as a yellow oil. LCMS: ESI m/z 251 [M + H]⁺. l-chloro-5,7-difluoroisoquinoline

[00316] Step A: To a solution of 3,5-difluoro-2-methylbenzoic acid (1 g, 5.81 mmol) in DMF (10 mL) were added NH₄C1 (0.37 g, 6.97 mmol), HATU (3.31 g, 8.71 mmol), and DIEA (2.25 g, 17.4 mmol). The reaction was stirred at rt under IShfor 2 hr. LCMS showed the reaction was completed. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO₄ and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 45-55%) to afford 3,5-difluoro-2-methylbenzene-l-carboxamide (900 mg, 5.26 mmol, 91%) as a white solid.

LCMS: 172[M-H]’.

[00317] Step B: A solution of 3,5-difluoro-2-methylbenzene-l-carboxamide (200 mg, 1.17 mmol) in DMF -DMA (3 mL) was stirred at 120 °C under N2 for 2 hr. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated to afford (3,5-difluoro-2- methylphenyl){[(E)-(dimethylamino)methylidene]amino}methanone (150 mg, 0.663 mmol, 57%) as a yellow solid. LCMS: 227 [M-H]’.

[00318] Step C: To a solution of (3,5-difluoro-2-methylphenyl){[(E)- (dimethylamino)methylidene]amino}methanone (50 mg, 0.221 mmol) in THF (3 mL) were added potassium 2-methylpropan-2-olate (49.6 mg, 0.442 mmol). The reaction was stirred at 70 °C under N2 for 1 hr. LCMS showed the reaction was 30%DP and 30% SM. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO₄ and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 45-55%) to afford the title compound 5,7- difluoro-l,2-dihydroisoquinolin-l-one (5 mg, 0.028 mmol, 12%) as a white solid. LCMS: ESI m/z 182 [M+H]⁺.

[00319] Step D: A mixture of 5,7-difluoro-l,2-dihydroisoquinolin-l-one (40 mg, 0.221 mmol) in POCI3 (5 mL) was stirred at 90 °C under N2 for 1 hr. LCMS showed the reaction was 80% DP. The cooled reaction mixture was concentrated, diluted aqueous NaHCO? and extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to afford l-chloro-5,7-difluoroisoquinoline (30 mg, 0.150 mmol, 68%) as a yellow solid. LCMS: ESI m/z 200 [M + H]⁺. l-chloro-7-fluoro-5-methylbenzo[2,l-d][l,2]diazine

O ^B O ,B._O B, POCI₃, 110 °C, 30 min

Pd(dppf)CI₂, K₂CO₃ dioxane/ H₂O Step E 100 ° C, O/N

Step D

[00320] Step A. To a stirred solution of methyl 3-bromo-5-fluoro-2-methylbenzoate (4.2 g, 17.8 mmol) in CC1₄ (30 mL) was added NBS (4.3 g, 24.3 mmol) and BENZOYL PEROXIDE (49 mg, 0.2 mmol) at rt. After stirred at 80 °C overnight, the cooled mixture was poured into brine (20 mL) and extracted with DCM (20 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-25 %, EtOAc in PE) to give methyl 3-bromo-2-(bromomethyl)- 5-fluorobenzoate (5.3 g, 16.2 mmol, 91 %) as a white solid. ^!H NMR (400 MHz, DMSO-d6) 8 7.97 (dd, J = 8.0, 2.8 Hz, 1H), 7.71 (dd, J = 8.9, 2.7 Hz, 1H), 5.00 (s, 2H), 3.90 (s, 3H)

[00321] Step B. To a stirred solution of methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (5.3 g, 16.2 mmol) in ACN (30 mL) was added NMO (3.8 g, 32.5 mmol) at rt. After stirred at rt for 2h, the cooled mixture was poured into brine (30 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated until there was no more drops. The residue was purified by chromatography (silica gel, 0-35 %, EtOAc in PE) to give methyl 3-bromo-5-fluoro-2-formylbenzoate (3 g, 1 1 .5 mmol, 71 %) as a colorless oil. ’H NMR (400 MHz, DMSO-d6) 8 10.20 (s, 1H), 8.02 (dd, J = 8.2, 2.5 Hz, 1H), 7.71 (dd, J = 8.5, 2.4 Hz, 1H), 3.85 (s, 3H).

[00322] Step C. To a stirred solution of methyl 3-bromo-5-fluoro-2-formylbenzoate (3 g, 11.5 mmol) in DCE (25 mL)/ TFA (5 mL) was added hydrazine (3.6 mL, 115 mmol) at rt. After stirred at rt for 3h, the cooled mixture was poured into brine (30 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 45 %, EtOAc in PE) to give 5-bromo-7-fluoro-l,2-dihydrobenzo[2,l-d][l,2]diazin-l-one (2.2 g, 9.1 mmol, 79 %) as a white solid. LCMS: m/z 243 [M+H]'. ’H NMR (400 MHz, DMSO-d6) 6 13.01 (s, 1H), 8.39 (s, 1H), 8.27 (dd, J= 8.4, 2.6 Hz, 1H), 7.96 (dd, J= 8.4, 2.6 Hz, 1H).

[00323] Step D. To a stirred solution of 5-bromo-7-fluoro-l,2-dihydrobenzo[2,l- d][l,2]diazin-l-one (200 mg, 0.82 mmol) in dioxane (5 mL)/ H2O (1 mL) was added 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane (310 mg, 2.5 mmol), Pd(dppf)Ch (60 mg, 0.08 mmol) and K2CO3 (341 mg, 2.4 mmol) at rt. After stirred at 100 °C overnight, the cooled mixture was poured into brine (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated until there was no more drops. The residue was purified by chromatography (silica gel, 0- 45 %, EtOAc in PE) to give 7-fluoro-5-methyl-l,2-dihydrobenzo[2,l-d][l,2]diazin-l-one (50 mg, 0.28 mmol, 34 %) as a white solid. LCMS: m/z 179 [M+H]-.

[00324] Step E. A mixture of 7-fluoro-5-methyl-l,2-dihydrobenzo[2,l-d][l,2]diazin-l-one (50 mg, 0.28 mmol) in POCI3 (3 mL) was stirred at 110 °C for 30 min. The mixture was concentrated to give crude l-chloro-7-fluoro-5-methylbenzo[2,l-d][l,2]diazine (50 mg, 0.25 mmol, 90 %) as a brown solid which may be used directly in the next step. LCMS: m/z 197 [M+H]⁺.

4-chloro-6-fluoro-2-methyl-8-(trifluoromethyl) quinazoline [00325] Step A: To 2-amino-5-fluoro-3-(trifluoromethyl) benzoic acid (2 g, 8.96 mmol) was added acetamide (25.3 mL) at rt. After stirred at 190 °C for 15 h, the cooled mixture was poured into water (200 mL) and extracted with EA (100 mL*3). The combined organic phase was washed with brine, dried with Na2SCU, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 6-fluoro-2-methyl-8-(trifluoromethyl)- 3,4-dihydroquinazolin-4-one (500 mg, 2.03 mmol, 22%) as a yellow solid. LCMS: m/z 247 [M+H]⁺

[00326] Step B: A mixture of 6-fhioro-2-methyl-8-(trifluoromethyl)-3,4-dihydroquinazolin-4- one (20 mg, 0.081 mmol) in POCE (1 mL) was stirred at 140 °C for 4h. The mixture was concentrated to give crude 4-chloro-6-fluoro-2-methyl-8-(trifluoromethyl) quinazoline (20 mg, 0.076 mmol, 93%) as a brown solid. LCMS: m/z 265 [M+H]⁺. l-chloro-7-fluoro-5-(fluoromethyl)benzo[2,l-d][l,2]diazine

[00327] Step A. To a stirred solution of 5-bromo-7-fluoro-l,2-dihydrobenzo[2,l- d][l,2]diazin-l-one (500 mg, 2.05 mmol) in dioxane (12 mL) was added (tributyl-X⁴- stannanyl)methanol (990 mg, 3.08 mmol) and dioxane (12 mL) at rt. After stirred at 110 °C overnight, the cooled mixture was quenched with brine (30 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 90 %, EtOAc in PE) to give crude 7-fhioro-5-(hydroxymethyl)-l,2-dihydrobenzo[2,l-d][l,2]diazin-l- one (210 mg, 0.86 mmol, 42%) as a brown solid. LCMS: m/z 195 [M+H]⁺.

[00328] Step B. A mixture of 7-fluoro-5-(hydroxymethyl)-l,2-dihydrobenzo[2, 1- d][l,2]diazin-l-one (200 mg, 1.03 mmol) in DAST (2 mL) was stirred at 0 °C under N2 atmosphere for 2 h. The mixture was quenched with ice-water and extracted with EtOAc (10 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, 0-35 %, EtOAc in PE) to give 7-fluoro-5-(fluoromethyl)-l,2-dihydrobenzo[2,l-d][l,2]diazin-l-one (50 mg, 0.25 mmol, 24%) as a white solid. LCMS: ESI m/z 197 [M + H]⁺.

[00329] Step C. A mixture of 7-fluoro-5-(fluoromethyl)-l,2-dihydrobenzo[2,l-d][l,2]diazin- 1-one (50 mg, 0.25 mmol) in POCI3 (3 mL) was stirred at 110 °C for 30 min. The cooled mixture was concentrated to give crude l-chloro-7-fluoro-5-(fluoromethyl)benzo[2,l-d][l,2]diazine (50 mg, 0.23 mmol, 91%) as a brown solid. LCMS: m/z 215 [M+H]⁺.

4-chloro-6-fluoro-8-(trifluoromethyl)cinnoline

[00330] Step A: To a solution of l-(2-amino-5-fluorophenyl)ethan-l-one (6.5 g, 42 mmol) in DCM (300 mL) was added NIS (12.4 g, 55.2 mmol) at rt. After stirred at rt for 24 h, the mixture was poured into water (200 mL) and extracted with DCM (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, 0-10%, EtOAc in PE) to give l-(2- amino-5-fluoro-3-iodophenyl) ethan-l-one (8 g, 28.7 mmol, 67%) as a brown solid. LCMS: m/z 280 [M+H]⁺ .

[00331] Step B: To a solution of l-(2-amino-5-fluoro-3 -iodophenyl) ethan-l-one (3.2 g, 11 mmol) in HC1 (6 mL) and H2O (1 mL) was cooled to -5 °C and a diazotized by the dropwise addition of a solution of sodium nitrite (0.87 g, 12 mmol) in H2O (1 mL). After stirring at -5 °C for another 1 hour, transfer the mixture to a preheated bath at 60 ⁰ C and react for 1 hour. The mixture was concentrated under vacuum to remove HC1. The residue was diluted with saturated aqueous NaHCCL. The following mixture was filtered. The filter cake was dried to give 6-fluoro- 8-iodocinnolin-4-ol (2.6 g, 8.96 mmol, 78%) as a brown solid. LCMS: ESI m/z 291 [M + H]⁺. [00332] Step C: To a stirred solution of 6-fluoro-8-iodocinnolin-4-ol (7 g, 24.1 mmol) in DMF (70 mL) was added 4-(chl orom ethyl)- 1 -methoxybenzene (4.91 g, 31.3 mmol) and K2CO3 (10 g, 72.4 mmol) at rt. After stirred at 60 °C for 2 h, the mixture was poured into water (100 mL) and extracted with EtOAc (300 mL*3). The combined organic phase was washed with brine, dried with NaiSCU, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 6-fluoro-8-iodo-4-{[(4- methoxyphenyl) methyl] oxy} cinnoline (9 g, 21.9 mmol, 90%) as a brown solid. LCMS: m/z 411 [M+H]⁺.

[00333] Step D: To a solution of 6-fluoro-8-iodo-4-{[(4- methoxyphenyl)methyl]oxy}cinnoline (2.4 g, 5.85 mmol) and methyl 2,2-difluoro-2- (fluorodioxo-X6-sulfanyl)acetate (3.37 g, 17.5 mmol) in DMA (30 mL) was added Cui (2.23 g, 11.7 mmol). The mixture was stirred at 100 °C under N2 for 12 hours. The mixture was concentrated under vacuum to remove DMA. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 80 %) to afford 6-fluoro-l-[(4- methoxyphenyl)methyl]-8-(trifluoromethyl)-l,4-dihydrocinnolin-4-one (1.3 g, 3.69 mmol, 63%) as a brown solid. LCMS: ESI m/z 353.2 [M + H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 8.61 (d, J= 1.2 Hz, 1H), 8.19 (d, J= 8.2 Hz, 1H), 7.99 (d, J= 8.2 Hz, 1H), 7.55 (d, J= 7.6 Hz, 2H), 6.96 (d, J= 7.6 Hz, 2H), 5.59 (s, 2H), 3.74 (d, J= 1.2 Hz, 3H).

[00334] Step E: To a solution of 6-fluoro-4-{[(4-methoxyphenyl)methyl]oxy}-8- (trifluoromethyl)cinnoline (1.2 g, 3.41 mmol) in TFA (10 mL) was added trifluoromethanesulfonic acid (0.5 mL). The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under vacuum to give 6-fluoro-8-(trifluoromethyl)-3,4- dihydrocinnolin-4-ol (790 mg, 3.37 mmol, 99%) as a brown solid. LCMS: ESI m/z 233.2 [M + H]⁺.

[00335] Step F: A solution of 6-fluoro-8-(trifluoromethyl)cinnolin-4-ol (790 mg, 3.40 mmol) in POCI3 (10 mL) was stirred at 90 °C for 1 hour. The mixture was concentrated under vacuum to give a crude, which was diluted with saturated NaHCCL, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to give 4-chloro-6- fluoro-8-(trifluoromethyl)cinnoline (850 mg, 3.39 mmol, 99%) as a black solid. LCMS: ESI m/z 251.1 [M + H]~.

4-chloro-8-(difluoromethyl)-6-fluoroquinazoline

Step F Step G Step H

[00336] Step A: A solution of 2-amino-3-bromo-5-fluorobenzoic acid (10 g, 42.7 mmol) in azanecarbaldehyde (100 mb) was stirred at 150 °C for 6h. The reaction mixture was cooled to room temperature and then poured into ice-water (80 mb). The formed precipitate was filtered to afford the crude product, which was washed with water to give 8-bromo-6-fluoro-3,4- dihydroquinazolin-4-one (8 g, 32.9 mmol, 77%) as a brown solid. LCMS: ESI m/z 243 [M + H]⁺.

[00337] Step B: A solution of 8-bromo-6-fluoro-3,4-dihydroquinazolin-4-one (2 g, 8.23 mmol) in dichlorophosphinyl chloride (20 mb) was stirred at 100 °C for 5h. The cooled mixture was concentrated to give 8-bromo-4-chloro-6-fluoroquinazoline (2 g, 7.65 mmol, 93%) as a yellow solid, which could be used without further purification. ESI m/z 261 [M + H]⁺. [00338] Step C: To a solution of 8-bromo-4-chloro-6-fluoroquinazoline (2 g, 7.65 mmol) in MeOH (20 mb) was added MeONa (9.2mL, 9.2 mmol, 1 moL/L in MeOH) at 0 °C. The reaction mixture was stirred at rt for 1 h. The mixture was concentrated and purified using silica gel column chromatography eluted with EA in PE (gradient: 0-10%) to give 8-bromo-6- fluoro-4-methoxyquinazoline (1.6 g, 6.22 mmol, 81%) as a white solid. LCMS: ESI m/z 257/259 [M + H] ¹ .

[00339] Step D: To a solution of 8-bromo-6-fluoro-4-methoxyquinazoline (1.6 g, 6.22 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added potassium vinyltrifluoroborate (1.25 g, 9.34 mmol), K2CO3 (1.72 g, 12.45 mmol) and Pd(dppf)C12 (0.46 g, 0.62 mmol). The reaction was stirred at 100 °C under N2 for 2h. The reaction mixture was concentrated and purified using silica gel column chromatography eluted with EA in PE (gradient: 0-20%) to give 6-fluoro-4- methoxy-8-vinylquinazoline (1.1 g, 5.39 mmol, 87%) as a white solid. LCMS: ESI m/z 205 [M + H]⁺.

[00340] Step E: To a solution of 6-fluoro-4-methoxy-8-vinylquinazoline (1.1 g, 5.39 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added K2OSO4 (0.20 g, 0.54 mmol) and NalCL (4.84 g, 22.63 mmol). The reaction was stirred at rt for 3h. The solution was filtered through a pad of celite and the celite was thoroughly washed with EA. Then the resulted filtrate was concentrated. The residue was purified using silica gel column chromatography eluting with PE in EA (gradient: 0-25%) to give 6-fluoro-4-methoxyquinazoline-8-carbaldehyde (360 mg, 1.75 mmol, 32%) as a white solid. LCMS: ESI m/z 207 [M + H]⁺.

[00341] Step F: To a solution of 6-fluoro-4-methoxyquinazoline-8-carbaldehyde (360 mg, 1.75 mmol)) in DCM (5 mL) was added DAST (0.5 mL, 3.5 mmol) at 0 °C. The mixture was stirred at rt for 3h. After completion, the mixture was quenched with ice-water. The mixture was extracted with DCM (15 mLx3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 0-20%) to give 8-(difluoromethyl)-6-fluoro-4- methoxyquinazoline (320 mg, 1.4 mmol, 80%) as a yellow solid. LCMS: ESI m/z 229 [M + H]⁺.

[00342] Step G: To a solution of 8-(difluoromethyl)-6-fluoro-4-methoxyquinazoline (100 mg, 0.44 mmol) in MeCN (3 mL) was added TMSI (0.2 mL, 2.19 mmol) at rt. The mixture was stirred at 50 °C for Ih. The reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to give 8- (difluoromethyl)-6-fluoroquinazolin-4-ol (80 mg, 0.37 mmol, 85%) as a yellow solid. LCMS: ESI m/z 215 [M + H]⁺.

I l l [00343] Step H: A solution of 8-(difluoromethyl)-6-fluoroquinazolin-4-ol (80 mg, 0.37 mmol) in POCI3 (2 mL) was heated 110 °C for 3h. The cooled mixture was concentrated to give 4-chloro-8-(difluoromethyl)-6-fluoroquinazoline (80 mg, 0.34 mmol, 92%) as a yellow solid, which was used without further purification.

4-chloro-8-(difluoromethyl)-6-fluorocinnoline

[00344] Step A: To a stirred solution of 6-fluoro-8-iodo-l-[(4-m ethoxyphenyl) methyl]-l,4- dihydrocinnolin-4-ol (3 g, 7.27 mmol) in H2O (1 mL) and dioxane (3 mL) was added potassium trifhioro(vinyl)borate (130.03 mg, 0.970 mmol), Pd(dppf)Ch (0.53 g, 0.728 mmol) and K2CO3 (3.02 g, 21.834 mmol) at rt. After stirred at 100 °C under N2 for Ih, the cooled mixture was poured into water (20 mL) and extracted with EtOAc (30 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, 0-100%, EtOAc in PE) to give 6-fluoro-l-[(4-methoxyphenyl) methyl]-8-vinyl-l,4-dihydrocinnolin-4-ol (900 mg, 2.88 mmol, 39%) as a yellow solid. LCMS: m/z 311 [M+H]⁺.

[00345] Step B: To a stirred solution of 6-fluoro-l-[(4-m ethoxyphenyl) methyl]-8-vinyl-l,4- dihydrocinnolin-4-ol (900 mg, 2.88 mmol) in H2O (0.6 mL) and dioxane (3 mL) was added NaIO4 (2481 mg, 11.6 mmol) and K2OSO4 (96.83 mg, 0.290 mmol) at rt. After stirred at rt for 3h, the mixture was poured into water (20 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-100%, EtOAc in PE) to give 6-fluoro- 4-hydroxy-l-[(4-methoxy phenyl) methyl]- l,4-dihydrocinnoline-8-carbaldehy de (500 mg, 1.59 mmol, 55 %) as a yellow solid. LCMS: m/z 313 [M+H]⁺ [00346] Step C: To a stirred solution of 6-fluoro-l-[(4-methoxyphenyl) methyl]-4- oxocinnoline-8-carbaldehyde (250 mg, 0.801 mmol) in DCM (5 mL) was added DAST (387 mg, 2.40 mmol) at rt. After stirred at rt for O/N, the mixture was poured into ice-water (20 mL) and extracted with EtOAc (30 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, 0-100%, EtOAc in PE) to give 8-(difluoromethyl)-6-fluoro-l-[(4-methoxyphenyl) methyl]- l,4-dihydrocinnolin-4-one (150 mg, 0.449 mmol, 56%) as a yellow solid. LCMS: m/z 335 [M+H]⁺

[00347] Step D: To a solution of 8-(difluoromethyl)-6-fluoro-l-[(4-m ethoxyphenyl) methyl]- l,4-dihydrocinnolin-4-one (150 mg, 0.449 mmol) in TFA (3 mL) was added TfOH (0.5 mL, 5.65 mmol). The mixture was stirred at 55 °C for 2 hours. The mixture was concentrated. The residue was diluted with saturated aqueous NaHCOa, extract with EA. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated to obtain 8-(difluoromethyl)-6- fluoro-l,4-dihydrocinnolin-4-one (90 mg, 0.420 mmol, 90%) as a yellow solid. LCMS: ESI m/z 215 [M + H]-.

[00348] Step E: A solution of 8-(difluoromethyl)-6-fluoro-l,4-dihydrocinnolin-4-one (90 mg, 0.420 mmol) in POCI3 (1 mL) was stirred at 140 °C for 4h. The cooled mixture was concentrated to give crude 4-chloro-8-(difluoromethyl)-6-fluorocinnoline (70 mg, 0.301 mmol, 70%) as a brown solid. LCMS: m/z 233 [M+H]⁺.

4-chloro-6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazine p

[00349] Step A: To a solution of 2-amino-5-fluoro-3-(trifluoromethyl)benzoic acid (2 g, 8.9mmol) in DMF (20 mL) was added NH4CI (0.58 g, 10.7 mmol), DIEA (3.48 g, 26.9 mmol) and HATU (5.11 g, 13.4 mmol). The reaction 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 0-50% ethyl acetate in petroleum ether to afford 2-amino-5-fluoro-3-(trifluoromethyl)benzamide (2 g, 8.1 mmol, 90%) as a white solid. LCMS: ESI m/z 223 [M + H]⁺.

[00350] Step B: To a solution of 2-amino-5-fhioro-3-(trifluoromethyl)benzamide (2 g, 9 mmol) in DMF (30 mL) was added HC1 (2M, 15 mL, 30 mmol) and sodium nitrite (0.75 g, 10.8 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with EA and washed with NaHCCh and brine. The organic layer was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford 6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazin-4(3H)-one (1 g, 4.29 mmol, 47%) as a white solid. LCMS: ESI m/z 234 [M + H]⁺.

[00351] Step C: A solution of 6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazin-4(3H)-one (200 mg, 0.86 mmol) in POCI3 (4 mL, 42.8 mmol) was stirred at 140 °C for 5h. The mixture was diluted with EA and washed with NaHCCL and brine. The organic layer was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford 4-chloro-6-fluoro-8- (trifluoromethyl)benzo[d][l,2,3]triazine (60 mg, 0.24 mmol, 27%) as a yellow solid. LCMS: ESI m/z 252 [M + H]⁺.

3-bromo-5-fluoro-7-(trifluoromethyl)benzo[d]isothiazole

[00352] Step A: To a solution of methyl methyl 2-bromo-5-fluoro-3-

(trifluoromethyl)benzoate (2.0 g, 6.64 mmol) in MeOH (10 mb) was added Water (10 mL) and LiOH (557 mg, 13.2 mmol). The reaction mixture was stirred at rt for 1 hours. The mixture was concentrated under vacuum. Imol/L HC1 (10 mL) was added to adjust pH= 3-4. The following mixture was extracted with EA (10 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford the product 2-bromo-5-fluoro-3- (trifluoromethyl)benzoic acid (1.8 g, 94%). LCMS (ESI): m/z 287, 289 [M+H]⁺.

[00353] Step B: To a solution of 2-bromo-5-fhioro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.97 mmol) in 2-chloro-2-oxoacetyl chloride (20 mL, 6.97 mmol) was added one drop DMF at 0 °C, the reaction mixture was stirred at 70 °C for 2 hours. The mixture was concentrated. The cooled reaction mixture was quenched by NEL solution (10 mL), extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% EA in PE to afford 2-bromo-5-fluoro-3-(trifluoromethyl)benzamide (1.0 g, 50%). LCMS (ESI): m/z 303, 305 [M+H]⁺.

[00354] Step C: To to a solution of 2-bromo-5-fluoro-3-(trifluoromethyl)benzamide (500 mg, 1.75 mmol) in DMF (5 mL) was added S (896 mg, 3.50 mmol) and K2CO3 (362 mg, 2.62 mmol), the reaction mixture was stirred at 110 °C under N2 overnight. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% EA in PE to afford 5-fluoro-7- (trifluoromethyl)benzo[d]isothiazol-3(2H)-one (80 mg, 19%).. LCMS (ESI): m/z 238 [M+H]⁺. [00355] Step D: To a solution of 5-fluoro-7-(trifhioromethyl)benzo[d]isothiazol-3(2H)-one (30 mg, 0.13 mmol) in CH3CN (5 mL) was added POBn (181 mg, 0.63 mmol) at 0 °C, the reaction mixture was stirred at 80 °C for 6 hours. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to afford 3-bromo-5-fluoro-7-(trifluoromethyl)benzo[d]isothiazole (30 mg, 79%) which was used directly.

Synthetic procedure for examples:

Example 1: 6-(2-chloro-5-fluorophenyl)-5-{[7-fluoro-5-(trifluoromethyl)isoquinolin-l- yl] amino}-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrrolo [4,3-e] indazol-8-one

Pd₂(dba)₃, xant-phos, Cs₂CO₃, dioxane, 125 °C Step A

[00356] Step A. To a stirred solution of l-chloro-7-fluoro-5-(trifluoromethyl)isoquinoline (25 mg, 0.1 mmol) in dioxane (3 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (48 mg, 0.12 mmol), Pd2(dba)s (9 mg, 0.01 mmol), xant-PHOS (11 mg, 0.02 mmol) and CS2CO3 (65 mg, 0.2 mmol) at rt . After stirred at 125 °C under N2 for 2h, 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 ISfeSCL, filtered and concentrated. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) and then prep-HPLC (C18, 40 ~ 90 % MeCN in H₂O with 0.1 % TFA) to give 6- (2-chloro-5-fluorophenyl)-5-{[7-fluoro-5-(trifluoromethyl)isoquinolin-l-yl]amino}-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (10 mg, 0.016 mmol, 16 %) as a white solid. LCMS: ESI m/z 612 [M + H]T 'H NMR (400 MHz, DMSO-d6) 5 9.47 (s, 1H), 9.14 (s, 1H), 8.52 (s, 1H), 8.17 - 8.13 (m, 1H), 8.07 - 8.01 (m, 2H), 7.93 (s, 1H), 7.21 (s, 1H), 7.01 - 6.85 (m, 2H), 6.25 (brs, 1H), 5.90 (brs, 1H), 5.65 - 5.48 (m, 2H).

Example 2: 6-(2-chloro-5-fluorophenyl)-5-{[6-fluoro-8-(trifluoromethyl)imidazo[l,5- a]pyridin-3-yl]amino}-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one

[00357] Step A: To a solution of 3-bromo-5-fluoropyridine-2-carboxylic acid (10 g, 45.4 mmol) in THF (100 mL) was added DIEA (11.7 g, 90.9 mmol) and N,O-dimethylhydroxylamine (3.33 g, 54.5 mmol). Then HATU (17.3 g, 45.4 mmol) was added and the mixture was stirred at 20 °C for 3 hours. The mixture was concentrated under vacuum to remove THF. The mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography eluted with PE in EA (gradient: 0-25%) to afford 3-bromo-5-fluoro-N- methoxy-N-methylpyridine-2-carboxamide (11.42 g, 43.4 mmol, 95%) as a white solid. LCMS: ESI m/z 263 [M + H]⁺. [00358] Step B: To a solution of 3-bromo-5-fluoro-N-methoxy-N-methylpyridine-2- carboxamide (11.4 g, 43.4 mmol) in DMF (120 mb) was added methyl 2,2-difluoro-2- (fluorodioxo-X6-sulfanyl)acetate (25 g, 130 mmol) and Cui (16.5 g, 86.8 mmol). The mixture was stirred at 100 °C for 3 hours. The cooled reaction mixture was filtrated and concentrated under vacuum to remove DMF. The reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography eluted with PE in EA (gradient: 0~25%) to afford 5-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)pyridine-2-carboxamide (8.58 g, 34.0 mmol, 78 %) as a yellow oil. LCMS: ESI m/z 253.2 [M + H]⁺.

[00359] Step C: To a solution of 5-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)pyridine-

2-carboxamide (7.5 g, 29.7 mmol) in DCM (120 mL) was added DIBAL-H (39.6 mL, 59.5 mmol, 1.5 M in toluene) at -65 °C. The mixture was allowed to warm to rt and stirred at rt for 2 hours. The reaction mixture was quenched with MeOH and EA, filtrated and concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 5-fluoro-3-(trifluoromethyl)pyridine-2- carbaldehyde (6.5 g, 26.9 mmol, 90 %) as a yellow oil, which was used for next step without further purification. LCMS: ESI m/z 194.1 [M + H]⁺.

[00360] Step D: To a solution of 5-fluoro-3-(trifhioromethyl)pyridine-2-carbaldehyde (6.5 g, 33.7 mmol) in MeOH (100 mL) was added (2,4-dimethoxyphenyl)methanamine (6.75 g, 40.4 mmol) and sodium cyanoboranuide (4.23 g, 67.3 mmol). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted in water (100 mL) and concentrated under vacuum to remove MeOH. The residue was extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluted with EA in PE (gradient: 0-50%) to afford 2-({[(2,4- dimethoxyphenyl)methyl]amino}methyl)-5-fluoro-3-(trifluoromethyl)pyridine (4.2 g, 12.2 mmol, 36%) as a yellow oil. LCMS: ESI m/z 345.2 [M + H]⁺.

[00361] Step E: To a solution of 2-({[(2,4-dimethoxyphenyl)methyl]amino}methyl)-5-fluoro-

3-(trifhioromethyl)pyridine (1.8 g, 5.23 mmol) in TFA (20 mL) was added TfOH (40 mg, 0.261 mmol). The reaction mixture was stirred at 60 °C for 5 hours. The mixture was concentrated. The residue was poured into saturation NaHCCL, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0 - 10% MeOH/DCM to afford [5-fluoro-3- (trifluoromethyl)pyridin-2-yl]methanamine (600 mg, 3.09 mmol, 59 %) as a yellow solid. LCMS: ESI m/z 195.1 [M + H] ¹.

[00362] Step F: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (50 mg, 0.125 mmol) in THF (5 mL) was added 4-nitrophenyl chi orom ethanoate (25.3 mg, 0.125 mmol). The reaction mixture was stirred at 60 °C for 1 hour. The mixture was used for next step without purification. LCMS: ESI m/z 564.3 [M + H]⁺.

[00363] Step G: To a solution of 4-nitrophenyl {[6-(2-chloro-5-fluorophenyl)-8-oxo-3 -(2,2,2- trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]amino}methanoate (70 mg, 0.124 mmol) in THF (5 mL) was added [5-fluoro-3-(trifluoromethyl)pyridin-2-yl]methanamine (48.2 mg, 0.248 mmol) and TEA (25 mg, 0.248 mmol). The mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under vacuum to give a crude, which was purified by pre- TLC (PE/EA=1 :2) to give l-{ [6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroethyl)-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]amino}-N-{[5-fluoro-3-(trifluoromethyl)pyridin-2- yl]methyl}methanamide (35 mg, 0.057 mmol, 46 %) as a brown solid. LCMS: ESI m/z 619.3 [M + H]⁺.

[00364] Step H: A solution of l-{[6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroethyl)- 7,8-dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]amino}-N-{[5-fluoro-3-(trifluoromethyl)pyridin-2- yl]methyl (methanamide (10 mg, 0.016 mmol) in POCL (1 mL) was stirred at 80 °C for 1 hour. Then the mixture was stirred at 90 °C for 1 hour. The mixture was concentrated under vacuum to give a crude, which was purified by prep-HPLC to give 6-(2-chloro-5-fluorophenyl)-5-{[6- fluoro-8-(trifluoromethyl)imidazo[l,5-a]pyridin-3-yl]amino}-3-(2,2,2-trifluoroethyl)-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-8-one (1.0 mg, 0.002 mmol, 10 %) as a yellow solid. LCMS: ESI m/z 600.6 [M + H]⁺. ’H NMR (400 MHz, CD3OD) 8 8.51 (s, 1H), 7.55 (s, 1H), 7.40 - 7.33 (m, 2H), 7.19 -7.15 (m, 2H), 7.00 - 6.92 (m, 1H), 6.31 (brs, 1H), 5.76 (brs, 1H), 5.30 - 5.24 (m, 2H).

Example 3: 6-(2-chloro-5-fluorophenyl)-3-(2,2,2-trifluoroethyl)-5-{[5- (trifluoromethyl)isoquinolin-l-yl]amino}-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one

Example 3

[00365] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2,2-trifluoroethyl)-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-8-one (30 mg, 0.075 mmol) in dioxane (6 mL) was added 1- chloro-5-(trifluoromethyl)isoquinoline (26.14 mg, 0.113 mmol), CS2CO3 (49.0 mg, 0.150 mmol), Xant-phos (8.71 mg, 0.015 mmol) and Pd2(dba)a (6.89 mg, 0.008 mmol). The reaction mixture was stirred 120 °C under N2 for 2 h. 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 by prep-HPLC afford the title compound 6-(2-chloro-5- fluorophenyl)-3 -(2,2,2-trifluoroethyl)-5 - { [5 -(trifluoromethyl)i soquinolin- 1 -yl] amino } -7,8- dihydro-6H-pyrrolo[4,3-e]indazol-8-one (2.2 mg, 0.004 mmol, 5%) as a white solid. LCMS: ESI m/z 594 [M+H]⁺. ’HNMR (400 MHz, DMSO-d6) 5 8.70 - 8.57 (m, 2H), 8.34 - 8.25 (m, 2H), 7.91 - 7.76 (m, 3H), 7.40 - 7.35 (m, 2H), 7.19 -7.15 (m, 3H), 5.43- 5.40 (m, 2H), 5.00 - 4.96 (m, 1H).

Example 4: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[7-fluoro-5- (trifluoromethyl)isoquinolin-l-yl]amino}-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one

Example 4 [00366] To a stirred solution of l-chloro-7-fluoro-5-(trifluoromethyl)isoquinoline (50 mg, 0.2 mmol) in dioxane (5 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-

7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (76 mg, 0.2 mmol), Pd2(dba)s (9 mg, 0.01 mmol), XANT PHOS (11 mg, 0.02 mmol) and CS2CO3 (65 mg, 0.2 mmol) at rt. After stirred at 125 °C under N2 for 2h, 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-TLC (DCM: MeOH= 10: 1) and then by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H₂O with 0.1 % TFA) to give 6-(2-chloro-5- fluorophenyl)-3-(2,2-difhioroethyl)-5-{[7-fluoro-5-(trifluoromethyl)isoquinolin-l-yl]amino}-

7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (8 mg, 0.01 mmol, 7 %) as a yellow solid. LCMS: ESI m/z 594 [M + H]⁺. ’H NMR (400 MHz, DMSO-d6) 5 9.45 (s, IH), 9.11 (s, IH), 8.47 (s, IH), 8.15 (d, J= 8.8 Hz, IH), 8.07 - 7.97 (m, 2H), 7.85 (s, IH), 7.21 (s, IH), 7.07 - 6.85 (m, 2H), 6.66 - 6.22 (m, 2H), 5.85 (brs, IH), 5.17 - 4.91 (m, 2H).

Example 5: 6-(2-chloro-5-fluorophenyl)-5-[(5,7-dichloroisoquinolin-l-yl)amino]-3-(2,2- difluoroethyl)-7,8-dihydro-6H-pyrrolo [4,3-e] indazol-8-one

[00367] Step A. To a stirred solution of 1, 5, 7-tri chloroisoquinoline (25 mg, 0.1 mmol) in dioxane (3 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-

7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (49 mg, 0.13 mmol), Pd2(dba)s (19 mg, 0.02 mmol), Xant-PHOS (25 mg, 0.04 mmol) and CS2CO3 (70 mg, 0.22 mmol) at rt. After stirred at 125 °C for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified chromatography (silica gel, 0-60 %, EtOAc in PE) to give crude 6-(2-chloro-5-fluorophenyl)-5-[(5,7-dichloroisoquinolin-l-yl)amino]-3-(2,2- difluoroethyl)-6-hydroxy-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (15 mg, 0.02 mmol,

23 %) as a yellow solid. LCMS: ESI m/z 593 [M + H]⁺.

[00368] Step B. To a stirred solution of 6-(2-chloro-5-fluorophenyl)-5-[(5,7- dichloroisoquinolin-l-yl)amino]-3-(2,2-difluoroethyl)-6-hydroxy-7,8-dihydro-6H-pyrrolo[4,3- e]indazol-8-one (15 mg, 0.02 mmol) in TFA (2 mL) was added EtiSiH (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 6-(2-chloro-5-fluorophenyl)-5- [(5,7-dichloroisoquinolin-l-yl)amino]-3-(2,2-difluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3- e]indazol-8-one (4 mg, 0.007 mmol, 27 %) as a yellow solid. LCMS: m/z 577 [M+H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.70 (brs, IH), 9.15 (s, IH), 8.48 (s, IH), 8.08 - 8.03 (m, 2H), 7.86 (s, IH), 7.28 (s, IH), 7.02 - 6.93 (m, 2H), 6.66 - 6.30 (m, 2H), 5.89 (brs, IH), 5.13 - 4.94 (m, 2H).

Example 6: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[5- (trifluoromethyl)isoquinolin-l-yl]amino}-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one

[00369] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-8-one (67 mg, 0.177 mmol) in dioxane (6 mL) was added 1- chloro-5-(trifluoromethyl)isoquinoline (28 mg, 0.118 mmol), CS2CO3 (77.0 mg, 0.236 mmol), Xant-phos (14mg, 0.024 mmol) and Pd2(dba)a (11 mg, 0.012 mmol). The reaction mixture was stirred at 110 °C under N2 for 1 h. 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 by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3- (2,2-difluoroethyl)-5-{[5-(trifluoromethyl)isoquinolin-l-yl]amino}-7,8-dihydro-6H-pyrrolo[4,3- e]indazoL8-one (9.9 mg, 0.017 mmol, 14%). LCMS: ESI m/z 576 [M+H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.52 (s, IH), 9.10 (s, IH), 8.46 (s, IH), 8.20 (d, J= 8.0 Hz, IH), 8.11 (d, J= 8.0 Hz, 1H), 8.05 - 7.94 (m, 1H), 7.85 (s, 1H), 7.62 - 7.58 (m, 1H), 7.20 (s, 1H), 6.95 - 6.90 (m, 2H), 6.51 - 6.48 (m, 1H), 6.30 (brs, 1H), 5.94 (brs, 1H), 5.10 - 4.95 (m, 2H).

Example 7 : 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((7-fluoro-5- (trifluoromethyl)isoquinolin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione

[00370] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (30 mg, 0.07 mmol) in 1,4-dioxane (5 mL) was added l-chloro-7-fluoro-5-(trifluoromethyl)isoquinoline (30 mg, 0.12 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos (13 mg, 0.023 mmol), CS2CO3 (47 mg, 0.15 mmol). The reaction was stirred at 125 °C under N2 for 2h. The solution was cooled to room temperature and filtered through a pad of celite and the celite was washed with EA. The resulted filtrate was concentrated to yield the crude product, which was purified by prep-TLC (PE: EtOAc=l : 1) and then by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2- difhioroethyl)-5-{[7-fluoro-5-(trifhioromethyl)isoquinolin-l-yl]amino}-l-(trideuteriomethyl)- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (4.3 mg, 0.007 mmol, 9%) as a green solid. LCMS: ESI m/z 627 [M + H]⁺. 'HNMR (400 MHz, DMSO-d6) 6 9.11 (s, 1H), 9.06 (s, 1H), 8.14 - 8.11 (m, 2H), 7.89 (d, J= 6.0 Hz, 1H), 7.39 (s, 1H), 7.09 (d, J= 3.6 Hz, 1H), 7.01 - 6.79 (m, 2H), 6.55 - 6.15 (m, 2H), 5.84 (brs, 1H), 4.57 - 4.20 (m, 2H).

Example 8: 6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5-(trifluoromethyl)isoquinolin-l- yl)amino)-l-(methyl-d3)-3-(2,2,2-trifluoroethyl)-l,3,6,7-tetrahydroimidazo[4,5-elisoindole- 2,8-dione

[00371] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-l-(methyl-d3)-3-(2,2,2- trifluoroethyl)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (30 mg, 0.070 mmol) in dioxane (5 mL) were added l-chloro-7-fluoro-5-(trifluoromethyl)isoquinoline (26.2 mg, 0.104 mmol), Pd2(dba)s (6.37 mg, 0.007 mmol), and xantphos (8.06 mg, 0.014 mmol), CS2CO3 (68 mg, 0.209 mmol)3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (14.3 mg, 0.069 mmol). The reaction was stirred at 125 °C under N2 for 2 hr. 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 by prep-TLC (PE: EtOAc= 1 :1) and then by prep-HPLC to afford 6-(2-chloro-5- fluorophenyl)-5-((7-fluoro-5-(tri fluoromethyl )isoquinolin-l-yl)amino)-l -(methyl -d3)-3-(2, 2, 2- trifluoroethyl)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (1.9 mg, 0.003 mmol, 4%) as a white solid. LCMS: 645/647 [M-H] ¹ . 1H NMR (400 MHz, DMSO-d6) 8 9.13 (s, 1H), 9.08 (s, 1H), 8.14 - 8.10 (m, 2H), 7.88 (d, J= 6.4 Hz, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.98 - 6.79 (m, 2H), 6.47 (brs, 1H), 5.85 (brs, 1H), 5.04 - 4.67 (m, 2H).

Example 9: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-5-((5- (trifluoromethyl)isoquinolin-l-yl)amino)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8- dione

Example 9

[00372] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (30 mg, 0.07 mmol) in 1,4-dioxane (5 mL) was added l-chloro-5-(trifluoromethyl)isoquinoline (30 mg, 0.130 mmol), Pd2(dba)3 (9.96 mg, 0.011 mmol), Xantphos (12.6 mg, 0.022 mmol), CS2CO3 (47.2 mg, 0.145 mmol). The reaction was stirred at 110 °C under N2 for 2h. The solution was cooled to room temperature and filtered through a pad of celite and the celite was washed with EA. The resulted filtrate was concentrated to yield the crude product, which was purified by prep-TLC (PE: EtOAc=l : 1) and then by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2- difhioroethyl)-5-{[7-fluoro-5-(trifhioromethyl)isoquinolin-l-yl]amino}-l-(trideuteriomethyl)- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (2.2 mg, 0.004 mmol, 5%) as a white solid. LCMS: ESI m/z 609 [M + H]⁺. ’HNMR (400 MHz, CD3OD) 5 8.14 - 8.01 (m, 2H), 7.88

- 7.76 (m, 1H), 7.56 - 7.62 (m, 1H), 7.41 (s, 1H), 7.28 - 7.17 (m, 1H), 6.87 - 6.77 (m, 1H), 6.75

- 6.67 (m, 1H), 6.48 - 6.03 (m, 3H), 4.46 - 4.33 (m, 2H).

Example 10: 6-(2-chloro-5-fluorophenyl)-l-(methyl-d3)-3-(2,2,2-trifluoroethyl)-5-((5- (trifluoromethyl)isoquinolin-l-yl)amino)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dion

Pd₂(dba)3,

Cs₂CO₃,xant phos, dioxane, 125 °C, 2h [00373] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-l-(methyl-d3)-3-(2,2,2- trifluoroethyl)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (30 mg, 0.070 mmol) in dioxane (5 mL) were added l-chloro-5-(trifluoromethyl)isoquinoline (24 mg, 0.104 mmol), Pd2(dba).3 (6.37 mg, 0.007 mmol), xantphos (8.06 mg, 0.014 mmol), CS2CO3 (68 mg, 0.209 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (14.3 mg, 0.069 mmol). The reaction was stirred at 125 °C under N2 for 2 hr. 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 by pre- TLC methanol in dichloroform gradient: (0-10%) to afford 6-(2-chl oro-5 -fluorophenyl)-!- (methyl-d3)-3-(2,2,2-trifluoroethyl)-5-((5-(trifluoromethyl)isoquinolin-l-yl)amino)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione crude, the residue was purified by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-l-(methyl-d3)-3-(2,2,2-trifluoroethyl)-5-((5- (trifluoromethyl)isoquinolin-l-yl)amino)- 1,3, 6, 7-tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (3.1 mg, 0.005 mmol, 7%) as a white solid. LCMS: ESI m/z 627 [M-H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.16 (s, 1H), 8.42 (brs, 1H), 8.21 (s, 1H), 7.74 - 7.70 (m, 2H), 7.55 (s, 1H), 7.17 - 7.02 (m, 1H), 6.88 - 6.84 (s, 2H), 6.69 - 6.48 (m, 1H), 5.94 (brs, 1H), 5.02 - 4.74 (m, 2H).

Example 11: 6-(2-chloro-5-fluorophenyl)-5-[(5,7-dichloroisoquinolin-l-yl)amino]-3-(2,2- difluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione

[00374] To a stirred solution of 1,5,7-trichloroisoquinoline (50 mg, 0.215 mmol) in dioxane (2 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-

(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (107 mg, 0.258 mmol) , Pd2(dba)s (19 mg, 0.022 mmol), CS2CO3 (140 mg, 0.430 mmol) and XANT PHO S (25 mg, 0.043 mmol) at rt. After stirred at 110 °C under N2 for 2 h, the mixture was poured into 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, 0-30%, EtOAc in PE) to give crude product (yellow solid) , and was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give 6-(2- chloro-5-fluorophenyl)-5-[(5,7-dichloroisoquinolin-l-yl)amino]-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (20.3 mg, 0.033 mmol, 16%) as a yellow solid. LCMS: ESI m/z 609 [M+H]⁺. 'H NMR (400 MHz, DMSO-d6) 5 9.16 (s, 1H), 9.0 (s, 1H), 8.08 (s, 1H), 7.98 - 7.89 (m, 2H), 7.37 (s, 1H), 7.20 (d, J = 6.0 Hz, 1H), 7.01 - 6.84 (m, 2H), 6.52 - 6.18 (m, 2H), 5.84 (brs, 1H), 4.45 - 4.33 (m, 2H).

Example 12: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione, Example 20: (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- ((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-l,3,6,7- tetrahydroimidazo [4, 5-e] isoindole-2, 8-dione and Example 21: (S)-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)- l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione

[00375] To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline (40 mg, 0.16 mmol) in CH3CN (5 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (66 mg, 0.16 mmol) and CS2CO3 (104 mg, 0.32 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with EA and washed with H2O and brine. The organic layer was concentrated under vacuum. The residue was purified using pre-HPLC to afford 6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-l- (methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (5.6 mg, 0.009 mmol, 6%) as a white solid. LCMS: ESI m/z 628 [M + H]L 'H NMR (400 MHz, DMSO-d6) 8 9.88 (s, 1H), 9.14 (s, 1H), 8.38 (s, 1H), 8.23 - 8.19 (m, 2H), 7.45 (s, 1H), 7.01 - 6.83 (m, 2H), 6.61(d, J = 8.0 Hz, 1H), 6.50 - 6.20 (m, 1H), 6.02 - 5.83 (m, 1H), 4.47 - 4.32 (m, 2H). 6-(2-chloro-5-fluorophenyl)- 3-(2,2-difluoroethyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)- 1,3, 6, 7-tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (180 mg, 0.29 mmol) was purified using prep-SFC (method 1) to afford (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6- fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e]isoindole-2, 8-dione (67.4 mg, 0.107 mmol, 37%) as a white solid. LCMS: ESI m/z 628 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.90 (s, 1H), 9.14 (s, 1H), 8.39 (s, 1H), 8.24 - 8.20 (m, 2H), 7.46 (s, 1H), 7.05 - 6.79 (m, 2H), 6.61(d, J = 8.0 Hz, 1H), 6.52 - 6.18 (m, 1H), 6.04 - 5.76 (m, 1H), 4.49 - 4.30 (m, 2H). And (S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6- fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e]isoindole-2, 8-dione (64.6 mg, 0.103 mmol, 36%) as a white solid. LCMS: ESI m/z 628 [M + H]⁺. ’H NMR (400 MHz, DMSO-d6) 8 9.88 (s, 1H), 9.14 (s, 1H), 8.40 (s, 1H), 8.24 - 8.20 (m, 2H), 7.46 (s, 1H), 7.05 - 6.77 (m, 2H), 6.61 (d, J = 8.0 Hz, 1H), 6.52 - 6.12 (m, 1H), 5.94 (brs, 1H), 4.48 - 4.25 (m, 2H).

Example 13: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyI)-5-{[6-fluoro-8- (trifluoromethyl)quinazolin-4-yl]amino}-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one [00376] To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline (25 mg, 0.100 mmol) in ACN (5 mL) were added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (37 mg, 0.100 mmol) and CS2CO3 (65 mg, 0.200 mmol). The reaction was stirred at rt under N2 for 2 hrs to complete. 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 6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl)quinazolin-4-yl]amino}-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-8-one (8.3 mg, 0.014 mmol, 14%) as a yellow solid. LCMS: ESI m/z 595 [M-H]⁺. 'H NMR (400 MHz, DMSO-d6) 5 10.14 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.25 (dd, J = 8.4, 2.4 Hz, 1H), 8.18 (d, J= 8.8 Hz, 1H), 7.99 (s, 1H), 7.02 - 6.85 (m, 2H), 6.66 - 6.30 (m, 2H), 5.99 (brs, 1H), 5.15 - 4.99 (m, 2H).

Example 14: 6-(2-chloro-5-fluorophenyl)-5-((5-chloro-7-fluoroisoquinolin-l-yl)amino)-3- (2,2-difluoroethyl)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2, 8-dione

[00377] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (30 mg, 0.072 mmol) in 1,4-dioxane (5 mL) was added l,5-dichloro-7-fluoroisoquinoline (31mg, 0.15 mmol), Pd2(dba)s (11 mg, 0.012 mmol), Xantphos (13 mg, 0.023 mmol), CS2CO3 (47 mg, 0.145 mmol). The reaction was stirred at 120 °C for 2h. The solution was cooled to room temperature and filtered through a pad of celite and the celite was washed with EA. Then the resulted filtrate was concentrated to yield the crude product, which was purified by prep-HPLC to afford 5-[(5- chloro-7-fluoroisoquinolin-l-yl)amino]-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (4.4 mg, 0.007 mmol, 10%) as a white solid. LCMS: ESI m/z 593 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.05 (s, 1H), 8.99 (s, 1H), 7.93 (dd, J= 8.8, 2.4 Hz, 1H), 7.86-7.82 (m, 2H), 7.39 (s, 1H), 7.20 (d, J= 6.0 Hz, IH), 6.97 (s, IH), 6.92 - 6.84 (m, IH), 6.58 - 6.14 (m, 2H), 5.85 (brs, IH), 4.56 - 4.17 (m, 2H).

Example 15: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5-fluoro-7- (trifluoromethyl)benzo[c]isoxazol-3-yl)amino)-l-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

Example 15

[00378] Step A: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-oxo-3-(trideuteriornethyl)benzo[d]imidazole-4-carbonitrile (30 mg, 0.063 mmol) in dioxane (1 mL) was added 5-fluoro-7-(trifluoromethyl)benzo[c]isoxazol-3-amine (13.8 mg, 0.063 mmol), Xantphos (7.30 mg, 0.013 mmol), CS2CO3 (61.6 mg, 0.189 mmol) and Pd2(dba).3 (5.78 mg, 0.006 mmol). The mixture was stirred at 110 °C under N2 for Ih. LCMS showed the reaction was completed. The mixture was poured in water (5 mL), extracted with EtOAc (5 mL*2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by prep-TLC (SiCL, Pet.ethere: EtOAc=l: 2) to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-6-{[5-fluoro-7- (trifluoromethyl)benzo[c]isoxazol-3-yl]amino}-2-oxo-3-(trideuteriomethyl)benzo[d]imidazole-4- carbonitrile (20 mg, 26%) as yellow oil. LCMS: ESI m/z 633 [M+H]⁺

[00379] Step B: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{ [5- fluoro-7-(trifluoromethyl)benzo[c]isoxazol-3-yl]amino}-6-hydroxy-l -(trideuteri omethyl)- l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (20 mg, 0.016 mmol) in TFA (2 mL, 26.1 mmol) was added EtsSiH (1 mL, 0.016 mmol) and the mixture was stirred at 70° C for 15 min. LCMS showed the reaction was completed. The cooled mixture was concentrated in vacuo and purified by prep-HPLC (TFA) to give 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5- {[5-fluoro-7-(trifluoromethyl)benzo[c]isoxazol-3-yl]amino}-l -(trideuteri omethyl)-!, 2, 3, 6, 7, 8- hexahydroimidazo[5,4-e]isoindole-2, 8-dione (1.7 mg, 17%) as white solid. [00380] LCMS: ESI m/z 617 [M+H]⁺. ’H NMR (400 MHz, CD3OD) 3 7.72 (d, J = 9.2 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 5.6 Hz, 1H), 7.02 (s, 1H), 6.82 - 6.79 (m, 1H), 6.41 - 6.01 (m, 3H), 4.50 - 4.35 (m, 2H).

Example 16: 5-[(5-chloro-7-fluoroisoquinolin-l-yl)amino]-6-(2-chloro-5-fluorophenyl)-3- (2,2-difluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one

Pd₂(dba)₃, xantphos, Cs₂CO₃, dioxane, 120 °C, 2h

[00381] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-8-one (40 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was added l,5-dichloro-7-fluoroisoquinoline (40 mg, 0.19 mmol), Pd2(dba)a (15 mg, 0.017 mmol) , Xantphos (20 mg, 0.034 mmol), CS2CO3 (68 mg, 0.210 mmol) . The reaction was stirred at 120 °C for 2h. The solution was cooled to room temperature and filtered through a pad of celite and the celite was washed with EA. The filtrate was concentrated to yield the crude product, which was purified by prep-TLC and then by prep-HPLC to afford 5-[(5-chloro-7- fluoroisoquinolin-l-yl)amino]-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8-dihydro- 6H-pyrrolo[4,3-e]indazol-8-one (8.0 mg, 0.014 mmol, 14%) as a green solid. LCMS: ESI m/z 560 [M + H]-. NMR (400 MHz, DMSO-d6) 8 9.33 (s, 1H), 9.11 (s, 1H), 8.46 (s, 1H), 7.98 - 7.95 (m, 2H), 7.84 (s, 1H), 7.75 (d, J= 10.0 Hz, 1H), 7.32 (d, J = 5.6 Hz, 1H), 7.04 - 6.88 (m, 2H), 6.66 - 6.20 (m, 2H), 5.88 (brs, 1H), 5.15 - 4.86 (m, 2H).

Example 17 : 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)quinoIin-4-yl)amino)-6,7-dihydropyrrolo[3,4-e]indazol-8(3H)-one

[00382] The mixture of 4-chloro-6-fluoro-8-(trifluoromethyl)quinoline (50 mg, 0.20 mmol), 5- amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol- 8-one (84 mg, 0.22 mmol), Pd2(dba)s (18 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol) and CS2CO3 (131 mg, 0.40 mmol) in dioxane (10 mL) was stirred at 110 °C under N2 for 3h. The mixture was purified by prep-HPLC to give 6-(2-chloro-5-fluorophenyl)-3-(2,2- difhioroethyl)-5-{[6-fluoro-8-(trifluoromethyl)quinolin-4-yl]amino}-7,8-dihydro-6H- pyrrolo[4,3-e]indazol-8-one (4.1 mg, 0.007 mmol, 3%) as a white solid. LCMS: ESI m/z 594 [M+H]⁺. ‘HNMR (400 MHz, DMSO-d6) 5 9.21 (s, 1H), 8.99 (s, 1H), 8.51 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.11 (dd, J= 10.2, 2.4 Hz, 1H), 8.05 (dd, J= 8.4, 2.8 Hz, 1H), 8.02 (s, 1H), 6.88 (s, 1H), 6.78 (s, 1H), 6.66 - 6.32 (m, 2H), 6.28 (d, J= 5.2 Hz, 1H), 5.94 (brs, 1H), 5.14 - 5.00 (m, 2H).

Example 18: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)quinolin-4-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione

Example 18

[00383] The mixture of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (40 mg, 0.097 mmol),4-chloro-6-fluoro-8-(trifluoromethyl)quinoline (29 mg, 0.116 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (11 mg, 0.019 mmol) and CS2CO3 (63 mg, 0.20 mmol) in dioxane (5 mL) was stirred at 110 °C under N2 for 3 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC to give 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6- fluoro-8-(trifluoromethyl)quinolin-4-yl]amino}-l -(trideuteri omethyl)-l, 2, 3, 6,7,8- hexahydroimidazo[5,4-e]isoindole-2, 8-dione (14.9 mg, 0.024 mmol, 25%) as a white solid.

LCMS: ESI m/z 627 [M+H]⁺. 'HNMR (400 MHz, DMSO-d6) 6 9.14 (s, 1H), 8.76 (s, 1H), 8.23 (d, J = 5.2 Hz, 1H), 8.20 (dd, J = 10.2, 2.4 Hz, 1H), 8.03 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (s, 1H), 6.84 (s, 1H), 6.71 - 6.68 (m, 2H), 6.52 - 6.18 (m, 1H), 6.02 (d, J = 5.2 Hz, 1H), 5.94 (brs, 1H), 4.49 - 4.35 (m, 2H).

Example 19: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5-ethynyl-7- fluoroisoquinolin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8- dione

[00384] Step A: To a solution of 5-bromo-l-chloro-7-fhioroisoquinoline (180 mg, 0.69 mmol) in 1,4-dioxane (5 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-! -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e]isoindole-2, 8-dione (229 mg, 0.55 mmol), Pd2(dba)s (63 mg, 0.07 mmol), Xantphos (80 mg, 0.14 mmol), CS2CO3 (450.29 mg, 1.382 mmol). The reaction was stirred at 120 °C under N2 for 2h. The reaction mixture was concentrated and purified by prep-HPLC to afford 5-((5-bromo-7-fluoroisoquinolin- l-yl)amino)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (40 mg, 0.063 mmol, 9%) as a white solid. LCMS: ESI m/z 637/639 [M + H] ¹.

[00385] Step B: To a solution of 5-[(5-bromo-7-fluoroisoquinolin-l-yl)amino]-6-(2-chloro-5- fluorophenyl)-3-(2, 2-difluoroethyl)-l -(trideuteri omethyl)- 1,2, 3,6,7, 8-hexahydroimidazo[4, 5- e]isoindole-2, 8-dione (20 mg, 0.031 mmol) in 1,4-dioxane (5 mL) was added tributyl(ethynyl)stannane (29 mg, 0.093 mmol) and Pd(PPh3)2Ch (10 mg, 0.014 mmol). The reaction was stirred at 120 °C under N2 for 2h. The reaction mixture was concentrated and purified by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5- ethynyl-7-fluoroisoquinolin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e]isoindole-2, 8-dione (2.2 mg, 0.004 mmol, 12%) as a yellow solid. LCMS: ESI m/z 583 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 5 9.17 (s, 1H), 8.24 - 7.85 (m, 2H), 7.76 - 7.44 (m, 2H), 7.38 - 7.23 (m, 1H), 7.06 - 6.77 (m, 2H), 6.59 (brs, 1H), 6.51 - 6.21 (m, 1H), 5.93 (brs, 1H), 4.91 (s, 1H), 4.50 - 4.25 (m, 3H).

Example 22: 6-(2-chloro-5-fluorophenyl)-5-{[6-fluoro-8-(trifluoromethyl)quinazolin-4- yl]amino}-3-(pentadeuterioethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5- e] isoindole-2, 8-dione

[00386] To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline (98.2 mg, 0.392 mmol) in z-PrOH (2 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3- (pentadeuterioethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8- dione (30 mg, 0.078 mmol) and the mixture was stirred at 90 °C for 30 min. The mixture was concentrated under vacuum to give a crude, which was purified by pre-HPLC to give 6-(2- chloro-5-fluorophenyl)-5-{[6-fluoro-8-(trifluoromethyl)quinazolin-4-yl]amino}-3-

(pentadeuterioethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8- dione (5.6 mg, 0.009 mmol, 12 %) as a yellow solid. LCMS: ESI m/z 597.2 [M + H]⁺. 'HNMR (400 MHz, DMSO-d6) 8 9.85 (s, 1H), 9.11 (s, 1H), 8.40 (s, 1H), 8.24 - 8.20 (m, 2H), 7.44 (s, 1H), 7.01 - 6.80 (m, 2H), 6.59 (d, J = 8.4 Hz, 1H), 5.95 (brs, 1H).

Example 23: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-5-((7-methyl- 5-(trifluoromethyl)isoquinolin-l-yl)amino)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8- dione

Example 23

[00387] A solution of 5-amino-6-(l-chloro-4-fluorobenzen-2-yl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (50 mg, 0.121 mmol), l-chloro-7-methyl-5-(trifluoromethyl)isoquinoline (29.7 mg, 0.121 mmol), Pd2(dba)s (11.1 mg, 12 pmol), Xantphos (14.0 mg, 24 pmol), CS2CO3 (118 mg, 0.362 mmol) in dioxane (2 mb) was stirred at 100 °C under N2 for 2h. The reaction mixture was concentrated in vacuo. The residue was purified by pre-HPLC to afford 6-(l-chloro-4-fluorobenzen-2-yl)-3-(2,2- difluoroethyl)-5-{[7-methyl-5-(trifluoromethyl)isoquinolin-l-yl]amino}-l-(trideuteriomethyl)- l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (13.7 mg, 22 pmol, 18 %) as a brown solid. LCMS: ESI m/z 623 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.10 (s, 2H), 8.08 (s, 1H), 8.01 (s, 1H), 7.91 (d, J= 5.6 Hz, 1H), 7.46 (s, 1H), 7.11 (s, 1H), 6.99 - 6.92 (m, 2H), 6.28 - 6.56 (m, 2H), 5.92 (s, 1H), 4.51 - 4.39 (m, 2H), 2.53 (s, 3H).

Example 24: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((7-methyl-5- (trifluoromethyl)isoquinolin-l-yl)amino)-6,7-dihydropyrrolo[3,4-e]indazol-8(3H)-one pd₂(dba)₃, xantphos, Cs₂CO₃, dioxane

[00388] A solution of 5-amino-6-(l-chloro-4-fluorobenzen-2-yl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (50 mg, 0.121 mmol), l-chloro-7-methyl-5-(trifluoromethyl)isoquinoline (32.3 mg, 0.131 mmol), Pd2(dba)s (12.0 mg, 13 pmol), Xantphos (15.2 mg, 26 pmol), CS2CO3 (128 mg, 0.394 mmol) in dioxane (2 mL) was stirred at 100 °C under N2 for 2h. The reaction mixture was cooled down and then concentrated. The residue was purified by pre-HPLC to afford 6-(l-chloro-4-fluorobenzen-2-yl)- 3-(2,2-difluoroethyl)-5-{[7-methyl-5-(trifluoromethyl)isoquinolin-l-yl]amino}-7,8-dihydro-6H- pyrrolo[4,3-e]indazol-8-one (11.9 mg, 20 pmol, 15%) as a brown solid. LCMS: ESI m/z 590 [M + H]⁺. ’H NMR (400 MHz, CD3OD) 8 8.66 (s, 1H), 8.30 - 8.22 (m, 2H), 8.12 (s, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 6.77 - 6.72 (m, 2H), 6.61 (d, J= 7.6 Hz, 1H), 6.54 - 6.16 (m, 2H), 5.02 - 4.80 (m, 2H), 2.66 (s, 3H).

Example 25: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5-(difluoromethyl)-7- fluoroisoquinolin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8- dione

[00389] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (40 mg, 0.097 mmol) in 1,4-di oxane (5 mL) was added l-chloro-5-(difluoromethyl)-7-fluoroisoquinoline (40 mg, 0.17 mmol), Pd2(dba)₃ (14 mg, 0.015 mmol), Xantphos (18 mg, 0.031 mmol), CS2CO3 (63 mg, 0.19 mmol) . The reaction was stirred at 120 °C for 2h. The reaction mixture was cooled down to rt then concentrated and purified by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)- 3-(2,2-difluoroethyl)-5-((5-(difluoromethyl)-7-fluoroisoquinolin-l-yl)amino)-l-(methyl-d3)- 1,3, 6, 7-tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (5.9 mg, 0.01 mmol, 10%) as a white solid. LCMS: ESI m/z 609 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 5 9.15 - 8.92 (m, 2H), 8.05 - 7.93 (m, 1H), 7.92 - 7.78 (m, 2H), 7.70 - 7.35 (m, 2H), 7.21 (d, J= 5.2 Hz, 1H), 7.02 - 6.80 (m, 2H), 6.54 - 6.16 (m, 2H), 5.86 (brs, 1H), 4.54 - 4.23 (m, 2H).

Example 26: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5-(difluoromethyl)-7- fluoroisoquinolin-1 -yl)amino)-6,7-dihydropyrrolo [3,4-e] indazol-8(3H)-one

Pd₂(dba)₃, xantphos, Cs₂CO₃, dioxane, 120°C, 2h

Example 26

[00390] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-8-one (40 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was added l-chloro-5-(difluoromethyl)-7-fluoroisoquinoline (40 mg, 0.17 mmol), Pd2(dba)s (16 mg, 0.018 mmol), Xantphos (20 mg, 0.034 mmol), CS2CO3 (69 mg, 0.21 mmol) . The reaction was stirred at 120 °C under N2 for 2h. The reaction mixture was cooled down to rt, then concentrated and purified by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5- (difluoromethyl)-7-fluoroisoquinolin-l-yl)amino)-6,7-dihydropyrrolo[3,4-e]indazol-8(3H)-one (5.5 mg, 0.01 mmol, 9%) as a white solid. LCMS: ESI m/z 576 [M + H]⁺. ’H NMR (400 MHz, DMSO-d6) 5 9.33 (s, 1H), 9.10 (s, 1H), 8.46 (s, 1H), 7.96 (d, J= 5.2 Hz, 1H), 7.92-7.88 (m, 2H), 7.84 (s, 1H), 7.65-7.50 (m, 1H), 7.32 (d, J= 5.6 Hz, 1H), 7.00 - 6.89 (m, 2H), 6.69 - 6.15 (m, 2H), 5.87 (brs, 1H), 5.17 - 4.90 (m, 2H).

Example 27: 6-(2-chloro-5-fluorophenyl)-5-[(5,7-dichloroisoquinolin-l-yl) amino]-3-(2,2- difluoroethyl)-! -(trideuteriomethyl)-l, 2, 3, 6, 7, 8-hexahydroimidazo[4,5-e] isoindole-2, 8- dione

Example 27

[00391] To a stirred solution of 4-bromo-6-fluoro-8-(trifluoromethyl)isoquinoline (30 mg, 0.102 mmol) in dioxane (2 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-! -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e]isoindole-2, 8-dione (51 mg, 0.122 mmol), Pd2(dba)a (10 mg, 0.011 mmol), CS2CO3 (66 mg, 0.204 mmol) and XANT PHOS (12 mg, 0.020 mmol) at rt. After stirred at 100 °C for 2 h, the mixture was poured into water (20 mL) and extracted with DCM (10 mL*3). The combined organic phase was washed with brine, dried with ISfeSCU, filtered and concentrated. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) and then prep-HPLC (C18, 40 ~ 90 % MeCN in H₂O with 0.1 % TFA) to give 6-(2-chloro-5-fluorophenyl)-5-[(5,7-dichloroisoquinolin-l-yl) amino]-3-(2,2-difluoroethyl)- l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e] isoindole-2, 8-dione (21.6 mg, 0.035 mmol, 36%) as a yellow solid. LCMS: ESI m/z 627 [M+H]⁺. 'H NMR (400 MHz, DMSO-d₆) 6 9.11 (s, 1H), 8.8 (d, J= 2.4 Hz, 1H), 8.15 - 8.00 (m, 3H), 7.22-7.16 (m, 2H), 6.88 - 6.60 (m, 3H), 6.50 - 6.20 (m, 1H), 5.87 (brs, 1H), 4.48 - 4.35 (m, 2H).

Example 28: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl) isoquinolin-4-yl] amino}-7,8-dihydro-6H-pyrrolo[4,3-e] indazol-8-one

Example 28

[00392] Step A. To a stirred solution of 4-bromo-6-fluoro-8-(trifluoromethyl) isoquinoline (30 mg, 0.102 mmol) in dioxane (4 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (43 mg, 0.112 mmol), Pd₂(dba)₃ (9.34 mg, 0.010 mmol), Cs₂CO₃ (67 mg, 0.205 mmol) and XANT PHOS (14 mg, 0.026 mmol) at rt. After stirred at 100 °C under N₂ for 2 h, the mixture was poured into water (20 mL) and extracted with DCM (10 mL*3). The combined organic phase was washed with brine, dried with Na₂SO4, fdtered and concentrated. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) and then prep-HPLC (C18, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give 6- (2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl) isoquinolin-4- yl] amino}-7,8-dihydro-6H-pyrrolo[4,3-e] indazol-8-one (13.6 mg, 0.023 mmol, 22%) as a yellow solid. LCMS: ESI m/z 584 [M+H]T 'H NMR (400 MHz, DMSO-d6) 5 9.16 (s, 1H), 8.90 (s, 1H), 8.49 - 8.29 (m, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.91 - 7.70 (m, 3H), 7.01 - 6.77 (m, 2H), 6.63 - 6.31 (m, 2H), 5.79 (brs, 1H), 5.09 - 4.88 (m, 2H).

Example 29: 6-(2-chloro-5-fluorophenyl)-5-((l-chloro-7-fluoroisoquinolin-5-yl)amino)-3- (2,2-difluoroethyl)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione

Pd₂(dba)3, Cs₂CO₃, xant phos, dioxane, 120 °C, 2h

Example 29 [00393] To a solution of 5-bromo-l -chloro-7-fluoroisoquinoline (50 mg, 0.19 mmol) in 1,4- dioxane (5 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (50 mg, 0.12 mmol), Pd2(dba)_3 (18 mg, 0.02 mmol) , Xantphos (22 mg, 0.038 mmol), CS2CO3 (125 mg, 0.38 mmol). The reaction was stirred at 120 °C under N2 for 2h. The reaction mixture was concentrated and purified by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-5-((l-chloro-7- fluoroi soquinolin-5 -yl)amino)-3 -(2,2-difluoroethyl)- 1 -(methyl-d3 )- 1 , 3 ,6, 7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (2 mg, 0.003 mmol, 2%) as a yellow solid. LCMS: ESI m/z 593 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.12 (s, 1H), 8.56 (s, 1H), 8.19 (d, J = 6.0 Hz, 1H), 7.98 (d, J= 5.6 Hz, 1H), 7.47 (s, 1H), 7.04 (dd, J= 9.6, 2.0 Hz, 1H), 6.88 - 6.60 (m, 3H), 6.52 - 6.13 (m, 1H), 6.06 - 5.79 (m, 2H), 4.51-4.28 (m, 2H).

Example 30: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((7-fluoro-5- (trifluoromethyl)phthalazin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione

Example 30

[00394] To a solution of l-chloro-7-fluoro-5-(trifluoromethyl)phthalazine (80 mg, 0.32 mmol) in dioxane (3 mL) and ACN (3 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difhioroethyl)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (132 mg, 0.32 mmol), and the mixture was stirred at 100 °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 pre-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((7- fluoro-5-(trifluoromethyl)phthalazin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e]isoindole-2, 8-dione (3 mg, 0.005 mmol, 2%) as a white solid. LCMS: ESI m/z 628 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.36 - 8.81 (m, 2H), 8.39 - 7.90 (m, 2H), 7.60 - 7.02 (m, 1H), 7.00 - 6.79 (m, 2H), 6.78 - 6.11 (m, 2H), 5.85 (brs, 1H), 4.55 - 4.24 (m, 2H). Example 31 : (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((7-fluoro-5- (trifluoromethyl)phthalazin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- el isoindole-2, 8-dione and Example 32: (S)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-5-((7-fluoro-5-(trifluoromethyl)phthalazin-l-yl)amino)-l-(methyl-d3)- l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione

[00395] 6-(2-chloro-5 -fluorophenyl)-3 -(2,2-difluoroethyl)-5 -((7 -fluoro-5-

(trifluoromethyl)phthalazin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e]isoindole-2, 8-dione (120 mg, 0.19 mmol) was purified using prep-SFC method 2 to afford (R)- 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((7-fluoro-5-(trifluoromethyl)phthalazin-l- yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (27.4 mg, 0.044 mmol, 46%) as a white solid. LCMS: ESI m/z 628 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.50 - 8.64 (m, 2H), 8.42 - 7.88 (m, 2H), 7.65 - 6.78 (m, 3H), 6.75 - 6.18 (m, 2H), 5.84 (brs, 1H), 4.52 - 4.27 (m, 2H). And (S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((7- fluoro-5-(trifluoromethyl)phthalazin-l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e]isoindole-2, 8-dione (28.5 mg, 0.045 mmol, 47%) as a white solid. LCMS: ESI m/z 628 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 6 9.27 - 8.84 (m, 2H), 8.52 - 7.80 (m, 2H), 7.51 - 6.79 (m, 3H), 6.76 - 6.16 (m, 2H), 5.84 (brs, 1H), 4.54 - 4.16 (m, 2H).

Example 33: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5,7-difluoroisoquinolin- l-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione

[00396] To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (30 mg, 0.073 mmol) in dioxane (3 mL) were added l-chloro-5,7-difluoroisoquinoline (21.7 mg, 0.109 mmol), Pd2(dba)3 (6.65 mg, 0.007 mmol), Xantphos (8.41 mg, 0.015 mmol) and CS2CO3 (47.3 mg, 0.145 mmol). The reaction was stirred at 100 °C under N2for 2 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford 6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5,7-difluoroisoquinolin-l-yl)amino)-l -(methyl- d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (15.2 mg, 0.026 mmol, 36%) as a white solid. LCMS: ESI m/z 577/579 [M + H]⁺. ’H NMR (400 MHz, DMSO-d6) 5 9.19 (s, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.17 (d, J= 6.0 Hz, 1H), 6.91 (d, J= 4.8 Hz, 1H), 6.62 (d, J= 6.4 Hz, 1H), 6.51-6.15 (m, 1H), 5.96 (brs, 1H), 4.45 - 4.37 (m, 2H).

Example 34: (R)-6-(2-chloro-5-fluorophenyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4- yl)amino)-3-(2-fluoroethyl-l,l,2,2-d4)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione and Example 35: (S)-6-(2-chloro-5-fluorophenyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-3-(2-fluoroethyl-l, 1,2, 2-d4)-l-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

[00397] The mixture of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(l,l,2,2-tetradeuterio-2- fluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (150 mg, 0.38 mmol) and 4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline (320 mg, 1.28 mmol) in IPA (10 mL) was stirred at 90 °C for Ih. The mixture was concentrated and purified by prep-HPLC to give 6-(2-chloro-5-fluorophenyl)-5-{ [6-fluoro-8-(trifluoromethyl)quinazolin-4- yl]amino}-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo[4,5-e]isoindole-2, 8-dione (80 mg, 0.13 mmol, 35%) as a yellow solid. LCMS: ESI m/z 614 [M+H]⁺. Then it was purified by prep-SFC method 3 to give: (S)-6-(2-chloro-5- fluorophenyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-3-(2-fluoroethyl-l, 1,2,2- d4)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (4.9mg, 7.98 mmol, 6%) as a yellow solid. LCMS: ESI m/z 614 [M+H]⁺. ’H NMR (400 MHz, DMSO-d6) 5 9.86 (s, IH), 9.12 (s, IH), 8.39 (s, IH), 8.23 - 8.19 (m, 2H), 7.44 (s, IH), 6.99 - 6.82 (m, 2H), 6.60 (d, J= 8.4 Hz, IH), 5.93 (brs, IH). And (R)-6-(2-chloro-5-fluorophenyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-3-(2-fluoroethyl- 1,1,2, 2-d4)-l -(methyl-d3)-l, 3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (48.7mg, 79 mmol, 61%) as a yellow solid. LCMS: ESI m/z 614[M+H]⁺. ’HNMR (400 MHz, DMSO-d6) 5 9.86 (s, IH), 9.12 (s, IH), 8.39 (s, IH), 8.23 - 8.19 (m, 2H), 7.44 (s, IH), 7.01 - 6.81 (m, 2H), 6.60 (d, J= 8.4 Hz, IH), 5.94 (brs, IH).

Example 36: (7?)-6-(2-chloro-5-fluorophenyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4- yl)amino)-3-(2-fluoroethyl)-l-(methyI-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8- dione and Example 37: (A)-6-(2-chloro-5-fluorophenyl)-5-((6-fluoro-8- (trifluoromethyl)quinazolin-4-yl)amino)-3-(2-fluoroethyl)-l-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

[00398] To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline (300 mg, 1.197 mmol) in IPA (6 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-l- (methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (142 mg, 0.359 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 Na2SC>4, filtered and concentrated. The residue was purified using prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)- 5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-3-(2-fluoroethyl)-l-(methyl-d3)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (60 mg, 0.098 mmol, 8%) as a white solid. LCMS: ESI m/z 610 [M+H]⁺. Then it was purified by prep-SFC method 4 to afford (R)-6-(2-chloro-5- fluorophenyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-3-(2-fluoroethyl)-l- (methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (23.9 mg, 0.039 mmol, 39%). LCMS: ESI m/z 610 [M + H]⁺. ^JH NMR (400 MHz, DMSO-d6) 8 9.86 (s, 1H), 9.12 (s, 1H), 8.39 (s, 1H), 8.23 - 8.19 (m, 2H), 7.44 (s, 1H), 7.03 - 6.85 (m, 2H), 6.60 (d, J= 8.0 Hz, 1H), 5.94 (brs, 1H), 4.77 - 4.72 (m, 1H), 4.65 - 4.61 (m, 1H), 4.26 - 4.18 (m, 2H). And (S)-6-(2-chloro-5- fluorophenyl)-5-((6-fluoro-8-(trifluoromethyl)quinazolin-4-yl)amino)-3-(2-fluoroethyl)-l- (methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (20.6 mg, 0.034 mmol, 34%) as a white solid. LCMS: ESI m/z 610 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.85 (s, 1H), 9.12 (s, 1H), 8.39 (s, 1H), 8.23 - 8.19 (m, 2H), 7.44 (s, 1H), 7.05 - 6.85 (m, 2H), 6.60 (d, J= 8.0 Hz, 1H), 5.94 (brs, 1H), 4.77 - 4.73 (m, 1H), 4.65 - 4.61 (m, 1H), 4.39 - 4.10 (m, 2H).

Example 38: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-[(7-fluoro-5- methylbenzo[d][l,2]diazin-l-yl)amino]-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo [4,5-eJ isoindole-2, 8-dione

Example 38

[00399] To a stirred solution of l-chloro-7-fluoro-5-methylbenzo[2,l-d][l,2]diazine (40 mg, 0.2 mmol) in dioxane (5 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-! -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e]isoindole-2, 8-dione (50 mg, 0.12 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), XANT PHOS (14 mg, 0.024 mmol) and CS2CO3 (197 mg, 0.6 mmol) at rt. After stirred at 100 °C overnight. The cooled mixture was poured into brine (20 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0 - 8%, MeOH in DCM) to give 6-(2-chloro-5- fluorophenyl)-3 -(2,2-difhioroethyl)-5-[(7-fluoro-5-methylbenzo[d] [ 1 ,2]diazin- 1 -yl)amino]- 1 - (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (5 mg, 0.009 mmol, 8 %) as a white solid. LCMS: m/z 574 [M+H]⁺. 'H NMR (400 MHz, DMSO-d6) 6 9.20 (s, 1H), 7.97 - 7.94 (m, 2H), 7.51 (s, 1H), 6.91- 6.88 (m, 2H), 6.70 (s, 1H), 6.52 - 6.30 (m, 1H), 5.95 (brs, 1H), 4.40 (m, 2H), 2.76 (s, 3H).

Example 39: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-2-methyl-8- (trifluoromethyl) quinazolin-4-yl] amino}-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo [4,5-e] isoindole-2, 8-dione

[00400] Step A: To a stirred solution of 4-chloro-6-fluoro-2-methyl-8-(trifluoromethyl) quinazoline (50 mg, 0.189 mmol) in TFE (3 mL) was added 5-amino-6-(2-chloro-5- fluorophenyl)-3-(2, 2-difluoroethyl)-l -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e] isoindole-2, 8-dione (78 mg, 0.189 mmol) at rt. After stirred at 80 °C for Ih concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give 6- (2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-2-methyl-8-(trifluoromethyl) quinazolin-4-yl] amino}-l -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e] isoindole- 2, 8-dione (7.3 mg, 0.011 mmol, 6 %) as a yellow solid. LCMS: m/z 642 [M+H]⁺. ^!H NMR (400 MHz, DMSO-t/e) 8 9.74 (s, IH), 9.13 (s, IH), 8.18 - 8.06 (m, 2H), 7.45 (s, IH), 6.99 - 6.80 (m, 2H), 6.62 - 6.58 (m, IH), 6.49 - 6.22 (m, IH), 5.96 (brs, IH), 4.47 - 4.33 (m, 2H), 2.31 (s, 3H).

Example 40: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[7-fluoro-5- (fluoromethyl)benzo[d][l,2]diazin-l-yl]amino}-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo [5,4-e] isoindole-2, 8-dione

Pd₂(dba)₃, xantphos Cs₂CO₃, dioxane, 110 °C

Step A

Example 40 [00401 ] Step A. To a stirred solution of 1 -chloro-7-fluoro-5-(fluoromethyl)benzo[2, 1 - d][l,2]diazine (50 mg, 0.23 mmol) in dioxane (5 mL) was added 5-amino-6-(2-chloro-5- fluorophenyl)-3-(2, 2-difluoroethyl)-l -(trideuteri omethyl)- 1,2, 3,6,7, 8-hexahydroimidazo[4, 5- e]isoindole-2, 8-dione (40 mg, 0.097 mmol), Pd2(dba)s (21 mg, 0.023 mmol), XANT PHOS (27 mg, 0.047 mmol) and CS2CO3 (379 mg, 1.16 mmol) at rt. After stirred at 110 °C under N2 overnight, the mixture was quenched with ice-water and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 8 %, MeOH in DCM) and then prep-HPLC (C18, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give 6-(2-chloro-5- fluorophenyl)-3 -(2,2-difluoroethyl)-5 - { [7-fluoro-5 -(fluoromethyl)benzo[d] [l,2]diazin-l- yl]amino}-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2, 8-dione (9 mg, 0.015 mmol, 6%) as a yellow solid. LCMS: m/z 592 [M+H]⁺. 'H NMR (400 MHz, DMSO-r/6) 8 9.23 - 8.85 (m, 2H), 8.16 - 7.95 (m, 2H), 7.44 (s, 1H), 6.93 - 6.84 (m, 2H), 6.68 (d, J= 8.0 Hz, 1H), 6.51 - 6.23 (m, 1H), 6.04 (brs, 1H), 5.96 - 5.86 (m, 2H), 4.43 - 4.34 (m, 2H).

Example 41 : (6R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)cinnolin-4-yl]amino}-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo [5, 4-e] isoindole-2, 8-dione and Example 42: (6S)-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl)cinnolin-4-yl]amino}-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[5, 4-e] isoindole-2, 8-dione

[00402] Step A: To a solution of 4-chloro-6-fluoro-8-(trifluorornethyl)cinnoline (80 mg, 0.319 mmol) in l,l-dideuterio-l-(deuteriooxidanyl)-2,2,2-trifluoroethane (5 mL) was added 5- amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo[5,4-e]isoindole-2, 8-dione (132 mg, 0.319 mmol) and HC1 (11 .64 mg, 0.319 mmol). The mixture was stirred at 90 °C for 12 hours. The mixture was concentrated under vacuum to give a crude, which was purified by pre-HPLC to give a yellow solid. It was purified by chiral prep-SFC method 5 to give (6R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difhioroethyl)-5- {[6-fluoro-8-(trifluoromethyl)cinnolin-4-yl]amino}-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo[5,4-e]isoindole-2, 8-dione (24.7 mg, 0.039 mmol, 12%) as a yellow solid. LCMS: ESI m/z 628.4 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.18 (s, 2H), 8.36 - 8.18 (m, 2H), 8.00 (s, IH), 7.58 (s, IH), 7.04 - 6.55 (m, 3H), 6.53 - 6.22 (m, IH), 6.00 (s, IH), 4.50 - 4.35 (m, 2H). And (6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)cinnolin-4-yl]amino}-l -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[5, 4- e]isoindole-2, 8-dione (23.7 mg, 0.038 mmol, 12%) as a yellow solid. LCMS: ESI m/z 628.4 [M + H]⁺. 'H NMR (400 MHz, DMSO-d6) 8 9.22 (s, 2H), 8.36 - 8.18 (m, 2H), 8.00 (s, IH), 7.58 (s, IH), 7.04 - 6.55 (m, 3H), 6.53 - 6.21 (m, IH), 5.99 (s, IH), 4.52 - 4.35 (m, 2H).

Example 43: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((8-(difluoromethyl)-6- fluoroquinazolin-4-yl)amino)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8- dione

[00403] Step A: To the mixture of 4-chloro-8-(difluoromethyl)-6-fluoroquinazoline (80 mg, 0.34 mmol) in propan-2-ol (2 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-l -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[5,4-e]isoindole-2, 8-dione (86 mg, 0.21 mmol). The mixture was stirred at 90 °C for Ih. The reaction was concentrated and the residue was purified by prep-HPLC (Cl 8, 5 ~ 95 % MeCN in H2O with 0.1 % FA) to give 6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[8-(difluoromethyl)-6-fluoroquinazolin-4- yl]amino]-l -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e]isoindole-2, 8-dione (54.3 mg, 0.089 mmol, 26%) as a white solid. LCMS: ESI m/z 610 [M + H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 9.82 (s, 1H), 9.15 (s, 1H), 8.38 (s, 1H), 8.14 - 8.06 (m, 1H), 8.05 - 7.96 (m, 1H), 7.87 - 7.53 (m, 1H), 7.47 (s, 1H), 7.04 - 6.78 (m, 2H), 6.67 - 6.55 (m, 1H), 6.53 - 6.18 (m, 1H), 6.08 - 5.82 (m, 1H), 4.52 - 4.28 (m, 2H).

Example 44: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[8-(difluoromethyl)-6- fluorocinnolin-4-yl] amino}-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e] isoindole-2, 8-dione

[00404] Step A: To a stirred solution of 4-chloro-8-(difluoromethyl)-6-fluorocinnoline (70 mg, 0.301 mmol) in TFE (3 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-! -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e] isoindole-2, 8-dione (124 mg, 0.301 mmol) at rt. The reaction mixture was stirred at 90 °C for Ih and then concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[8-(difluoromethyl)-6- fluorocinnolin-4-yl] amino}- 1 -(trideuteri omethyl)- 1,2, 3, 6, 7, 8-hexahydroimidazo[4,5-e] isoindole-2, 8-dione (35.8 mg, 0.059 mmol, 19 %) as a yellow solid. LCMS: m/z 610 [M+H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 9.36 - 8.95 (m, 2H), 8.20 - 8.11 (m, IH), 8.09 - 7.78 (m, 3H), 7.58 (s, IH), 6.78 - 6.64 (m, 2H), 6.50 - 6.21 (m, IH), 6.00 (brs, IH), 4.47 - 4.38 (m, 2H).

Example 45: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)benzo[d] [1,2, 3]triazin-4-yl)amino)-l-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

[00405] Step A: To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazine (40 mg, 0.16 mmol) in l,l-dideuterio-l-(deuteriooxidanyl)-2,2,2-trifluoroethane (5 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (66 mg, 0.16 mmol). The mixture was stirred at 100 °C for 5 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 di chloroform and then purified using pre-HPLC to afford 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)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (28.3 mg, 0.045 mmol, 28%) as a yellow solid. LCMS: ESI m/z 629 [M + H]⁺. 'H NMR (400 MHz, DMSO-i/6) 5 10.1 1 (s, 1H), 9.17 (s, 1H), 8.57 - 8.41 (m, 1H), 8.35 - 8.16 (m, 1H), 7.50 (s, 1H), 6.96 - 6.74 (m, 2H), 6.71 - 6.58 (m, 1H), 6.56 - 6.17 (m, 1H), 5.91 (brs, 1H), 4.48 - 4.35 (m, 2H).

Example 46: (6R)-6-(2-chloro-5-fluorophenyl)-5-{[6-fluoro-8-(trifluoromethyl)cinnolin-4- yl]amino}-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahy droimidazo [4,5-e] isoindole-2, 8-dione

Example 47 : (6S)-6-(2-chloro-5-fluorophenyl)-5-{[6-fluoro-8-(trifluoromethyl)cinnolin-4- yl]amino}-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahy droimidazo [4,5-e] isoindole-2, 8-dione

Example 46 Example 47

[00406] Step A: To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)cinnoline (100 mg, 0.399 mmol) in l,l-dideuterio-l-(deuteriooxidanyl)-2,2,2-trifluoroethane (5 mL) was added 5- amino-6-(2-chloro-5-fluorophenyl)-3 -(1,1, 2, 2-tetradeuterio-2-fluoroethyl)-l -(trideuteri omethyl)- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (160 mg, 0.399 mmol) and a drop of con.HCl (14.6 mg, 0.399 mmol). The mixture was stirred at 90 °C for 12 hours. The mixture was concentrated under vacuum to give a crude, which was purified by prep-HPLC to give a yellow solid. It was purified by chiral prep-SFC method 6 to give (6R)-6-(2-chloro-5- fluorophenyl)-5-{[6-fluoro-8-(trifluoromethyl)cinnolin-4-yl]amino}-3-(l,l,2,2-tetradeuterio-2- fluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (37.5 mg, 0.061 mmol, 15 %) as a yellow solid. LCMS: ESI m/z 614.1 [M + H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 9.32 - 9.01 (m, 2H), 8.33 - 8.17 (m, 2H), 8.00 (s, 1H), 7.56 (s, 1H), 6.99 - 6.46 (m, 3H), 5.99 (s, 1H). And (6S)-6-(2-chloro-5-fluorophenyl)-5-{[6-fluoro-8- (trifluoromethyl)cinnolin-4-yl]amino} -3 -(1,1 ,2,2-tetradeuterio-2-fluoroethyl)- 1 - (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (35.7 mg, 0.058 mmol, 15 %) as a yellow solid. LCMS: ESI m/z 614.1 [M + H]⁺. 'H NMR (400 MHz, DMSO- d6) 8 9.32 - 9.01 (m, 2H), 8.33 - 8.17 (m, 2H), 8.00 (s, 1H), 7.56 (s, 1H), 6.99 - 6.46 (m, 3H), 5.98 (s, 1H).

Example 48: (6R)-6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)cinnolin-4-yl]amino}-l-(trideuteriomethyl)-l,2,3,6,7,8- hexahydroimidazo [4, 5-e] isoindole-2, 8-dione and Example 49: (6S)-6-(2-chloro-5- fluorophenyl)-3-(2-fluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl)cinnolin-4-yl]amino}-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4, 5-e] isoindole-2, 8-dione

[00407] Step A: To a stirred solution of 4-chloro-6-fluoro-8-(trifluoromethyl) cinnoline (100 mg, 0.399 mmol) in TFE (2 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2- fluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e] isoindole-2, 8-dione (158 mg, 0.399 mmol) and HC1 (0.1 mL) at rt. The reaction mixture was stirred at 90 °C O/N. 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 6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-5-{[6- fluoro-8-(trifluoromethyl) cinnolin-4-yl] amino}- 1 -(trideuteri omethyl)-l, 2, 3, 6,7,8- hexahydroimidazo[4,5-e] isoindole-2, 8-dione (55 mg, 0.090 mmol, 22%) as a yellow solid. LCMS: m/z 610.1 [M+H]⁺.

[00408] It was purified by chiral prep-SFC method 7 to give (6R)-6-(2-chloro-5- fluorophenyl)-3-(2-fluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl)cinnolin-4-yl]amino}-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (20.5 mg, 0.034 mmol, 37%) as a yellow solid. LCMS: m/z 610.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 9.26 - 9.10 (m, 2H), 8.29 - 8.21 (m, 2H), 7.99 (s, 1H), 7.55 (s, 1H), 6.86 - 6.55 (m, 3H), 5.98 (brs, 1H), 4.76 — 4.61 (m, 2H), 4.31 - 4.21 (m, 2H). And (6S)-6-(2-chloro-5-fluorophenyl)-3-(2- fluoroethyl)-5-{ [6-fluoro-8-(trifluoromethyl)cinnolin-4-yl]amino}-l -(trideuteri omethyl)- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (17.4 mg, 0.029 mmol, 31%) as a yellow solid. LCMS: m/z 610.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-t/6) 5 9.26 - 9.10 (m, 2H), 8.29 - 8.21 (m, 2H), 7.99 (s, 1H), 7.55 (s, 1H), 6.86 - 6.55 (m, 3H), 5.98 (brs, 1H), 4.76 - 4.61 (m, 2H), 4.31 - 4.21 (m, 2H).

Example 50: (R)-6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5-(trifluoromethyl)phthalazin-l- yl)amino)-3-(2-fluoroethyl)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8- dione and Example 51: (S)-6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5- (trifluoromethyl)phthalazin-l-yl)amino)-3-(2-fluoroethyl)-l-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

[00409] Step A: To a solution of l-chloro-7-fluoro-5-(trifluoromethyl)benzo[2,l- d][l,2]diazine (150 mg, 0.599 mmol) and 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2- fluoroethyl)-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (237 mg, 0.599 mmol) in 2,2,2-trifluoroethanol (3 mL) was added con.HCl (0.3 mL). The reaction was stirred at 95 °C for 16 h, then diluted with EA and H2O. The organic layer was separated, dried over Na2SC>4 and concentrated in vacuo. The residue was purified by pre-HPLC to afforded 6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-5-{[7-fluoro-5-(trifluoromethyl)benzo[2,l- d][l,2]diazin-l-yl]amino}-l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole- 2,8-dione (32 mg, 52 pmol, 8.8%) as a yellow solid. LCMS: 610.1 [M+H]⁺. It was purified by chiral prep-SFC method 8 to give (R)-6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5- (trifluoromethyl)phthalazin-l-yl)amino)-3-(2-fhioroethyl)-l-(methyl-d3)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (4.0 mg) as a white solid. LCMS: 610.1 [M+H]⁺. NMR (400 MHz, DMSO-t/6) 8 9.08 (m, 2H), 8.35 (s, 1H), 8.18 (s, 1H), 7.37 - 7.24 (m, 1H), 6.94 - 6.86 (m, 2H), 6.60 (s, 1H), 5.86 (s, 1H), 4.76 - 4.64 (m, 2H), 4.26 - 4.20 (m, 2H). (S)-6- (2-chloro-5-fluorophenyl)-5-((7-fluoro-5-(trifluoromethyl)phthalazin-l-yl)amino)-3-(2- fluoroethyl)-! -(methyl-d3)- 1,3, 6, 7-tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (2.2 mg) (ee=95) as a white solid. LCMS: 610.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-t/6) 6 9.08 (m, 2H), 8.35 (s, 1H), 8.18 (s, 1H), 7.37 - 7.24 (m, 1H), 6.94 - 6.86 (m, 2H), 6.60 (s, 1H), 5.86 (s, 1H), 4.76 - 4.64 (m, 2H), 4.26 - 4.20 (m, 2H).

Example 52: (R)-6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5-(trifluoromethyl)phthalazin-l- yl)amino)-3-(2-fluoroethyl-l,l,2,2-d4)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione Example 53: (S)-6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5-(trifluoromethyl)phthalazin-1 - yl)amino)-3-(2-fluoroethyl-l,l,2,2-d4)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5- el isoindole-2, 8-dione

Example 52 Example 53

[00410] Step A: To a solution of l-chloro-7-fluoro-5-(trifluoromethyl)benzo[2,l- d][l,2]diazine (150 mg, 0.599 mmol) and 5-amino-6-(2-chloro-5-fhiorophenyl)-3-(l, 1,2,2- tetradeuterio-2-fluoroethyl)-l -(trideuteri omethyl)- 1,2, 3,6,7, 8-hexahy droimidazo[4, 5-e]isoindole-

2.8-dione (239 mg, 0.599 mmol) in 2,2,2-trifluoroethanol (3 mL) was added con.HCl (0.3 mL). The reaction was stirred at 95 °C for 16 h. The cooled 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 by pre-HPLC to afforded 6-(2-chloro-5-fluorophenyl)-5-{[7-fluoro-5- (trifluoromethyl)benzo[2,l-d][l,2]diazin-l-yl]amino}-3-(l,l,2,2-tetradeuterio-2-fluoroethyl)-l- (trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (32 mg, 52 pmol, 9%) as a yellow solid. LCMS: 614.2 [M+H]⁺. Then it was separated by chiral prep-SFC method 9 to give (R)-6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5-(trifluoromethyl)phthalazin-l- yl)amino)-3-(2-fluoroethyl- 1,1,2, 2-d4)- l-(methyl-d3)-l, 3,6, 7-tetrahy droimidazo[4, 5-e]isoindole-

2.8-dione(18.1 mg) as a white solid. LCMS: 614.2 [M+H]⁺. ‘H NMR (400 MHz, DMSO-t/6) 8 9.09 (s, 1H), 8.70 (s, 1H), 8.34 (brs, 1H), 8.20 (brs, 1H), 7.30 (s, 1H), 6.93 - 6.87 (m, 2H), 6.63 (brs, 1H), 5.86 (brs, 1H). And (S)-6-(2-chloro-5-fluorophenyl)-5-((7-fluoro-5- (trifluoromethyl)phthalazin- 1 -yl)amino)-3 -(2-fluoroethyl- 1 , 1 ,2,2-d4)-l -(methyl-d3)- 1 ,3 ,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (1.5 mg) (ee=89) as a white solid. LCMS: 614.2[M+H]-. ‘H NMR (400 MHz, DMSO-d6) 8 9.09 (s, 1H), 8.70 (s, 1H), 8.34 (brs, 1H), 8.20 (brs, 1H), 7.30 (s, 1H), 6.93 - 6.87 (m, 2H), 6.63 (brs, 1H), 5.86 (brs, 1H).

Example 54: (S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)benzo[d] [1,2, 3]triazin-4-yl)amino)-1-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

Example 55: (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((6-fluoro-8- (trifluoromethyl)benzo[d] [1,2, 3]triazin-4-yl)amino)-l-(methyl-d3)-l, 3,6,7- tetrahydroimidazo [4,5-e] isoindole-2, 8-dione

Example 54 Example 55

[00411] Step A: 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)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (55 mg, 0.090 mmol) was purified by chiral prep- SFC method 10 to give (S)-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)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (12.7 mg, 0.021 mmol, 23%) as a yellow solid. LCMS: m/z 629.4 [M+H]⁺. ’HNMR (400 MHz, DMSO-c/6) 8 10.14 (s, 1H), 9.18 (s, 1H), 8.54 - 8.45 (m, 1H), 8.32 - 8.23 (m, 1H), 7.52 (s, 1H), 6.96 - 6.74 (m, 2H), 6.70 - 6.61 (m, 1H), 6.51 - 6.22 (m, 1H), 5.92 (brs, 1H), 4.47 - 4.34 (m, 2H). And (R)-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)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (22.5 mg, 0.037 mmol, 40%) as a yellow solid. LCMS: m/z 629.4 [M+H]⁺. ’HNMR (400 MHz, DMSO-i/6) 8 10.14 (s, 1H), 9.18 (s, 1H), 8.54 - 8.45 (m, 1H), 8.32 - 8.23 (m, 1H), 7.52 (s, 1H), 6.96 - 6.74 (m, 2H), 6.70 - 6.61 (m, 1H), 6.51 - 6.22 (m, 1H), 5.92 (brs, 1H), 4.47 - 4.34 (m, 2H).

Example 56: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l -(difluoromethyl)-5-((6- fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazin-4-yl)amino)-l,3,6,7-tetrahydroimidazo[4,5- el isoindole-2, 8-dione

Example 56

[00412] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-(difluoromethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (35 mg, 0.08 mmol) in 1, 1 -di deuteri o-l -(deuteri ooxidanyl)-2, 2, 2-trifluoroethane (5 mL) was added 4-chloro- 6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazine (60 mg, 0.24 mmol), and the mixture was stirred at 100 °C for 6 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 di chloroform and then purified using prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- (difluoromethyl)-5-((6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazin-4-yl)amino)-l,3,6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (2.2 mg, 0.003 mmol, 4%) as a red solid. LCMS: ESI m/z 662.3 10.30 - 10.1 1 (m, 1H), 9.54 (s, 1H), 9.17 (t, J= 57.2 Hz, 1H), 8.58 - 8.44 (m, 1H), 8.33 - 8.19 (m, 1H), 7.63 (s, 1H), 6.97 - 6.76 (m, 3H), 6.58 - 6.23 (m, 1H), 6.06 - 5.89 (m, 1H), 4.57 - 4.34 (m, 3H).

Example 57 : (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-5-((6- fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazin-4-yl)amino)-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione and Example 58: (S)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-l-(difluoromethyl)-5-((6-fluoro-8-(trifluoromethyl)benzo[d][l,2,3]triazin-4- yl)amino)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione

Example 57 Example 58

[00413] Step A: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-5-((6- fluoro-8-(trifluoromethyl)benzo[d][ 1,2, 3]triazin-4-yl)amino)- 1,3, 6, 7-tetrahy droimidazo[4, 5- e]isoindole-2, 8-dione (50 mg, 0.076 mmol) was purified with chiral prep-SFC method 11 to afford (R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-5-((6-fluoro-8- (trifluoromethyl)benzo[d][ 1,2, 3]triazin-4-yl)amino)- 1,3,6, 7-tetrahy droimidazo[4, 5-e]isoindole- 2, 8-dione (13.8 mg, 0.021 mmol, 55%) as a yellow solid. LCMS: ESI m/z 662.3 [M + H]⁺. ^rH NMR (400 MHz, CD₃OD) 8 9.12 (t, J= 56.6 Hz, 1H), 8.37 - 8.21 (m, 1H), 8.10 - 7.92 (m, 1H), 7.51 (s, 1H), 6.90 - 6.58 (m, 3H), 6.44 - 6.10 (m, 2H), 4.48 - 4.31 (m, 2H). And (S)-6-(2-chloro- 5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(difluoromethyl)-5-((6-fluoro-8- (trifluoromethyl)benzo[d][ 1,2, 3]triazin-4-yl)amino)- 1,3, 6, 7-tetrahy droimidazo[4, 5-e]isoindole- 2, 8-dione (13.7 mg, 0.021 mmol, 55%) as a yellow solid. LCMS: ESI m/z 662.3 [M + H]⁺. 'H NMR (400 MHz, CD3OD) 8 9.12 (t, J= 56.6 Hz, 1H), 8.37 - 8.21 (m, 1H), 8.10 - 7.92 (m, 1H), 7.51 (s, 1H), 6.90 - 6.58 (m, 3H), 6.44 - 6.10 (m, 2H), 4.48 - 4.31 (m, 2H).

Example 59: 5-(benzo[d]isoxazol-3-ylamino)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-l-(methyl-d3)-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione

Example 59 [00414] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-(trideuteriomethyl)-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (202.1 mg, 0.49 mmol) in THF (1.47 mL, 1.47 mmol) was added lithium bis(trimethylsilyl)azanide (1.47 mL, 1.47 mmol, IM in THF) and the mixture was stirred at 0 °C for 15min, then 3- chlorobenzo[d]isoxazole (150 mg, 0.98 mmol) was added to the mixture and the mixture was stirred at 0 °C for 12h. The mixture was quenched with water (10 mL), extracted with EtOAc (10 mL). The combined organic layer was dried over Na?SO4, fdtered and the fdtrate was concentrated in vacuo and purified by prep-TLC (SiCL, EA) to give 6-(benzo[d]isoxazol-3- ylamino)-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-2-oxo-3- (trideuteriomethyl)benzo[d]imidazole-4-carbonitrile (2.3 mg, 1%). LCMS (ESI): m/z 531 [M+H]⁺. 'H NMR (400 MHz, CD₃OD) 8 7.44 - 7.58 (m, 3H), 7.36 - 7.41 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.19 - 7.21 (m, 1H), 7.04 - 7.08 (m, 1H), 6.75 - 6.80 (m, 1H), 6.5 - 6.60 (m, 1H), 6.05 - 6.35 (m, 2H), 4.38 - 4.40 (m, 2H).

Example 60: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5-fluoro-7- (trifluoromethyl)benzo[d]isothiazol-3-yl)amino)-l-methyl-l,3,6,7-tetrahydroimidazo[4,5- e] isoindole-2, 8-dione [00415] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-methyl-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione (42 mg, 0.10 mmol) in dioxane (5 mL) was added 3-bromo-5-fluoro-7-(trifluoromethyl)benzo[d]isothiazole (30 mg, 0.10 mmol), Pd2(dba)s (18 mg, 0.02 mmol), XANT PHOS (12 mg, 0.02 mmol) and CS2CO3 (98 mg, 0.30 mmol), the reaction mixture was stirred at 110 °C under N2 for 3 hours. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 20 - 70% EA in PE to afford 6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-5-((5-fluoro-7-(trifluoromethyl)benzo[d]isothiazol-3- yl)amino)-6-hydroxy-l -methyl- 1,3, 6, 7-tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (10 mg crude, 4%). LCMS: 628 [M+H]⁺.

[00416] Step B: To a solution of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5- fluoro-7-(trifluoromethyl)benzo[d]isothiazol-3-yl)amino)-6-hydroxy-l -methyl- 1,3, 6,7- tetrahydroimidazo[4,5-e]isoindole-2, 8-dione (10 mg crude) in TFA (2 mL) was added Et3SiH (1 mL) at 0 °C, the reaction mixture was stirred at 60 °C for 3 hours. The mixture was concentrated in vacuum and quenched by NaHCOs solution, then the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified prep-HPLC (Cl 8, acetonitrile/FEO, 0.1% trifluoroacetic acid modifier, 5% to 95% gradient, 15 min run) to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-((5-fluoro-7- (trifluoromethyl)benzo[d]isothiazol-3-yl)amino)-l-methyl-l,3,6,7-tetrahydroimidazo[4,5- e]isoindole-2, 8-dione (2 mg, 41%). LCMS (ESI): m/z 630 [M+H]⁺. 'H NMR (400 MHz, DMSO- <76) 5 9.33 (s, 1H), 9.11 (s, 1H), 8.26 - 7.96 (m, 2H), 7.47 (s, 1H), 7.14 - 6.98 (m, 1H), 6.98 - 6.75 (m, 1H), 6.63 - 6.13 (m, 2H), 5.98 (s, 1H), 4.54 - 4.22 (m, 2H), 3.92 (s, 3H).

Example 61: (6R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)quinazolin-4-yl]amino}-l-methyl-l,2,3,6,7,8-hexahydroimidazo[4,5- e] isoindole-2, 8-dione and Example 62: (6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-5-{[6-fluoro-8-(trifluoromethyl)quinazolin-4-yl]amino}-l-methyl-l,2,3,6,7,8- hexahydroimidazo [4, 5-e] isoindole-2, 8-dione

[00417] Step A: To a solution of 4-chloro-6-fluoro-8-(trifluoromethyl)quinazoline (500 mg, 2.00 mmol) in 2,2,2-trifluoroethan-l-ol (5 mL) was added 5-amino-6-(2-chloro-5-fluorophenyl)- 3-(2,2-difluoroethyl)-l-methyl-l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2, 8-dione (245.90 mg, 0.60 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 1 h. The TFE was removed under vacuum to give a crude product which was purified by prep-HPLC to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)quinazolin-4-yl]amino}-l-methyl-l,2,3,6,7,8-hexahydroimidazo[4,5- e]isoindole-2, 8-dione (240 mg, 0.38 mmol, 19%) as a yellow solid. LCMS (ESI): m/z 625 [M+H]⁺.

[00418] Then 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)quinazolin-4-yl]amino}-l-methyl-l,2,3,6,7,8-hexahydroimidazo[4,5- e]isoindole-2, 8-dione (250 mg, 0.40 mmol) was separated by chiral prep-SFC method 12 to give (6R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifluoromethyl)quinazolin-4-yl]amino}-l-methyl-l,2,3,6,7,8-hexahydroimidazo[4,5- e]isoindole-2, 8-dione (80.5 mg, 32%) as white solid. LCMS: ESI m/z 625 [M + H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 9.87 (s, 1H), 9.14 (s, 1H), 8.39 (s, 1H), 8.21 (d, J= 8.0 Hz, 2H), 7.46 (s, 1H), 6.95 - 6.76 (m, 2H), 6.61 (d, J= 8.0 Hz, 1H), 6.51 - 6.18 (m, 1H), 5.94 (s, 1H), 4.49 - 4.28 (m, 2H), 3.94 (s, 3H). And (6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6- fluoro-8-(trifluoromethyl)quinazolin-4-yl]amino}-l -methyl- 1,2, 3,6,7, 8-hexahydroimidazo[4, 5- e]isoindole-2, 8-dione (82.9 mg, 33%) as white solid. LCMS: ESI m/z 625 [M + H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 9.87 (s, 1H), 9.14 (s, 1H), 8.39 (s, 1H), 8.21 (d, J= 8.0 Hz, 2H), 7.46 (s, 1H), 6.95 - 6.76 (m, 2H), 6.61 (d, J= 8.0 Hz, 1H), 6.51 - 6.18 (m, 1H), 5.94 (s, 1H), 4.49 - 4.28 (m, 2H), 3.94 (s, 3H).

Example 63: 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[5-fluoro-7- (trifluoromethyl)benzo[d]isoxazol-3-yl]amino}-l-methyl-l,2,3,6,7,8-hexahydroimidazo[4,5- e] isoindole-2, 8-dione

Example 63

[00419] Step A: To a solution of 4-fluoro-2-(trifluoromethyl)phenol (3 g, 16.66 mmol) in TFA (30 mL) was added l,3,5,7-tetrazatricyclo[3.3.1.13,7]decane (4.67 g, 33.3 mmol) and the mixture was stirred at 90 °C overnight. The mixture was quenched with water (50 mL), extracted with EtOAc (50 mL). The combined organic layer was concentrated in vacuo and purified by flash silica gel column chromatography, eluting with a gradientof 3-15% EtOAc in petroleum ether to afford 5-fluoro-2-hydroxy-3- (trifluoromethyl)benzene-l-carbaldehyde (1.2 g, 34%) as white solid.

[00420] Step B: To a solution of 5-fluoro-2-hydroxy-3-(trifluoromethyl)benzene-l- carbaldehyde (1 g, 4.81 mmol) in EtOH (10 mL) were added azanol hydrochloride (0.67 g, 9.61 mmol) and Na2CCh (1.53 g, 14.4 mmol). The mixture was stirred at 60 °C for 3h. The reaction mixture was filtered and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford (Z)-[5- fluoro-2-hydroxy-3-(trifluoromethyl)phenyl]methanal oxime (1 g, 4.48 mmol, 93%) as a white solid. LCMS: ESI m/z 223.1 [M + H]⁺.

[00421] Step C: To a solution of (Z)-[5-fluoro-2-hydroxy-3-(trifluoromethyl)phenyl]methanal oxime (300 mg, 1.34 mmol) in DMF (5 mL) was added NCS (269 mg, 2.02 mmol). The mixture was stirred at 40 °C overnight. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na?SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford [(E)-chloro[5-fluoro-2-hydroxy-3- (trifluoromethyl)phenyl]methylidene]hydroxylamine (200 mg, 0.78 mmol, 58%) as a white solid. LCMS: ESI m/z 257.6 [M + H]⁺.

[00422] Step D: To a solution of [(Z)-chloro[5-fluoro-2-hydroxy-3- (trifluoromethyl)phenyl]methylidene]hydroxylamine (150 mg, 0.58 mmol) in dioxane (5 mL) were added 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methyl- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (359 mg, 0.87 mmol) and NaHCCh (147 mg, 1.75 mmol). The mixture was stirred at 60 °C ON. 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 methanol in dichloroform (gradient: 0-10%) to afford 6-(2-chloro-5-fluorophenyl)-3-(2,2- difhioroethyl)-5-{[5-fluoro-7-(trifluoromethyl)benzo[d]isoxazol-3-yl]amino}-l -methyl- l,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindole-2,8-dione (1.5 mg, 0.00 mmol, 0.42%) as a yellow solid. LCMS: ESI m/z 614.2 [M + H]⁺. 'HNMR (400 MHz, CDOD) 8 7.50 (s, 1H), 7.24 - 7.03 (m, 3H), 6.84 - 6.75 (m, 1H), 6.68 - 6.42 (m, 1H), 6.42 - 6.03 (m, 2H), 4.45 - 4.33 (m, 2H), 4.02 (s, 3H).

Example 64: (S)-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-l,3,6,7- tetrahydroimidazo [4, 5-e] isoindole-2, 8-dione and Example 65: (R)-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-l,3,6,7-tetrahydroimidazo[4,5-e]isoindole-2,8-dione

Example 64 Example 65 [00423] Step A: A mixture of 4-chloro-6-fluoro-8-(trifluoromethyl)benzo[2,l - d][l,2,3]triazine (200 mg, 0.80 mmol) and 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-! -methyl- 1,2, 3, 6, 7, 8-hexahydroimidazo[5,4-e]isoindole-2, 8-dione (326.58 mg, 0.80 mmol) in 2,2,2-trifluoroethan-l-ol (5 mL) was stirred at 100 °C for 2 hrs. The reaction was monitored by analysis of LCMS. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC and then by chiral prep-SFC method 13 to afford: (6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5-{[6-fluoro-8- (trifhjoromethyl)benzo[2,l-d][l,2,3]triazin-4-yl]amino}-l-methyl-l,2,3,6,7,8- hexahydroimidazo[5,4-e]isoindole-2, 8-dione (46.8 mg, 9%) as a yellow solid. LCMS (ESI): m/z 626 [M+H]⁺. Tl NMR (400 MHz, DMSO-t/6) 8 10.11 (s, 1H), 9.17 (s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.52 (s, 1H), 6.93 - 6.78 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.36 (t, J = 54.6 Hz, 1H), 6.00 - 5.83 (m, 1H), 4.41 (t, J = 16.8 Hz, 2H), 3.95 (s, 3H). And (6R)-6-(2-chloro-5-fluorophenyl)-3- (2,2-difluoroethyl)-5- { [6-fluoro-8-(trifluoromethyl)benzo[2, 1 -d] [ 1 ,2,3 ]triazin-4-yl]amino } - 1 - methyl-l,2,3,6,7,8-hexahydroimidazo[5,4-e]isoindole-2,8-dione (45.8 mg, 9%) as a yellow solid.. LCMS (ESI): m/z 626 [M+H]⁺. 'H NMR (400 MHz, DMSO-t/6) 8 10.11 (s, 1H), 9.17 (s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.52 (s, 1H), 6.93 - 6.78 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.36 (t, J= 54.6 Hz, 1H), 6.00 - 5.83 (m, 1H), 4.41 (t, J= 16.8 Hz, 2H), 3.95 (s, 3H).

PI3Ka enzymatic ADP-Glo assay

Table 2. Materials

Table 3. Instruments

[00424] All the compounds were initially prepared as 10 mM stock solution in 100% DMSO. The stock solution was then serially diluted 3-fold in 100% DMSO to 10 concentrations. 50 nL of each compound dilution was subsequently added to 384-well plate in duplicate. To each well, 2.5 pL of enzyme solution containing PI3Ka protein (PI3Ka WT, H1047R, E542K, E545K) with final concentrations 0.15 pg/ml for WT, 0.05 pg/ml for PI3Ka H1047R, 0.07 pg/ml for PI3Ka E542K, and 0.07 pg/ml for PI3Ka E545K, respectively in 1 * Kinase buffer (50 mM HEPES pH 7.5, 3 mM MgCl₂, 2 mM DTT and 0.03% CHAPS, lOOmM NaCl, ImM EGTA). For negative control, 2.5 uL of assay buffer was added instead. The mixture was incubated at room temperature for 10 min. 2.5 pL of substrate solution containing PIP2 peptide (final concentrations 50 pg/ml) and ATP (final concentration 25 pM for WT and H1047R, 68 pM and 100 pM for E542K and E545K, respectively) in 1 x Kinase buffer was added into each well to initiate each reaction. All the reactions were incubated at room temperature for 60 min. Then 5 pL of ADP-Glo reagent 1 was subsequently added to stop the reactions. After equilibrating for 120 min at room temperature, 10 pL ADP-Glo reagent 2 was added to each well, followed by shaking for 1 min and equilibrating for 30 min at room temperature. All the samples were then subjected to analysis using Envision to read luminescence RLU values. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.

[00425] Results of the ADP-Glo Biochemical PI3Ka enzymatic assays using PI3Ka H1047R, E545K, E542K and WT enzymes are presented in Table 4. Compounds having an IC50 less than or equal to 200 nM are represented as “A”; Compounds having an IC50 greater than 200 nM but less than or equal to 1 uM are represented as “B”; Compounds having an IC50 greater than 1 uM but less than 10 uM are represented as “C”; Compounds having an IC50 greater than or equal to 10 uM are represented as “D”.

Table 4. Biochemical Potency for Exemplary Compounds

Material and instrument information for cellular assays

Table 5. Materials

Table 6. Instruments

HTRF PHOSPHO- AKT (SER473) assay

[00426] HCC1954 cells (American Type Culture Collection, Catalog#: CRL-2338, Lot #:

70032967)) are maintained by culturing in the medium recommended by the provider. To each well of a flat-bottom 384-well plate, 10,000 cells were added in a volume of 35 pL of RPMI1640 culture medium with 10%FBS. Cells were allowed to recover overnight. On the following day, the plated cells were treated with 9 concentrations of compounds in 3-fold serial dilution or with DMSO. Compounds were prepared as 10 mM DMSO stock solution, and 100 pL of the diluted compounds were added to the cells, with a final concentration of 0.1% DMSO. Cells were treated for 2 h and the culture medium was removed by aspiration. To each well, 20 pL of lysis buffer were added (Perkin Elmer phospho- AKT Ser473 kit) and the plates were incubated for 30 minutes at room temperature. AKT phosphorylation at Ser473 was detected using a pair of donor and acceptor antibodies specific for the total and phosphorylated protein provided in the assay kit. A pre-mixed antibody solution was added to each well of cell lysate and the plates were incubated at room temperature for 16 h. Fluorescence emission by the two antibodies was measured at 665 and 620 nm in a plate reader.

[00427] Data analysis:

Calculate the ratio of the acceptor and donor emission signals for each individual well.

Signal 665 nm Ratio = — . - xlO⁴

Signal 620 nm

Cell Proliferation Assay

[00428] Cancer cells were grown in culture media according to vendors’ instructions. Cells were plated in clear bottom tissue culture treated 96-well plates at a density of 1250-5000 cells/well in a volume of 100 pL and allowed to recover overnight. The edge wells were filled with cell culture media only. The plated cells were treated with a 3-fold 9-point serial dilution doses of test compounds, or DMSO control. Compounds were prepared as 10 mM DMSO stock solution and added to the cells with a HP D300 digital dispenser. The top final concentration varied from 10 to 1 pM depending on the potency of the compounds, with the final concentration of DMSO to be 0.1%. Following 7 days of drug treatment, 100 gl. of CellTiter-Glo (CTG) (Promega, G7570) reagent was added to the cells using a Multidrop Combi instrument and the plates were placed on an orbital shaker for 15 minutes. The luminescence signal was read on an Envision plate reader with a measurement time of 0.1 s.

[00429] Cell proliferation percent inhibition values were calculated using the following equation:

Inhibition% = [l-(T168_eompound-T168biank)/(T168_DMso- T168biank)]^x 100%.

T 168_compound: the signals from compound-treated wells;

T168biank: the signals from blank wells;

T168DMSO: the signals from 0.1%DMSO-treated wells.

[00430] XLfit software (Fit model: Dose response one site/ ²⁰⁵ [fit = (A+((B-A)/(I+((C/X)'^,'D))))] ) was used for curve fitting and IC50 calculation.

[00431] Results of the HTRF pAKT assay on HCC1954 cell line and CTG cell proliferation assay on NCI-H1048 cell line are presented in Table 7. Compounds having an IC50 less than or equal to 500 nM are represented as “A”; Compounds having an IC50 greater than 500 nM but less than or equal to 1 uM are represented as “B”; Compounds having an IC50 greater than 1 uM but less than 10 uM are represented as “C”; Compounds having an IC50 greater than or equal to 10 uM are represented as “D”.

Table 7. Cellular Potency for Exemplary Compounds

[00432] 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.

[00433] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[00434] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[00435] 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. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.

Incorporation by Reference

[00436] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

Equivalents

[00437] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

What is claimed is: CLAIMS

1. A compound having the structural formula (I): or a pharmaceutically acceptable form or an isotope derivative thereof, wherein

Z¹ is N-R²;

Z² is N or C=O;

R³ is NH-R³ ; each of R³ and R⁴ is independently

H, 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, O and S, optionally substituted with one or more R^b or R^c, respectively; each of R^b and R^c is independently D, oxo, halogen, CN, N0₂, OR, SR, NRR’, SF₅, S(O)₂R, S(O)₂NRR’, S(O)R, S(O)NRR’, S(O)(NR)R, C(O)R, C(O)OR, C(0)NRR’, C(0)N(R)0R, OC(O)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(O)₂R; or a substituted or unsubstituted group selected from Ci-6 alkyl, C₂-4 alkynyl or 4- to 6-membered carbocyclic ring; each of R and R’ is independently selected from H, unsubstituted or substituted Ci-4 alkyl, 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.

2. The compound of claim 1, wherein Z² is C=0 and Z³ is N-R¹, having the structural formula (II):

3. The compound of claim 2, wherein R² is CR^2aR^2bR^2c, having the structural formula (II^A): wherein

R^2a is H, D or halogen; R^2b is H, D or halogen; and

R^2c is

4. The compound of claim 3, wherein R¹ is CR^laR^lbR^lc, having the structural formula (II^B): wherein

R^la is H, D or halogen;

R^lb is H, D or halogen; and

R^lc is

5. The compound of claim 4, wherein R^2c is CR^2dR^2eR^2f, having the structural formula (II^C): wherein

R^2d is H, D or halogen; and each of R^2e and R^2f is independently

6. The compound of any one of claims 3-5, wherein one of R^la and R^lb is H.

7. The compound of any one of claims 3-5, wherein two of R^la and R^lb is H.

8. The compound of any one of claims 3-5, wherein each of R^la, R^lb and R^lc is H.

9. The compound of any one of claims 3-5, wherein one of R^la and R^lb is D.

10. The compound of any one of claims 3-5, wherein two of R^la and R^lb is D.

11. The compound of any one of claims 3-5, wherein each of R^la, R^lb and R^lc is D.

12. The compound of claim 5, wherein R^lc is CR^ldR^leRⁿ, having the structural formula (II^D): wherein

R^ld is H, D or halogen; each of R^le and R^lf is independently H, D, halogen, CN, OR, SR, or NRR’; or an unsubstituted or substituted C1-5 alkyl, C3-6 carbocyclic or heterocyclic group, or 5- or 6-membered aryl or heteroaryl group.

13. The compound of any one of claims 3-12, wherein one of R^2a and R^2b is H.

14. The compound of any one of claims 3-12, wherein two of R^2a and R^2b is H.

15. The compound of any one of claims 3-12, wherein one of R^2a and R^2b is D.

16. The compound of any one of claims 3-12, wherein two of R^2a and R^2b is D.

17. The compound of any one of claims 3-8, wherein each of R^2a, R^2b and R^2c is H.

18. The compound of any one of claims 3-8, wherein each of R^2a, R^2b and R^2c is D.

19. The compound of any one of claims 5-16, wherein at least one of R^2d, R^2e and R^2t is a halogen atom.

20. The compound of claim 19, wherein one of R^2d, R^2e and R^2f is F.

21. The compound of claim 19, wherein two of R^2d, R^2c and R^2f is F.

22. The compound of claim 19, wherein each of R^2d, R^2e and R^2f is F.

23. The compound of any one of claims 5-16, wherein at least one of R^2d, R^2e and R^2f is a D.

24. The compound of claim 23, wherein one of R^2d, R^2e and R^2f is D.

25. The compound of claim 23, wherein two of R^2d, R^2e and R^2f is D.

26. The compound of claim 23, wherein each of R^2d, R^2e and R²¹ is D.

27. The compound of claim 1, wherein Z² is N and Z³ is C-R¹, having the structural formula

(HI)

28. The compound of claim 27, wherein R² is CR^2aR^2bR^2e, having the structural formula (III^A): wherein

R^2a is H, D or halogen;

R^2b is H, D or halogen; and

R^2c is

29. The compound of claim 27 or 28, wherein R¹ is H or D.

30. The compound of claim 29, wherein R^2e is CR^2dR^2eR^2f, having the structural formula (III^B) or (in^c):

R^2d is H, D or halogen; and each of R^2e and R^2f is independently

31. The compound of claim 27 or 28, wherein R¹ is CR^laR^lbR^lc, having the structural formula (III^D): wherein

R^la is H, D or halogen;

R^lb is H, D or halogen; and

R^le is

32. The compound of claim 31, wherein R^2c is CR^2dR^2eR^2f, having the structural formula

(III^E) wherein

R^2d is H, D or halogen; and each of R^2e and R^2t is independently

33. The compound of any one of claims 30-32, wherein one of R^la and R^lb is H.

34. The compound of any one of claims 30 -32, wherein two of R^la and R^lb is H.

35. The compound of any one of claims 30 -32, wherein each of R^la, R^lb and R^lc is H.

36. The compound of any one of claims 30 -32, wherein one of R^la and R^lb is D.

37. The compound of any one of claims 30 -32, wherein two of R^la and R^lb is D.

38. The compound of any one of claims 30-32, wherein each of R^la, R^lb and R^lc is D.

39. The compound of claim 32, wherein R^lc is CR^ldR^leR^lf, having the structural formula

(III^F) wherein

R^ld is H, D or halogen; and each of R^le and R^lf is independently

40. The compound of any one of claims 28-39, wherein one of R^2a and R^2b is H.

41. The compound of any one of claims 28-39, wherein two of R^2a and R^2b is H.

42. The compound of any one of claims 28-39, wherein one of R^2a and R^2b is D.

43. The compound of any one of claims 28-39, wherein two of R^2a and R^2b is D.

44. The compound of any one of claims 28-39, wherein each of R^2a, R^2b and R^2c is H.

45. The compound of any one of claims 28-39, wherein each of R^2a, R^2b and R^2c is D.

46. The compound of any one of claims 30-43, wherein at least one of R^2d, R^2e and R^2f is a halogen atom.

47. The compound of claim 46, wherein one of R^2d, R^2e and R^2f is F.

48. The compound of claim 46, wherein two of R^2d, R^2e and R^2f is F.

49. The compound of claim 46, wherein each of R^2d, R^2e and R²¹ is F.

50. The compound of any one of claims 1, 2 and 27, wherein R¹ and R² are independently selected from:

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,

51. The compound of any one of claims 1-50, wherein R⁴ is 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 R^cs,

52. The compound of claim 51, wherein R⁴ is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

53. The compound of claim 52, wherein R⁴ is a substituted or unsubstituted phenyl.

54. The compound of claim 52, wherein R⁴ is a substituted or unsubstituted pyridyl.

55. The compound of claim 52, wherein R⁴ is a substituted or unsubstituted pyridazinyl.

56. The compound of claim 52, wherein R⁴ is a substituted or unsubstituted pyrazinyl.

57. The compound of any one of claims 1-50, wherein R⁴ is selected from:

The compound of claim 57, wherein R⁴ is:

59. The compound of any one of claims 1-58, wherein R³ is a 9- or 10-membered bicyclic aryl or heteroaryl with 0-4 ring heteroatoms independently selected from N, O and S, substituted with 0-6 R^bs.

60. The compound of claim 59, wherein R³ is a 9-membered bicyclic heteroaryl comprising a 5-membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

61. The compound of claim 60, wherein R³ has the structural formula (IV): wherein q is 0, 1, 2, 3 or 4;

X¹ is N, O, S or CH;

X² is N, O, S or CH;

X³ is N or C; and

62. The compound of claim 61, wherein R³ is selected from:

63. The compound of claim 61 or 62, wherein each R^b is independently selected from CF3,

CHF₂, CH₂F, CH₃, F, Cl, Br, CN, OR, SF₅, S(O)₂R and C_2.4 alkynyl.

64. The compound of any one of claims 61-63, wherein q is 1 or 2.

65. The compound of any one of claims 61-64, wherein R³ is selected from:

66. The compound of claim 58, wherein R³ is a 10-membered bicyclic heteroaryl comprising a 6-membered heteroaryl ring fused to a 6-membered aryl or heteroaryl ring.

67. The compound of claim 66, wherein R³ has the structural formula (V): wherein p is 0, 1, 2, 3 or 4; each of Y¹, Y² and Y³ is independently selected from N and CH; each of Y⁴ and Y⁵ is independently selected from N and CH with the proviso that, when one of Y⁴ and Y⁵ is N, the other is C, and when each of Y² and Y³ is N, Y¹ is CH and Y⁴ is C.

68. The compound of claim 67, wherein R³ is selected from:

69. The compound of claim 67 or 68, wherein each R^b is independently selected from CF₃, CHF₂, CH₂F, CH₃, F, Cl, Br, CN, OR, SF₅, S(O)₂R and C_2.4 alkynyl.

70. The compound of any one of claims 67-69, wherein p is 1 or 2.

71. The compound of any one of claims 67-70, wherein R³ is selected from:

2. The compound of claim 1, having the structural formula (VI^A): wherein each of p and r is independently 0, 1, 2, 3 or 4; each of Y¹, Y² and Y³ is independently selected from N and CH; each of Y⁴ and Y⁵ is independently selected from N and CH with the proviso that, when one of Y⁴ and Y⁵ is N, the other is C, and when each of Y² and Y³ is N, Y¹ is CH and Y⁴ is C.

73. The compound of claim 1, having the structural formula (VI^B): wherein each of p and r is independently 0, 1, 2, 3 or 4; each of Y¹, Y² and Y³ is independently selected from N and CH; each of Y⁴ and Y⁵ is independently selected from N and CH with the proviso that, when one of Y⁴ and Y⁵ is N, the other is C, and when each of Y² and Y³ is N, Y¹ is CH and Y⁴ is C.

74. The compound of claim 1, having the structural formula (VI^C): wherein each of q and r is independently 0, 1, 2, 3 or 4;

X¹ is N, O, S or CH; X² is N, O, S or CH;

X³ is N or C; and

75. The compound of claim 1, having the structural formula (VI^D): wherein each of q and r is independently 0, 1, 2, 3 or 4;

X¹ is N, O, S or CH;

X² is N, O, S or CH;

X³ is N or C; and

76. The compound of any one of claims 1-75, having the chirality shown in formula (VII^A):

77. The compound of any one of claims 1-75, having the chirality shown in formula (VII^B):

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

79. The compound of any of claims 1-78, having one or more deuterium atoms in place of one or more hydrogen atoms.

80. The compound of any of claims 1-79, having one deuterium atom in place of a hydrogen atom.

81. A pharmaceutical composition comprising a compound according to any one of claims 1- 80 and a pharmaceutically acceptable excipient, carrier, or diluent.

82. The pharmaceutical composition of claim 81, being suitable for oral administration.

83. A unit dosage form comprising a pharmaceutical composition according to claim 81 or 82.

84. The unit dosage form of claim 83, being in the form of a tablet or capsule.

85. 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 1-80.

86. A method for modulating phosphoinositide 3-kinase a (PI3Ka) activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-80.

87. A method for reducing phosphoinositide 3-kinase a (PI3Ka) activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-80.

88. A method for treating a disease or disorder mediated by phosphoinositide 3-kinase a (PI3Ka), comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1-80.

89. The method of claim 88, wherein the disease or disorder is a cellular proliferative disease.

90. 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 1-80.

91. The method of claim 90, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

92. The method of claim 90 or 91, 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.

93. The method of any one of claims 90-92, wherein the subject has a mutated class IA PI3K pl 10a.

94. The method of any one of claims 90-93, wherein the subject has at least one of the following PI3Ka mutations: H1047R, E542K, E545K and H1047X.

95. The method of any one of claims 90-94, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

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

97. The use of claim 96, wherein the disease or disorder is a cellular proliferative disease.

98. The use of claim 97, wherein the disease or disorder is cancer.

99. The use of claim 98, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

100. The use of claim 98, 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.

101. The use of claim 98, wherein the cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas.