Urea derivatives of tricyclic compounds, and compositions and methods thereof

Abstract

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

Description

[0001] Priority statement and related applications This application claims priority to U.S. Provisional Application No. 63 / 627,117, filed January 31, 2024, and U.S. Provisional Application No. 63 / 729,148, filed December 6, 2024, the entire contents of each of which are incorporated herein by reference for all purposes. Technical Field

[0002] This invention generally relates to novel compounds and their therapeutic uses. More specifically, the invention provides novel urea derivatives of tricyclic compounds that have been shown to be potent and selective inhibitors of phosphatidylinositol 3-kinase α (PI3Kα). The invention also provides pharmaceutical compositions comprising the compounds of the invention, and methods for treating diseases and conditions (such as various types of cancer) associated with or related to PI3Kα activity. Background Technology

[0003] Phosphatidylinositol 3-kinase (PI3K) is a family of related intracellular signal transduction enzymes that phosphorylate the 3-hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns). PI3K has been associated with a highly diverse range of cellular functions, including cell growth, proliferation, differentiation, motility, survival, and intracellular transport. The PI3K signaling pathway is one of the most frequently mutated pathways in human cancer and is also a major factor in many other human diseases. For example, PI3K signaling is associated with allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetic complications, and acute coronary syndrome.

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

[0005] Class IA PI3K p110α (PI3Kα) is mutated in various human cancers. Angiogenesis has been shown to selectively require the PI3Kα isoform in the control of endothelial cell migration. The encoding PI3Kα (…PIK3CA Mutations in the PI3Kα gene or upregulation of PI3Kα occur in a variety of human cancers, such as ovarian cancer, cervical cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, hepatocellular carcinoma, small cell and non-small cell lung cancer, thyroid cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma. In cancers, PI3Kα mutations are typically hotspot point mutations in the helical domain or kinase domain, such as H1047R, E542K, E545K, and H1047X. (Graupera) et al 2008 Nature 453: 662-6; Campbell et al. 2004 Cancer Res 64, 7678-7681; Levine et al 2005 Clin Cancer Res 11, 2875-2878; Wang et al 2005 Hum Mutat 25, 322; Lee et al 2005 Gynecol Oncol 97, 26-34; Bachman, et al 2004 Cancer Biol Ther 3, 772-775; Li et al 2006 Breast Cancer Res Treat 96, 91-95; Saal et al. 2005 Cancer Res 65, 2554-2559; Samuels and Velculescu2004 Cell Cycle 3, 1221-1224; Samuels, et al 2004 Science 304, 554; Velho et al 2005 Eur J Cancer 41, 1649-1654; Oda et al 2005 Cancer Res. 65, 10669-10673; Byun et al 2003 Int J Cancer 104, 318-327; Lee et al. 2005 Oncogene 24, 1477-1480; Tang et al 2006 Lung Cancer 51, 181-191; Massion et al2004 Am J Respir Crit Care Med 170, 1088-1094; Wu et al 2005 J Clin Endocrinol Metab 90, 4688-4693; Sujobert et al 1997 Blood 106, 1063-1066; Hickey and Cotter2006 J Biol Chem 281, 2441-2450; Hartmann et al 2005 Acta Neuropathol ( Berl ) 109, 639-642.) There remains an urgent and unmet need for effective and selective PI3Kα inhibitors that are safe and effective in treating PI3Kα-related diseases and conditions, such as various types of cancer (e.g., breast cancer, ovarian cancer, colorectal cancer, lung cancer). Summary of the Invention

[0006] This invention provides novel urea derivatives of tricyclic compounds that act as PI3Kα inhibitors, exhibiting a more favorable potency and selectivity profile than known PI3Kα inhibitors. These novel compounds selectively target, bind to, inhibit, and / or modulate the activity of PI3Kα. These compounds also possess oral availability and their pharmacokinetic characteristics are suitable for development into orally administered therapeutic agents for the treatment of a variety of diseases and conditions, such as various types of cancer, associated with or related to PI3Kα activity.

[0007] In one aspect, the present invention generally relates to a compound having structural formula (I):

[0008] (I) Or its pharmaceutically acceptable form or isotopic derivative. in R 1 and R 2 Each is independently assigned to one of 0-8 R's. A Replacement C 1-6 Alkyl, C 2-5 alkenyl or C 2-5 alkynyl group, wherein R A Independently selected from D, halogen, CN, OR, SR, NRR', unsubstituted or substituted C 3-6 Carbocyclic or heterocyclic groups, and unsubstituted or substituted 5- or 6-membered aryl or heteroaryl groups; and R and R' are independently H, unsubstituted or substituted C. 1-4Alkyl groups, or unsubstituted or substituted 3- to 6-membered carbon rings, or, where R and R' are attached to the same C or N atom, together form unsubstituted or substituted 4- to 6-membered heterocycles.

[0009] In another aspect, the present invention generally relates to a pharmaceutical composition comprising the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, or diluents.

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

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

[0012] In yet another aspect, the present invention generally relates to a method for modulating (e.g., reducing) PI3Kα activity in cells, comprising contacting the cells with compounds disclosed herein.

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

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

[0015] In another aspect, the present invention generally relates to the use of the compounds disclosed herein, as well as pharmaceutically acceptable excipients, carriers, or diluents, in the preparation of medicaments for treating diseases or conditions.

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

[0017] As used in this article, "at least" a specific value is understood to mean that value and all values ​​greater than that value.

[0018] The term "comprising," when used to define compositions and methods, is intended to mean that the composition and method include the listed elements, but does not exclude other elements. The term "consistently composed of," when used to define compositions and methods, should mean that the composition and method include the listed elements and exclude other elements that are of any substantial importance to the composition and method. For example, "consistently composed of" means the application of a explicitly listed pharmacologically active agent and excludes pharmacologically active agents that are not explicitly listed. The term "consistently composed of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "composed of," when used to define compositions and methods, should mean the exclusion of trace amounts of other ingredients and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of this invention.

[0019] Unless otherwise specified or obvious from the context, as used herein, the term “about” is understood to mean within normal tolerances in the art, such as within two 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. All numerical values ​​provided herein may be modified by the term “about” unless the context clearly indicates otherwise.

[0020] In this specification and the appended claims, the singular forms “a” and “the” include plural references unless the context clearly indicates otherwise.

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

[0022] As used herein, the term "co-administration" refers to the simultaneous presence of two pharmacological agents in a subject's body (e.g., in the blood). These two pharmacologically active agents may be administered simultaneously or sequentially.

[0023] The terms “disease,” “symptom,” and “symptom” are used interchangeably in this document unless otherwise stated.

[0024] As used herein, the terms “effective amount” or “therapeutic effective amount” refer to the amount of the compound or pharmaceutical composition described herein that is sufficient to achieve the intended application (including, but not limited to, the treatment of a disease as illustrated below).

[0025] In some implementations, the amount is sufficient to negatively regulate or inhibit the activity of PI3Kα. In some implementations, the amount is effective in reducing or improving symptoms to stop or reverse the progression of a disease or condition, such as cancer. In some implementations, the amount is effective for: detectably killing or inhibiting the growth or spread of cancer cells; tumor size or number; or providing other measures of cancer level, stage, progression, or severity.

[0026] The therapeutically effective dose can vary depending on the intended application, or the subject being treated and the disease condition, such as the expected biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the patient's weight and age, all of which can be readily determined by those skilled in the art. This dose can be administered as a single dose or according to a regimen. The term also applies to doses that will induce a specific response in target cells (e.g., reduce cell migration). Specific doses will vary based on, for example, the specific compound selected, the subject's species and age / pre-existing health condition or health risk, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the time of administration, the tissue of administration, and the physical delivery system carrying the compound.

[0027] As used herein, “inhibitor” of “PI3Kα” refers to the compounds of this invention that are capable of negatively regulating or inhibiting all or part of the activity of PI3Kα.

[0028] As used in this article, “PI3Kα-related disease or condition” refers to a disease or condition that is associated with or mediated by PI3Kα, or that has one or more PI3Kα mutations. Examples of PI3Kα-related diseases or conditions include various types of cancer. PI3Kα-related diseases or conditions may also refer to allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetic complications, or acute coronary syndrome.

[0029] As used herein, the term "contact" refers to bringing together a specified portion in vitro or in vivo. For example, "contacting" cells with a compound disclosed herein includes administering the compound to a subject in need, and, for example, introducing the compound into a sample containing cells or a purified formulation. In some embodiments, cells desired to inhibit PI3Kα activity are contacted with an effective amount of the compound disclosed herein or a pharmaceutically acceptable form thereof to negatively modulate PI3Kα activity. By negatively modulating PI3Kα activity, the methods disclosed herein are designed to inhibit undesirable cell proliferation resulting from enhanced intracellular PI3Kα activity. The cells may be contacted in single or multiple doses depending on a specific treatment regimen to achieve the desired negative modulation of PI3Kα. The ability of a compound to bind PI3Kα in vitro can be monitored using methods known in the art. The inhibitory activity of an exemplary compound in cells can be monitored, for example, by measuring the inhibition of PI3Kα activity using methods known in the art.

[0030] As used herein, the terms “unsubstituted or substituted” and “optionally substituted” are used interchangeably and refer to a given chemical moiety (e.g., alkyl) that can (but is not required to) bond with other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any position on the chain. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents for optional substitutions of the group include, but are not limited to: halogen, oxo, CN, -COOH, -CH2CN, -O-C1-C6 alkyl, C1-C6 alkyl, -OC1-C6 alkenyl, -OC1-C6 alkynyl, -C1-C6 alkenyl, -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -S(O)2-C1-C6 alkyl, -S(O)NHC1-C6 alkyl and S(O)N(C1-C6 alkyl)2.

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

[0032] In some implementations, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with a subject's tissues without excessive toxicity, irritation, allergic reactions, etc., and that are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in J. Pharmaceutical Sciences Pharmaceutically acceptable salts are described in detail in (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups 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 salts formed by other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. In some implementations, the organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0033] 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 the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N2 salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates). Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0034] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to an ester that hydrolyzes in vivo and includes those esters that readily decompose in the human body to leave behind a parent compound or its salts. Such esters act as prodrugs as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl esters, alkenyl esters, alkynyl esters, aryl esters, aralkyl esters, and cycloalkyl esters of acidic groups (including, but not limited to, carboxylic acids, phosphoric acids, phosphonic acids, sulfinic acids, sulfonic acids, and boric acids). Examples of esters include formate esters, acetate esters, propionate esters, butyrate esters, acrylate esters, and ethyl succinate esters. The esters may be formed from the hydroxyl or carboxylic acid groups of the parent compound.

[0035] In some embodiments, the pharmaceutically acceptable form is a "solvent" (e.g., a hydrate). As used herein, the term "solvent" refers to a compound that further comprises a stoichiometric or non-stoichiometric solvent bound by non-covalent intermolecular forces. A solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are, for example, complexes comprising, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses the compound and its solvates, as well as mixtures thereof.

[0036] In some embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in the blood). In some cases, a prodrug has improved physical and / or delivery properties relative to the parent compound. A prodrug may improve the bioavailability of the compound when administered to a subject (e.g., by allowing enhanced absorption into the bloodstream after oral administration) or enhance delivery to a target biological compartment (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of the disclosed compound that have enhanced water solubility relative to the parent compound or are actively transported via the intestinal membrane.

[0037] Prodrug compounds often offer advantages in terms of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). For a discussion of prodrugs, see Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. Both of these references are incorporated herein by reference in their entirety. Exemplary advantages of prodrugs may include, but are not limited to, their physical properties, such as enhanced water solubility at physiological pH for parenteral administration compared to the parent compound, or their ability to enhance absorption from the digestive tract, or their ability to enhance drug stability during long-term storage.

[0038] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting a target drug agent from one organ or body site to another. Each carrier must be "acceptable," meaning it is compatible with other components of the formulation and harmless to the patient. Some examples of materials that can be used 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; tragacanth gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymers, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0039] As used herein, the term “subject” refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that will be the recipient of a particular treatment. Generally, the terms “subject” and “patient” are used interchangeably herein to refer to human subjects.

[0040] In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or condition to be treated with the compounds disclosed herein and / or the methods disclosed herein. In some embodiments, the subject has been identified or diagnosed with cancer having one or more PI3Kα mutations. In some embodiments, the subject has PI3Kα mutation-positive cancer. In some embodiments, the subject is suspected of having PI3Kα gene-related cancer.

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

[0042] As used herein, the term "treatment" refers to a method of reducing, delaying, or improving a disease or condition before or after its onset. Treatment may target one or more effects or symptoms of the disease and / or the underlying pathology. Treatment aims to achieve a beneficial or desired outcome, including but not limited to therapeutic and / or preventative benefits. A therapeutic benefit means the eradication or improvement of the underlying condition being treated. Furthermore, a therapeutic benefit is achieved when one or more physiological symptoms associated with the underlying condition are eradicated or improved, resulting in an observed improvement in the patient, even though the patient may still have the underlying condition. For preventative benefits, pharmaceutical compounds and / or compositions may be administered to patients at risk of developing a specific disease, or to patients reporting one or more physiological symptoms of the disease, even if the disease may not yet be diagnosed. Treatment can be any reduction and can be, but is not limited to, the complete elimination of the disease or its symptoms. Such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% compared to a comparable untreated control, as measured by any standard technique.

[0043] As used herein, the term "therapeutic effect" refers to the therapeutic and / or preventive benefits as described herein. Preventive effects include delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping, or reversing the progression of a disease or symptom, or any combination thereof.

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

[0045] This document also considers solvates and polymorphs of the compounds of the present invention. Solvates of the compounds of the present invention include, for example, hydrates.

[0046] As used herein, the terms "isolated" or "substantially isolated" molecules (such as polypeptides or polynucleotides) refer to molecules that have been manipulated to be present at a higher concentration than naturally occurring or have been removed from their natural environment. For example, a target antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, of the non-target antibody material associated with the target antibody in its natural state has been removed. For example, polynucleotides or polypeptides naturally present in living animals are not "isolated," but the same polynucleotides or polypeptides isolated from materials coexisting in their natural state are "isolated." Furthermore, recombinant DNA molecules contained in a vector are considered isolated for the purposes of this 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. Therefore, not all "isolated" molecules must be "purified."

[0047] As used herein, the term "purified," when used to refer to a molecule, means that the concentration of the purified molecule has been increased relative to the molecules associated with it in its natural environment or in the environment in which it was produced, discovered, 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 of the purified molecule or to facilitate its purification. According to this definition, the purity of a substance can be 5% or higher, 10% or higher, 20% or higher, 30% or higher, 40% or higher, 50% or higher, 60% or higher, 70% or higher, 80% or higher, 90% or higher, 95% or higher, 98% or higher, 99% or higher, or 100% when considered relative to its contaminants.

[0048] The definitions of specific functional groups and chemical terms are described in more detail below. When value ranges are listed, the aim is to cover every value within the range and every subrange. For example, “C 1-4 "Alkyl" is intended to encompass C1, C2, C3, C4, C 1-3 C 1-2 C 2-4 C 3-4 and C 2-3 alkyl.

[0049] As used herein, the term “aliphatic” or “aliphatic group” refers to a straight or branched, substituted or unsubstituted, fully saturated or containing one or more unsaturated hydrocarbon chains, or a fully saturated or containing one or more unsaturated monocyclic or bicyclic hydrocarbon, but not aromatic.

[0050] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which contains no unsaturated bonds and has one to ten carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 1-10 Alkyl). Whenever it appears herein, numerical ranges such as “1 to 10” refer to each integer within the given range; for example, “1 to 10 carbon atoms” means that an alkyl group can consist of and include 10 carbon atoms, up to and including 10 carbon atoms, although this definition also covers the occurrence of the term “alkyl” when no numerical range is specified. In some embodiments, “alkyl” may be C 1-6 Alkyl groups. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl group is attached to the parent molecule by a single bond. Unless otherwise specified in the specification, the alkyl group may optionally be substituted by one or more substituents independently comprising: acyl, alkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidine, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfoxide, sulfonate, urea, -Si(R x 3. -OR x -SR x -OC(O)-R x -N(R) x )2、-C(O)R x -C(O)OR x -OC(O)N(R) x )2、-C(O)N(R x )2、-N(R x )C(O)OR x -N(R) x )C(O)R x -N(R) x )C(O)N(R x )2、-N(R x )C(NR x )N(R x)2、-N(R x S(O) t N(R x )2 (where t is 1 or 2), -P(=O)(R x (R) x ), or -OP(=O)(OR x )2, where each R x Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties may be optionally substituted as defined herein. In a non-limiting embodiment, the substituted alkyl group may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0051] Unless otherwise defined, the term "aromatic" or "aryl" refers to a cyclic aromatic hydrocarbon group having one or two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be single-point connected (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted by one or more substituents (e.g., one to five substituents) at any connection point. Exemplary substituents include, but are not limited to, H, halogens, -O-C1-C6 alkyl, C1-C6 alkyl, -C1-C6 alkenyl, -OC1-C6 ynyl, -C1-C6 alkenyl, -C1-C6 ynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(O)2-C1-C6 alkyl, -S(O)NHC1-C6 alkyl, and S(O)N(C1-C6 alkyl)2. The substituent itself may be optionally substituted. Furthermore, when containing two fused rings, the aryl group defined herein may have an unsaturated or partially saturated ring fused to a fully unsaturated ring. Exemplary cyclic systems of these aryl groups include indenyl, indenyl, tetrahydronaphthyl, and tetrahydrobenzocycloheptenyl.

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

[0053] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons common in the cyclic array; and having one to three heteroatoms selected from the group consisting of N, O, and S, in addition to carbon atoms. Examples of heteroaryl groups include acridinel, azacyclooctatetraenyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenel, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolel, benzoisoxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbazolyl, benzodihydropyranyl, benzopyranyl, borazolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazole Linolyl, imidazolyl, 1H-indazolel, indoleenyl, dihydroindolel, indoleyl, 3H-indolel, isobenzofuranyl, isobenzodihydropyranyl, isoindazolel, isodihydroindolel, isoindolel, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl Alkyl, oxazolyl, oxazolyl, pyrimidinyl, phenanthridine, phenanthrolinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperinyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylalkyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoazinyl, pyridoxazazole, pyridoimidazole, pyridothiazazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quininecycloyl, tetra Hydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, phenylthio, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthonyl. "Heteroaryl" also refers to bicyclic ring systems in which each ring, excluding the carbon atom, has one to three heteroatoms selected from the group consisting of N, O, and S, and one of the ring systems may be saturated or partially saturated.

[0054] The heteroaryl group may be substituted by 0, 1, 2, 3, or 4 substituents independently selected from the following: alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxyl, carboxylalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2)carbonyl. As used herein, the term "NZ1Z2" refers to two groups Z1 and Z2 connected to the parent molecule moiety via a nitrogen atom. Z1 and Z2 are each independently selected from the group consisting of: hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetamino, and acetylmethylamino.

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

[0056] As used herein, the terms "cycloalkyl" and "carbocyclic" each refer to a monocyclic or polycyclic group containing only carbon and hydrogen and which may be saturated or partially unsaturated. Unless otherwise stated in the specification, the term is intended to include substituted and unsubstituted cycloalkyl groups. A partially unsaturated cycloalkyl group may be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or as "cycloynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-13 cycloalkyl. Whenever it appears herein, numerical ranges such as “3 to 10” refer to each integer within the given range; for example, “3 to 13 carbon atoms” means that a cycloalkyl group can consist of and include 13 carbon atoms, up to and including 3, 4, 5, etc. carbon atoms. The term “cycloalkyl” also includes bridged rings and spirofused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, “cycloalkyl” may be C 3-8 Cycloalkyl. In some embodiments, "cycloalkyl" may be C10. 3-5 Cycloalkyl groups. Exemplary examples of cycloalkyl groups include, but are not limited to, the following components: C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-7 Examples of carbocyclic groups include norbornyl (C7). 3-8 Examples of carbocyclic groups include the C mentioned above. 3-7Carbocyclic groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. 3-13 Examples of carbocyclic groups include the C mentioned above. 3-8 Carbocyclic groups and octahydro-1H-indenyl, decahydronaphthyl, spiro[4.5]decyl, etc. Unless otherwise stated in the specification, cycloalkyl groups may optionally be substituted by one or more substituents that independently include: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidyl, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfoxide, sulfonate, urea, -Si(R a 3. -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a (R) a ), or -OP(=O)(OR a )2, where each R aIndependently, it can be hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties may be optionally substituted as defined herein. The terms “cycloalkenyl” and “cycloynyl” mirror the above description of “cycloalkyl”, wherein the prefix “alkane” is replaced by “ene” or “ynyne” respectively, and the parent terms “alkenyl” or “ynyne” are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloynyl group may have 5 to 13 ring atoms.

[0057] As used herein, the term "heterocyclic alkyl" refers to a cycloalkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as O, N, S, P, or combinations thereof. Unless otherwise stated in the specification, the term is intended to include substituted and unsubstituted heterocyclic alkyl groups. Exemplary examples of heterocyclic alkyl groups include 2-hydroxy-aziridin-1-yl, 3-oxo-1-oxetane-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazin-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, etc.

[0058] As used herein, the terms "heterocyclic," "heterocyclic," or "heterocyclic group" refer to a fully saturated or partially unsaturated cyclic group, such as a 3- to 8-membered monocyclic ring, a 7- to 12-membered bicyclic ring, or a 10- to 15-membered spirocyclic or tricyclic ring system, wherein at least one ring has at least one heteroatom (selected from the group consisting of N, O, and S), wherein 0, 1, 2, or 3 atoms in each ring may be substituted with substituents. Each ring of a heterocyclic group containing heteroatoms may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic group may be attached via any heteroatom or carbon atom of the ring or ring system. The heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but are not limited to, epoxy groups, aziridine groups, aziridinyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups, pyrrolidine groups, pyrrolidone groups, piperidinyl groups, piperazinyl groups, imidazoalkyl groups, imidazopyridinyl groups, thiazoalkyl groups, dithiazoalkyl groups, trithiazoalkyl groups, dioxazolidinyl groups, oxazolidinone groups, decahydroquinolinyl groups, piperidinone groups, 4-piperidinone groups, quininecycloyl groups, thiomorpholinyl groups, thiomorpholinyl 1,1-dioxide groups, morpholinyl groups, aziridine heptyl groups, oxazacycloheptyl groups, aziridine bicyclohexyl groups, aziridine bicycloheptyl groups, aziridine bicyclooctyl groups, aziridine bicyclononyl groups (e.g.) For example, octahydroindene, azaspiroheptane, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin], hexahydro-1H-pyrrolizinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindene, oxazaspirononyl, oxazaspironoctyl, diazaspirononyl, oxazabicycloheptane, hexahydropyrrolizinyl 4(1H)-oxide, and tetrahydro-2H-thiaranyl 1-oxide and tetrahydro-2H-thiaranyl 1,1-dioxide. Detailed Implementation

[0059] This invention is partly based on the discovery of novel urea derivatives of tricyclic compounds that are inhibitors of PI3Kα. These compounds exhibit selective targeting, binding, inhibition, and / or modulation of PI3Kα activity. The compounds are orally available and can be used to treat a variety of diseases and conditions associated with or related to PI3Kα activity, such as various types of cancer.

[0060] In one aspect, the present invention generally relates to a compound having structural formula (I):

[0061] (I) Or its pharmaceutically acceptable form or isotopic derivative. in R 1 and R2 Each is independently assigned to 0-8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, or 8) R. A Replacement C 1-6 (For example, C) 1-3 ) alkyl, C 2-5 (For example, C) 2-3 alkenyl, or C 2-5 (For example, C) 2-3 ) ynyl group, where each R A Independently selected from D, halogen, CN, OR, SR, NRR', unsubstituted or substituted C 3-6 Carbocyclic or heterocyclic groups, and unsubstituted or substituted 5- or 6-membered aryl or heteroaryl groups; and R and R' are independently H, unsubstituted or substituted C. 1-4 Alkyl, or unsubstituted or substituted 3 to 6 (e.g., 3, 4, 5 or 6) carbon rings, or, where R and R' are attached to the same C or N atom, together forming an unsubstituted or substituted 4 to 6 (e.g., 4, 5 or 6) heterocycle.

[0062] In some implementations of (I), R 2 For CR 2a R 2b R 2c The compound has the structural formula (I) A ):

[0063] (I) A ) in R 2a It is H, D or halogen; R 2b It is H, D or halogen; and R 2c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0064] in (I A In some implementations of ), R 1 For CR 1a R 1b R 1c The compound has the structural formula (I) B ):

[0065] (I) B ) in R 1a It is H, D or halogen; R 1b It is H, D or halogen; and R 1c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0066] in (I B In some implementations of ), R 2c For CR 2d R 2e R 2f The compound has the structural formula (I) C ):

[0067] (I) C ) in R 2d It is H, D or halogen; and R 2e and R 2f Each independently H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0068] in (I A )-(I C In some implementations of ), R 2a and R 2b Each is represented by H.

[0069] in (I A )-(I C In some implementations of ), R 2a and R 2b Each is D.

[0070] in (I C In some implementations of ), R 2d R 2e and R2f At least one of them is a halogen atom. In (I) C In some implementations of ), R 2d R 2e and R 2f One of them is F. In (I) C In some implementations of ), R 2d R 2e and R 2f Both of them are F. In (I) C In some implementations of ), R 2d R 2e and R 2f Each is F.

[0071] in (I A )-(I C In some implementations of ), R 2d R 2e and R 2f At least one of them is D. In (I) C In some implementations of ), R 2d R 2e and R 2f One of them is D. In (I) C In some implementations of ), R 2d R 2e and R 2f Both of them are D. In (I) C In some implementations of ), R 2d R 2e and R 2f Each is D.

[0072] in(I)-(I C In some implementations of ), R 1 It is CH3.

[0073] in(I)-(I C In some implementations of ), R 1 It is CD3.

[0074] in(I)-(I C In some implementations of ), R 1 It is not CH3.

[0075] in(I)-(I C In some implementations of ), R 1 Not CD3.

[0076] In some implementations of (I), R 1 For CR 1a R 1b R 1cThe compound has the structural formula (I) D ):

[0077] (I) D ) in R 1a It can be H, D, or halogen; R 1b It is H, D or halogen; and R 1c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0078] in (I D In some implementations of ), R 2 For CR 2a R 2b R 2c The compound has the structural formula (I) E ):

[0079] (I) E ) in R 2a It is H, D or halogen; R 2b It is H, D or halogen; and R 2c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0080] in (I E In some implementations of ), R 1c For CR 1d R 1e R 1f The compound has the structural formula (I) F ):

[0081] (I) F ) in R 1d It is H, D or halogen; and R 1e and R 1f Each independently H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0082] in (I D )-(I F In some implementations of ), R 1a and R 1b Each is represented by H.

[0083] in (I D )-(I F In some implementations of ), R 1a and R 1b Each is D.

[0084] in (I D )-(I F In some implementations of ), R 1a R 1b and R 1c Each is D.

[0085] in (I F In some implementations of ), R 1d R 1e and R 1f At least one of them is a halogen atom. In (I) F In some implementations of ), R 1d R 1e and R 1f One of them is F. In (I) F In some implementations of ), R 1d R 1e and R 1f Both of them are F.

[0086] in (I D )-(I F In some implementations of ), R 2 It is CH3 or CD3.

[0087] in (I D )-(I F In some implementations of ), R 2 It is neither CH3 nor CD3.

[0088] in (I), (I C ) and (I F In some embodiments of the compound, the compound has the structural formula (I) G ): .

[0089] (I) G ) in (I G In some implementations of ), R 2a and R 2b Each is represented by H.

[0090] in (I G In some implementations of ), R 2a and R 2b Each is D.

[0091] in (I G In some implementations of ), R 2d R 2e and R 2f At least one of them is a halogen atom. In (I) G In some implementations of ), R 2d R 2e and R 2f One of them is F. In (I) G In some implementations of ), R 2d R 2e and R 2f Both of them are F. In (I) G In some implementations of ), R 2d R 2e and R 2f Each is F.

[0092] in (I G In some implementations of ), R 2d R 2e and R 2f At least one of them is D.

[0093] in (I G In some implementations of ), R 2d R 2e and R 2f One of them is D. In (I) G In some implementations of ), R 2d R 2e and R 2f Both of them are D. In (I) G In some implementations of ), R 2d R 2e and R2f Each is D.

[0094] in (I G In some implementations of ), R 1a and R 1b Each is represented by H.

[0095] in (I G In some implementations of ), R 1a and R 1b Each is D.

[0096] in (I G In some implementations of ), R 1d R 1e and R 1f Each is either H or D.

[0097] In some implementations of (I), R 1 and R 2 Selected independently from: R 1 : CH3, CH2D, CHD2, CD3, CH2F, CHF2, CD2F, CDF2, CF3, CH2CH3, CD2CH3, CH2CD3, CD2CD3, CH2CN, CH2CH2N(CH3)2, ;and R 2 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 .

[0098] In some embodiments of (I), the compound has the structural formula (II). A ):

[0099] (II) A ) in R 2a For H or D; R 2bFor H or D; and R 2f For D, F, CN, OR, NRR', or unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl or C 3-5 Carbon cyclic group or heterocyclic group.

[0100] In (II) A In some implementations of ), R 2a and R 2b Each of the two atoms is H, and the compound has the structural formula (II). B ): .

[0101] (II) B ) In some embodiments of (I), the compound has the structural formula (II). C ):

[0102] (II) C ) Where R 2c CN, OR, SR, NRR', unsubstituted or substituted C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0103] In some embodiments of (I), the compound has the structural formula (II). E ):

[0104] (II) E ) in R 2a For H or D; R 2b For H or D; and R 2f For D, F, CN, OR, NRR', or unsubstituted or substituted C 1-5 (For example, C) 1-3 ) alkyl or C 3-5 Carbon cyclic group or heterocyclic group.

[0105] In (II) E In some implementations of ), R 2a and R 2b Each of the two atoms is H, and the compound has the structural formula (II). F ): .

[0106] (II) F ) In some embodiments of (I), the compound has the structural formula (II). G ):

[0107] (II) G ) Where R 2c CN, OR, SR, NRR', unsubstituted or substituted C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

[0108] In (I)-(II G In some embodiments of the compound, the compound has the formula (III) A Chirality as shown: .

[0109] (III) A ) In (I)-(II G In some embodiments of the compound, the compound has the formula (III) B Chirality as shown: .

[0110] (III) B ) Non-limiting exemplary compounds of the present invention can also be found in Table 1 of the Examples section.

[0111] In some embodiments, the compounds of the present invention have one or more deuterium atoms instead of hydrogen atoms. In some embodiments, the compounds of the present invention have one deuterium atom instead of one hydrogen atom.

[0112] In another aspect, the present invention generally relates to a pharmaceutical composition comprising the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, or diluents.

[0113] In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0114] In another aspect, the present invention generally relates to a unit dosage form comprising the pharmaceutical compositions disclosed herein.

[0115] In some implementations, the unit dosage form is a tablet or capsule.

[0116] Pharmaceutically acceptable carriers, adjuvants, and mediators that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates, glycine, sorbic acid, potassium sorbate, and mixtures of glycerides of saturated vegetable fatty acids), water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0117] The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. In some embodiments, the compounds in this text are administered transdermally (e.g., using transdermal patches). Other formulations may be readily available in unit dosage forms, such as tablets and sustained-release capsules, as well as liposomes, and may be prepared by any method well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[0118] Such preparation methods involve the step of associating the molecule to be applied with components such as a carrier constituting one or more auxiliary ingredients. Typically, the composition is prepared by uniformly and tightly associating the active ingredient with a liquid carrier, liposomes, or finely dispersed solid carrier, or both, and then shaping the product if necessary.

[0119] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or their derivatives are mixed with at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (i) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silica; (ii) a binder, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (iii) a humectant, such as glycerin; (iv) a disintegrant, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain complex silicates, and sodium carbonate; (v) a solution retarder, such as paraffin; (vi) an absorption promoter, such as quaternary ammonium compounds; (vii) a wetting agent, such as cetyl alcohol and glyceryl monostearate; (viii) an adsorbent, such as kaolin and bentonite; and (ix) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art.

[0120] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, or mixtures of these substances. In addition to such inert diluents, the composition may also include other agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, or aromatizers.

[0121] In another aspect, the present invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting cells with an effective amount of the compound disclosed herein.

[0122] In yet another aspect, the present invention generally relates to a method for regulating PI3Kα activity in cells, comprising contacting the cells with compounds disclosed herein.

[0123] In yet another aspect, the present invention generally relates to a method for reducing PI3Kα activity in cells, comprising contacting the cells with compounds disclosed herein.

[0124] In another aspect, the present invention generally relates to a method for treating a disease or condition mediated by PI3Kα, comprising administering a therapeutically effective amount of the compound disclosed herein to a subject in need.

[0125] In some implementations, the disease or condition is a cell proliferation disorder.

[0126] In another aspect, the present invention generally relates to a method for treating or alleviating cancer or related diseases or conditions, comprising administering a therapeutically effective amount of the compound disclosed herein to a subject in need.

[0127] In some implementations, the cancer is selected from the group consisting of: carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0128] Examples of cancers targeted by this invention include, but are not specifically limited to, head and neck cancer, digestive organ cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (e.g., gallbladder cancer and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer and rectal cancer), etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancers (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urinary system cancers (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumors), hematopoietic system tumors (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myeloma), sarcomas (e.g., osteosarcoma and soft tissue sarcoma), skin cancer, brain tumors, carcinomas, squamous cell carcinomas, adenocarcinomas, neuromas, melanomas, etc. Examples include lung cancer, pancreatic cancer, rectal cancer, colon cancer, colorectal cancer, and uterine cancer. In some embodiments, squamous cell carcinoma is cancer of the cervix, tarsal bone, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus. In one embodiment, adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, or ovary. In some embodiments, tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, leukemia, or uterine cancer.

[0129] In some implementations, the cancer is selected from the group consisting of: ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, small cell and non-small cell lung cancer, endometrial cancer, appendix cancer, bile duct epithelial carcinoma, bladder urothelial carcinoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, thyroid cancer, and hematologic malignancies.

[0130] In some implementations, the cancer is selected from the group consisting of: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.

[0131] In some implementations, the subject has a mutated IA-type PI3K p110α.

[0132] In some implementations, the subject has at least one of the following PI3Kα mutations: H1047R, E542K, E545K, and H1047X.

[0133] In some implementations, the subject does not have the PI3Kα mutant protein.

[0134] In some implementations, the treated subject may be further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormone therapy.

[0135] In another aspect, the present invention generally relates to the use of the compounds disclosed herein, as well as pharmaceutically acceptable excipients, carriers, or diluents, in the preparation of medicaments for treating diseases or conditions.

[0136] In another aspect, the present invention generally relates to the use of the compounds disclosed herein for the treatment of diseases or conditions.

[0137] The amount of active compound administered will depend on the subject being treated, the severity of the condition or symptom, the route of administration, the disposal of the compound, and the prescribing physician's judgment. In some cases, dose levels below the lower limit of the above range may be sufficient, while in others, larger doses may be used without causing any harmful side effects; such larger doses are usually divided into several smaller doses administered throughout the day.

[0138] It can be administered via any suitable route, such as oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalation, buccal, intraperitoneal, rectal, intrapleural, and intrathecal administration. The most appropriate route of administration for a particular patient will depend on the nature and severity of the disease or symptom being treated, the nature of the therapy being used, and the nature of the active compound.

[0139] In some preferred embodiments, the compound is administered orally. Pharmaceutical compositions of the present invention suitable for oral administration can be presented as discrete units, such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; as oil-in-water or water-in-oil liquid emulsions; or packaged in liposomes; and as pellets, etc. Soft gelatin capsules can be used to contain such suspensions, which can advantageously increase the absorption rate of the compound.

[0140] Tablets can be prepared by compression or molding, optionally containing one or more excipients. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, the active ingredient optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. The tablet may optionally be coated or scored and can be formulated to provide sustained or controlled release of the active ingredient therein. Methods for formulating such sustained or controlled-release compositions of pharmaceutically active ingredients (such as those described herein and other compounds known in the art) are known in the art and described in several granted U.S. patents, some of which include, but are not limited to, U.S. Patent Nos. 4,369,172 and 4,842,866 and their cited references. Coating can be used to deliver compounds to the intestine (see, for example, U.S. Patent Nos. 6,638,534, 5,217,720, 6,569,457, 6,461,631, 6,528,080, 6,800,663 and their cited references). One useful formulation of the compounds of the present invention is in the form of enteric-coated microspheres, wherein the enteric layer comprises hydroxypropyl methylcellulose acetate succinate.

[0141] In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administering an aqueous suspension orally, the active ingredient is mixed with emulsifiers and suspending agents. Sweeteners and / or flavorings and / or colorings may be added if desired.

[0142] Compositions suitable for topical application include lozenges containing ingredients in a flavoring matrix (typically sucrose and gum arabic or astragalus gum); and soft lozenges containing active ingredients in an inert matrix (such as gelatin and glycerin, or sucrose and gum arabic).

[0143] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions containing antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. The formulation may be in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only immediate addition of a sterile liquid carrier, such as water for injection, before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0144] Such injectable solutions may be in the form of, for example, sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents (such as, for example, Tween 80) and suspending agents according to techniques known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils are routinely used as solvents or suspension media. For this purpose, any mild fixative oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glycerol derivatives, can be used to prepare injectables, as can pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylene versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0145] The compounds of the present invention can also be administered in liposome form. As is known in the art, liposomes are typically derived from phospholipids or other lipid substances. Liposomes are formed from a single or multiple layer of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes may be used. The compositions of the present invention in liposome form may contain stabilizers, preservatives, excipients, etc., in addition to the compounds of the present invention. Preferred lipids are phospholipids and phosphatidylcholine (lecithin), including both natural and synthetic ones. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0146] The pharmaceutical compositions of this invention can be administered in suppository form for rectal use. These compositions can be prepared by mixing the compound of this invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thus melting in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0147] The pharmaceutical compositions of this invention can be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as saline solutions using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0148] Topical application of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves areas or organs easily accessible through topical application. For topical application to the skin, the pharmaceutical composition should be formulated as a suitable ointment containing an active ingredient suspended or dissolved in a carrier. Carriers for topical application of the compounds of the invention include, but are not limited to, mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene / polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing an active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestine via rectal suppository formulations or suitable enema formulations. Topical transdermal patches and iontophoresis are also included in the present invention.

[0149] The treatment methods disclosed herein may be used in combination with other therapies or as a supplement to other therapies. In some implementations, the treated subject may be further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy.

[0150] Exemplary additional therapeutic agents include, but are not limited to, small organic molecules such as pharmaceutical compounds, such as those approved by the U.S. Food and Drug Administration (FDA) under Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0151] In some embodiments, the compounds of the present invention may be administered in combination with endocrine therapy, for example, in combination with agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0152] In some embodiments, the compounds of the present invention may be administered in combination with chemotherapeutic agents, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, or vinorelbine. In other embodiments, the compounds of the present invention may be administered in combination with anti-HER2 agents, such as trastuzumab or pertuzumab.

[0153] In some implementations, the methods disclosed herein are combined with one or more of immune checkpoint blockade, T-cell co-signaling, and tumor-targeted antibody therapy.

[0154] In some implementations, the method further includes administering a chemotherapy agent to the subject.

[0155] In some embodiments, the method further includes administering radiation therapy to the subject. In some embodiments, the method further includes administering targeted therapy to the subject. In some embodiments, the method further includes administering immunotherapy to the subject. In some embodiments, the method further includes administering hormone therapy to the subject.

[0156] As used in this article, the term "chemotherapeutic agent" refers to chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include: erlotinib (TARCEVA). ® Genentech / OSI Pharm., bortezomib (VELCADE) ® Millennium Pharm., fulvestrant (FASLODEX) ® AstraZeneca, sunitinib (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), lonafenib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib (IRESSA) ® AstraZeneca), AG1478, AG1571 (SU 5271; Sugen); alkylating agents, such as thiotepa and CYTOXAN ®Cyclophosphamide; alkyl sulfonates, such as busulfan, indomethacin, and piperosulfan; aziridines, such as benzodopa, carboquinone, metoprolol, and uridedopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and tris(hydroxymethylmelamine); anomericactones (especially bratasin and bratasinone); camptothecin (including the synthetic analogue topotecan); lichenin; carboxystatin; CC-1065 (including its synthetic analogues adolaxine, carzolinone, and bizarrexine); cryptophytic acid (especially cryptophytic acid 1 and cryptophytic acid 8); sea haretoxin; docalotoxin Mistar (including synthetic analogs KW-2189 and CB1-TM1); ilexelose; hygroscopicine; carnivorous spores; sponge statins; nitrogen mustards, such as chlorambucil, naphthylambucil, chlorphosphamide, estradiol, ifosfamide, nitrogen mustard, nitrogen oxychloride hydrochloride, melphalan, neo-embezzin, benzyl mustard cholesterol, prednimustine, trazophos, uracil mustard; nitrosoureas, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ramustine; antibiotics, such as enediyne antibiotics (e.g., chachimycin, especially chachimycin γII and chachimycin ωII (Angew Chem. Intl. Ed. Engl.).(1994) 33: 183-186); danendomycin (including danendomycin A); bisphosphonates (such as clophosphonates); esperamycin; and new carcinogen chromophores and related chromophores, enedyne antibiotic chromophores), aclarubicin, actinomycin, atrazoserine, bleomycin, actinomycin C, carabin, carminoxamycin, chromomycin, actinomycin D, daunorubicin, detoxin, 6-diazo-5-oxo-L-leucine, ADRIAMYCIN® (doxorubicin) Morpholine doxorubicin, cyanomorpholine doxorubicin, 2-pyrrololine doxorubicin and deoxydoxorubicin, epirubicin, isorubicin, idarubicin, maseromycin, mitomycins (such as mitomycin C), mycophenolic acid, nogamycin, olivomycin, pepromycin, pofibromycin, puromycin, queramycin, rhodorubicin, streptomycin, strepzotocin, tuberculin, ubenmex, fenestrated statin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues, such as pterin... Rosin, methotrexate, pteroyltriglutamate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thimipurine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmoflu, cytarabine, dideoxyuridine, docefluuridine, enoxabin, fluorouridine; androgens, such as capprotestone, drotalonone propionate, cyclothionol, meandrolone, testrolide; antiadrenergic drugs, such as aminoglutethimide, mitotane, trelostan; folic acid supplements, such as folinic acid; aceglucan lactone Aldolphosphatidylglycoside; Aminolevulinic acid; Enoxacin; Acridine; Betabucil; Bismuth subcitrate; Idatraxa; Difamethoxine; Diacinone; Eflunomide; Eridane acetate; Epomycin; Etoglobulin; Gallium nitrate; Hydroxyurea; Lentinan; Lonidanin; Maytansine derivatives (such as Maytansine and Ansericin); Mitoguanidine hydrazone; Mitoantrone; Moperadol; Nitrarin; Pentostatin; Finasteride; Pirarubicin; Loxoantrone; Podophyllic acid; 2-Ethylhydrazine; Procarbazine; PSK® polysaccharide complex (JHS) Natural Products, Eugene, Oreg.); Razosen; Rhizomycin; Cizonan; Spirogeron; Tenuric acid; Triaminoquinone; 2,2',2"-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, Verrucosporin A, Bacitracin A and Serpentin); Ethyl carbamate; Vinpocetine; Dacarbazine; Mannomustine; Dibromomannitol; Dibromoeusol; Piperbromo; Garcitocin; Cytarabine (“Ara-C”); Cyclophosphamide; Thiotepa; Taxanes, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ)ABRAXANE® (cremophor-free), paclitaxel albumin engineered nanoparticle formulations (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (docetaxel; Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vincristine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novotoxin; teniposide; edaraxazole; daunorubicin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above. .

[0157] Examples of the second (or further) agent or therapy may include, but are not limited to: immunotherapies (e.g., PD-1 inhibitors (pembrolizumab, nivolumab, cimiprimab), PD-L1 inhibitors (atelizumab, avelumab, durvalumab), CTLA4 antagonists); cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, tesimolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, etc.). Ranibizumab, pergatanib, panitumumab, etc.; mitotic inhibitors (e.g., paclitaxel, vincristine, vinblastine, etc.); alkylating agents (e.g., cisplatin, cyclophosphamide, chlorambucil, carmustine, etc.); antimetabolites (e.g., methotrexate, 5-FU, etc.); intercalating anticancer agents (e.g., actinomycin, anthracyclines, bleomycin, mitomycin-C, etc.); topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide, etc.); immunotherapeutic agents (e.g., interleukins, interferons, etc.); and antihormonal agents (e.g., tamoxifen, raloxifene, etc.).

[0158] Certain compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, all of which fall within the scope of this invention. Additional asymmetric carbon atoms may also be present in the substituents (such as alkyl groups). All such isomers and mixtures thereof are intended to be included in this invention.

[0159] According to the present invention, mixtures of isomers containing any of a variety of isomer ratios can be used. For example, in the case of combining only two isomers, the present invention covers mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. Those skilled in the art will readily understand that similar ratios are also covered for more complex isomer mixtures.

[0160] For example, if a particular enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomer salt can be formed with a suitable optically active acid or base, and the resulting diastereomer can then be resolved by fractional crystallization or chromatographic methods known in the art, followed by recovery of the pure enantiomer.

[0161] Isotope-labeled compounds are also within the scope of this disclosure. As used herein, "isotope-labeled compound" means a compound of this disclosure, including its pharmaceutically acceptable salts and prodrugs (each as described herein), wherein one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl.

[0162] By isotopically labeling the compounds disclosed herein, these compounds can be used for drug and / or substrate tissue distribution determination. Tritium ( 3 H) and carbon-14 ( 14 Compounds labeled with C are particularly preferred due to their ease of preparation and detectability. Furthermore, compounds labeled with heavier isotopes (such as deuterium) are also preferred. 2H)) substitution may offer certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. The isotopically labeled compounds disclosed herein, including their pharmaceutically acceptable salts, esters, and prodrugs, can be prepared by any means known in the art.

[0163] In addition, hydrogen (of average abundance) 1 H) Substitution with a heavier isotope, such as deuterium, can provide certain therapeutic advantages, for example, resulting in drugs with improved efficacy, safety, and / or tolerability due to improved absorption, distribution, metabolism, and / or excretion (ADME) properties. 13 C replaces the usual abundance 12 C may also benefit. (See WO 2007 / 005643, WO2007 / 005644, WO 2007 / 016361 and WO 2007 / 016431.) Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed herein, as well as racemic mixtures, diastereomer mixtures and other mixtures of such isomers, are all within the scope of this disclosure.

[0164] After preparation, the compounds of the present invention are preferably separated and purified to obtain a composition containing an amount equal to or greater than 95% (“substantially pure”) by weight, which is then used or formulated as described herein. In some embodiments, the compounds of the present invention have a purity greater than 99%.

[0165] This document also considers solvates and polymorphs of the compounds of the present invention. Solvates of the compounds of the present invention include, for example, hydrates.

[0166] It can be administered via any suitable route, such as parenteral, intravenous, subcutaneous, intramuscular, intravenous, intraperitoneal, rectal, or oral. The most appropriate route of administration for a particular patient will depend on the symptoms and severity of the disease or condition being treated, the nature of the therapy being used, and the nature of the active compound.

[0167] Compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersants, suspensions, or emulsions, as well as sterile powders reconstituted into sterile injectable solutions or dispersants immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate flowability can be maintained, for example, by using coating materials (such as lecithin), in the case of dispersants by maintaining the desired particle size, and by using surfactants.

[0168] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents, such as sugars and sodium chloride, may also be desired. Absorption of injectable drug forms can be prolonged by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0169] The compounds of the present invention can also be administered in liposome form. As is known in the art, liposomes are typically derived from phospholipids or other lipid substances. Liposomes are formed from a single or multiple layer of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes may be used. The compositions of the present invention in liposome form may contain stabilizers, preservatives, excipients, etc., in addition to the compounds of the present invention. Preferred lipids are phospholipids and phosphatidylcholine (lecithin), including both natural and synthetic ones. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0170] The total daily dose of the composition of the present invention administered to a human or other mammalian host may be given in a single or divided dose, for example, from 0.0001 to 300 mg / kg body weight per day, more typically from 1 to 300 mg / kg body weight per day. This dose of 0.0001 to 300 mg / kg body weight may be administered twice daily.

[0171] The materials, compositions, and components disclosed herein can be used, combined with, or used to prepare the methods and compositions disclosed herein, or their products. It should be understood that when combinations, subsets, interactions, groups, etc., of these materials are disclosed, each is specifically considered and described herein, although specific references to every individual and collective combination and arrangement of these compounds may not be explicitly disclosed. For example, if a method is disclosed and discussed, and various modifications to the plurality of molecules included in the method are discussed, then every combination and arrangement of the method and modifications is specifically considered unless explicitly stated to the contrary. Similarly, any subsets or combinations of these are also specifically considered and disclosed. This concept applies to all aspects of this disclosure, including but not limited to steps in methods using the disclosed compositions. Therefore, if multiple additional steps are possible, it should be understood that each of these additional steps may be performed in conjunction with any particular method step or combination of method steps of the disclosed method, and each such combination or subcombination is specifically considered and should be considered as disclosed.

[0172] Example The following examples are used to illustrate the present invention, but are not intended to limit the scope or spirit of the invention.

[0173] The compounds of this invention, including those specifically disclosed above and below, can be prepared according to the following embodiments. Although the invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that modifications, variations, and equivalent substitutions made to the invention within its scope are all within the protection scope of this invention. Table 1. exemplary compound

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] List of abbreviations

[0181] General LCMS method: Shimadzu LCMS2020, reversed-phase column (Shim-Pack Scepter C18, 33 × 3.0 mm, 3 μm), eluent A: H2O / MeCN / FA = 90 / 10 / 0.05; B: MeCN; detection: MS, ELS, UV (100 μL split to MS, which is equipped with an online UV detector); MS ionization mode: electrospray (positive and negative ions). ES-API = electrospray-atmospheric pressure ionization.

[0182] General HPLC purification method: Instrument = Shimadzu FRC 40; Shimadzu LH 40; Shimadzu LC 8A; GX 281. Chromatographic column = YMC Triart C18, 250 mm 20 mm, 5 μm; Welch Ultimate XB C18, 250 mm 21.2 mm, 5 μm. Detection wavelengths: 220 nm, 254 nm. Flow rate: 15 ml / min - 20 ml / min; Run time: 8 min; Column temperature: 25℃.

[0183] Exemplary chiral preparative SFC conditions and methods for the separation of racemic compounds: Preparative separation method 1: Instrument: Shimadzu PREP SOLUTION SFC Column: (R,R)-WHELK, 250 mm × 30 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 35% Flow rate: 60 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 5 min Washout time: 2 hours Preparative separation method 2: Instrument: Shimadzu PREP SOLUTION SFC Column: (R,R)-WHELK, 250 mm × 30 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 40% Flow rate: 60 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 5 min Washout time: 2 hours Preparative separation method 3: Instrument: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 150 mm × 20 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 15% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 10 min Washout time: 3 hours Preparative separation method 4: Instrument: Shimadzu PREP SOLUTION SFC Column: ChiralPak AD, 250 mm × 30 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 30% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 7 min Washout time: 2 hours Preparative separation method 5: Instrument: Shimadzu PREP SOLUTION SFC Column: ChiralPak AD, 250 mm × 20 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 20% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 7 min Injection volume: 3.4 mL Washout time: 2 hours Preparative separation method 6: Instrument: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 150 mm × 20 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 10% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 15 min Washout time: 2 hours Preparative separation method 7: Instrument: Waters Thale 80 preparative SFC Column: ChiralPak IA, 250 mm × 30 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 30% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Runtime: 10 min Cycle time: 6 min Injection volume: 1.5 mL Washout time: 2 hours Preparative separation method 8: Instrument: Shimadzu PREP SOLUTION SFC Column: ChiralPakC-IG, 250 mm × 30 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 30% Flow rate: 60 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 6 min Injection volume: 2 mL Washout time: 2 hours Preparative separation method 9: Instrument: Shimadzu PREP SOLUTION SFC Column: ChiralPak C-IG, 250 mm × 30 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 30% Flow rate: 60 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 5 min Injection volume: 3 mL Washout time: 2 hours Preparative separation method 10: Instrument: Shimadzu PREP SOLUTION SFC Column: ChiralPak IA, 250 mm × 20 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 30% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 10 min Washout time: 2 hours Preparative separation method 11: Instrument: Waters Thale 80 preparative SFC Column: (R,R)-WHELK, 250 mm × 20 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 50% Flow rate: 35 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle time: 5 min Runtime: 10 min Injection volume: 3 mL Washout time: 2 hours Preparative separation method 12: Instrument: Waters Thale 80 preparative SFC Column: ChiralPak IA, 250 mm × 20 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 25% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Runtime: 15 min Cycle time: 9 min Washout time: 3 hours Preparative separation method 13: Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IH, 250×20 mm ID, 5µm Mobile phase: A is CO2 and B is MeOH Gradient: B 13% Flow rate: 40 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 7 min Injection volume: 1.5 mL Number of injection needles: 10 Washout time: 2 hours Preparative separation method 14: Instrument: Waters Thale 80 preparative SFC Column: ChiralPak IH, 250 mm × 30 mm ID, 5 µm Mobile phase: A is CO2 and B is MeOH Gradient: B 20% Flow rate: 60 mL / min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Runtime: 8 min Cycle time: 8 min Injection volume: 3 mL Number of injection needles: 3 Washout time: 2 hours Example synthesis procedure: General Synthetic Route I:

[0184] Using this general route I, different R are introduced in step G. 1 , and R 2 This is introduced by an SNAr reaction with different amines in an earlier step D. In some cases, product Io is obtained directly from intermediate Il in step I-1. In other cases, intermediate Io is generated in a two-step sequence, firstly by forming In in step I-2, for example, when step I-2 is carried out under more diluted conditions, In is isolated, and then cyclized under basic conditions in step J to form Io.

[0185] General route II for the synthesis of intermediate Ik:

[0186] Using this general route II, the protection base (PG) is used as R. 2 In the earlier step D, different R are introduced. 1 And in subsequent step F, R is introduced after PG deprotection. 2 .

[0187] Synthesis of intermediate 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one

[0188] Step A: Concentrated HNO3 (43.4 g, 468 mmol) was added dropwise to a solution of 2,6-dibromo-4-fluorobenzyl-1-carboxaldehyde (110 g, 390 mmol) in concentrated H2SO4 (550 mL) at 0 °C. The reaction mixture was stirred at rt for 4 hours. The reaction mixture was poured into ice water and filtered. The resulting solid was dissolved in EtOAc and washed with water to remove residual acid. It was dried over Na2SO4 and concentrated under vacuum to give 2,6-dibromo-4-fluoro-3-nitrobenzyl-1-carboxaldehyde (115 g, 352 mmol, 90%) as a black solid. LCMS: ESI m / z 328 [M + H] + .

[0189] Step B: Magnesium 2-chloro-5-fluorophenyl (734 mL, freshly prepared, 0.5 M in THF) was added to a solution of 2,6-dibromo-4-fluoro-3-nitrobenzene-1-carboxaldehyde (40 g, 122 mmol) in THF (400 mL) at 0 °C. The mixture was stirred at rt for 1 hour. The reaction mixture was quenched with an aqueous solution of NH4Cl and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (eluting with EA / PE = 0-20%) to give a brown oily (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrobenzene)methanol (50 g, 109 mmol, 89%) (crude matter). LCMS: ESI m / z 458 [M + H] + .

[0190] Step C: DMP (170 g, 400 mmol) was added to a solution of (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl)methanol (122 g, 267 mmol) in DCM (1500 mL) at 0 °C. The reaction mixture was stirred at rt for 1 hour. The reaction mixture was diluted with water and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-20%) to give crude (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) methyl ketone as a brown solid. The crude substance was wet-milled in 500 mL (EA:PE = 1:10). The suspension was filtered to give (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) methyl ketone (88 g, 193 mmol, 72%) as a white solid. LCMS: ESI m / z 456 [M + H] + .

[0191] Step D: Add DIEA (38.3 g, 296 mmol) and 2,2,2-trifluoroethyl-1-amine hydrochloride (26.8 g, 198 mmol) to a solution of (2-chloro-4-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) methyl ketone (45 g, 98.8 mmol) in tetrahydrofuran (450 mL). Stir the mixture at 65 °C for 16 hours. Dilute the reaction mixture with water and extract with EA. Separate the organic layer, wash with brine, dry with Na₂SO₄, and concentrate under vacuum. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-10%, with 5% DCM) to give the title compound (2-chloro-4-fluorophenyl){2,6-dibromo-3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl} methyl ketone (22 g, 41.2 mmol, 41%) as a yellow solid.

[0192] Step E: Add Fe (15.7 g, 281 mmol) and NH4Cl (15.2 g, 281 mmol) to a solution of (2-chloro-4-fluorophenyl){2,6-dibromo-3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl} ketone (30 g, 56.1 mmol) in EtOH (300 mL) and H2O (75 mL). Stir the reaction mixture at 80 °C for 2 hours. Filter the cooled reaction mixture. Concentrate the filtrate, dilute with water, and extract with EtOAc (100 mL × 3). Wash the organic layer with brine, dry over Na2SO4, and concentrate. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-20%) to give an orange solid {{3-amino-2,6-dibromo-4-[(2,2,2-trifluoroethyl)amino]phenyl}(2-chloro-4-fluorophenyl)methyl ketone (26 g, 51.5 mmol, 92%). LCMS: ESI m / z 505 [M + H] + .

[0193] Step F: Triphosgene (1.47 g, 4.96 mmol) was added to a solution of {3-amino-2,6-dibromo-4-[(2,2,2-trifluoroethyl)amino]phenyl}(2-chloro-4-fluorophenyl) methyl ketone (5 g, 9.91 mmol), TEA (2.76 mL, 19.8 mmol), and THF (50 mL) at 0 °C. The reaction mixture was stirred at rt for 2 hours. An aqueous solution of NaHCO3 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 by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-30%) to give 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (5 g, 9.43 mmol, 95%) as a white solid. LCMS: m / z 531 [M+H] + .

[0194] In step D below, different amines are synthesized via the same general route with different R values. 2 intermediate:

[0195] For example, the synthesis of the intermediate 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one was achieved using similar conditions via the same sequence.

[0196]

[0197] Synthesis of intermediate 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-oxo-3H-benzo[d]imidazolium-4-carboxynitrile

[0198] Synthesis of intermediate 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideuterated methyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one

[0199] Step A: Ethyl[di(prop-2-yl)]amine (13.7 mL, 79.0 mmol) and 2,2-difluoroethyl-1-amine hydrochloride (3.95 g, 33.6 mmol) were added to a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) ketone (18.0 g, 39.5 mmol) in 1,4-dimethylamine (200 mL). The mixture was stirred at room temperature for 72 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography with PE / EA / DCM = 100 / 5 / 5 elution to give the starting material (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) methyl ketone (3.8 g), followed by elution with DCM / EA = 50 / 50 to give a yellow solid of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl} methyl ketone (14.0 g, 27.1 mmol, 69%). LCMS: ESI m / z 517 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6)δ 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).

[0200] Step B: Fe (9.46 g, 169.4 mmol) and NH4Cl (9.1 g, 169.4 mmol) were added to a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl} ketone (17.5 g × 2, 33.9 mmol × 2, in parallel) in EtOH (170 mL) and H2O (34 mL). The reaction mixture was stirred at 80 °C for 2 hours. The cooled reaction mixture was filtered, concentrated, diluted with water, and extracted with EtOAc (100 mL × 2). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was wet-milled (PE / EA = 4 / 1) to give an orange solid {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methyl ketone (26.0 g, 53.4 mmol, 79%). LCMS: ESI m / z 487 [M + H] + .

[0201] Step C: Triphosgene (7.93 g, 26.7 mmol) was added to a solution of {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl)amino]phenyl}(2-chloro-4-fluorophenyl) methyl ketone (26.0 g, 53.4 mmol), TEA (10.8 g, 106 mmol), and THF (260 mL) at 0 °C. The reaction mixture was stirred at rt for 2 hours. Water was added, and the mixture was diluted with EtOAc (1000 mL × 3) to extract the mixture. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude material was wet-milled using DCM / EA = 10 / 1 to give a brown solid, 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (21.3 g, 41.6 mmol, 78%). LCMS: ESI m / z 513 [M + H] + .

[0202] Synthetic intermediate 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-sideoxy-3H-benzo[d]imidazolium-4-carboxynitrile

[0203] Step A: CuCN (53.1 g, 592.0 mmol) was added to a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl} methyl ketone (300.0 g, 581.0 mmol) in DMSO (500 mL) at 90 °C. The reaction mixture was stirred at 90 °C for 30 min. LCMS showed that the reaction was complete. The cooled reaction mixture was poured into EA and water was added. The suspension was filtered through diatomaceous earth, and the filtrate was diluted with water and EA. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was wet-milled with PE:EA = 15:1 and IPA to obtain 5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-[(2,2-difluoroethyl)amino]-2-nitrobenzene-1-carboxylonitrile (252 g, 545 mmol, 94%) as a yellow solid.

[0204] LCMS: ESI m / z 462.61 [M+H] + .

[0205] Step B: Fe (212.0 g, 3804.0 mmol) was added to a solution of 5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-[(2,2-difluoroethyl)amino]-2-nitrobenzene-1-carboxynitrile (320.0 g, 692.0 mmol) in EtOH (2.4 L), acetic acid (600 mL), and H₂O (480 mL). The reaction mixture was stirred at an internal temperature of 75 °C for 30 min. The reaction was confirmed to be complete by LCMS. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water and extracted with EtOAc (1500 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography with petroleum ether containing ethyl acetate (gradient: 0-50%) to obtain a crude product. The crude product was wet-milled with PE:DCM = 1:1 to obtain a yellow solid 2-amino-5-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-[(2,2-difluoroethyl)amino]benzene-1-carboxynitrile (190.0 g, 439.2 mmol, 63.5%).

[0206] LCMS: ESI m / z 432.63 [M+H] + .

[0207] Step C: Triphosgene (0.69 g, 2.31 mmol) was added to a solution of 6-amino-3-bromo-2-[(2-chloro-4-fluorophenyl)carbonyl]-5-[(2,2-difluoroethyl)amino]benzyl-1-carboxylonitrile (1 g, 2.31 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at rt for 6 hours. The mixture was diluted with H2O and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was wet-milled with EA:PE = 5:1 to give 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-sideoxy-3H-benzo[d]imidazolium-4-carboxylonitrile (1 g, 2.18 mmol, 94%) as a brown solid. LCMS: ESI m / z 458.0 [M - H] + .

[0208] Synthetic intermediate 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one

[0209] Step A: DIEA (5.36 g, 41.4 mmol) and (2,4-dimethoxyphenyl)methylamine (2.78 g, 16.6 mmol) were added to a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) ketone (9.45 g, 20.7 mmol) in dimethyl ether (100 mL). The mixture was stirred at 100 °C for 2 hours. The cooled mixture was concentrated, and the residue was purified by silica gel chromatography (20 g column) using 0–10% EtOAc / hexane to give (2-chloro-5-fluorophenyl)(2,6-dibromo-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-nitrophenyl) ketone (8.8 g, 14.6 mmol, 70%) as a yellow solid. LCMS: ESI m / z 601 [M - H] - .

[0210] Step B: Add Fe (4.89 g, 87.6 mmol) and NH4Cl (3.91 g, 73.0 mmol) to a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-nitrophenyl) ketone (8.8 g, 14.6 mmol) in EtOH (80 mL) and H2O (20 mL). Stir the mixture at 80 °C for 2 hours. Filter the mixture and concentrate it under vacuum to remove EtOH. Pour the mixture into saturated NaHCO3 and extract with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give a brown solid (3-amino-2,6-dibromo-4-{[(2,4-dimethoxyphenyl)methyl]amino}phenyl)(2-chloro-5-fluorophenyl) methyl ketone (8.3 g, 14.5 mmol, 99%). LCMS: ESI m / z 573 [M + H] + .

[0211] Step C: TEA (4.45 g, 44.0 mmol) and trichloromethyl [(trichloromethyl)oxy]formate (4.35 g, 14.7 mmol) were added to a solution of (3-amino-2,6-dibromo-4-{[(2,4-dimethoxyphenyl)methyl]amino}phenyl)(2-chloro-5-fluorophenyl) ketone (8.4 g, 14.7 mmol) in THF (100 mL) at 0 °C, and the mixture was stirred for 1 hour. The mixture was diluted with water and extracted with EA. The organic phase was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (20 g column) using 0–30% EtOAc / hexane to give a brown solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (8.6 g, 14.3 mmol, 98%). LCMS: ESI m / z 599 [M + H] + .

[0212] Step D: Add NaH (0.27 g, 6.68 mmol, 60% in mineral oil) to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (2 g, 3.34 mmol) in THF (30 mL) at 0 °C. Stir the mixture for 10 minutes. Then add trideuterium (iodine)methane (0.97 g, 6.68 mmol) and stir the mixture at 0 °C for 1 hour. Quench the mixture with MeOH. The mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (30 g column) using 0–30% EtOAc / hexane to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (2 g, 3.25 mmol, 97%). LCMS: ESI m / z 616 [M + H] + .

[0213] Step E: Add TfOH (50 mg, 0.325 mmol) to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (2 g, 3.25 mmol) in TFA (30 mL). Stir the mixture at 50 °C for 2 hours. Concentrate the mixture under vacuum to remove TFA. Pour the residue into saturated NaHCO3 and extract with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give a yellow solid, 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (1.5 g, 3.22 mmol, 99%). LCMS: ESI m / z 466 [M +H] + .

[0214] In step D below, different R are used via the same general route. 1 Synthesis with different R 1 intermediate:

[0215] Example 1: (R)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 2: (S)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0216] Step A: NaH (82.9 mg, 2.07 mmol, 60% in mineral oil) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (550 mg, 1.04 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, followed by the addition of CD3I (301 mg, 2.07 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was quenched with water, and the mixture was extracted with EtOAc (15 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0% to 20%) to give a brown solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(trideutermethyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (450 mg, 0.822 mmol, 79%). LCMS: ESI m / z 546 [M + H] + .

[0217] Step B: CuCN (85.9 mg, 0.959 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(trideutermethyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 0.913 mmol) in NMP (10 mL), and the mixture was stirred at 130 °C under N2 for 3 hours. The cooled reaction mixture was diluted with H2O and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0% to 30%) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(trideutermethyl)-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (140 mg, 0.284 mmol, 31%) as a brown solid. LCMS: ESI m / z 493 [M + H] + .

[0218] Step C-1: A solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(trideutermethyl)-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (50 mg, 0.101 mmol), 5-fluoro-3-(trifluoromethyl)benzene-1-carboxamide (22 mg, 0.106 mmol), Pd2(dba)3 (9.28 mg, 10 µmol), Xantphos (11.7 mg, 20 µmol), Cs2CO3 (99 mg, 0.304 mmol), and dimethyl ether (2 mL) was stirred at 100 °C for 2 hours. The cooled reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with elution using DCM containing MeOH (gradient: 0% to 10%) to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-(difluoromethyl)-3-fluorobenzamide (50 mg, 40 µmol, 40%) as a brown solid. (50% DP). LCMS: ESI m / z 638 [M + H] + .

[0219]

[0220] Step C-2: A solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(trideutermethyl)-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (5.6 g, 11.3 mmol), 5-fluoro-3-(trifluoromethyl)benzene-1-carboxamide (2.35 g, 11.3 mmol), pd2(dba)3 (1.04 g, 1.13 mmol), xantphos (1.31 g, 2.26 mmol), and Cs2CO3 (11.1 g, 34.0 mmol) in dimethyl ether (300 mL) was stirred at 100 °C under N2 for 2 hours. The cooled reaction mixture was then concentrated. The residue was purified by silica gel column chromatography with elution using DCM containing MeOH (gradient: 0% to 10%) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-sideoxy-1-(trideutermethyl)-3-(2,2,2-trifluoroethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (5.9 g, 9.52 mmol, 84%) as the crude product (70% DP). LCMS: ESI m / z 620 [M + H] + .

[0221] Step D: At room temperature, KOH (2.85 g, 50.8 mmol) was added to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-sideoxy-1-(trideutermethyl)-3-(2,2,2-trifluoroethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (6.3 g, 10.2 mmol) in ACN (60 mL) and H₂O (6 mL). The reaction mixture was stirred at rt for 30 minutes. The mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (50 mL × 2), dried over Na₂SO₄, and concentrated to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (5 g, 7.84 mmol, 77%) as a brown solid. LCMS: ESI m / z 638 [M + H] + .

[0222] Step E: Add Et3SiH (0.2 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-5-(difluoromethyl)-3-fluorobenzamide (50 mg, 81 µmol) in TFA (2 mL). Stir the reaction mixture at 60 °C for 30 minutes. Concentrate the cooled reaction mixture. The residue was purified by preparative HPLC to obtain N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-di-sideoxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (3 mg, 5 µmol, 6%) as a white solid. LCMS: ESI m / z 622 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ 7.69-7.62 (m, 3H), 7.42 (s,1H), 7.24 (dd, J = 8.8, 5.0 Hz, 1H), 6.99 (td, J = 8.4, 3.0 Hz, 1H), 6.59 (s,1H), 6.21 (s, 1H), 4.74 (q,J = 8.8 Hz, 2H).

[0223] N-[6-(1-chloro-4-fluorophenyl-2-yl)-2,8-disideloxy-1-(trideutermethyl)-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (83 mg) was separated by preparative SFC method 1 to obtain (R)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-disideloxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (12.4 mg, 21 µmol, 15%) as a white solid. LCMS: 622 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.69-7.62 (m, 3H), 7.42 (s, 1H), 7.24 (dd, J = 8.8, 5.0 Hz, 1H), 6.99(td, J = 8.4, 3.0 Hz, 1H), 6.59 (s, 1H), 6.21 (s, 1H), 4.74 (q, J = 8.8 Hz, 2H). and (S)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-di-sideoxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (11.7 mg, 19 µmol, 14%) as a white solid. LCMS: 622 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.69-7.62 (m,3H), 7.42 (s, 1H), 7.24 (dd, J = 8.8, 5.0 Hz, 1H), 6.99 (td, J = 8.4, 3.0 Hz,1H), 6.59 (s, 1H), 6.21 (s, 1H), 4.74 (q, J = 8.8 Hz, 2H).

[0224] Example 3: N-[(6R)-6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-dioxo-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide and Example 4: N-[(6S)-6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-dioxo-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0225] Step A: NaH (90 mg, 2.26 mmol, 60% in mineral oil) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (600 mg, 1.13 mmol) in THF (15 mL) at 0 °C. After stirring at 0 °C for 1 hour, CH3I (240 mg, 1.69 mmol) was added. The reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (silica gel, 0-20%, PE containing EtOAc) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 0.91 mmol, 81%) as a white solid.

[0226] Step B: CuCN (90 mg, 1.01 mmol) was added to a stirred solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 0.91 mmol) in NMP (8 mL) under reflux. After stirring at 120 °C under N2 for 2 hours, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxy-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (160 mg, 0.32 mmol, 35%) as a yellow solid. LCMS: m / z 491 [M+H] + .

[0227] Step C: Under reflux, 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (50 mg, 0.24 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), Xant-PHOS (37 mg, 0.06 mmol), and Cs2CO3 (106 mg, 0.32 mmol) were added to a stirred solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxy-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (80 mg, 0.16 mmol) in dimethyl ether (6 mL). After stirring at 100 °C for 3 hours, the mixture was poured into ice water (10 mL) and extracted with DCM (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to obtain N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-2-sideoxy-3-(2,2,2-trifluoroethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.09 mmol, 59%) as a brown solid. LCMS: m / z 617 [M+H] + .

[0228] Step D: KOH (16 mg, 0.29 mmol) was slowly added to a stirred solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-2-sideoxy-3-(2,2,2-trifluoroethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.09 mmol) in ACN (3 mL) / H2O (1 mL) under rt. After stirring for 1 hour under rt, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain a crude white solid, N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-dioxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.06 mmol, 65%). LCMS: m / z 635 [M+H] + .

[0229] Step E: Under rt, add Et3SiH (0.5 mL) to a stirred solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-dioxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.06 mmol) in TFA (2 mL). After stirring at 70 °C for 1 hour, concentrate the cooled mixture. The residue was purified by chromatography (silica gel, 0-10%, DCM containing MeOH) followed by preparative TLC (DCM:MeOH = 20:1) to give N-(6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-di-sideoxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.04 mmol, 64%) as a white solid. LCMS: m / z 619 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.35 (s, 1H), 9.20 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 -7.05 (m, 1H), 6.59 (brs, 1H), 6.02 (brs, 1H), 4.96 - 4.77 (m, 2H), 3.92 (s,3H).

[0230] Next, 19 mg of racemic N-(6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-disideoxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide was separated by chiral preparative SFC method 2 to obtain N-[(6R)-6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-disideoxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3.6 mg, 0.006 mmol, 19%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.36(s, 1H), 9.20 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.71(s, 1H), 7.48 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.58 (brs, 1H), 6.02 (brs, 1H), 4.96 - 4.77 (m, 2H), 3.92 (s, 3H). And N-[(6S)-6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-disideloxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3.9 mg, 0.006 mmol, 21%) as a white solid. LCMS: m / z 619 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 10.36 (s, 1H), 9.20 (s,1H), 7.93 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.49(s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 - 7.04 (m, 1H), 6.64 (brs, 1H), 6.01 (brs, 1H), 4.96 - 4.74 (m, 2H), 3.92 (s, 3H).

[0231] Example 5: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 6: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0232]

[0233]

[0234] Step A: NaH (1.58 g, 39.61 mmol, 60% purity in mineral oil) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (10.1 g × 2, 19.8 mmol × 2, in parallel) in THF (150 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, followed by the addition of CD3I (3.70 mL, 59.41 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was quenched with 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 wet-milled and filtered (PE / EA = 10 / 1) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (19.1 g, 36.0 mmol, 91%) as a white solid. LCMS: ESI m / z 530 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0235] Step B: CuCN (1.77 g, 39.6 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (10 g × 2, 18.9 × 2 mmol, in parallel) in NMP (150 mL). The reaction mixture was stirred at 120 °C under N2 for 3 hours. The cooled reaction mixture was diluted with EA and filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (100 mL × 3). The organic phase was washed five times with brine, dried over Na2SO4, and concentrated. The residue was wet-milled three times with MeOH, followed by two wet-millings with MeCN and filtration to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (5.5 g, 11.5 mmol, 31%) as a white solid. LCMS: ESI m / z 530 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0236] Step C: A solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (500 mg, 1.05 mmol), 5-fluoro-3-(trifluoromethyl)benzene-1-carboxamide (218 mg, 1.05 mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), Xantphos (122 mg, 0.210 mmol), and Cs2CO3 (1.03 g, 3.15 mmol) in dimethyl ether (25 mL) was stirred at 100 °C under N2 for 2 hours. The reaction mixture was concentrated to obtain the residue. The residue was purified by silica gel column chromatography with elution using DCM containing MeOH (gradient: 0% to 10%) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (500 mg, 0.831 mmol, 79%) as a brown solid. LCMS: ESI m / z 602 [M + H] + .

[0237] Step D: Add KOH (25.2 mg, 0.449 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.150 mmol) in CH3CN (8 mL) and H2O (2 mL). Stir the mixture at 20 °C for 30 minutes. Dilute the mixture with water and extract with EA. The organic phase was dried and concentrated with Na₂SO₄ to give N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.145 mmol, 97%) as a brown solid. LCMS: ESI m / z 618 [M - H] - .

[0238] Step E: Add Et3SiH (0.25 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2,8-di-side-oxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.065 mmol) in TFA (1 mL) and stir the mixture at 70 °C for 30 minutes. The mixture was concentrated and the residue was purified by preparative TLC (PE / EA = 1:1) to obtain a crude product. This crude product was then separated by chiral preparative SFC method 3 to obtain a white solid (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (12.1 mg, 0.020 mmol, 31%). LCMS: ESI m / z 604.2 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.33 (s, 1H), 9.18 (s, 1H), 7.93 (d, J = 8.4 Hz,1H), 7.80 - 7.66 (m, 2H), 7.40 (s, 1H), 7.30 - 7.23 (m, 1H), 7.11 - 7.06 (m,1H), 6.65 (brs, 1H), 6.36 (t, J = 54.7 Hz, 1H), 6.00 (brs, 1H), 4.54 - 4.22(m, 2H). And (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (12.7 mg, 0.021 mmol, 32%), a white solid. LCMS: ESI m / z 604.2 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.33 (s, 1H), 9.18 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.80 - 7.66(m, 2H), 7.40 (s, 1H), 7.30 - 7.23 (m, 1H), 7.11 - 7.06 (m, 1H), 6.65 (brs,1H), 6.36 (t, J = 54.7 Hz, 1H), 6.00 (brs, 1H), 4.54 - 4.22 (m, 2H) Example 7: N-(6-(2-chloro-5-fluorophenyl)-1-(cyanomethyl)-2,8-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 11: N-[6-(2-chloro-5-fluorophenyl)-1-[2-(dimethylamino)ethyl]-2,8-dioxo-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0239]

[0240] Step A: Add bromoacetonitrile (136 mg, 1.13 mmol) and NaH (33.9 mg, 1.41 mmol, 60% in mineral oil) to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 0.943 mmol) in DCM (5 mL). Stir the reaction mixture overnight at 0°C to RT. Dilute the reaction mixture with water and extract with EA. Wash the organic layer with brine, dry with Na2SO4, and concentrate. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-30%) to give a white solid {5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(2,2,2-trifluoroethyl)benzo[d]imidazol-1-yl}acetonitrile (500 mg, 0.878 mmol, 93%). LCMS: ESI m / z 536.79 [M + H] + .

[0241] Step B: CuCN (78.6 mg, 0.878 mmol) was added to a solution of {5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(2,2,2-trifluoroethyl)benzo[d]imidazol-1-yl}acetonitrile (500 mg, 0.878 mmol) in NMP (5 mL). The reaction mixture was stirred at 130 °C for 4 hours. The cooled reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-30%) to give the title compound 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(cyanomethyl)-2-sideoxy-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (100 mg, 0.194 mmol, 22%) as a white solid. LCMS: ESI m / z 515.65 [M + H] + .

[0242] Step C: Add 2-methylpropyl-2-yl carbamate (4.22 mg, 0.036 mmol), Pd2(dba)3 (17.8 mg, 0.019 mmol), XANTPHOS (22.4 mg, 0.039 mmol), and Cs2CO3 (190 mg, 0.582 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(cyanomethyl)-2-sideoxy-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (100 mg, 0.194 mmol) in dimethyl ether (5 mL). Stir the reaction mixture at 100 °C for 2 hours. Dilute the cooled reaction mixture with water and extract with EA. Wash the organic layer with brine, dry over Na2SO4, and concentrate. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-30%) to give the title compound N-(6-(2-chloro-5-fluorophenyl)-1-(cyanomethyl)-6-hydroxy-2,8-disideloxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.045 mmol, 23%) as a yellow solid. LCMS: ESI m / z 659.88 [M + H] + .

[0243] Step D: Add Et3SiH (1 mL) to a solution of N-(6-(2-chloro-5-fluorophenyl)-1-(cyanomethyl)-6-hydroxy-2,8-disideloxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.045 mmol) in TFA (3 mL). Stir the reaction mixture at 50 °C for 2 hours. Concentrate the reaction mixture under vacuum. The residue was purified by preparative HPLC (C18, 0-80% acetonitrile in H2O) to give N-(6-(2-chloro-5-fluorophenyl)-1-(cyanomethyl)-2,8-disideloxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.5 mg, 0.004 mmol, 9%) as a white solid. LCMS: ESI m / z 643.88 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6)δ 10.45 (s, 1H), 9.42 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz,1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.34 - 7.23 (m, 1H), 7.14 - 7.05 (m, 1H), 6.82 - 6.44 (m, 1H), 6.08 (s, 1H), 5.86 - 5.72 (m, 2H), 5.03 - 4.82 (m, 2H).

[0244] Step E: Add Raney Ni (0.13 mg, 0.002 mmol) and paraformaldehyde (13.8 mg, 0.460 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-1-(cyanomethyl)-2,8-dioxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.023 mmol) in MeOH (3 mL). Stir the reaction mixture at room temperature under H2 for 4 hours. LCMS showed a reaction volume of 30% DP. Filter the reaction mixture. Concentrate the filtrate. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-1-[2-(dimethylamino)ethyl]-2,8-disideloxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (1 mg, 0.001 mmol, 6%) as a white solid. LCMS: ESI m / z 676 [M + H] + . 1 H NMR (400 MHz, MeOD- d 4) δ 7.71 - 7.62(m, 3H), 7.48 (s, 1H), 7.28 - 7.25 (m, 1H), 7.03 - 6.99 (m, 1H), 5.34 (t, J =4.4 Hz, 2H), 3.50 - 3.46 (m, 2H), 3.15 - 3.12 (m, 2H), 3.07 (s, 6H).

[0245] Example 8: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(ethyl-d5)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 9: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(ethyl-d5)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0246] Step A: NaH (0.22 g, 5.58 mmol, 60% in mineral oil) was added to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (1.3 g, 2.79 mmol) in DCM (20 mL) at 0 °C. The mixture was stirred for 10 minutes. Then, 2-bromo-1,1,1,2,2-pentadeuterethane (0.64 g, 5.58 mmol) was added, and the mixture was stirred for 6 hours. The mixture was quenched with H₂O and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography using PE containing EtOAc (gradient: 0-30%) to give a brown solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(pentadeuterylethyl)-3-(trideuterylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (1 g, 2.01 mmol, 72%). LCMS: ESI m / z 499.1 [M + H] + .

[0247] Step B: CuCN (0.18 g, 2 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(pentadeuterylethyl)-3-(trideuterylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (1 g, 2 mmol) in NMP (15 mL). The mixture was stirred at 130 °C under N2 for 5 hours. The cooled mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE containing EtOAc (gradient: 0-30%) to give a brown solid, 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-(pentadeuterylethyl)-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (360 mg, 0.810 mmol, 29%). LCMS: ESIm / z 446.1 [M + H] + .

[0248] Step C: Add XANT PHOS (46.8 mg, 0.081 mmol), Cs₂CO₃ (264 mg, 0.810 mmol), and Pd₂(dba)₃ (37.1 mg, 0.040 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-(pentadeuterethyl)-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (180 mg, 0.405 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (101 mg, 0.486 mmol) in dimethyl ether (8 mL). Stir the mixture 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 0–30% EtOAc / hexane to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-3-(pentadeuterethyl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.068 mmol, 17%) as a brown solid. LCMS: ESI m / z 589 [M + H] + .

[0249] Step D: Add Et3SiH (0.5 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-3-(pentadeuterethyl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.136 mmol) in TFA (2 mL). Stir the mixture at 60 °C for 1 hour. Concentrate the mixture. Pour the residue into NaHCO3 and extract with EtOAc. Wash the organic layer with brine, dry with Na2SO4 and concentrate under vacuum to obtain the residue, which is purified by preparative TLC (PE / EA = 1:1) to obtain the crude substance. It was separated by preparative SFC method 4 to obtain (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(ethyl-d5)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.3 mg, 0.004 mmol, 2.97%) as a white solid. LCMS: ESI m / z 573.3 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.81 - 7.66 (m, 2H), 7.36 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.14 -7.02 (m, 1H), 6.64 (brs, 1H), 6.01 (brs, 1H). And (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(ethyl-d5)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.0 mg, 0.004 mmol, 2.58%), a white solid. LCMS: ESI m / z 573.3 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.81 - 7.66 (m, 2H), 7.36 (s, 1H), 7.28 (dd, J = 8.8,5.2 Hz, 1H), 7.14 - 7.02 (m, 1H), 6.64 (brs, 1H), 6.01 (brs, 1H).

[0250] Example 10: N-(6-(2-chloro-5-fluorophenyl)-3-(cyanomethyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0251] Step A: NaH (0.55 g, 13.7 mmol, 60% in minerals) was added to a solution of 5,7-dibromo-6-(2-chloro-5-fluorobenzoyl)-1-(methyl-d3)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3.2 g, 6.8 mmol) in DCM (30 mL) at 0 °C, and the mixture was stirred for 10 minutes. Then, bromoacetonitrile (1.65 g, 13.7 mmol) was added, and the mixture was stirred for 2 hours. The mixture was quenched with H₂O, diluted with EA, and washed with H₂O and brine. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in petroleum ether containing 0-30% ethyl acetate to give the title compound 2-(4,6-dibromo-5-(2-chloro-5-fluorobenzoyl)-3-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetonitrile (2.5 g, 4.96 mmol, 72%) as a yellow solid. LCMS: ESI m / z 503 [M + H] + .

[0252] Step B: CuCN (0.16 g, 1.78 mmol) was added to a solution of 2-(4,6-dibromo-5-(2-chloro-5-fluorobenzoyl)-3-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetonitrile (1 g, 1.98 mmol) in NMP (15 mL). The mixture was stirred at 130 °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 by silica gel column chromatography with elution in petroleum ether containing 0-30% ethyl acetate to give the title compound 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(cyanomethyl)-3-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (240 mg, 0.53 mmol, 27%) as a yellow solid. LCMS: ESI m / z 450 [M + H] + .

[0253] Step C: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(cyanomethyl)-3-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (80 mg, 0.17 mmol) in dimethyl ether (5 mL), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (40.4 mg, 0.19 mmol), XANT PHOS (20.5 mg, 0.036 mmol), Cs₂CO₃ (116 mg, 0.36 mmol) and Pd₂(dba)₃ (16.3 mg, 0.018 mmol) were added. The mixture was stirred at 100 °C under N₂ for 4 hours. The mixture was diluted with EA and washed with H₂O and brine. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in petroleum ether containing 0-50% ethyl acetate to give the title compound NN-(6-(2-chloro-5-fluorophenyl)-3-(cyanomethyl)-6-hydroxy-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.034 mmol, 19%) as a yellow solid. LCMS: ESI m / z 595 [M + H] + .

[0254] Step D: Add Et3SiH (20 mg, 0.17 mmol) to a solution of N-(6-(2-chloro-5-fluorophenyl)-3-(cyanomethyl)-6-hydroxy-1-(methyl-d3)-2,8-di-side-oxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.034 mmol) in TFA (2 mL). Stir the mixture at 70 °C for 1 hour. Concentrate the mixture under vacuum. The residue was purified by preparative HPLC to give the title compound N-(6-(2-chloro-5-fluorophenyl)-3-(cyanomethyl)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.2 mg, 0.004 mmol, 11%) as a white solid. LCMS: ESI m / z 579 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s,1H), 9.22 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70(s, 1H), 7.52 (s, 1H), 7.31 - 7.24 (m, 1H), 7.14 - 7.04 (m, 1H), 6.65 (brs, 1H), 6.03 (brs, 1H), 5.21 (s, 2H).

[0255] Example 12: N-[6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-2,8-dioxo-1-(trideuterated methyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide; Example 20: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-1-(methyl-d3)-2,8-dioxo-1 2,3,6,7,8-Hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 21: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0256]

[0257]

[0258] In step A, 2-fluoroethyl-1-amine (0.50 g, 7.91 mmol) and DIEA (1.70 g, 13.2 mmol) were added to a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) methyl ketone (3 g, 6.58 mmol) in dimethyl ether (30 mL) at 0 °C. After stirring overnight under a nitrogen atmosphere at rt, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2-fluoroethyl)amino]-3-nitrophenyl} methyl ketone (1.6 g, 3.21 mmol, 48%) as a white solid. LCMS: ESI m / z 499 [M + H] + .

[0259] In step B, NH4Cl (0.52 g, 9.63 mmol) and Fe (1.79 g, 32.1 mmol) were added to a solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2-fluoroethyl)amino]-3-nitrophenyl} ketone (1.6 g, 3.21 mmol) in EtOH (15 mL) / H2O (5 mL) under reflux. After stirring at 80 °C under a N2 atmosphere for 3 hours, the mixture was filtered and concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to obtain a white solid {3-amino-2,6-dibromo-4-[(2-fluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methyl ketone (420 mg, 0.896 mmol, 28%). LCMS: ESI m / z 468 [M + H] + .

[0260] In step C, triphosgene (380 mg, 1.28 mmol) and TEA (0.2 mL, 1.71 mmol) were added to a solution of {3-amino-2,6-dibromo-4-[(2-fluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl) methyl ketone (400 mg, 0.854 mmol) in tetrahydrofuran (8 mL) at 0 °C. After stirring at rt under a N2 atmosphere for 2 hours, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-fluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (280 mg, 0.566 mmol, 66%) as a white solid. LCMS: ESI m / z 495 [M + H] + .

[0261] In step D, NaH (41 mg, 1.70 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-fluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (280 mg, 0.566 mmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C under N2 for 10 min. CD3I (410 mg, 2.83 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature under N2 for 1 h. The reaction was detected as complete by TLC. The cooled reaction mixture was dissolved in EA (50 mL), washed with H2O (30 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with PE containing 0-50% EA) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-fluoroethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (270 mg, 0.528 mmol, 93%). LCMS: ESI m / z 510 / 511 / 512 [M+H] + .

[0262] In step E, CuCN (47 mg, 0.528 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-fluoroethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (270 mg, 0.528 mmol) in NMP (2 mL). The reaction mixture was stirred at 130 °C under N2 for 2 hours. The reaction was detected as complete by LCMS. The cooled reaction mixture was dissolved in H2O, extracted with EA (20 mL), washed (10 mL) and with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with PE containing 0-100% EA) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-fluoroethyl)-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (240 mg, 0.524 mmol, 99%) as a yellow solid. LCMS: ESI m / z 457 / 459 [M + H] + .

[0263] In step F, 3-fluoro-5-(trifluoroethyl)-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (150 mg, 0.328 mmol) was added to a stirred solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-fluoroethyl)-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (5 mL) in dimethyl ether (5 mL). Pd2(dba)3 (30 mg, 0.033 mmol), Cs2CO3 (213 mg, 0.655 mmol), and Xant-PHOS (38 mg, 0.066 mmol) were added. After stirring at 100 °C for 2 hours, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to obtain N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2-fluoroethyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.086 mmol, 26%) as a yellow solid. LCMS: ESI m / z 583 [M+H] + In step G, potassium hydroxide (48 mg, 0.856 mmol) was added to a stirred solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2-fluoroethyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.086 mmol) in ACN (4 mL) and H2O (1 mL). After stirring at rt for 0.5 hours, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude form of the title compound, N-[6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.083 mmol, 97%), was obtained as a white solid. LCMS: ESI m / z 584 [M+H] + In step H, N-[6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.083 mmol) was added to a stirred solution of TFA (1 mL) and Et3SiH (1 mL) at rt. After stirring at 70 °C for 0.5 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN in H2O containing 0.1% TFA) to obtain N-[6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.017 mmol, 20%) as a white solid. LCMS: ESI m / z 586.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ10.32 (s, 1H), 9.16 (s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.75 - 7.70 (m, 2H),7.38 (s, 1H), 7.28 (dd, J = 8.0, 4.0 Hz, 1H), 7.08 (dd, J = 8.4, 3.2 Hz, 1H), 6.62 (brs, 1H), 6.00 (brs, 1H), 4.76 (t, J = 4 Hz, 1H), 4.64 (t, J = 4 Hz, 1H),4.28 - 4.18 (m, 2H).

[0264] Next, N-[6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (100 mg) was separated by chiral preparative SFC method 5 to obtain (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (43 mg, 0.073 mmol, 43%) as a white solid. LCMS: ESI m / z 586.2 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.31 (s, 1H), 9.16 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.75 -7.70 (m, 2H), 7.38 (s, 1H), 7.28 (dd, J = 8.0, 4.0 Hz, 1H), 7.08 (dd, J = 8.4,3.2 Hz, 1H), 6.65 (brs, 1H), 6.00 (s, 1H), 4.76 (t, J = 4.0 Hz, 1H), 4.64 (t, J=4.0 Hz, 1H), 4.28–4.18 (m, 2H). And (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (35.1 mg, 0.060 mmol, 35%) as a white solid. LCMS: ESI m / z 586.2 [M+ H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.15 (s, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.85 - 7.61 (m, 2H), 7.38 (s, 1H), 7.28 (dd, J = 8.0, 4.0 Hz, 1H),7.14 - 7.03 (m, 1H), 6.65 (brs, 1H), 6.01 (s, 1H), 4.76 (t, J = 4.0 Hz, 1H), 4.64 (t, J = 4.0 Hz, 1H), 4.28 - 4.18 (m, 2H).

[0265] Example 13: N-[6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2,8-dioxo-1-(trideuterated methyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide; Example 45: N-[(6S)-6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2,8-dioxo-1-(trideuterated methyl) N-[(6R)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide and Example 46: N-[(6R)-6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2,8-dioxo-1-(trideuteratedmethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0266]

[0267]

[0268] Step A: NaH (0.34 g, 8.59 mmol) was added to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (2 g, 4.30 mmol) in DCM (30 mL) at 0 °C. The mixture was stirred at rt for 10 min. Then, (bromomethyl)cyclopropane (0.87 g, 6.44 mmol) was added, and the mixture was stirred at 20 °C for 12 h. The mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography using PE containing EtOAc (gradient: 0-20%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(cyclopropylmethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (780 mg, 1.50 mmol, 35%). LCMS: ESIm / z 520.1 [M + H] + .

[0269] Step B: CuCN (133 mg, 1.48 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(cyclopropylmethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (770 mg, 1.48 mmol) in NMP (10 mL). The reaction mixture was stirred at 130 °C for 2 hours. The cooled mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE containing EtOAc (gradient: 0-30%) to give a brown solid, 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(cyclopropylmethyl)-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (230 mg, 0.494 mmol, 33%). LCMS: ESI m / z 467.2 [M + H] + .

[0270] Step C: Add Cs₂CO₃ (294 mg, 0.902 mmol), Xant-PHOS (52.2 mg, 0.090 mmol), and Pd₂(dba)₃ (41.3 mg, 0.045 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(cyclopropylmethyl)-2-sideoxy-3-(trideuterylmethyl)benzene-1-carboxamide (112 mg, 0.541 mmol) in dimethyl ether (10 mL). Stir the mixture at 100 °C under N₂ for 2 hours. Dilute the cooled reaction mixture with water and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(cyclopropylmethyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (260 mg, 0.439 mmol, 97%) as a brown solid. LCMS: ESI m / z 592.3 [M + H] + .

[0271] Step D: Add KOH (41.7 mg, 0.743 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(cyclopropylmethyl)-2-sideoxy-1-(trideuterylmethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (220 mg, 0.372 mmol) in CH3CN (10 mL) and H2O (2.5 mL). Stir the mixture at 20 °C for 1 hour. Dilute the reaction mixture with water and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to give N-[6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (220 mg, 0.361 mmol, 97%), a brown solid. LCMS: ESI m / z 608.3 [M - H] - .

[0272] Step E: Add Et3SiH (2 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (250 mg, 0.410 mmol) in TFA (10 mL). Stir the reaction mixture at 70 °C for 1 hour. The cooled mixture was concentrated, and the residue was purified by silica gel chromatography (2 g column) using hexane containing 0-60% EtOAc to give a yellow crude substance. This crude substance was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (22.6 mg, 0.038 mmol, 9%) as a white solid. LCMS: ESI m / z 594.4 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.76 - 7.72 (m, 2H), 7.41 (s, 1H), 7.27 (dd, J = 8.8,5.2 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.66 (brs, 1H), 6.02 (brs, 1H), 3.79 (d, J= 7.2 Hz, 2H), 1.25 - 1.16 (m, 1H), 0.51 - 0.45 (m, 2H), 0.44 - 0.37 (m, 2H).

[0273] Next, N-[6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (90 mg) was isolated in a chiral preparative SFC (Method 12) to obtain N-[(6S)-6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (17.2 mg, 0.029 mmol, 19%) as a white solid. LCMS: ESI m / z 594.2 [M + H] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.13 (s, 1H), 7.93 (d, J = 8.4 Hz,1H), 7.76 - 7.72 (m, 2H), 7.42 (s, 1H), 7.27 (dd, J = 8.8, 5.2 Hz, 1H), 7.10- 7.08 (m, 1H), 6.63 (brs, 1H), 6.02 (brs, 1H), 3.79 (d, J = 7.2 Hz, 2H), 1.25 - 1.16 (m, 1H), 0.52 - 0.45 (m, 2H), 0.44 - 0.38 (m, 2H). And N-[(6R)-6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (19.9 mg, 0.034 mmol, 22%), a white solid. LCMS: ESI m / z 594.2 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H),9.13 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.76 - 7.72 (m, 2H), 7.42 (s, 1H),7.27 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.66 (s, 1H), 6.01 (s,1H), 3.79 (d, J = 7.2 Hz, 2H), 1.25 - 1.16 (m, 1H), 0.52 - 0.45 (m, 2H), 0.44- 0.38 (m, 2H).

[0274] Example 14: N-(6-(2-chloro-5-fluorophenyl)-3-((2,2-difluorocyclopropyl)methyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0275]

[0276]

[0277] Step A: Pyridine (0.8 mL, 9.25 mmol) and TsCl (1.3 g, 6.939 mmol) were added to a solution of (2,2-difluorocyclopropyl)methanol (500 mg, 4.626 mmol) in DCM (6 mL). The reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE containing EA [gradient: 15%] to give the title compound, methyl 4-methylbenzenesulfonic acid (2,2-difluorocyclopropyl) methyl ester (800 mg, 3.050 mmol, 65%), as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 4.33 - 4.17 (m,1H), 4.00 (ddd, J= 12.0, 8.0, 4.0 Hz, 1H), 2.19 - 2.04 (m, 1H), 1.69 (tdd, J =12.0, 8.0, 4.0 Hz, 1H), 1.54 - 1.35 (m, 1H).

[0278] Step B: Add Cs₂CO₃ (280 mg, 0.859 mmol) and methyl 4-methylbenzyl[d]imidazolium-2-one (400 mg, 0.859 mmol) to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazolium-2-one (225 mg, 0.859 mmol) in DMA (6 mL). Stir the reaction mixture at 70 °C under N₂ for 3 hours. Dilute the cooled reaction mixture with H₂O and extract with EA. Wash the organic phase with brine, dry to Na₂SO₄, filter, and concentrate. The residue was purified by silica gel column chromatography using PE containing EA [gradient: 10%] to give a white solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,2-difluorocyclopropyl)methyl]-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (180 mg, 0.324 mmol, 37%). LCMS: ESI m / z 556 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.73 (dd, J 1.66 (ddd, J = 12.0, 8.0, 4.0 Hz, 1H), 1.46(ddd, J = 12.0, 8.0, 4.0 Hz, 1H).

[0279] Step C: CuCN (48 mg, 0.540 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,2-difluorocyclopropyl)methyl]-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (150 mg, 0.270 mmol) in NMP (5 mL). The cooled reaction mixture was stirred at 120 °C under N2 for 2 hours. The reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE containing EA [gradient: 15%] to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,2-difluorocyclopropyl)methyl]-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (70 mg, 0.140 mmol, 52%) as a white solid. LCMS: ESI m / z 503 [M+H] + Step D: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,2-difluorocyclopropyl)methyl]-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (70 mg, 0.140 mmol) in dimethyl ether (10 mL), Cs₂CO₃ (90 mg, 0.279 mmol), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (28 mg, 0.140 mmol), Xant-phos (16 mg, 0.028 mmol), and Pd₂(dba)₃ (12 mg, 0.014 mmol) were added. The reaction mixture was stirred at 100 °C under N₂ for 1 hour. The reaction mixture was diluted with H₂O and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE containing EA [gradient: 15%] to give the title compound N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-[(2,2-difluorocyclopropyl)methyl]-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.096 mmol, 68%) as a white solid. LCMS: ESI m / z 628 [M+H] + Step E: Add potassium hydroxide (26 mg, 0.478 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-[(2,2-difluorocyclopropyl)methyl]-2-sideoxy-1-(trideuterylmethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.096 mmol) in MeCN / H2O (5 mL). Stir the reaction mixture at RT for 1 hour. Dilute the reaction mixture with H2O and extract with EA. Wash the organic phase with brine, dry to Na2SO4, filter, and concentrate. The residue yielded the title compound N-[6-(2-chloro-5-fluorophenyl)-3-[(2,2-difluorocyclopropyl)methyl]-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.077 mmol, 81%) as a white solid. LCMS: ESI m / z 645 [M+H] + Step F: Add Et3SiH (21 mg, 0.186 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-3-[(2,2-difluorocyclopropyl)methyl]-6-hydroxy-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.093 mmol) in TFA (5 mL). Stir the reaction mixture at 70 °C for 1 hour. Dilute the cooled reaction mixture with H2O and extract with EA. Wash the organic phase with brine, dry to Na2SO4, filter, and concentrate. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-3-[(2,2-difluorocyclopropyl)methyl]-2,8-di-sideoxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (12.5 mg, 0.020 mmol, 21%) as a white solid. LCMS: ESI m / z 630 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J = 4.0 Hz, 1H),9.16 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.74 (d, J= 12.0 Hz, 2H), 7.43 (s, 1H), 7.28 (dd, J = 8.0, 4.0 Hz, 1H), 7.09 (s, 1H), 6.65 (s, 1H), 6.02 (s, 1H), 4.20- 3.91 (m, 2H), 2.32 - 2.09 (m, 1H), 1.73 - 1.61 (m, 1H), 1.47 (s, 1H).

[0280] Example 15: N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-dioxo-3-propyl-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; Example 33: (S)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-dioxo-3-propyl-1 2,3,6,7,8-Hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 34: (R)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-dioxo-3-propyl-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0281]

[0282] Step A: Cs₂CO₃ (1.04 g, 3.222 mmol) and 1-iodopropane (0.157 mL, 1.611 mmol) were added to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 1.074 mmol) in DMA (6 mL). The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with H₂O and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE containing EA [gradient: 10%] to give the title compound 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-propyl-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (200 mg, 0.394 mmol, 37%) as a white solid. LCMS: ESI m / z 508 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.75 -7.70 (m, 2H), 7.63 - 7.55 (m, 1H), 7.47 (dd, J = 8.0, 4.0 Hz, 1H), 3.85 (t, J =8.0 Hz, 2H), 1.69 - 1.63 (m, 2H), 0.89 (t, J = 8.0 Hz, 3H).

[0283] Step B: CuCN (14 mg, 0.158 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-propyl-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (200 mg, 0.394 mmol) in NMP (5 mL). The reaction mixture was stirred at 120 °C for 2 hours. The reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE containing EA [gradient: 15%] to give the title compound 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-propyl-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (120 mg, 0.264 mmol, 67%) as a white solid. LCMS: ESIm / z 455 [M+H] + Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-propyl-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (120 mg, 0.264 mmol) in dimethyl ether (5 mL), Cs₂CO₃ (172 mg, 0.529 mmol), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (54 mg, 0.264 mmol), Xant-phos (30.61 mg, 0.053 mmol), and Pd₂(dba)₃ (24 mg, 0.026 mmol) were added. The reaction mixture was stirred at 100 °C under N₂ for 1 hour. The reaction mixture was diluted with H₂O and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE containing EA [gradient: 15%] to give the title compound N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-sideoxy-3-propyl-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.155 mmol, 58%) as a white solid. LCMS: ESI m / z 580 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.53 (s, 1H), 7.42 (dd, J = 8.0, 4.0 Hz, 1H), 7.30 - 7.16 (m,2H), 3.87 (t, J = 8.0 Hz, 2H), 1.71 - 1.66 (m, 2H), 0.90 (t, J = 8.0 Hz, 3H).

[0284] Step D: Add potassium hydroxide (43 mg, 0.776 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-sideoxy-3-propyl-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.155 mmol) in MeCN / H2O (5 mL). Stir the reaction mixture at RT for 1 hour. Dilute the reaction mixture with H2O and extract with EA. Wash the organic phase with brine, dry to Na2SO4, filter, and concentrate. The residue was purified by silica gel column chromatography using PE [gradient: 30%] containing EA to give the title compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-3-propyl-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (70 mg, 0.117 mmol, 75%) as a white solid. LCMS: ESI m / z 598 [M+H] + Step E: Add Et3SiH (40 mg, 0.351 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-3-propyl-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (70 mg, 0.117 mmol) in TFA (5 mL). Stir the reaction mixture at 70 °C for 1 hour. Dilute the cooled reaction mixture with H2O and extract with EA. Wash the organic phase with brine, dry over Na2SO4, filter, and concentrate. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-2,8-dioxy-3-propyl-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (47.9 mg, 0.082 mmol, 70%) as a white solid. LCMS: ESI m / z 582 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.28 (s, 1H), 9.13 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 7.27 (dd, J= 8.0, 4.0 Hz, 1H),7.10 - 7.07 (m, 1H), 6.65 (brs, 1H), 6.01 (brs, 1H), 3.89 - 3.80 (m, 2H),1.71 - 1.65 (m, 2H), 0.89 (t, J = 8.0 Hz, 3H). N-[6-(2-chloro-5-fluorophenyl)-2,8-di-sideoxy-3-propyl-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (45 mg, 0.079 mmol) was purified by chiral preparative SFC method 9 to give the title compound (R)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-di-sideoxy-3-propyl-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (12.9 mg, 0.022 mmol, 28%) as a white solid. LCMS: ESI m / z 606 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H),9.13 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.37 (s, 1H), 7.27(dd, J = 8.0, 4.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.66 (brs, 1H), 6.01 (brs,1H), 3.87 - 3.82 (m, 2H), 1.71 - 1.65 (m, 2H), 0.89 (t, J = 8.0 Hz, 3H). and (S)-N-(6-(2-chloro-5-fluorophenyl)-1-(methyl-d3)-2,8-di-sideoxy-3-propyl-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15.5 mg, 0.027 mmol, 33%) as a white solid. LCMS: ESI m / z 606 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H),9.13 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.37 (s, 1H), 7.27(dd, J = 8.0, 4.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.66 (brs, 1H), 6.01 (brs,1H), 3.87 - 3.82 (m, 2H), 1.71 - 1.65 (m, 2H), 0.89 (t, J = 8.0 Hz, 3H).

[0285] Example 16: N-[6-(2-chloro-5-fluorophenyl)-3-(2-hydroxyethyl)-2,8-dioxo-1-(trideuterated methyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0286] Step A: Add NaH (0.17 g, 4.30 mmol, 60% in mineral oil) to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (1 g, 2.15 mmol) in DCM (15 mL) at 0 °C. Stir the mixture for 10 minutes. Then add 2-bromoethane-1-ol (400 mg, 3.22 mmol) and stir the mixture at 70 °C for 3 hours. Quench the cooled mixture with MeOH and pour it into water, then extract with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography using PE containing EtOAc (gradient: 0-60%) to give a brown solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-hydroxyethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (450 mg, 0.883 mmol, 41%). LCMS: ESI m / z 509.9 [M + H] + .

[0287] Step B: CuCN (75.6 mg, 0.844 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-hydroxyethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (430 mg, 0.844 mmol) in NMP (5 mL). The mixture was stirred at 130 °C under N2 for 2 hours. The cooled mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to obtain a residue. This residue was purified by silica gel chromatography (10 g column) using hexane containing 0-60% EtOAc to give a brown solid, 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-hydroxyethyl)-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (300 mg, 0.658 mmol, 78%). LCMS: ESI m / z 457.1 [M + H] + .

[0288] Step C: Add XANT PHOS (38.2 mg, 0.0658 mmol), Cs₂CO₃ (430 mg, 1.32 mmol), and Pd₂(dba)₃ (60.5 mg, 0.0658 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-hydroxyethyl)-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (300 mg, 0.661 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (164 mg, 0.792 mmol) in dimethyl ether (10 mL). Stir the mixture at 100 °C under N₂ for 2 hours. The cooled mixture was concentrated and the residue was purified by silica gel column chromatography using DCM containing MeOH (gradient: 10%) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2-hydroxyethyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.086 mmol, 13%) as a brown solid. LCMS: ESI m / z 600.3 [M + H] + .

[0289] Step D: Add Et3SiH (0.5 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2-hydroxyethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.050 mmol) in TFA (2 mL). Stir the mixture at 70 °C for 10 minutes. After cooling, dilute the mixture with H2O and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to obtain a residue. This residue was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-(2-hydroxyethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.2 mg, 0.004 mmol, 7%) as a white solid. LCMS: ESI m / z 584.3 [M + H] + . 1 H NMR(400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.13 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H),7.79 - 7.67 (m, 2H), 7.34 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 -7.07 (m, 1H), 6.66 (brs, 1H), 6.00 (brs, 1H), 4.00 - 3.86 (m, 2H), 3.67 (t, J= 5.6 Hz, 2H).

[0290] Example 17: N-(6-(2-chloro-5-fluorophenyl)-3-((1-fluorocyclopropyl)methyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; Example 43: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-((1-fluorocyclopropyl)methyl)-1-(methyl-d3)-2,8- Dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 44: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-((1-fluorocyclopropyl)methyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0291] Step A: 4-Methylbenzenesulfonic acid (2.29 g, 13.32 mmol) was added fractionally to a solution of (fluorocyclopropyl)methanol (600 mg, 6.67 mmol) and TEA (1.35 g, 13.32 mmol) in anhydrous DCM (6 mL) at 0 °C. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by FCC elution with EA / PE (10%) to give a yellow oily methyl 4-methylbenzenesulfonic acid (fluorocyclopropyl) methyl ester (980 mg, 4.01 mmol, 60%), which was used directly as crude product.

[0292] Step B: A mixture of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (934 mg, 2.0 mmol), methyl 4-methylbenzenesulfonic acid (fluorocyclopropyl) methyl ester (980 mg, 4.0 mmol), and Cs₂CO₃ (1.96 g, 6.0 mmol) in DMA (23 mL) was stirred at 70 °C for 80 minutes. The cooled mixture was poured into cold water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by FCC elution with EA / PE (20%) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(fluorocyclopropyl)methyl]-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (520 mg, 0.77 mmol, 38%) as a white solid. LCMS: m / z 538 [M+H] + .

[0293] Step C: CuCN (200 mg, 2.2 mmol) was added to a mixture of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(fluorocyclopropyl)methyl]-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (400 mg, 0.74 mmol) in NMP (4 mL). The mixture was stirred at 120 °C under N2 for 3 hours. The cooled mixture was diluted with EA and water. The mixture was filtered and the filtrate was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by FCC elution with EA / PE (20%) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(fluorocyclopropyl)methyl]-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (70 mg, 0.145 mmol, 19%) as a white solid. LCMS: ESI m / z 483 [M + H] + 485 [M + H] + .

[0294] Step D: A mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(fluorocyclopropyl)methyl]-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (97 mg, 0.20 mmol), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (45.7 mg, 0.22 mmol), Pd2(dba)3 (18.4 mg, 0.02 mmol), Xantphos (23.2 mg, 0.04 mmol), and Cs2CO3 (130.7 mg, 0.40 mmol) in dimethyl ether (5 mL) was stirred at 100 °C for 3 hours. 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 used directly in the next step.

[0295] Step E: Add 3 mL of water containing potassium hydroxide (124 mg, 2.21 mmol) to a mixture of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-[(fluorocyclopropyl)methyl]-2-sideoxy-1-(trideuterylmethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (134.8 mg, 0.22 mmol) in acetonitrile (10 mL). Stir the mixture at room temperature for 30 minutes. Dilute the mixture with water and extract with EA. Wash the organic layer with brine, dry with Na2SO4, and concentrate. The residue was purified by FCC elution with EA / PE (0-50%) to give N-[6-(2-chloro-5-fluorophenyl)-3-[(fluorocyclopropyl)methyl]-6-hydroxy-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (70 mg, 0.11 mmol, 50%) as a yellow solid. LCMS: m / z 626 [MH] - .

[0296] Step F: The mixture of N-[6-(2-chloro-5-fluorophenyl)-3-[(fluorocyclopropyl)methyl]-6-hydroxy-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.096 mmol) in TFA (5 mL) and Et3SiH (0.5 mL) was stirred at 50 °C for 30 minutes. The mixture was concentrated and purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-[(fluorocyclopropyl)methyl]-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (35 mg, 0.06 mmol, 60%) as a white solid. LCMS: m / z 612 [M+H] + . 1H NMR(400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.15 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.37 (s, 1H), 7.28 (dd, J = 8.8, 5.2Hz, 1H), 7.10 - 7.08 (m, 1H), 6.66 (brs, 1H), 6.01 (brs, 1H), 4.46 - 4.21 (m,2H), 1.11 - 1.02 (m, 2H), 1.03 - 0.95 (m, 2H).

[0297] N-[6-(2-chloro-5-fluorophenyl)-3-[(fluorocyclopropyl)methyl]-2,8-disideoxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg) was separated by chiral preparative SFC (Method 11) to give (R)-N-(6-(2-chloro-5-fluorophenyl)-3-((1-fluorocyclopropyl)methyl)-1-(methyl-d3)-2,8-disideoxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10.9 mg, 17.8 mmol, 33%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 10.32 (s, 1H), 9.15 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz,1H), 7.70 (s, 1H), 7.37 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 - 7.08(m, 1H), 6.63 (brs, 1H), 6.00 (brs, 1H), 4.46 - 4.21 (m, 2H), 1.11 - 1.03 (m,2H), 1.03 - 0.95 (m, 2H). LCMS: ESI m / z 612 [M + H] +And (S)-N-(6-(2-chloro-5-fluorophenyl)-3-((1-fluorocyclopropyl)methyl)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidozono[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10.7 mg, 17.5 mmol, 32%), which is a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.15 (s, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.37 (s, 1H), 7.28 (dd, J = 8.8,5.2 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.58 (brs, 1H), 5.97 (brs, 1H), 4.46 - 4.21(m, 2H), 1.11 - 1.03 (m, 2H), 1.03 - 0.96 (m, 2H). LCMS: ESI m / z 612 [M + H] + .

[0298] Example 18: N-(6-(2-chloro-5-fluorophenyl)-3-methyl-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0299] Step A: Add NaH (120 mg, 3.00 mmol, 60% in mineral oil) to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (700 mg, 1.50 mmol) in N,N-dimethylformamide (20 mL). Stir the mixture at 0 °C for 5 minutes. Add iodomethane (0.244 mL, 3.007 mmol). Stir the mixture at room temperature for 4 hours. Dilute the mixture with water and extract with EA. Wash the organic layer with brine, dry with Na₂SO₄, and concentrate. The residue was purified by FCC elution with EA / PE (0-20%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (220 mg, 0.46 mmol, 31%). LCMS: m / z 480 [M+H] + .

[0300] Step B: CuCN (82 mg, 0.92 mmol) was added to a mixture of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (220 mg, 0.46 mmol) in NMP (10 mL). The mixture was stirred at 130 °C under N2 for 2 hours. The cooled mixture was diluted with EA and water. The mixture was filtered and the filtrate was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by FCC elution with EA / PE (0-20%) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (38 mg, 0.09 mmol, 19%) as a white solid. LCMS: m / z 425 [M+H] + .

[0301] Step C: A mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (38 mg, 0.09 mmol), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (28 mg, 0.13 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), Xantphos (10 mg, 0.018 mmol), and Cs2CO3 (58 mg, 0.18 mmol) in dimethyl ether (5 mL) was stirred at 100 °C under N2 for 3 hours. 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 used directly in the next step. LCMS: m / z 552 [M+H] + .

[0302] Step D: Add 2 mL of H₂O containing potassium hydroxide (33 mg, 0.59 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-methyl-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (65 mg, 0.12 mmol) in acetonitrile (5 mL). Stir the mixture at room temperature for 20 minutes. Dilute the mixture with water and extract with EA. Wash the organic layer with brine, dry with Na₂SO₄, and concentrate. The residue was purified by elution with EA / PE (0-70) by FCC to obtain N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methyl-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.053 mmol, 45%) as a white solid.

[0303] Step E: Add Et3SiH (0.2 mL) to a mixture of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methyl-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (33 mg, 0.058 mmol) in 2,2,2-trifluoroacetaldehyde (2 mL). Stir the mixture at 50 °C for 40 minutes. The mixture was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-3-methyl-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (8 mg, 0.014 mmol, 25%) as a white solid. LCMS: m / z 554 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.77 - 7.67(m, 2H), 7.33 - 7.21 (m, 2H), 7.10 - 7.07 (m, 1H), 6.53 (brs, 1H), 6.02 (brs,1H), 3.39 (s, 3H).

[0304] Example 19: N-(6-(2-chloro-5-fluorophenyl)-3-(2-methoxyethyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0305] Step A: NaH (172 mg, 4.30 mmol, 60% purity in mineral oil) was added to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (1.0 g, 2.15 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred for 10 min, followed by the addition of 2-bromo-1-methoxyethane (0.4 mL, 4.30 mmol). The mixture was stirred at 50 °C for 18 h. The reaction mixture was quenched with water, and the mixture was extracted with EtOAc (15 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0% to 30%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-methoxyethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (520 mg, 0.99 mmol, 46%). LCMS: ESI m / z 524 [M + H] + .

[0306] Step B: CuCN (94 mg, 1.04 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-methoxyethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (520 mg, 0.99 mmol) in NMP (10 mL). The reaction mixture was stirred at 120 °C under N2 for 3 hours. The cooled reaction mixture was diluted with EA and filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (10 mL × 3). The organic phase was washed three times with brine, dried over Na2SO4, and concentrated. The crude substance was then purified by preparative HPLC to obtain a yellow solid, 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-methoxyethyl)-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (120 mg, 0.26 mmol, 26%). LCMS: ESI m / z 469 / 471 [M + H] + .

[0307] Step C: Add 3-fluoro-5-(trifluoromethyl)benzimidazole-4-carboxynitrile (120 mg, 0.26 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-methoxyethyl)-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (5 mL) in 1,4-dimethylethane (79 mg, 0.38 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), Xantphos (47 mg, 0.08 mmol), and Cs2CO3 (166.48 mg, 0.511 mmol) to the solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2-methoxyethyl)-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (37 mg, 0.04 mmol), Xantphos (47 mg, 0.08 mmol), and Cs2CO3 (166.48 mg, 0.511 mmol). Stir the reaction mixture at 100 °C under N2 for 2 hours. Concentrate the reaction mixture. The residue was purified by silica gel chromatography (PE / EA = 3 / 1) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2-methoxyethyl)-2-sideoxy-1-(trideuterylmethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (120 mg, 0.20 mmol, 79%) as a yellow solid. LCMS: ESI m / z 596 [M + H] + .

[0308] Step D: Add KOH (23 mg, 0.40 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2-methoxyethyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (120 mg, 0.20 mmol) in MeCN (5 mL) and H2O (1 mL). Stir the reaction mixture at room temperature for 2 hours. LCMS showed that the reaction was complete. Dilute the reaction mixture with brine and extract with EA. Wash the organic phase with brine, dry to Na2SO4, and concentrate. The organic layer was separated and concentrated to obtain N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2-methoxyethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.18 mmol, 89%) as a yellow solid. LCMS: ESI m / z 614 [M+ H] + .

[0309] Step E: Add triethylsilane (1 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2-methoxyethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.18 mmol) in TFA (2 mL). Stir the reaction mixture at 70 °C for 20 min. LCMS showed that the reaction was complete. The cooled reaction mixture was concentrated and purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-(2-methoxyethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (49.5 mg, 0.08 mmol, 42%) as a white solid. LCMS: ESI m / z 598 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s,1H), 9.13 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.71 (s,1H), 7.35 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 - 7.07 (m, 1H), 6.65(brs, 1H), 5.98 (brs, 1H), 4.13 - 3.97 (m, 2H), 3.62 (t, J = 5.2 Hz, 2H), 3.23 (s, 3H).

[0310] Example 22: N-{3-[2-(azacyclobutan-1-yl)ethyl]-6-(2-chloro-5-fluorophenyl)-2,8-dioxo-1-(trideuterated methyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide

[0311]

[0312] Step A: Add NaH (0.34 g, 8.59 mmol, 60% in mineral oil) to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (2 g, 4.30 mmol) in DMF (30 mL) at 0 °C. Stir the mixture at 0 °C for 10 minutes. Then add 1-bromo-4,4,5,5-tetramethyl-3-oxa-4-silazhexane (1.54 g, 6.44 mmol) and stir the mixture at 70 °C for 5 hours. Dilute the mixture with H₂O and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to obtain a residue. This residue was purified by silica gel chromatography (10 g column) using hexane containing 0-30% EtOAc to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (630 mg, 1.01 mmol, 23%). LCMS: ESI m / z 624.0 [M + H] + .

[0313] Step B: CuCN (105 mg, 1.17 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(4,4,5,5-tetramethyl-3-oxa-4-silazhe-1-yl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (610 mg, 0.978 mmol) in NMP (10 mL). The mixture was stirred at 130 °C under N2 for 3 hours. The cooled mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to obtain a residue. This residue was purified by silica gel chromatography (10 g column) using hexane containing 0-30% EtOAc to give a brown solid, 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (220 mg, 0.386 mmol, 39%). LCMS: ESI m / z 571.1 [M + H] + .

[0314] Step C: Add XANTPHOS (40.6 mg, 0.070 mmol) and Pd2(dba)3 (32.1 mg, 0.035 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-(4,4,5,5-tetramethyl-3-oxa-4-silazhe-1-yl)-3-(trideuterylmethyl)benzimidazole-4-carboxynitrile (200 mg, 0.351 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (87.2 mg, 0.421 mmol) in dimethyl ether (10 mL). Stir the mixture at 100 °C under N2 for 2 hours. Dilute the cooled mixture with H2O and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-sideoxy-3-(4,4,5,5-tetramethyl-3-oxa-4-silazhe-1-yl)-1-(trideuterylmethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (230 mg, 0.330 mmol, 94%) as a brown solid. It was used in the next step without purification. LCMS: ESI m / z 696.2 [M+ H] + .

[0315] Step D: KOH (37.1 mg, 0.661 mmol) was added to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-sideoxy-3-(4,4,5,5-tetramethyl-3-oxa-4-silazhe-1-yl)-1-(trideuterylmethyl)benzimidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (230 mg, 0.330 mmol) in CH3CN (10 mL) and H2O (2 mL). The mixture was stirred at 20 °C for 1 hour. TLC (PE / EA = 1:1) showed the consumption of the starting material and the observation of new spots. The mixture was concentrated and the residue was purified by silica gel column chromatography using PE (gradient: 50%) containing EA to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-disideloxy-3-(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (127 mg, 0.178 mmol, 54%) as a brown solid. LCMS: ESI m / z 712 [M - H] - .

[0316] Step E: Add TBAF (0.328 mL, 0.328 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-di-side-oxy-3-(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (117 mg, 0.164 mmol) in THF (5 mL). Stir the mixture at 20 °C for 1 hour. Dilute the mixture with HCl (1 M) and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to obtain a residue. This residue was purified by silica gel chromatography (4 g column) using hexane containing 0-70% EtOAc to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2-hydroxyethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (90 mg, 0.150 mmol, 91%) as a yellow solid. LCMS: ESI m / z 600.3 [M + H] + .

[0317] Step F: Add Dysmart (63.6 mg, 0.150 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2-hydroxyethyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.050 mmol) in DCM (5 mL). Stir the mixture at 20 °C for 1 hour. Dilute the mixture with H2O and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to give N-[6-(2-chloro-5-fluorophenyl)-3-(formylmethyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.030 mmol, 60%) as a white solid. LCMS: ESI m / z 596.2 [M + H] + .

[0318] Step G: Add aziridine (4.30 mg, 0.075 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(formylmethyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.050 mmol) in MeOH (5 mL). Stir the mixture at 20 °C for 1 hour. Then add sodium cyanoborohydride (9.46 mg, 0.151 mmol) and stir the mixture at 20 °C for 1 hour. Dilute the mixture with H2O and extract with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to obtain a residue. This residue was purified by preparative TLC (DCM / MeOH = 10:1) to give N-{3-[2-(azacyclobut-1-yl)ethyl]-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 31%) as a white solid. LCMS: ESI m / z 639.3 [M + H] + .

[0319] Step H: Add Et3SiH (0.5 mL, 0.008 mmol) to a solution of NN-{3-[2-(azacyclobut-1-yl)ethyl]-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (2 mL). Stir the mixture at 70 °C for 30 minutes. Concentrate the mixture under vacuum to remove TFA and Et3SiH. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to obtain a solid, which was then purified by preparative HPLC to give N-{3-[2-(azacyclobut-1-yl)ethyl]-6-(2-chloro-5-fluorophenyl)-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (2.3 mg, 0.004 mmol, 23%) as a white solid. LCMS: ESI m / z 623.4 [M + H] + . 1H NMR (400 MHz, MeOD) δ 7.72 -7.66 (m, 2H), 7.63 (d, J = 9.2 Hz, 1H), 7.37 (s, 1H), 7.24 (dd, J = 8.8, 5.2Hz, 1H), 7.00 - 6.97 (m, 1H), 6.54 (brs, 1H), 6.23 (brs, 1H), 4.05 (td, J =5.6, 2.4 Hz, 2H), 3.60 (t, J = 7.2 Hz, 4H), 3.09 (t, J = 5.6 Hz, 2H), 2.22(p, J = 7.6 Hz, 2H).

[0320]

[0321] Step A: 1-Bromo-4,4,5,5-Tetramethyl-3-oxa-4-silazhexane (4.06 g, 17 mmol) and NaH (0.27 g, 11.3 mmol, 60% in mineral oil) were added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (3 g, 5.66 mmol) in DMA (35 mL). The reaction mixture was stirred at 70 °C under N2 for 6 hours. LCMS showed the reaction was complete. The reaction mixture was quenched with H2O at 0 °C and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 30-40%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.5 g, 5.08 mmol, 90%). LCMS: 687 / 689 [MH] - .

[0322] Step B: CuCN (0.55 g, 6.1 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.5 g, 5.08 mmol) in NMP (40 mL). The reaction mixture was stirred at 130 °C under N2 for 2 hours. LCMS showed a reaction with 30% DP. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in DCM containing ethyl acetate (gradient: 20-30%) to give a yellow oil of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)-1-(2,2,2-trifluoroethyl)benzo[d]imidazolium-4-carboxynitrile (500 mg, 0.787 mmol, 16%). LCMS: 634 / 635 [MH] - .

[0323] Step C: To a solution of 6-bromo-3-(2-((tributyldimethylsilyl)oxy)ethyl)-5-(2-chloro-5-fluorobenzoyl)-2-sideoxy-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (500 mg, 0.787 mmol) in dimethyl ether (5 mL), 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (244 mg, 1.18 mmol), Pd2(dba)3 (72.1 mg, 0.079 mmol), xantphos (91.1 mg, 0.157 mmol), and Cs2CO3 (256 mg, 0.787 mmol) were added. The reaction mixture was stirred at 100 °C under N2 for 2 hours. The reaction was complete as indicated by LCMS. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 15-20%) to give the title compound N-(1-(2-((tributyldimethylsilyl)oxy)ethyl)-6-(2-chloro-5-fluorobenzoyl)-7-cyano-2-sideoxy-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (240 mg, 0.315 mmol, 40%). LCMS: ESI m / z 761 / 763 [M+H] + .

[0324] Step D: KOH (35.4 mg, 0.631 mmol) was added to a solution of N-(1-(2-((tributyldimethylsilyl)oxy)ethyl)-6-(2-chloro-5-fluorobenzoyl)-7-cyano-2-sideoxy-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (240 mg, 0.315 mmol) in H2O (1 mL) and ACN (5 mL). The reaction mixture was stirred at room temperature under N2 for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The organic layer was separated and concentrated to obtain N-(1-(2-((tributyldimethylsilyl)oxy)ethyl)-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-disideloxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (200 mg, 0.257 mmol, 81%), a yellow solid. LCMS: ESI m / z 779 / 781 [M + H] + .

[0325] Step E: Add TBAF (134 mg, 0.513 mmol) to a solution of N-(1-(2-((tributyldimethylsilyl)oxy)ethyl)-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-di-side-oxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (200 mg, 0.257 mmol) in THF (5 mL). Stir the reaction mixture under N2 at rt for 4 hours. LCMS showed the reaction was complete. Dilute the reaction mixture with brine and extract with EA. Wash the organic phase with brine, dry to Na2SO4, and concentrate. The organic layer was separated and concentrated to obtain N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-(2-hydroxyethyl)-2,8-di-sideoxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (120 mg, 0.180 mmol, 70%) as a yellow solid. LCMS: ESI m / z 665 / 667 [M + H] + .

[0326] Step F: Add DMP (76.6 mg, 0.180 mmol) to a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-(2-hydroxyethyl)-2,8-di-side-oxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (40 mg, 0.06 mmol) in DCM (3 mL). Stir the mixture at rt for 1 hour. LCMS showed the reaction was complete. Dilute the reactants with DCM and H2O. Separate the organic layer and concentrate under vacuum. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 40-50%) to give N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-di-sideoxy-1-(2-sideoxyethyl)-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.045 mmol, 75%) as a yellow solid. LCMS: ESI m / z 663 / 665 [M + H] + .

[0327] Step G: Add aziridine (7.75 mg, 0.136 mmol) and sodium cyanoborohydride (8.53 mg, 0.136 mmol) to a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-di-side-oxy-1-(2-side-oxyethyl)-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.045 mmol) in MeOH (5 mL). Stir the reaction mixture under N2 at rt for 2 hours. LCMS showed the reaction was complete. Dilute the reaction mixture with water and extract with EA. Wash the organic phase with brine, dry to Na2SO4, and concentrate. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 50-60%) to give N-(1-(2-(azacyclobut-1-yl)ethyl)-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-disideoxy-3-(2,2,2-trifluoroethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (13 mg, 0.018 mmol, 41%). LCMS: ESI m / z 704 / 706 [M + H] + .

[0328] Step H: Add Et3SiH (0.010 mL, 0.028 mmol) to a solution of N-{1-[2-(azacyclobut-1-yl)ethyl]-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-dioxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.028 mmol) in TFA (3 mL). Stir the reaction mixture at 70 °C for 1 hour. LCMS showed that the reaction was complete. Concentrate the cooled reaction mixture, dilute with aqueous NaHCO3 solution, and extract with EA. Wash the organic phase with brine, dry over Na2SO4, and concentrate. The residue was purified by preparative HPLC to obtain N-{1-[2-(azacyclobut-1-yl)ethyl]-6-(2-chloro-5-fluorophenyl)-2,8-dioxy-3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (4.4 mg, 0.006 mmol, 23%) as a white solid. LCMS: ESI m / z 688 / 690 [M + H] + . 1 HNMR(400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.73 (s, 1H), 9.32 (s, 1H), 7.95(d, J = 7.6 Hz, 1H), 7.80 - 7.67 (m, 2H), 7.55 (s, 1H), 7.28 (s, 1H), 7.10(s, 1H), 6.64 (brs, 1H), 6.07 (brs, 1H), 5.04 - 4.77 (m, 2H), 4.68 - 4.61 (m,2H), 4.18 - 4.12 (m, 4H), 3.72 - 3.66 (m, 2H), 2.44 - 2.19 (m, 2H).

[0329] Example 24: N-(6-(2-chloro-5-fluorophenyl)-3-(2-(dimethylamino)ethyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0330] Step A: Add Desmond-Martin periodane (28.3 mg, 0.067 mmol) to a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2-hydroxyethyl)-1-(methyl-d3)-2,8-di-side-oxy-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (40 mg, 0.067 mmol) in DCM (3 mL). Stir the mixture at room temperature for 1 hour. LCMS showed the reaction was complete. Dilute the reactants with DCM and H2O. The organic layer was separated and concentrated under vacuum to give N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-(methyl-d3)-2,8-di-sideoxy-3-(2-sideoxyethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.034 mmol, 50%) as a yellow solid. LCMS: 598 / 600 [MH] - .

[0331] Step B: Dimethylamine hydrochloride (5.46 mg, 0.067 mmol) was added to a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-(methyl-d3)-2,8-di-side-oxy-3-(2-side-oxyethyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.034 mmol) in MeOH (3 mL). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (6.32 mg, 0.101 mmol). The reaction mixture was stirred at room temperature for 1 hour. LCMS showed a reaction of 50% DP. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC using a dichloroform gradient (0-10%) containing methanol to obtain N-(6-(2-chloro-5-fluorophenyl)-3-(2-(dimethylamino)ethyl)-6-hydroxy-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10.5 mg, 0.017 mmol, 50%) as a yellow solid. LCMS: 627 / 629 [MH] - .

[0332] Step C: Add Et3SiH (0.4 mL, 2.5 mmol) to a solution of N-(6-(2-chloro-5-fluorophenyl)-3-(2-(dimethylamino)ethyl)-6-hydroxy-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.032 mmol) in TFA (3 mL). Stir the reaction mixture at 70 °C for 1 hour. LCMS showed that the reaction was complete. Concentrate the cooled reaction mixture, dilute with aqueous NaHCO3 solution, and extract with EA. Wash the organic phase with brine, dry over Na2SO4, and concentrate. The residue was purified by preparative HPLC to obtain N-(6-(2-chloro-5-fluorophenyl)-3-(2-(dimethylamino)ethyl)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1.8 mg, 0.003 mmol, 9%) as a white solid. LCMS: ESI m / z 611 / 613 [M+H] + . 1 H NMR(400 MHz, MeOD-d4) δ7.74 - 7.70 (m, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.24 (dd, J =8.8, 5.0 Hz, 1H), 7.04 - 6.92 (m, 1H), 6.57 (brs, 1H), 6.27 (brs, 1H), 4.42 -4.38 (m, 2H), 3.62 - 3.58 (m, 2H), 3.05 (s, 6H).

[0333] Example 25: N-(6-(2-chloro-5-fluorophenyl)-3-(3,3-difluoropropyl)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0334] Step A: Pyridine (0.84 mL, 10.41 mmol) and 4-methylbenzenesulfonyl chloride (1.19 g, 6.25 mmol) were added to a solution of 3,3-difluoroprop-1-ol (0.45 mL, 5.20 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at rt for 2 hours. The reaction mixture was quenched with H2O and extracted with DCM (three times). The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE containing EA (gradient: 0-20%) to give 3,3-difluoropropane 4-methylbenzenesulfonic acid (700 mg, 2.80 mmol, 54%) as a yellow oil. LCMS: ESIm / z 251 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 6.10 (tt, J = 56.0, 4.4 Hz, 1H), 4.14 (t, J = 6.2 Hz, 2H), 2.43(s, 3H), 2.30 - 2.11 (m, 2H).

[0335] Step B: Cs₂CO₃ (1.89 g, 5.80 mmol) was added to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (900 mg, 1.93 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, followed by the addition of 3,3-difluoropropyl 4-methylbenzenesulfonic acid (700 mg, 2.80 mmol). The mixture was stirred at 60 °C for 18 h. The reaction mixture was quenched with 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 by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-30%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(3,3-difluoropropyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (800 mg, 1.47 mmol, 76%). LCMS: ESI m / z 544 [M + H] + .

[0336] Step C: CuCN (138 mg, 1.55 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(3,3-difluoropropyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (800 mg, 1.47 mmol) in NMP (10 mL). The reaction mixture was stirred at 120 °C for 2 hours. The cooled reaction mixture was diluted with EA and filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (10 mL × 3). The organic phase was washed three times with brine, dried over Na2SO4, and concentrated. The crude substance was then purified by preparative HPLC to obtain 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(3,3-difluoropropyl)-2-sideoxy-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (80 mg, 0.16 mmol, 11%) as a yellow solid. LCMS: ESI m / z 489 / 491 [M + H] + .

[0337] Step D: Add 3-fluoro-5-(trifluoromethyl)benzimidazole-4-carboxynitrile (80 mg, 0.16 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(3,3-difluoropropyl)-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (5 mL) in 1,4-dimethylalkanes (51 mg, 0.25 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (19 mg, 0.033 mmol), and Cs2CO3 (106 mg, 0.33 mmol) to the solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(3,3-difluoropropyl)-2-sideoxy-3-(trideuterylmethyl)benzo[d]imidazolium-4-carboxynitrile (50 mg, 0.16 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (19 mg, 0.033 mmol), and Cs2CO3 (106 mg, 0.33 mmol). Stir the reaction mixture at 100 °C under N2 for 2 hours. The reaction mixture was concentrated and chromatographically analyzed (PE / EA = 2 / 1) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(3,3-difluoropropyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.13 mmol, 80%) as a yellow solid. LCMS: ESI m / z 616 [M + H] + .

[0338] Step E: Potassium hydroxide (15 mg, 0.26 mmol) was added to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(3,3-difluoropropyl)-2-sideoxy-1-(trideutermethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.13 mmol) in MeCN (5 mL) and H2O (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was shown to be complete by LCMS. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The organic layer was separated and concentrated to obtain N-[6-(2-chloro-5-fluorophenyl)-3-(3,3-difluoropropyl)-6-hydroxy-2,8-disideloxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.13 mmol, 97%) as a yellow solid. LCMS: ESI m / z 616 [M-OH] + .

[0339] Step F: Add triethylsilane (1 mL, 0.110 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(3,3-difluoropropyl)-6-hydroxy-2,8-dioxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (70 mg, 0.11 mmol) in TFA (2 mL). Stir the reaction mixture at 70 °C for 20 min. LCMS showed that the reaction was complete. The reaction mixture was concentrated and purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-(3,3-difluoropropyl)-2,8-di-sideoxy-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (34.5 mg, 0.056 mmol, 51%) as a white solid. LCMS: ESI m / z 618 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s,1H), 9.15 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.38 (s, 1H), 7.28 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 - 7.06 (m, 1H), 6.65 (s, 1H), 6.39 - 5.87(m, 2H), 4.14 - 3.96 (m, 2H), 2.36 - 2.17 (m, 2H).

[0340] Example 26: N-[(6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-methyl-2,8-dioxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide and Example 27: N-[(6R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-methyl-2,8-dioxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0341]

[0342] Step A. Add 2,2-difluoroethyl-1-amine (0.7 g, 8.7 mmol) and DIPEA (2.5 g, 19.7 mmol) to a stirred solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl) methyl ketone (4.5 g, 9.8 mmol) in dimethyl ether (50 mL). After stirring at rt under a nitrogen atmosphere for 72 hours, pour the mixture into ice water (100 mL) and extract with EtOAc (60 mL × 3). Wash the combined organic phases with brine, dry to Na2SO4, filter, and concentrate. The residue was purified by chromatography (silica gel, 0-15%, PE containing EtOAc) to give (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl} methyl ketone (4.5 g, 8.7 mmol, 88%) as a yellow solid. No LCMS was observed.

[0343] Step B. Fe (4.8 g, 87.1 mmol) and NH4Cl (0.9 g, 17.4 mmol) were added to a stirred solution of (2-chloro-5-fluorophenyl){2,6-dibromo-4-[(2,2-difluoroethyl)amino]-3-nitrophenyl} ketone (4.5 g, 8.7 mmol) in EtOH (50 mL) / H2O (10 mL). After stirring at 80 °C under a N2 atmosphere for 2 hours, the mixture was poured into ice water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-25%, PE containing EtOAc) to obtain a yellow solid {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methyl ketone (3.9 g, 8.1 mmol, 92%). LCMS: ESI m / z 487 [M + H] + .

[0344] Step C. Triphosgene (3.48 g, 11.716 mmol) was slowly added to a stirred solution of {3-amino-2,6-dibromo-4-[(2,2-difluoroethyl)amino]phenyl}(2-chloro-5-fluorophenyl)methyl ketone (3.8 g, 7.811 mmol) in THF (40 mL). After stirring at 0 °C under a N2 atmosphere for 2 hours, the mixture was poured into ice water (80 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-35%, PE containing EtOAc) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.5 g, 6.8 mmol, 87%) as a white solid. No LCMS was observed.

[0345] Step D. Add NaH (900 mg, 22.6 mmol, 60% in mineral oil) to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.5 g, 6.8 mmol) in THF (50 mL) at 0 °C. After stirring at 0 °C for 1 hour, add CH3I (2.4 g, 16.9 mmol). Stir the reaction mixture overnight at rt. Dilute the reaction mixture with H2O, extract with EA, wash with brine, and concentrate. The residue was purified by chromatography (silica gel, 0-25%, PE containing EtOAc) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.2 g, 6.1 mmol, 89%) as a white solid, which was used directly in the next step.

[0346] Step E. CuCN (710 mg, 7.9 mmol) was added to a stirred solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (3.2 g, 6.1 mmol) in NMP (35 mL). After stirring at 130 °C for 2 hours, the cooled mixture was poured into brine (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated until no more droplets remained. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give 6-amino-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-methyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (1 g, 2.4 mmol, 40%) as a yellow solid. LCMS: m / z 474 [M+H] + .

[0347] Step F. Add 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (660 mg, 3.2 mmol), Pd₂(dba)₃ (190 mg, 0.21 mmol), XANT PHOS (240 mg, 0.42 mmol), and Cs₂CO₃ (1.7 g, 5.2 mmol) to a stirred solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-methyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (1 g, 2.1 mmol) in dimethyl ether (30 mL). After stirring at 100 °C under N₂ for 3 hours, pour the mixture into ice water (80 mL) and extract with EtOAc (30 mL × 3). Wash the combined organic phases with brine, dry to Na₂SO₄, filter, and concentrate. The residue was purified by chromatography (silica gel, 0-60%, PE containing EtOAc) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-1-methyl-2-sideoxybenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (1 g, 1.6 mmol, 79%) as a brown solid. LCMS: m / z 600 [M+H] + .

[0348] Step G. KOH (0.5 g, 8.3 mmol) was slowly added to a stirred solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-1-methyl-2-sideoxybenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (1 g, 1.6 mmol) in ACN (12 mL) / H₂O (4 mL) under rt. After stirring for 1 hour under rt, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain a crude white solid, N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (1 g, 1.6 mmol, 97%). LCMS: m / z 617 [M+H] + .

[0349] Step H. Under rt, add Et3SiH (4 mL) to a stirred solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (1 g, 1.6 mmol) in TFA (16 mL). After stirring at 70 °C for 1 hour, concentrate the cooled mixture. The residue was purified by chromatography (silica gel, 0-10%, DCM containing MeOH) to give N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-methyl-2,8-disideloxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (900 mg, 1.5 mmol, 92%) as a white solid. LCMS: m / z 601 [M+H] + .

[0350] The product was purified using chiral preparative SFC method 6 to obtain N-[(6S)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-methyl-2,8-disideloxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (26 mg, 0.04 mmol, 26%), which was a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 10.34 (s, 1H), 9.18 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.2 Hz,1H), 7.70 (s, 1H), 7.40 (s, 1H), 7.31 - 7.23 (m, 1H), 7.14 - 7.05 (m, 1H),6.36 (t, J = 54.4 Hz, 1H), 6.01 (brs, 1H), 4.47 - 4.32 (m, 2H), 3.91 (s, 3H). and N-[(6R)-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-methyl-2,8-disideloxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (26 mg, 0.04 mmol, 26%). LCMS: m / z 601 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.18 (s, 1H), 7.93(d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.70 (s, 1H), 7.40 (s, 1H), 7.32 -7.24 (m, 1H), 7.13 - 7.04 (m, 1H), 6.36 (t, J = 54.8 Hz, 1H), 6.00 (brs, 1H), 4.47 - 4.31 (m, 2H), 3.91 (s, 3H).

[0351] Example 28: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(ethyl-d5)-1-methyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 29: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(ethyl-d5)-1-methyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0352]

[0353] Step A: Cs₂CO₃ (2.11 g, 6.49 mmol) was added to a solution of 5,7-dibromo-6-[(2-chloro-4-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (1 g, 2.16 mmol) and 1-bromo-1,1,2,2,2-pentadeuterium ethane (0.49 g, 4.32 mmol) in N,N-dimethylacetamide (15 mL). The mixture was stirred at 60 °C for 5 hours. The cooled reaction mixture was diluted with H₂O and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography (eluting with EA:PE = 30%) to give 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-3-methyl-1-(pentadeuterylethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (600 mg, 1.21 mmol, 56%) as a brown solid. LCMS: ESI m / z 496 [M + H] + .

[0354] Step B: CuCN (108 mg, 1.21 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(pentadeuterethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (600 mg, 1.21 mmol) in NMP (6 mL), and the mixture was stirred at 130 °C under N2 for 2 hours. The mixture was then stirred at 60 °C for 5 hours. The cooled reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0% to 30%) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxy-1-(pentadeuterylethyl)benzo[d]imidazolium-4-carboxynitrile (200 mg, 0.453 mmol, 37%) as a brown solid. LCMS: ESI m / z 441 [M + H] + .

[0355] Step C: A solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxy-1-(pentadeuterethyl)benzo[d]imidazolium-4-carboxynitrile (210 mg, 0.475 mmol), 5-fluoro-3-(trifluoromethyl)benzyl-1-carboxamide (108 mg, 0.523 mmol), Pd2(dba)3 (43.5 mg, 48 µmol), Xantphos (55.0 mg, 95 µmol), and Cs2CO3 (465 mg, 1.43 mmol) in dimethyl ether (11 mL) was stirred at 100 °C for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography with elution using DCM containing MeOH (gradient: 0% to 10%) to give N-{6-[(1-chloro-4-fluorophenyl-2-yl)carbonyl]-7-cyano-1-methyl-2-sideoxy-3-(pentadeuterylethyl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (198 mg, 0.349 mmol, 73%) as a brown solid. LCMS: ESI m / z 568 [M +H] + .

[0356] Step D: At room temperature, KOH (98.8 mg, 1.76 mmol) was added to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-2-sideoxy-3-(prop-2-yl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (200 mg, 0.347 mmol) in ACN (2 mL) and H2O (0.2 mL). The reaction mixture was stirred at rt for 30 minutes, and then diluted with EA and H2O. The combined organic phases were washed with brine (10 mL × 2), dried over Na₂SO₄, and concentrated to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-dioxy-3-(propyl-2-yl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.252 mmol, 73%) as a brown solid. LCMS: ESI m / z 586 [M + H] + .

[0357] Step E: Add Et3SiH (0.2 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-di-sideoxy-3-(propyl-2-yl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.252 mmol) in TFA (2 mL). Stir the reaction mixture at 60 °C for 30 minutes. Then concentrate the reaction mixture to obtain the residue. The residue was purified by preparative HPLC to obtain N-[6-(1-chloro-4-fluorophenyl-2-yl)-1-methyl-2,8-dioxy-3-(pentadeuterylethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (140 mg, 0.246 mmol, 96%) as a white solid. LCMS: ESI m / z 570 [M + H] + .

[0358] Step F: N-(6-(2-chloro-5-fluorophenyl)-3-(ethyl-d5)-1-methyl-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (120 mg) was separated by chiral preparative SFC method 7 to yield N-[(6S)-6-(1-chloro-4-fluorophenyl-2-yl)-1-methyl-2,8-disideloxy-3-(pentadeuterethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (41 mg, 0.072 mmol, 34%, ee=99). LCMS: ESI m / z 570 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ10.29 (s, 1H), 9.13 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 7.29 - 7.26 (m, 1H), 7.10 - 7.06 (m, 1H), 6.65 (brs, 1H), 6.01 (brs, 1H), 3.89 (s, 3H). and N-[(6R)-6-(1-chloro-4-fluorophenyl-2-yl)-1-methyl-2,8-disiderol-3-(pentadeuterethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (38.5 mg, 0.068 mmol, 32%, ee=99). LCMS: ESI m / z 570 [M + H] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 7.29 - 7.26 (m, 1H), 7.10- 7.05 (m, 1H), 6.65 (brs, 1H), 6.01 (brs, 1H), 3.89 (s, 3H).

[0359] Example 30: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl-1,1,2,2-d4)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 31: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl-1,1,2,2-d4)-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0360]

[0361] Step A: A mixture of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (460 mg, 0.988 mmol), 2-bromo-1,1,2,2-tetradeuterylethanol-1-ol (255 mg, 1.98 mmol), Cs₂CO₃ (870 mg, 2.67 mmol), and NaI (444 mg, 2.97 mmol) in DMF (10 mL) was stirred at 100 °C for 2 hours. 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 elution with EA / PE (0% to 50%) by FCC to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(1,1,2,2-tetradeuter-2-hydroxyethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (180 mg, 0.28 mmol, 28%). LCMS: ESI m / z 514 [M+H] + .

[0362] Step B: Diethyl(trifluoro-λ4-hydrothio)amine (527 mg, 3.27 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(1,1,2,2-tetradeuter-2-hydroxyethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (840 mg, 1.64 mmol) in DCM (40 mL) at 0 °C. The mixture was stirred overnight at room temperature. The mixture was quenched with cold water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by FCC elution with EA / PE (0-20%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(1,1,2,2-tetradeuter-2-fluoroethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (640 mg, 1.24 mmol, 76%). LCMS: ESI m / z 516 [M+H] + .

[0363] Step C: A mixture of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(1,1,2,2-tetradeuter-2-fluoroethyl)-3-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (560 mg, 1.09 mmol) and copper cyano(I) (292 mg, 3.26 mmol) in NMP (28 mL) was stirred at 140 °C for 2 hours. 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 elution with EA / PE (0-20%, 10% DCM) to give a pink solid, 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-(1,1,2,2-tetradeuter-2-fluoroethyl)-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (170 mg, 0.37 mmol, 34%). LCMS: ESI m / z 461 [M+H] + .

[0364] Step D: A mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-1-(1,1,2,2-tetradeuter-2-fluoroethyl)-3-(trideutermethyl)benzo[d]imidazolium-4-carboxynitrile (170 mg, 0.37 mmol), 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (114 mg, 0.55 mmol), tris(1E,4E)-1,5-diphenylpentan-1,4-dien-3-one]bis[palladium(0)] (34 mg, 0.037 mmol), Xantphos (43 mg, 0.074 mmol), and Cs₂CO₃ (240 mg, 0.74 mmol) in dimethyl ether (20 mL) was stirred at 100 °C under N₂ for 2 hours. 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 used directly in the next step.

[0365] Step E: Add 10 mL of water containing potassium hydroxide (191 mg, 3.40 mmol) to a mixture of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-sideoxy-3-(1,1,2,2-tetradeuter-2-fluoroethyl)-1-(trideutermethyl)benzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (200 mg, 0.34 mmol) in acetonitrile (20 mL). Stir the mixture at room temperature for 1 hour. Dilute the mixture with water and extract with EA. Wash the organic layer with brine, dry with Na2SO4, and concentrate. The residue was purified by FCC elution with EA / PE (0-80%) followed by MeOH / DCM (10%) to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-disideloxy-3-(1,1,2,2-tetradeuter-2-fluoroethyl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (200 mg, 0.33 mmol, 97%) as a yellow solid. LCMS: ESI m / z 606 [M+H] + .

[0366] Step F: The mixture of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,8-disideloxy-3-(1,1,2,2-tetradeuter-2-fluoroethyl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (220 mg, 0.36 mmol) in 2,2,2-trifluoroacetaldehyde (5 mL) and triethylsilane (0.5 mL) was stirred at 50 °C for 30 minutes. The mixture was then concentrated. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-2,8-disideloxy-3-(1,1,2,2-tetradeuter-2-fluoroethyl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.17 mmol, 47%) as a white solid. LCMS: ESI m / z 590.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s,1H), 9.15 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (s,1H), 7.38 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 - 7.04 (m, 1H), 6.63 (s, 1H), 5.99 (s, 1H).

[0367] Step G: N-[6-(2-chloro-5-fluorophenyl)-2,8-disideloxy-3-(1,1,2,2-tetradeuter-2-fluoroethyl)-1-(trideutermethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (120 mg, 0.20 mmol) was purified by chiral preparative SFC method 8 to obtain (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl-1,1,2,2-d4)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (47.8 mg) as a white solid. mg, 0.08 mmol, 40%). LCMS: ESI m / z 590.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.15 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 - 7.04 (m, 1H), 6.64 (brs, 1H), 6.01 (brs, 1H). And (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl-1,1,2,2-d4)-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (51.6 mg, 0.087 mmol, 43%) as a white solid. LCMS: ESI m / z 590.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.15 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J =8.8 Hz, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 -7.04 (m, 1H), 6.64 (brs, 1H), 6.01 (brs, 1H).

[0368] Example 32: N-[6-(2-chloro-5-fluorophenyl)-1-methyl-3-(2-methylpropyl)-2,8-dioxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0369]

[0370] Step A: To a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 1.08 mmol) in DMA (8 mL), add 1-bromo-2-methylpropane (0.177 mL, 1.62 mmol) and Cs₂CO₃ (1056 mg, 3.24 mmol). The reaction mixture was stirred at 80 °C under N₂ for 2 hours. LCMS showed the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 15-25%) to give the title compound 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(2-methylpropyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (380 mg, 0.733 mmol, 68%) as a yellow solid. LCMS: ESI m / z 517 / 519 [MH] - .

[0371] Step B: CuCN (67.4 mg, 0.752 mmol) was added to a solution of 4,6-dibromo-5-(2-chloro-5-fluorobenzoyl)-1-isobutyl-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (300 mg, 0.578 mmol) in NMP (5 mL). The reaction mixture was stirred at 120 °C under N2 for 2 hours. LCMS showed a reaction with 30% DP. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in dichloroform containing ethyl acetate (gradient: 15-20%) to give 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-isobutyl-3-methyl-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (80 mg, 30%) as a yellow solid. LCMS: 464 / 466 [MH] - .

[0372] Step C: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-isobutyl-3-methyl-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (60 mg, 0.129 mmol) in dimethyl ether (5 mL), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (40.1 mg, 0.194 mmol), Pd2(dba)3 (11.8 mg, 0.013 mmol), XANTPHOS (14.9 mg, 0.026 mmol), and Cs2CO3 (126 mg, 0.387 mmol) were added. The reaction mixture was stirred at 100 °C under N2 for 2 hours. LCMS showed that the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 10-20%) to give the title compound N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-(2-methylpropyl)-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (45 mg, 0.076 mmol, 59%), as a yellow oil. LCMS: ESI m / z 591 / 593 [M+H] + .

[0373] Step D: KOH (7.60 mg, 0.135 mmol) was added to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-(2-methylpropyl)-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (40 mg, 0.068 mmol) in H2O (1 mL) and ACN (3 mL). The reaction mixture was stirred at room temperature under N2 for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The organic layer was separated and concentrated to obtain N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-3-(2-methylpropyl)-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (35 mg, 0.057 mmol, 85%) as a yellow solid. LCMS: ESI m / z 609 / 611 [M + H] + .

[0374] Step E: Add Et3SiH (191 mg, 1.64 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-3-(2-methylpropyl)-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.082 mmol) in TFA (3 mL). Stir the reaction mixture at 70 °C for 1 hour. LCMS showed that the reaction was complete. Concentrate the cooled reaction mixture, dilute with aqueous NaHCO3 solution, and extract with EA. Wash the organic phase with brine, dry over Na2SO4, and concentrate. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-1-methyl-3-(2-methylpropyl)-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (18.4 mg, 0.031 mmol, 38%) as a white solid. LCMS: ESI m / z 593 / 595 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.14(s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.80 - 7.65 (m, 2H), 7.35 (s, 1H), 7.27 (dd, J = 8.8, 5.2 Hz, 1H), 7.08 (dd, J = 8.4, 3.2 Hz, 1H), 6.66 (brs, 1H), 6.00 (brs,1H), 3.90 (s, 3H), 3.76 - 3.57 (m, 2H), 2.20 - 2.00 (m, 1H), 0.90 (dd, J = 6.8, 3.2 Hz, 6H).

[0375] Example 35: N-(3-(azacyclobutane-3-ylmethyl)-6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0376] Step A: Add Cs₂CO₃ (1.05 g, 3.243 mmol) and 2-methylpropyl-2-yl 3-(bromomethyl)azacyclobutane-1-carboxylic acid (432 mg, 1.730 mmol) to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazolium-2-carboxylic acid in DMA (4 mL). Stir the reaction mixture at 80 °C for 2 hours. Dilute the cooled reaction mixture with H₂O and extract with EA. Wash the organic phase with brine, dry over Na₂SO₄, filter, and concentrate. The residue was purified by silica gel column chromatography with elution in PE containing EA [gradient: 40%] to give the title compound 3-({4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxybenzo[d]imidazol-1-yl}methyl)azacyclobutane-1-carboxylic acid 2-methylpropyl-2-yl ester (350 mg, 0.554 mmol, 51%) as a white solid. LCMS: ESI m / z 632 / 576 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.73(dd, J = 8.0, 4.0 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.46 (dd, J = 8.0, 4.0 Hz, 1H), 4.13 (d, J = 8.0 Hz, 2H), 3.87 (t, J = 8.0 Hz, 2H), 3.68 (s, 2H), 3.62 (s, 3H), 3.00 - 2.94 (m, 1H), 1.37 (s, 9H).

[0377] Step B: CuCN (99 mg, 1.108 mmol) was added to a solution of 3-({4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxybenzo[d]imidazol-1-yl}methyl)azacyclobutane-1-carboxylic acid 2-methylpropyl-2-yl ester (350 mg, 0.554 mmol) in NMP (5 mL). The reaction mixture was stirred at 130 °C for 2 hours. The reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE containing EA [gradient: 40%] to give the title compound 3-({6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-3-methyl-2-sideoxybenzo[d]imidazol-1-yl}methyl)azacyclobutane-1-carboxylic acid 2-methylpropyl-2-yl ester (150 mg, 0.260 mmol, 47%) as a white solid. LCMS: ESI m / z 578 / 523 [M+H] + Step C: To a solution of 2-methylpropyl-2-yl 3-({6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-3-methyl-2-sideoxybenzo[d]imidazol-1-yl}methyl)azacyclobutane-1-carboxylic acid (150 mg, 0.260 mmol) in dimethyl ether (4 mL), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (80 mg, 0.389 mmol), Cs₂CO₃ (169 mg, 0.519 mmol), Xant-phos (15 mg, 0.026 mmol), and Pd₂(dba)₃ (47 mg, 0.519 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was diluted with H₂O and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography with elution in PE containing EA [gradient: 65%] to give the title compound 3-({5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-6-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-3-methyl-2-sideoxybenzo[d]imidazol-1-yl}methyl)azacyclobutane-1-carboxylic acid 2-methylpropyl-2-yl ester (120 mg, 0.170 mmol, 65%) as a white solid. LCMS: ESI m / z 704 / 648 [M+H] + .

[0378] Step D: Add potassium hydroxide (56 mg, 0.994 mmol) to a solution of 2-methylpropyl-2-yl 3-({5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-6-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-3-methyl-2-sideoxybenzo[d]imidazol-1-yl}methyl)azacyclobutane-1-carboxylic acid (120 mg, 0.199 mmol) in CH3CN / H2O (5 mL). Stir the reaction mixture at RT for 1 hour. Dilute the reaction mixture with H2O and extract with EA. Wash the organic phase with brine, dry to Na2SO4, filter, and concentrate. The residue was purified by silica gel column chromatography with elution in PE containing EA [gradient: 60%] to give the title compound 3-{[6-(2-chloro-5-fluorophenyl)-5-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-3-yl]methyl}azacyclobutane-1-carboxylic acid 2-methylpropyl-2-yl ester (120 mg, 0.166 mmol, 83%) as a white solid. LCMS: ESI m / z 722 / 648 / 622 [M+H] + Step E: Add Et3SiH (32 mg, 0.277 mmol) to a solution of 3-{[6-(2-chloro-5-fluorophenyl)-5-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-3-yl]methyl}azacyclobutane-1-carboxylic acid 2-methylpropyl-2-yl ester (100 mg, 0.138 mmol) in TFA (6 mL). Stir the reaction mixture at 50 °C for 1 hour. Dilute the reaction mixture with H2O and extract with EA. Wash the organic phase with brine, dry to Na2SO4, filter, and concentrate. The residue was purified by preparative HPLC to give the title compound N-[3-(azacyclobut-3-ylmethyl)-6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (28 mg, 0.046 mmol, 33%) as a white solid. LCMS: ESI m / z 606 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.38(brs, 1H), 9.16 (s, 1H), 8.37 (s, 1H), 7.94 (d, J= 8.0 Hz, 1H), 7.76 - 7.73(m, 2H), 7.46 (s, 1H), 7.28 (dd, J = 8.0, 4.0 Hz, 1H), 7.10 - 7.07 (m, 1H), 6.66 (brs, 1H), 6.01 (brs, 1H), 4.19 - 4.12 (m, 2H), 3.89 (s, 3H), 3.84 -3.81 (m, 2H), 3.71 - 3.63 (m, 2H), 3.16 - 3.12 (m, 1H).

[0379] Example 36: N-(6-(2-chloro-5-fluorophenyl)-3-isopropyl-1-methyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0380]

[0381] Step A: NaH (1.47 g, 36.7 mmol, 60% purity in mineral oil) was added to a solution of 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (11 g, 18.4 mmol) in THF (3 mL) at 0 °C. The mixture was stirred for 10 min, followed by the addition of iodomethane (5.22 g, 36.7 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was quenched with water, and the mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give a brown solid, 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (11 g, 18.0 mmol, 98%). LCMS: ESI m / z 611 [M + H] + .

[0382] Step B: Add TfOH (11 mL) to a solution of 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (11 g, 18.0 mmol) in TFA (110 mL). Stir the mixture at 70 °C for 16 hours. Concentrate the mixture. Dilute the residue with aqueous solutions of EA and NaHCO3. Filter the suspension and dilute with H2O (5 V). 3) and EA (5 V) 3) Wash the filter cake. Dry the solid under vacuum to give a purple solid of 5,7-dibromo-6-[(2-chloro-4-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (7 g, 15.1 mmol, 84.3%). LCMS: ESI m / z 461 [M + H] + .

[0383] Step C: Add Cs₂CO₃ (1.05 g, 3.24 mmol) to a solution of 5,7-dibromo-6-[(2-chloro-4-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 1.08 mmol) and 2-bromopropane (266 mg, 2.16 mmol) in N,N-dimethylacetamide (5 mL). Stir the mixture at 60 °C for 5 hours. Dilute the cooled reaction mixture with H₂O and extract with EA. Wash the organic phase with brine, dry to Na₂SO₄, and concentrate. The residue was purified by column chromatography (eluting with EA:PE = 30%) to give 4,6-dibromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-3-methyl-1-(prop-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (136 mg, 0.270 mmol, 25%) as a brown solid. LCMS: ESIm / z 505 [M + H] + .

[0384] Step D: CuCN (24.1 mg, 0.270 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(prop-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (136 mg, 0.270 mmol) in NMP (2 mL). The reaction mixture was stirred at 120 °C under N2 for 2 hours. The cooled reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0% to 20%) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxy-1-(prop-2-yl)benzo[d]imidazolium-4-carboxynitrile (55 mg, 0.122 mmol, 45%) as a brown solid. LCMS: ESI m / z 450 [M + H] + .

[0385] Step E: A solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(trideutermethyl)-1-(2,2,2-trifluoroethyl)benzimidazole-4-carboxynitrile (55 mg, 0.111 mmol), 5-fluoro-3-(trifluoromethyl)benzene-1-carboxamide (27.8 mg, 0.134 mmol), Pd2(dba)3 (11.2 mg, 12 µmol), Xantphos (14.1 mg, 24 µmol), and Cs2CO3 (119 mg, 0.366 mmol) in dimethyl ether (5 mL) was stirred at 100 °C under N2 for 2 hours. The cooled reaction mixture was then concentrated. The residue was purified by silica gel column chromatography with elution using DCM containing MeOH (gradient: 0% to 10%) to give N-{6-[(1-chloro-4-fluorophenyl-2-yl)carbonyl]-7-cyano-1-methyl-2-sideoxy-3-(prop-2-yl)benzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.087 mmol, 71%) as a brown solid. LCMS: ESI m / z 577 [M + H] + .

[0386] Step F: Add KOH (24.3 mg, 0.433 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-2-sideoxy-3-(prop-2-yl)benzimidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 87 µmol) in ACN (2 mL) and H2O (0.2 mL). Stir the reaction mixture at rt for 30 min. Dilute the mixture with water (10 mL) and extract with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL × 2), dried over Na₂SO₄, and concentrated to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-dioxy-3-(propyl-2-yl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 84 mmol, 97%) as a brown solid. LCMS: ESI m / z 595 [M + H] + .

[0387] Step G: Add Et3SiH (0.2 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-di-sideoxy-3-(propyl-2-yl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 84 µmol) in TFA (2 mL). Stir the reaction mixture at 60 °C for 30 minutes. Then concentrate the reaction mixture to obtain the residue. The residue was purified by preparative HPLC to obtain N-[6-(1-chloro-4-fluorophenyl-2-yl)-1-methyl-2,8-dioxy-3-(propyl-2-yl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (18.4 mg, 0.032 mmol, 38%) as a white solid. LCMS: ESI m / z 579 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.12 (s, 1H), 7.93(d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.71 (s, 1H), 7.43 (s, 1H), 7.28(dd, J= 8.8, 5.2 Hz, 1H), 7.10 - 7.07 (m, 1H), 6.65 (brs, 1H), 5.99 (brs, 1H), 4.80 - 4.52 (m, 1H), 3.88 (s, 3H), 1.49 - 1.46 (m, 6H).

[0388] Example 37: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 38: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-(methyl-d3)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0389]

[0390] Step A: Iodethane (252 mg, 1.62 mmol) and Cs₂CO₃ (1.05 g, 3.24 mmol) were added to a solution of 5,7-dibromo-6-(2-chloro-5-fluorobenzoyl)-1-(methyl-d₃)-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, 1.080 mmol) in DMA (8 mL). The reaction mixture was stirred in a sealed system at 80 °C under N₂ for 2.5 h. The reaction was confirmed by LCMS. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 15-25%) to give the title compound 4,6-dibromo-5-(2-chloro-5-fluorobenzoyl)-1-ethyl-3-(methyl-d3)-1,3-dihydro-2H-benzo[d]imidazol-2-one (350 mg, 0.713 mmol, 66%) as a yellow solid. LCMS: 492 / 494 [MH] - .

[0391] Step B: CuCN (78.3 mg, 0.874 mmol) was added to a solution of 4,6-dibromo-5-(2-chloro-5-fluorobenzoyl)-1-ethyl-3-(methyl-d3)-1,3-dihydro-2H-benzo[d]imidazol-2-one (330 mg, 0.672 mmol) in NMP (5 mL). The reaction mixture was stirred at 130 °C under N2 for 2 hours. LCMS showed a reaction volume of 60% DP. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in dichloroform containing ethyl acetate (gradient: 10-20%) to give 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-ethyl-3-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (160 mg, 0.365 mmol, 54%) as a yellow solid. LCMS: 439 / 441 [MH] - .

[0392] Step C: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-ethyl-3-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (150 mg, 0.342 mmol) in dimethyl ether (10 mL), 3-fluoro-5-(trifluoromethyl)benzamide (106 mg, 0.514 mmol), Pd2(dba)3 (31.4 mg, 0.034 mmol), XANTPHOS (39.7 mg, 0.068 mmol), and Cs2CO3 (334 mg, 1.02 mmol) were added. The reaction mixture was stirred at 100 °C under N2 for 2 hours. LCMS showed that the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 10-20%) to give the title compound N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-ethyl-1-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (140 mg, 0.248 mmol, 72%), as a yellow oil. LCMS: ESI m / z 566 / 568 [M+H] + .

[0393] Step D: Add KOH (19.9 mg, 0.354 mmol) to a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-ethyl-1-(methyl-d3)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.177 mmol) in ACN (5 mL) and H2O (1.5 mL). Stir the reaction mixture at room temperature under N2 for 1 hour. LCMS showed that the reaction was complete. Dilute the reaction mixture with brine and extract with EA. Wash the organic phase with brine, dry to Na2SO4, and concentrate. The organic layer was separated and concentrated to obtain N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-6-hydroxy-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.137 mmol, 78%) as a yellow solid. LCMS: ESI m / z 584 / 586 [M + H] + .

[0394] Step E: Add Et3SiH (30 mg, 0.257 mmol) to a solution of N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-6-hydroxy-1-(methyl-d3)-2,8-di-side-oxy-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 0.026 mmol) in TFA (3 mL). Stir the reaction mixture at 70 °C for 1 hour. LCMS showed that the reaction was complete. Concentrate the cooled reaction mixture, dilute with aqueous NaHCO3 solution, and extract with EA. Wash the organic phase with brine, dry over Na2SO4, and concentrate. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 40-50%) to give N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (4 mg, 0.007 mmol, 27%) as a white solid. LCMS: ESI m / z 568 / 570 [M + H] + .

[0395] Step F: A solution of N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (55 mg, 0.097 mmol) was purified by chiral preparative SFC method 10 to give a white solid (R)-N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (13.8 mg, 0.024 mmol, 18%). LCMS: ESI m / z 568 [M + H] + . 1 HNMR (400 MHz, MeOD-d4) δ 7.70 - 7.60 (m, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.35(s, 1H), 7.24 (dd, J = 8.8, 5.0 Hz, 1H), 6.98 (dd, 1H), 6.59 (brs, 1H), 6.20(brs, 1H), 4.07 - 3.95 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H). And (S)-N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-(methyl-d3)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (17 mg, 0.030 mmol, 22%), a white solid. LCMS: ESI m / z 568 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 7.70 - 7.60 (m, 2H), 7.63 (d, J = 8.8Hz, 1H), 7.35 (s, 1H), 7.24 (dd, J = 8.8, 5.0 Hz, 1H), 6.98 (dd, 1H), 6.59(brs, 1H), 6.20 (brs, 1H), 4.07 - 3.95 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H).

[0396] Example 39: N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-methyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0397]

[0398] Step A: Cs₂CO₃ (1.06 g, 3.24 mmol) was added to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 1.08 mmol) in DMF (8 mL) at 0 °C. The mixture was stirred for 10 min, followed by the addition of iodoethane (0.13 mL, 1.62 mmol). The mixture was stirred at 70 °C for 2 h. The cooled reaction mixture was quenched with water, and the mixture was extracted with EtOAc (20 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 0-30%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-ethyl-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (280 mg, 0.57 mmol, 53%). LCMS: ESI m / z 491 [M + H] + .

[0399] Step B: CuCN (54 mg, 0.60 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-ethyl-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (280 mg, 0.57 mmol) in NMP (5 mL). The reaction mixture was stirred at 120 °C under N2 for 2 hours. The cooled reaction mixture was diluted with EA and filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (10 mL × 3). The organic phase was washed five times with brine, dried over Na2SO4, and concentrated. The crude material was then purified by preparative HPLC to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-ethyl-3-methyl-2-sideoxybenzo[d]imidazol-4-carboxynitrile (80 mg, 0.18 mmol, 32%) as a yellow solid. LCMS: ESI m / z436 / 438 [M + H] + .

[0400] Step C: Add 3-fluoro-5-(trifluoromethyl)benzyl-1-ethyl-3-methyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (80 mg, 0.18 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-ethyl-3-methyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (80 mg, 0.18 mmol) in 1,4-dimethylethane (5 mL), 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (57 mg, 0.26 mmol), Pd2(dba)3 (17 mg, 0.02 mmol), Xantphos (21 mg, 0.04 mmol), and Cs2CO3 (120 mg, 0.37 mmol) to the solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-ethyl-3-methyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (80 mg, 0.18 mmol) in 1,4-dimethylethane (5 mL). Stir the reaction mixture at 100 °C under N2 for 2 hours. The reaction mixture was concentrated and chromatographically analyzed (PE / EA = 3 / 1) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-ethyl-1-methyl-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.16 mmol, 87%) as a yellow solid. LCMS: ESI m / z 563 [M + H] + .

[0401] Step D: Potassium hydroxide (18 mg, 0.32 mmol) was added to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-ethyl-1-methyl-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.16 mmol) in MeCN (5 mL) and H2O (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was shown to be complete by LCMS. The reaction mixture was diluted with brine and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The organic layer was separated and concentrated to obtain N-[6-(2-chloro-5-fluorophenyl)-3-ethyl-6-hydroxy-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.16 mmol, 97%) as a yellow solid. LCMS: ESI m / z 563 [M-OH] + .

[0402] Step E: Add triethylsilane (1 mL) to a solution of N-[6-(2-chloro-5-fluorophenyl)-3-ethyl-6-hydroxy-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 0.16 mmol) in TFA (2 mL). Stir the reaction mixture at 70 °C for 20 minutes. LCMS showed that the reaction was complete. The cooled reaction mixture was concentrated and purified by preparative HPLC to give N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-1-methyl-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (56.7 mg, 0.10 mmol, 65%) as a white solid. LCMS: ESI m / z 565 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79 - 7.67 (m, 2H), 7.36 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz,1H), 7.14 - 7.01 (m, 1H), 6.64 (s, 1H), 6.02 (s, 1H), 3.98 - 3.90 (m, 2H),3.89 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).

[0403] Example 40: N-(6-(2-chloro-5-fluorophenyl)-1-methyl-3-(oxetane-3-yl)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0404]

[0405] Step A: Add 3-iodooxetine (557 mg, 3.03 mmol) to a mixture of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (700 mg, 1.51 mmol) and Cs₂CO₃ (986 mg, 3.03 mmol) in N,N-dimethylformamide (15 mL). Stir the mixture at 100 °C for 24 hours. Dilute the cooled mixture with water and extract with EA. Wash the organic layer with brine, dry with Na₂SO₄, and concentrate. The crude substance was purified by elution with EA / PE (0-20%) using FCC to obtain a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetanebut-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (240 mg, 0.37 mmol, 24%). LCMS: m / z 519 [M+H] + .

[0406] Step B: A mixture of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetanebut-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (220 mg, 0.42 mmol) and CuCN (114 mg, 1.27 mmol) in NMP (10 mL) was stirred at 140 °C for 70 min. The cooled mixture was diluted with water and EA. The mixture was filtered and separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (EA / PE = 4:5) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetanebut-3-yl)-2-sideoxybenzo[d]imidazol-4-carboxynitrile (53 mg, 0.114 mmol, 27%) as a yellow solid. LCMS: m / z 466 [M+H] + .

[0407] Step C: A mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetane-3-yl)-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (53 mg, 0.114 mmol), 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (35 mg, 0.17 mmol), tris(1E,4E)-1,5-diphenylpentan-1,4-dien-3-one]bis[palladium(0)] (10.44 mg, 0.011 mmol), Xantphos (13 mg, 0.023 mmol), and Cs₂CO₃ (74 mg, 0.23 mmol) in dimethyl ether (5 mL) was stirred at 100 °C for 2 hours. The 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 preparative TLC (EA / PE 4:5, twice) to obtain N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-(oxetanebut-3-yl)-2-sideoxybenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.068 mmol, 59%) as a yellow solid. LCMS: m / z 591 [M+H] + .

[0408] Step D: Add potassium hydroxide (38 mg, 0.68 mmol) to a mixture of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-(oxetanebut-3-yl)-2-sideoxybenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.068 mmol) in acetonitrile (10 mL) and H2O (2 mL). Stir the mixture at room temperature for 30 minutes. Dilute the mixture with water and extract with EA. The organic layer was washed with brine, dried and concentrated with Na2SO4 to obtain N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-3-(oxacyclobut-3-yl)-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.066 mmol, 97%), which was a yellow solid.

[0409] Step F: The mixture of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-3-(oxetanebut-3-yl)-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.066 mmol) in TFA (5 mL) and Et3SiH (0.5 mL) was stirred at 50 °C for 8 to 10 minutes. The mixture was poured into a cold NaHCO3 solution to adjust the pH to 8. The mixture was extracted with EA and concentrated. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-1-methyl-3-(oxetanebut-3-yl)-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (13.1 mg, 0.022 mmol, 34%) as a white solid. LCMS: m / z 593 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s,1H), 9.18 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68 (s,1H), 7.60 (s, 1H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (td, J = 8.4, 2.8 Hz,1H), 6.63 (s, 1H), 6.05 (s, 1H), 5.66 - 5.50 (m, 1H), 5.08 (td, J = 6.4, 3.6Hz, 2H), 4.96 (dd, J = 13.6, 6.8 Hz, 2H), 3.89 (s, 3H).

[0410] Example 41: N-[6-(2-chloro-5-fluorophenyl)-3-(2H-pyrazol-3-ylmethyl)-1-methyl-2,8-dioxo-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0411] Step A: 5-(chloromethyl)-1H-pyrazole (164 mg, 1.4 mmol) and Cs₂CO₃ (704 mg, 2.16 mmol) were added to a stirred solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 1.08 mmol) in DMF (12 mL) under reflux. After stirring at reflux for 2 hours, the cooled mixture was poured into brine (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated until no more droplets remained. The residue was purified by chromatography (silica gel, 0-10%, DCM containing MeOH) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2H-pyrazol-3-ylmethyl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (480 mg, 0.88 mmol, 82%). LCMS: m / z 543 [M+H] + .

[0412] Step B: CuCN (107 mg, 1.2 mmol) was added to a stirred solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2H-pyrazol-3-ylmethyl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (480 mg, 0.88 mmol) in NMP (15 mL) under stirring at rt. After stirring at 130 °C under N2 for 2 hours, the cooled mixture was poured into brine (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated until no more droplets remained. The residue was purified by chromatography (silica gel, 0-10%, DCM containing MeOH) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2H-pyrazol-3-ylmethyl)-3-methyl-2-sideoxybenzo[d]imidazol-4-carboxynitrile (100 mg, 0.2 mmol, 22%) as a yellow solid. LCMS: m / z 489 [M+H] + .

[0413] Step C: Under reflux, 3-fluoro-5-(trifluoromethyl)benzolium-1-(2H-pyrazol-3-ylmethyl)-3-methyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (100 mg, 0.2 mmol) in dimethyl ether (8 mL) was added to a stirred solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2H-pyrazol-3-ylmethyl)-3-methyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (100 mg, 0.2 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), XANT PHOS (24 mg, 0.04 mmol), and Cs2CO3 (166 mg, 0.51 mmol). After stirring at 100 °C under N2 for 2 hours, the mixture was poured into ice water (12 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10%, DCM containing MeOH) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2H-pyrazol-3-ylmethyl)-1-methyl-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.04 mmol, 19%) as a brown solid. LCMS: m / z 615 [M+H] + .

[0414] Step D: KOH (27 mg, 0.49 mmol) was slowly added to a stirred solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2H-pyrazol-3-ylmethyl)-1-methyl-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.05 mmol) in ACN (4 mL) / H2O (1 mL) under rt. After stirring for 1 hour under rt, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain a crude white solid, N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2H-pyrazol-3-ylmethyl)-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.04 mmol, 81%). LCMS: m / z 633 [M+H] + .

[0415] Step E: Under rt, add Et3SiH (0.5 mL) to a stirred solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2H-pyrazol-3-ylmethyl)-1-methyl-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.04 mmol) in TFA (2 mL). After stirring at 70 °C for 1 hour, concentrate the cooled mixture. The residue was purified by preparative HPLC (C18, containing 40-90% MeCN in H2O and 0.1% TFA) to obtain N-[6-(2-chloro-5-fluorophenyl)-3-(2H-pyrazol-3-ylmethyl)-1-methyl-2,8-disideloxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3 mg, 0.005 mmol, 12%) as a white solid. LCMS: m / z 617 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ10.29 (s, 1H), 9.14 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H),7.67 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.30 - 7.21 (m, 2H), 7.11 - 7.05 (m,1H), 6.61 (brs, 1H), 6.18 (d, J = 2.0 Hz, 1H), 5.96 (brs, 1H), 5.13 - 5.01 (m,2H), 3.92 (s, 3H).

[0416]

[0417] Step A: A mixture of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (600 mg, 1.30 mmol), 3-(bromomethyl)oxetane (294 mg, 1.95 mmol), and cesium carbonate (845 mg, 2.60 mmol) in N,N-dimethylformamide (15 mL) was stirred at 70 °C for 2 hours. 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 elution with EA / PE (0-70%) to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetanebut-3-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (248 mg, 0.47 mmol, 36%). LCMS: m / z 533 [M+H] + .

[0418] Step B: A mixture of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetane-3-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (248 mg, 0.47 mmol) and CuCN (125 mg, 1.40 mmol) in NMP (5 mL) was stirred at 140 °C for 70 minutes. The cooled mixture was diluted with water and EA. The mixture was filtered and the filtrate was extracted with EA. The combined organic layers were washed twice with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (acetone:PE=1:2) to obtain 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetanebut-3-ylmethyl)-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (60 mg, 0.13 mmol, 27%) as a yellow solid.

[0419] Step C: A mixture of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-(oxetane-3-ylmethyl)-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (73 mg, 0.152 mmol), 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (47 mg, 0.23 mmol), tris(1E,4E)-1,5-diphenylpentan-1,4-dien-3-one]bis[palladium(0)] (14 mg, 0.015 mmol), Xantphos (18 mg, 0.03 mmol), and Cs₂CO₃ (99 mg, 0.31 mmol) in dimethyl ether (10 mL) was stirred at 110 °C under N₂ for 2 hours. 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 preparative TLC (EA / PE = 5:4, twice) to obtain N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-(oxetanebut-3-ylmethyl)-2-sideoxybenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (49 mg, 0.08 mmol, 53%) as a yellow solid. LCMS: m / z 605 [M+H] + .

[0420] Step D: Add KOH (46 mg, 0.83 mmol) to a mixture of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-(oxetanebut-3-ylmethyl)-2-sideoxybenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.08 mmol) in H2O (1 mL) and MeCN (5 mL). Stir the mixture at room temperature for 30 minutes. Dilute the mixture with water and extract with EA. Wash the organic layer with brine, dry over Na2SO4, and concentrate. Use the residue directly in the next step. LCMS: m / z 623 [M+H] + .

[0421] Step E: A mixture of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-3-(oxetanebut-3-ylmethyl)-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.024 mmol) in TFA (3 mL) and Et3SiH (0.3 mL) was stirred at 50 °C for 8 minutes. The mixture was added dropwise to a cold solution of NaHCO3 in water. The mixture was extracted with EA. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-1-methyl-3-(oxetanebut-3-ylmethyl)-2,8-dioxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (1.0 mg, 0.002 mmol, 7%) as a white solid. LCMS: m / z 607 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 7.93 (s, 1H), 7.77 - 7.61 (m, 4H), 7.28 (dd, J = 8.8, 5.0 Hz, 1H),7.05 - 6.99 (m, 1H), 6.44 (s, 1H), 5.16 - 5.12 (m, 1H), 4.96 - 4.87 (m, 1H),4.56 - 4.47 (m, 1H), 4.34 (s, 3H), 4.29 - 4.22 (m, 1H), 3.87 - 3.80 (m, 2H), 2.82 (s, 1H).

[0422]

[0423]

[0424] Step A: Add 4-(chloromethyl)-1-methylpyrazole (211 mg, 1.62 mmol) and Cs₂CO₃ (1.01 g, 3.24 mmol) to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (500 mg, 1.08 mmol) in DMA (10 mL). Stir the reaction mixture at 80 °C under N₂ for 2 hours. Dilute the cooled reaction mixture with water and extract with EA. Wash the organic phase with brine, dry to Na₂SO₄, and concentrate. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 45-55%) to give the title compound 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (400 mg, 0.719 mmol, 66%) as a yellow solid. LCMS: 555 / 557 [MH] - .

[0425] Step B: CuCN (96.5 mg, 1.08 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (400 mg, 0.719 mmol) in NMP (5 mL). The reaction mixture was stirred at 130 °C under N2 for 1.5 h. LCMS showed a reaction rate of 40% DP. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in DCM containing ethyl acetate (gradient: 20-30%) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-[(1-methylpyrazol-4-yl)methyl]-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (100 mg, 0.199 mmol, 28%) as a yellow solid. LCMS: 502 / 504 [MH] - .

[0426] Step C: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-1-[(1-methylpyrazol-4-yl)methyl]-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (80 mg, 0.159 mmol) in dimethyl ether (5 mL), 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (49.4 mg, 0.239 mmol), Pd2(dba)3 (14.5 mg, 0.016 mmol), xantphos (18.4 mg, 0.032 mmol), and Cs2CO3 (130 mg, 0.398 mmol) were added. The reaction mixture was stirred at 100 °C under N2 for 2 hours. LCMS showed that the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with elution in petroleum ether containing ethyl acetate (gradient: 10-20%) to give the title compound N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-[(1-methylpyrazol-4-yl)methyl]-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.127 mmol, 80%) as a yellow solid. LCMS: ESI m / z 629 / 631 [M+H] + .

[0427] Step D: Add KOH (7.14 mg, 0.127 mmol) to a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-1-methyl-3-[(1-methylpyrazol-4-yl)methyl]-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.127 mmol) in H2O (1 mL) and ACN (3 mL). Stir the reaction mixture at room temperature under N2 for 1 hour. LCMS showed that the reaction was complete. Dilute the reaction mixture with brine and extract with EA. Wash the organic phase with brine, dry to Na2SO4, and concentrate. The organic layer was separated and concentrated to obtain N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-3-[(1-methylpyrazol-4-yl)methyl]-2,8-disideloxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (40 mg, 0.062 mmol, 49%) as a yellow solid. LCMS: ESIm / z 647 / 649 [M + H] + .

[0428] Step E: Add Et3SiH (8.99 mg, 0.077 mmol) to a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-3-[(1-methylpyrazol-4-yl)methyl]-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.077 mmol) in TFA (3 mL). Stir the reaction mixture at 70 °C for 1 hour. LCMS showed that the reaction was complete. Concentrate the cooled reaction mixture, dilute with aqueous NaHCO3 solution, and extract with EA. Wash the organic phase with brine, dry over Na2SO4, and concentrate. The residue was purified by preparative HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-1-methyl-3-[(1-methylpyrazol-4-yl)methyl]-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (27.6 mg, 0.044 mmol, 57%) as a white solid. LCMS: ESI m / z 631 / 633 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ10.27 (s, 1H), 9.13 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H),7.71 - 7.69 (m, 2H), 7.44 (s, 1H), 7.36 (s, 1H), 7.26 (dd, J = 8.8, 5.2 Hz,1H), 7.13 - 7.03 (m, 1H), 6.61 (brs, 1H), 5.97 (brs, 1H), 4.94 (s, 2H), 3.90 (s, 3H), 3.75 (s, 3H).

[0429] Example 49: N-(6-(2-chloro-5-fluorophenyl)-3-(3-fluoropropyl)-1-methyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0430] Step A: 1-Fluoro-3-iodopropane (366 mg, 1.95 mmol) and Cs₂CO₃ (1057 mg, 3.24 mmol) were added to a stirred solution of 5,7-dibromo-6-(2-chloro-5-fluorobenzoyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, 1.081 mmol) in DMA (3 mL) under reflux. After stirring at 100 °C for 1 hour, the mixture was poured into water (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give 4,6-dibromo-5-(2-chloro-5-fluorobenzoyl)-1-(3-fluoropropyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (230 mg, 0.440 mmol, 40%) as a white solid. LCMS: m / z 521 [M+H] + .

[0431] Step B: CuCN (59 mg, 0.66 mmol) was added to a stirred solution of 4,6-dibromo-5-(2-chloro-5-fluorobenzoyl)-1-(3-fluoropropyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (230 mg, 0.44 mmol) in NMP (6 mL) under rt. After stirring at 130 °C for 1.5 h, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-30%, PE containing EtOAc) to give 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(3-fluoropropyl)-3-methyl-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (80 mg, 0.171 mmol, 39%) as a white solid. LCMS: m / z 468 [M+H] + .

[0432] Step C: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(3-fluoropropyl)-3-methyl-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (50 mg, 0.107 mmol) in dimethyl ether (3 mL), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (33.15 mg, 0.160 mmol), Xantphos (12.35 mg, 0.021 mmol), Cs₂CO₃ (70 mg, 0.213 mmol) and Pd₂(dba)₃ (9.77 mg, 0.011 mmol) were added. The reaction mixture was stirred at 100 °C under N₂ for 2 hours. The cooled reaction mixture was diluted with H₂O and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography with elution in dichloroform containing 0-10% methanol to give the title compound N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(3-fluoropropyl)-1-methyl-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.101 mmol, 95%) as a yellow solid. LCMS: ESI m / z 595 [M + H] + .

[0433] Step D: KOH (28.3 mg, 0.504 mmol) was added to a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(3-fluoropropyl)-1-methyl-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (60 mg, 0.101 mmol) in ACN (5 mL) and H2O (1 mL), and 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 by silica gel column chromatography with elution in dichloroform containing 0-10% methanol to give the title compound N-(6-(2-chloro-5-fluorophenyl)-3-(3-fluoropropyl)-6-hydroxy-1-methyl-2,8-di-sideoxy-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.082 mmol, 81%) as a white solid. LCMS: ESI m / z 613 [M + H] + .

[0434] Step E: Add Et3SiH (47 mg, 0.408 mmol) to a solution of N-(6-(2-chloro-5-fluorophenyl)-3-(3-fluoropropyl)-6-hydroxy-1-methyl-2,8-di-side-oxy-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.082 mmol) in TFA (2 mL), and stir the mixture at 50 °C for 1 hour. Concentrate the cooled mixture under vacuum. The residue was purified by preparative HPLC to give N-(6-(2-chloro-5-fluorophenyl)-3-(3-fluoropropyl)-1-methyl-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (8.6 mg, 0.014 mmol, 18%) as a white solid. LCMS: ESI m / z 597 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.14 (s,1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.35(s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 - 7.07 (m, 1H), 6.61 (brs, 1H), 6.02 (brs, 1H), 4.57 (t, J = 5.8 Hz, 1H), 4.46 (t, J = 5.8 Hz, 1H), 4.05 -3.94 (m, 2H), 3.89 (s, 3H), 2.11 - 1.98 (m, 2H).

[0435] Example 50: N-[6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-dioxo-3-(3,3,3-trifluoropropyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)cyclohexyl-2,4-diene-1-carboxamide

[0436] Step A: Add 1,1,1-trifluoro-4-iodobutane (102 mg, 0.430 mmol) and Cs₂CO₃ (210 mg, 0.644 mmol) to a solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-(trideutermethyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (100 mg, 0.215 mmol) in DMA (3 mL). Stir the reaction mixture at 100 °C under N₂ for 2 hours. TLC showed that the reaction was complete. Pour the cooled mixture into water (10 mL) and extract with EtOAc (10 mL × 2). The combined organic layers were dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum and purified by preparative TLC (SiO2, PE:EtOAc=5:1) to obtain a yellow oily 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(trideutermethyl)-1-(4,4,4-trifluorobutyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (35 mg, 25%).

[0437] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.74 (dd, J = 8.8, 4.9 Hz,1H), 7.65 - 7.57 (m, 1H), 7.52 - 7.43 (m, 1H), 4.18 (t, J = 6.8 Hz, 2H), 3.63(s, 3H), 2.84 - 2.69 (m, 2H).

[0438] Step B: CuCN (46.6 mg, 0.521 mmol) was added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-(trideutermethyl)-1-(4,4,4-trifluorobutyl)-2,3-dihydro-1H-benzo[d]imidazol-2-one (150 mg, 0.261 mmol) in NMP (2 mL). The reaction mixture was stirred at 130 °C under N2 for 2 hours. LCMS showed a half-inversion. The mixture was poured into water (5 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum and purified by preparative TLC (TFA) to give a yellow oily 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-sideoxy-3-(trideutermethyl)-1-(4,4,4-trifluorobutyl)benzo[d]imidazolium-4-carboxynitrile (50 mg, 0.086 mmol, 33%). LCMS: ESI m / z 504 / 506 [M + H] + .

[0439] Step C: Add 3-fluoro-5-(trifluoromethyl)benzamide (13.8 mg, 0.063 mmol), xantphos (5.73 mg, 0.010 mmol), Cs₂CO₃ (48.42 mg, 0.149 mmol), and Pd₂(dba)₃ (4.54 mg, 0.005 mmol) to a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-3-methyl-2-sideoxy-1-(3,3,3-trifluoropropyl)benzo[d]imidazolium-4-carboxynitrile (25 mg, 0.050 mmol) in dimethyl ether (1 mL), 3-fluoro-5-(trifluoromethyl)benzamide, 5-xantphos, 0.010 mmol, Cs₂CO₃ (48.42 mg, 0.149 mmol), and Pd₂(dba)₃ (4.54 mg, 0.005 mmol). Stir the reaction mixture at 110 °C under N₂ for 2 hours. TLC showed that the reaction was complete. Pour the mixture into water (5 mL) and extract with EtOAc (5 mL × 2). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum and purified by preparative TLC (SiO₂, PE:EtOAc = 2:1) to obtain a yellow oily N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-1-methyl-2-sideoxy-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.032 mmol, 64%). LCMS: ESI m / z 631 [M + H] + .

[0440] Step D: Add KOH (6.67 mg, 0.119 mmol) to a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-1-methyl-2-sideoxy-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.040 mmol) in MeCN (2 mL) and H₂O (0.5 mL). Stir the reaction mixture at rt for 30 minutes. The reaction was complete as indicated by LCMS. Pour the mixture into water (5 mL) and extract with EtOAc (5 mL × 2). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to obtain a yellow oily N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-di-sideoxy-3-(3,3,3-trifluoropropyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 47%). LCMS: ESIm / z 649 [M+H] + .

[0441] Step E: Triethylsilane (0.5 mL, 0.023 mmol) was added to a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-2,8-di-sideoxy-3-(3,3,3-trifluoropropyl)-1,2,3,6,7,8-hexahydroimidazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 0.023 mmol) in TFA (2 mL). The reaction mixture was stirred at 70 °C for 15 minutes. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum and purified by preparative HPLC (TFA) to give N-(6-(2-chloro-5-fluorophenyl)-1-methyl-2,8-di-sideoxy-3-(3,3,3-trifluoropropyl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.8 mg, 18%) as a white solid. LCMS: ESI m / z 633 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ10.31 (s, 1H), 9.17 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.82 - 7.66 (m, 2H), 7.43 (s, 1H), 7.29 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.63 (brs,1H), 6.00 (brs, 1H), 4.25 - 4.08 (m, 2H), 3.90 (s, 3H), 2.77 - 2.74 (m, 2H).

[0442] Example 51: N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-2,8-dioxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[0443] Step A: Iodine ethane (1.04 g, 6.68 mmol) and Cs₂CO₃ (1.09 g, 3.34 mmol) were added to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-2,3-dihydro-1H-benzo[d]imidazol-2-one (2 g, 3.34 mmol) in DMF (20 mL) under rt. After stirring at 60 °C for 2 h, the reaction mixture was monitored by TLC. The cooled mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography using hexane containing 0-50% EtOAc to give a yellow solid, 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-3-ethyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (1.5 g, 2.39 mmol, 71%). LCMS: ESI m / z 626 [M + H] + .

[0444] Step B: Add TfOH (60 mg, 0.352 mmol) to a solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-[(2,4-dimethoxyphenyl)methyl]-3-ethyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (1.1 g, 1.755 mmol) in TFA (30 mL). Stir the mixture at 60 °C for 2 hours. Concentrate the cooled mixture under vacuum to remove TFA. Pour the residue into saturated NaHCO3 and EA. Filter the mixture to obtain a purple solid of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-ethyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (800 mg, 1.679 mmol, 95%). LCMS: ESI m / z 476 [M + H] + .

[0445] Step C: 1-Fluoro-3-iodopropane (73.2 mg, 0.389 mmol) and Cs₂CO₃ (1846 mg, 5.66 mmol) were added to a stirred solution of 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-1-methyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (100 mg, 0.216 mmol) in DMA (20 mL) under reflux. After stirring at 70 °C for 3 hours, the cooled mixture was poured into water (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-ethyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (600 mg, 1.110 mmol, 58%) as a white solid. LCMS: m / z 539 [M+H] + .

[0446] Step D: Under reflux, NMP (6 mL) was added to a stirred solution of 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-ethyl-2,3-dihydro-1H-benzo[d]imidazol-2-one (600 mg, 1.110 mmol) in NMP (6 mL). After stirring at 130 °C for 2 hours, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-30%, PE containing EtOAc) to give 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-ethyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (200 mg, 0.411 mmol, 37.0%) as a white solid. LCMS: m / z 486 [M+H] + Step E: 3-fluoro-5-(trifluoromethyl)benzyl-1-carboxamide (96 mg, 0.462 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), Cs2CO3 (201 mg, 0.616 mmol), and Xant-PHOS (36 mg, 0.062 mmol) were added to a stirred solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-ethyl-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (150 mg, 0.308 mmol) in dimethyl ether (5 mL) under stirring at rt. After stirring at 100 °C under N2 for 2 hours, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, PE containing EtOAc) to give N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-1-ethyl-2-sideoxybenzo[d]imidazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (150 mg, 0.245 mmol, 79%), a brown oil. LCMS: m / z 614 [M+H] + .

[0447] Step F: Potassium hydroxide (91 mg, 1.632 mmol) was added to a stirred solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-3-(2,2-difluoroethyl)-1-ethyl-2-sideoxybenzo[d]imidazol-5-yl}-3-fluoro-5-(trifluoromethyl)benzamide (200 mg, 0.326 mmol) in ACN (5 mL) and H2O (1 mL) under rt. After stirring for 1 hour under rt, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH containing DCM) to give N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-6-hydroxy-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.174 mmol, 53%), which was a white oil. LCMS: m / z 631 [M+H] + .

[0448] Step G: Under rt, Et3SiH (92.1 mg, 0.793 mmol) was added to a stirred solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-6-hydroxy-2,8-dioxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.159 mmol) in TFA (3 mL). After stirring at 60 °C for 1 hour, the cooled mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (C18, containing 40-90% MeCN in H2O and 0.1% TFA) to obtain N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-2,8-disideloxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (18.5 mg, 0.030 mmol, 18%) as a white solid. LCMS: m / z 615 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ 10.35 (s, 1H), 9.18 (s, 1H), 7.96 - 7.88 (m, 1H), 7.80 - 7.68 (m, 2H), 7.42 (s, 1H), 7.2 (dd, J = 8.8, 5.2 Hz, 1H), 7.17 - 7.01 (m, 1H), 6.77- 6.22 (m, 2H), 6.02 (brs, 1H), 4.65 - 4.48 (m, 2H), 4.47 - 4.14 (m, 2H), 1.28 (t, J = 6.8 Hz, 3H).

[0449] Example 52: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide Example 53: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide Example 54: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide Step A: K₂CO₃ (181 mg, 1.31 mmol) and methyl 2-bromo-2,2-difluoroethyl) were added to a solution of 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-2-sideoxy-3H-benzo[d]imidazolium-4-carboxynitrile (300 mg, 0.654 mmol) in DMF (6 mL). The reaction mixture was stirred at 80 °C for 16 hours. The cooled mixture was diluted with H₂O and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was wet-milled with EA:PE at a ratio of 1:5 to give 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-(difluoromethyl)-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (170 mg, 0.334 mmol, 51%) as a brown solid. LCMS: ESIm / z 510.1 [M + H]+ .

[0450] Step B: A solution of 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-1-(2,2-difluoroethyl)-3-(difluoromethyl)-2-sideoxybenzo[d]imidazolium-4-carboxynitrile (80 mg, 0.158 mmol), 5-fluoro-3-(trifluoromethyl)benzyl-1-carboxamide (32.6 mg, 0.158 mmol), Pd2(dba)3 (14.4 mg, 16 µmol), xantphos (18.22 mg, 32 µmol), and Cs2CO3 (154 mg, 0.473 mmol) in dimethyl ether (4 mL) was stirred at 100 °C for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography with elution using DCM containing MeOH (gradient: 0-10%) to give N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.126 mmol, 80%) as a brown solid. (Crude matter). LCMS: ESI m / z 635.1 [M + H] + .

[0451] Step C: Add KOH (44.3 mg, 0.789 mmol) to a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.158 mmol) in ACN (2 mL) and H2O (0.2 mL). Stir the reaction mixture at rt for 30 minutes. Dilute the mixture with water (10 mL) and extract with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL × 2), dried over Na₂SO₄, and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-6-hydroxy-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (80 mg, 0.123 mmol, 78%) as a brown solid. LCMS: ESI m / z 653.2 [M - H] + .

[0452] Step D: Add Et3SiH (0.2 mL) to a solution of N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-6-hydroxy-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 23 µmol) in TFA (1 mL). Stir the reaction mixture at 60 °C for 30 min. Concentrate the reaction mixture to obtain the residue. The residue was purified by preparative HPLC to obtain N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2,8-disideloxy-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (4.3 mg, 7 µmol, 29%) as a white solid. LCMS: ESI m / z 637.0 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ 9.11 (t, J =56.0 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.47 (s, 1H), 7.27 - 7.24 (m, 1H), 7.02 -6.98 (m, 1H), 6.63 (brs, 1H), 6.39 - 6.10 (m, 2H), 4.45 - 4.35 (m, 2H).

[0453] Step E: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2,8-disideoxy-1,2,3,6,7,8-hexahydroimidozono[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (120 mg, 0.19 mmol) was purified by SFC method 13 to give (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2,8-disideoxy-1,2,3,6,7,8-hexahydroimidozono[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (26.3 mg, 0.041 mmol, 44%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.46 (s, 1H), 9.55 (s, 1H), 9.14 (t, J= 56.0 Hz, 1H), 7.98 - 7.89 (m,1H), 7.79 - 7.72 (m, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 7.36 - 7.24 (m, 1H),7.15 - 7.05 (m, 1H), 6.93 - 6.63 (m, 1H), 6.59 - 6.24 (m, 1H), 6.20 - 5.93 (m, 1H), 4.53 - 4.31 (m, 2H). (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-(difluoromethyl)-2,8-di-side-oxy-1,2,3,6,7,8-hexahydroimidozono[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (26.8 mg, 0.042 mmol, 45%) is a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ10.46 (s, 1H), 9.55 (s, 1H), 9.14 (t, J = 56.0 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.79 - 7.72 (m, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 7.36 - 7.24 (m, 1H), 7.15 -7.05 (m, 1H), 6.93 - 6.63 (m, 1H), 6.59 - 6.23 (m, 1H), 6.20 - 5.93 (m, 1H), 4.54 - 4.31 (m, 2H).

[0454] Example 56: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide Example 57: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0455] Step A: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-2,8-disideoxy-1,2,3,6,7,8-hexahydroimidozono[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (16.3 mg, 0.03 mmol) was purified by SFC method 14 to give (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-2,8-disideoxy-1,2,3,6,7,8-hexahydroimidozono[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (5.2 mg, 0.01 mmol, 64%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.34(s, 1H), 9.17 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.41 (s,1H), 7.33 - 7.25 (m, 1H), 7.13 - 7.04 (m, 1H), 6.77 - 5.73 (m, 3H), 4.64 -4.49 (m, 2H), 4.46 - 4.31 (m, 2H), 1.31 - 1.25 (m, 3H). (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-1-ethyl-2,8-di-side-oxy-1,2,3,6,7,8-hexahydroimidozono[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (5.3 mg, 0.01 mmol, 65%) is a white solid. 1 H NMR(400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.17 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H),7.77 - 7.66 (m, 2H), 7.41 (s, 1H), 7.33 - 7.25 (m, 1H), 7.13 - 7.04 (m, 1H),6.77 - 5.73 (m, 3H), 4.64 - 4.49 (m, 2H), 4.46 - 4.31 (m, 2H), 1.31 - 1.25 (m, 3H).

[0456] Example 58: N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2,8-dioxo-1-(prop-2-yn-1-yl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0457] Step A: 3-Bromoprop-1-yne (0.29 g, 2.40 mmol) and Cs₂CO₃ (1.42 g, 4.36 mmol) were added to a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(2,2-difluoroethyl)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (1 g, 2.18 mmol) in DMF (10 mL). The reaction mixture was stirred at 60 °C for 2 hours. The mixture was diluted with H₂O and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The crude product was purified by rapid silica gel chromatography followed by elution with petroleum ether containing 0-50% ethyl acetate to give a yellow solid, 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(2,2-difluoroethyl)-2-sideoxy-3-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (0.9 g, 1.81 mmol, 83%). LCMS: ESI m / z 495.8 / 497.8 [M + H] + .

[0458] Step B: A solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(2,2-difluoroethyl)-2-sideoxy-3-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (300 mg, 0.60 mmol), 3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.72 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), XantPhos (70 mg, 0.12 mmol), and Cs2CO3 (394 mg, 1.21 mmol) in dimethyl ether (10 mL) was purged three times with nitrogen and stirred at 100 °C for 2 hours. The cooled mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by rapid silica gel chromatography followed by gradient elution with petroleum ether containing 0-100% ethyl acetate to give N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2-difluoroethyl)-2-sideoxy-1-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.24 mmol, 40%) as a yellow solid. LCMS: ESI m / z 623.0 [M + H] + .

[0459] Step C: KOH (68 mg, 1.20 mmol) was added to a stirred mixture of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(2,2-difluoroethyl)-2-sideoxy-1-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.24 mmol) in MeCN (2 mL) and H2O (0.5 mL), and the mixture was stirred at rt for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, and the combined extracts were dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by rapid silica gel chromatography with elution in petroleum ether containing 0-100% EtOAc to give N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2,8-disideloxy-1-(prop-2-yn-1-yl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.17 mmol, 71%) as a yellow solid. LCMS: ESI m / z 641.4 [M + H] + .

[0460] Step D: To a solution of N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2,8-di-side-oxy-1-(prop-2-yn-1-yl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.08 mmol) in MeCN (2 mL), NaI (59 mg, 0.39 mmol) and TMSCl (42 mg, 0.39 mmol) were added. The reaction mixture was stirred at rt for 1 hour. The reaction mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC to obtain N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2,8-di-sideoxy-1-(prop-2-yn-1-yl)-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (7 mg, 0.01 mol, 14%) as a yellow solid. LCMS: ESI m / z 625.0 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ 7.77 - 7.57 (m, 3H), 7.42 (s, 1H), 7.25 (dd, J =8.8, 5.0 Hz, 1H), 6.99 (td, J = 8.2, 3.0 Hz, 1H), 6.57 - 6.07 (m, 2H), 5.56(dd, J = 17.2, 2.4 Hz, 1H), 5.45 (dd, J = 17.2, 2.4 Hz, 1H), 4.39 (td, J = 15.0,3.2 Hz, 2H), 2.67 (s, 1H).

[0461] Example 59: N-(1-allyl-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2,8-dioxo-1,2,3,6,7,8-hexahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0462] Step A: 3-bromoprop-1-ene (286 mg, 2.40 mmol) and Cs₂CO₃ (1.42 g, 4.36 mmol) were added to a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(2,2-difluoroethyl)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (1 g, 2.18 mmol) in DMF (10 mL). The reaction mixture was stirred at 50 °C for 2 hours. The mixture was diluted with H₂O and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The crude product was purified by rapid silica gel chromatography followed by elution with petroleum ether containing 0-50% ethyl acetate to give a yellow solid, 3-allyl-6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(2,2-difluoroethyl)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (0.9 g, 1.81 mmol, 83%). LCMS: ESI m / z 497.9 / 499.9 [M + H] + .

[0463] Step B: A solution of 3-allyl-6-bromo-5-(2-chloro-5-fluorobenzoyl)-1-(2,2-difluoroethyl)-2-sideoxy-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxynitrile (100 mg, 0.26 mmol), 3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.24 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), XantPhos (23 mg, 0.04 mmol), and Cs2CO3 (131 mg, 0.40 mmol) in dimethyl ether (5 mL) was purged three times with nitrogen and stirred at 100 °C for 2 hours. The cooled mixture was filtered, and the filter cake was was...

Claims

1. A compound having structural formula (I): （I） Or its pharmaceutically acceptable form or isotopic derivative. in R 1 and R 2 Each is independently assigned to one of 0-8 R's. A Replacement C 1-6 Alkyl, C 2-5 alkenyl, or C 2-5 alkynyl group, where each R A Independently, D, halogen, CN, OR, SR, NRR', unsubstituted or substituted C 3-6 Carbocyclic or heterocyclic, or unsubstituted or substituted 5- or 6-membered aryl or heteroaryl; and R and R' are independently H, unsubstituted or substituted C. 1-4 Alkyl groups, or unsubstituted or substituted 3- to 6-membered carbon rings, or, where R and R' are attached to the same C or N atom, together form unsubstituted or substituted 4- to 6-membered heterocycles.

2. The compound according to claim 1, wherein R 2 For CR 2a R 2b R 2c The compound has the structural formula (I) A ): （I A ） in R 2a It is H, D or halogen; R 2b It is H, D or halogen; and R 2c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 Alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

3. The compound according to claim 2, wherein R 1 For CR 1a R 1b R 1c The compound has the structural formula (I) B ): （I B ） in R 1a It is H, D or halogen; R 1b It is H, D or halogen; and R 1c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 Alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

4. The compound according to claim 3, wherein R 2c For CR 2d R 2e R 2f The compound has the structural formula (I) C ): （I C ） in R 2d It is H, D or halogen; and R 2e and R 2f Each independently H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 Alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

5. The compound according to any one of claims 2-4, wherein R 2a and R 2b Each is represented by H.

6. The compound according to any one of claims 2-4, wherein R 2a and R 2b Each is D.

7. The compound according to any one of claims 4-6, wherein R 2d R 2e and R 2f At least one of them is a halogen atom.

8. The compound according to claim 7, wherein R 2d R 2e and R 2f One of them is F.

9. The compound according to claim 7, wherein R 2d R 2e and R 2f Both of them are F.

10. The compound according to claim 7, wherein R 2d R 2e and R 2f Each is F.

11. The compound according to any one of claims 4-6, wherein R 2d R 2e and R 2f At least one of them is D.

12. The compound according to claim 11, wherein R 2d R 2e and R 2f One of them is D.

13. The compound according to claim 11, wherein R 2d R 2e and R 2f Both of them are D.

14. The compound according to claim 11, wherein R 2d R 2e and R 2f Each is D.

15. The compound according to any one of claims 1-14, wherein R 1 It is CH3.

16. The compound according to any one of claims 1-14, wherein R 1 It is CD3.

17. The compound according to any one of claims 1-14, wherein R 1 It is not CH3.

18. The compound according to any one of claims 1-14, wherein R 1 Not CD3.

19. The compound according to claim 1, wherein R 1 For CR 1a R 1b R 1c The compound has the structural formula (I) D ): （I D ） in R 1a It is H, D or halogen; R 1b It is H, D or halogen; and R 1c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 Alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

20. The compound according to claim 19, wherein R 2 For CR 2a R 2b R 2c The compound has the structural formula (I) E ): （I E ） in R 2a It is H, D or halogen; R 2b It is H, D or halogen; and R 2c for H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 Alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

21. The compound according to claim 20, wherein R 1c For CR 1d R 1e R 1f The compound has the structural formula (I) F ): （I F ） in R 1d It is H, D or halogen; and R 1e and R 1f Each independently H, D, halogen, CN, OR, SR, or NRR'; or Unsubstituted or substituted C 1-5 Alkyl, C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

22. The compound according to any one of claims 19-21, wherein R 1a and R 1b Each is represented by H.

23. The compound according to any one of claims 19-21, wherein R 1a and R 1b Each is D.

24. The compound according to claim 22, wherein R 1c For H.

25. The compound according to claim 23, wherein R 1c The answer is D.

26. The compound according to any one of claims 21-23, wherein R 1d R 1e and R 1f At least one of them is a halogen atom.

27. The compound according to claim 26, wherein R 1d R 1e and R 1f One of them is F.

28. The compound according to any one of claims 19-27, wherein R 2 It is CH3 or CD3.

29. The compound according to any one of claims 19-27, wherein R 2 It is neither CH3 nor CD3.

30. The compound according to claim 4 or 21, wherein the compound has the structural formula (I G ): （I G ）。 31. The compound according to claim 30, wherein R 2a and R 2b Each is represented by H.

32. The compound according to claim 30, wherein R 2a and R 2b Each is D.

33. The compound according to any one of claims 30-32, wherein R 2d R 2e and R 2f At least one of them is a halogen atom.

34. The compound according to claim 33, wherein R 2d R 2e and R 2f One of them is F.

35. The compound according to claim 33, wherein R 2d R 2e and R 2f Both of them are F.

36. The compound according to claim 33, wherein R 2d R 2e and R 2f Each is F.

37. The compound according to any one of claims 30-32, wherein R 2d R 2e and R 2f At least one of them is D.

38. The compound according to claim 37, wherein R 2d R 2e and R 2f One of them is D.

39. The compound according to claim 37, wherein R 2d R 2e and R 2f Both of them are D.

40. The compound according to claim 37, wherein R 2d R 2e and R 2f Each is D.

41. The compound according to any one of claims 30-40, wherein R 1a and R 1b Each is represented by H.

42. The compound according to any one of claims 30-40, wherein R 1a and R 1b Each is D.

43. The compound according to claim 41 or 42, wherein R 1d R 1e and R 1f Each is either H or D.

44. The compound according to claim 1, wherein R 1 and R 2 Selected independently from: R 1 :CH3、CH2D、CHD2、CD3、CH2F、CHF2、CD2F、CDF2、CF3、CH2CH3、CD2CH3、CH2CD3、CD2CD3、CH2CN、CH2CH2N(CH3)2、 ;and R 2 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 。 45. A compound according to claim 1, wherein the compound has the structural formula (II) A ): (II A ) in R 2a For H or D; R 2b For H or D; and R 2f For D, F, CN, OR, NRR', or unsubstituted or substituted C 1-5 Alkyl or C 3-5 Carbon cyclic group or heterocyclic group.

46. ​​The compound according to claim 45, wherein R 2a and R 2b Each of the two is H, and the compound has the structural formula (II). B ): (II B )。 47. A compound according to claim 1, wherein the compound has the structural formula (II) C ): (II C ) Where R 2c CN, OR, SR, NRR', unsubstituted or substituted C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

48. A compound according to claim 1, wherein the compound has the structural formula (II) E ): (II E ) in R 2a For H or D; R 2b For H or D; and R 2f For D, F, CN, OR, NRR', or unsubstituted or substituted C 1-3 Alkyl or C 3-5 Carbon cyclic group or heterocyclic group.

49. The compound according to claim 48, wherein R 2a and R 2b Each of the two is H, and the compound has the structural formula (II). F ): (II F )。 50. The compound according to claim 1, wherein the compound has the structural formula (II) G ): (II G ) Where R 2c CN, OR, SR, NRR', unsubstituted or substituted C 3-6 Carbocyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl.

51. The compound according to any one of claims 1-50, wherein the compound has the formula (III) A Chirality as shown: (III A )。 52. The compound according to any one of claims 1-50, wherein the compound has the formula (III) B Chirality as shown: (III B )。 53. A compound selected from Table 1, or a pharmaceutically acceptable form or isotopic derivative thereof.

54. The compound according to any one of claims 1-53, wherein the compound has one or more deuterium atoms in place of hydrogen.

55. A pharmaceutical composition comprising a compound according to any one of claims 1-54 and a pharmaceutically acceptable excipient, carrier, or diluent.

56. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is suitable for oral administration.

57. A unit dosage form comprising the pharmaceutical composition according to claim 55 or 56.

58. The unit dosage form according to claim 57, wherein the unit dosage form is in tablet or capsule form.

59. A method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of the compound according to any one of claims 1-54.

60. A method for regulating the activity of phosphatidylinositol 3-kinase α (PI3Kα) in cells, the method comprising contacting the cells with a compound according to any one of claims 1-54.

61. A method for reducing the activity of phosphatidylinositol 3-kinase α (PI3Kα) in cells, the method comprising contacting the cells with a compound according to any one of claims 1-54.

62. A method for treating a disease or condition mediated by phosphatidylinositol 3-kinase α (PI3Kα), the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-54.

63. The method of claim 62, wherein the disease or condition is a cell proliferation disease.

64. A method for treating or alleviating cancer or related diseases or conditions, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-54.

65. The method of claim 64, wherein the cancer is selected from the group consisting of: carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

66. The method according to claim 64 or 65, wherein the cancer is selected from the group consisting of: breast cancer, ovarian cancer, pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendiceal cancer, bile duct epithelial carcinoma, bladder urothelial carcinoma, gastric cancer, bile duct cancer, and hematologic malignancies.

67. The method according to any one of claims 64-66, wherein the subject has a mutated IA class PI3Kp110α.

68. The method according to any one of claims 64-67, wherein the subject has at least one of the following PI3Kα mutations: H1047R, E542K, E545K, and H1047X.

69. The method according to any one of claims 64-68, wherein the treated subject is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormone therapy.

70. Use of the compound according to any one of claims 1-54, and pharmaceutically acceptable excipients, carriers, or diluents, in the preparation of a medicament for treating a disease or condition.

71. The use according to claim 70, wherein the disease or condition is a cell proliferation disease.

72. The use according to claim 71, wherein the disease or condition is cancer.

73. The use according to claim 72, wherein the cancer is selected from the group consisting of: carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma and lymphoma.

74. The use according to claim 72, wherein the cancer is selected from the group consisting of: ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, small cell and non-small cell lung cancer, endometrial cancer, appendiceal cancer, bile duct epithelial carcinoma, bladder urothelial carcinoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, thyroid cancer, and hematologic malignancies.

75. The use according to claim 72, wherein the cancer is selected from the group consisting of: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.

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