Tricyclic aryl derivatives and compositions and methods thereof

Abstract

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

Description

[Technical Field]

[0001] Priority claims and related applications This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 393,564, filed July 29, 2022, and 63 / 471,488, filed June 6, 2023, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] The present invention generally relates to novel compounds and their therapeutic uses. More specifically, the present invention provides novel tricyclic compounds that are shown to be potent and selective phosphoinositide 3-kinase alpha (PI3Kα) inhibitors. The present invention also provides pharmaceutical compositions containing the compounds of the present invention and methods for treating diseases and disorders associated with or related to PI3Kα activity, such as various types of cancer. [Background technology]

[0003] Phosphoinositide 3-kinases (PI3Ks) are a family of related intracellular signal transducer enzymes that can phosphorylate the hydroxyl group at the 3 position of the inositol ring of phosphatidylinositol (PtdIns). PI3Ks are associated with a wide variety of cellular functions, including cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. 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 disorder, psoriasis, multiple sclerosis, asthma, diabetic complications, and acute coronary syndrome.

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

[0005] Class IA PI3K p110α (PI3Kα) is mutated in many human cancers. Angiogenesis has been shown to selectively require the PI3Kα isoform in regulating endothelial cell migration. Mutations in the gene encoding PI3Kα (PIK3CA) or upregulation of PI3Kα occur in many human cancers, including ovarian, cervical, breast, colorectal, endometrial, gastric, hepatocellular carcinoma, small-cell and non-small-cell lung cancer, thyroid cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.In cancer, PI3Kα mutations are often hotspot point mutations in the helical or kinase domain, such as E542K, E545K, and H1047R (Graupera et al. 2008 Nature 453: 662-6; Campbell et al. 2004 Cancer Res 64, 7678-7681; Levine et al. 2005 Clin Cancer Res 11, 2875-2878; Wang et al. 2005 Hum Mutat 25, 322; Lee et al. 2005 Gynecol Oncol 97, 26-34; Bachman, et al. 2004 Cancer Biol Ther 3, 772-775; Li et al. 2006 Breast Cancer Res Treat 96, 91-95; Saal et al. 2005 Cancer Res 65, 2554-2559;Samuels and Velculescu 2004 Cell Cycle 3, 1221-1224;Samuels, et al. 2004 Science 304, 554;Velho et al. 2005 Eur J Cancer 41, 1649-1654;Oda et al. 2005 Cancer Res. 65, 10669-10673;Byun et al. 2003 Int J Cancer 104, 318-327;Lee et al. 2005 Oncogene 24, 1477-1480;Tang et al. 2006 Lung Cancer 51, 181-191;Massion et al. 2004 Am J Respir Grit 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 Cotter 2006 J Biol Chem 281, 2441-2450;Hartmann et al. 2005 Acta Neuropathol (Berl) 109, 639-642.). Summary of the Invention [Problem to be solved by the invention]

[0006] There remains an urgent unmet need for potent and selective PI3Kα inhibitors that are safe and effective for treating PI3Kα-associated diseases and conditions, such as various types of cancer (e.g., breast cancer, ovarian cancer, colorectal cancer, lung cancer).

[0007] The present invention provides novel tricyclic compounds and derivatives thereof as PI3K alpha inhibitors, which are herein shown to exhibit more advantageous potency and selectivity profiles than known PI3K alpha inhibitors. These novel compounds selectively target, bind to, and inhibit and / or modulate the activity of PI3K alpha. The compounds are also orally available with pharmacokinetic profiles suitable for development into orally administered therapeutic agents for the treatment of various diseases and disorders associated with or related to PI3K alpha activity, such as various types of cancer. [Means for solving the problem]

[0008] In one aspect, the present invention generally provides a compound of structural formula (I): [ka] [In the formula, Ring A is 0 to 6 R a is a 5- or 6-membered aromatic ring substituted with R 1 is Z B -R B and R 2 is Z C -R C and V is C or N; W is C or N; X is N, CH or CR X and R X is Z X -R X’ and Z B , Z C and Z X each independently represents a covalent bond, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O), NRS(O), S(O)NR, or C, optionally independently substituted with a heteroatom selected from the group consisting of N, S, and O. 1~4 is a linking group selected from saturated or unsaturated divalent hydrocarbon groups, R B and R C Each of the 1~6 a 5-10 membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from an aliphatic chain, N, O and S, each of which is selected from one or more R b , R c or R x are substituted appropriately with R X is deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR', or -N(R)S(O)2R; R a , R b , R c and R x Each of the H, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR' or -N(R)S(O)2R, or C 1~6 an optionally substituted group selected from alkyl or a 4- to 6-membered carbocyclic ring; However, at least one R a is not H, which is substituted on ring A, Each of R and R' is independently H, unsubstituted or substituted C 1~4 alkyl, or an unsubstituted or substituted 4- to 6-membered carbocyclic ring, or R and R', when attached to the same C or N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; i is 1, 2, 3, 4, 5, or 6] or a pharmaceutically acceptable form or isotopic derivative thereof.

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

[0010] In yet another aspect, the invention generally relates to unit dosage forms that include the pharmaceutical compositions disclosed herein.

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

[0012] In yet another aspect, the invention generally relates to a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound disclosed herein.

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

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

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

[0016] In yet another aspect, the invention generally relates to the use of the compounds disclosed herein to treat diseases or disorders, such as various types of cancer. DETAILED DESCRIPTION OF THE INVENTION

[0017] 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 belongs. General principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0018] As used herein, "at least" a particular value is understood to be that value and all values above that value.

[0019] The term "comprising," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term "consisting essentially of," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but exclude other elements of any essential importance to the compositions and methods. For example, "consisting essentially of" refers to the administration of explicitly recited pharmacologically active agents, but excludes pharmacologically active agents not explicitly recited. The term "consisting essentially of" does not exclude pharmacologically non-active or inactive agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, is intended to mean excluding trace elements and substantial method steps of other components. Embodiments defined by each of these transition terms are within the scope of this invention.

[0020] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. About can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein may be modified by the term about.

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

[0022] As used herein, the term "administration" or "administering" a disclosed compound includes delivery of a compound described herein, or a prodrug or other pharmaceutically acceptable form thereof, to a subject using any suitable formulation or route of administration described herein.

[0023] As used herein, the term "co-administered" means that two pharmacological agents are present in a subject's body (e.g., in the blood) at the same time. The two pharmacological agents may be administered simultaneously or sequentially.

[0024] Unless otherwise indicated, the terms "disease," "disorder," and "condition" are used interchangeably.

[0025] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a compound or pharmaceutical composition described herein that is sufficient to fulfill its intended use, including, but not limited to, the treatment of diseases, as described below.

[0026] In some embodiments, the amount is sufficient to negatively regulate or inhibit the activity of PI3K alpha. In some embodiments, the amount is effective to reduce or improve symptoms, or to stop or reverse the progression of a disease or disorder, such as cancer. In some embodiments, the amount is effective to detectably reduce or inhibit the growth or spread of cancer cells; the size or number of tumors; or other measures of the level, stage, progression, or severity of cancer.

[0027] The therapeutically effective amount may vary depending on the intended use, or the subject and disease state to be treated, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the patient's weight and age, and can be easily determined by those skilled in the art.Such an amount may be administered as a single dose or according to a regimen.This term also applies to the dose that induces a specific response in target cells, such as reducing cell migration.The specific dose will vary depending on, for example, the specific compound selected, the species of subject and their age / current health condition or risk of health condition, the administration regimen followed, the severity of the disease, whether it is administered in combination with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0028] As used herein, an "inhibitor" of "PI3K alpha" refers to a compound of the present invention that is capable of negatively regulating or inhibiting all or part of the activity of PI3K alpha.

[0029] As used herein, "PI3K alpha-related" disease or disorder refers to a disease or disorder that is related to or mediated by PI3K alpha or has one or more PI3K alpha mutations. Examples of PI3K alpha-related diseases or disorders include various types of cancer. PI3K alpha-related diseases or disorders can also refer to allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diabetic complications, or acute coronary syndrome.

[0030] As used herein, the term "contacting" refers to bringing the indicated moieties together in vitro or in vivo. For example, "contacting" a cell with a compound disclosed herein includes administering the compound to a subject in need thereof, as well as introducing the compound into a sample containing the cell or a purified preparation, for example. In some embodiments, cells in which inhibition of PI3K α activity is desired are contacted with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable form thereof, to negatively regulate PI3K α activity. By negatively regulating PI3K α activity, the methods disclosed herein are designed to inhibit undesired cell proliferation resulting from enhanced PI3K α activity in cells. Cells can be contacted with a single dose or multiple doses according to a specific treatment regimen to achieve the desired negative modulation of PI3K α. The ability of a compound to bind to PI3K α can be monitored in vitro using methods known in the art. The inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring inhibition of PI3K α activity using methods known in the art.

[0031] As used herein, the terms "unsubstituted or substituted" and "optionally substituted" are used interchangeably and refer to a situation in which a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be bonded at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any additional functional groups. Suitable substituents used for appropriate substitution of the described groups include, but are not limited to, halogen, oxo, CN, -COOH, -CHCN, -O-Ci-C alkyl, Ci-C alkyl, -O-Ci-C alkenyl, -O-Ci-C alkynyl, -Ci-C alkenyl, -Ci-C alkynyl, -OH, -O-P(O)(OH), -OC(O)Ci-C alkyl, -C(O)Ci-C alkyl, -OC(O)O-Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), -NHC(O)Ci-C alkyl, -C(O)NHCi-C alkyl, -S(O)-Ci-C alkyl, -S(O)NHCi-C alkyl, and S(O)N(Ci-C alkyl).

[0032] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In some embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0033] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of suitable salts include benzoate, benzoyl peroxide ...In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0034] Salts may 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 appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, 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, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0035] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to an ester that hydrolyzes in vivo, including those that readily decompose in the human body to leave the parent compound or its salt. Such esters can act as prodrugs, as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids, and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates. Esters may be formed using hydroxy or carboxylic acid groups of the parent compound.

[0036] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be of the disclosed compounds or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that may include, 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. The term "compound," as used herein, will be understood to encompass compounds and solvates of compounds, as well as mixtures thereof.

[0037] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to a compound that is converted in vivo to produce a pharmaceutically acceptable form of the disclosed compound or compound. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can increase the bioavailability of a compound when administered to a subject (e.g., by enabling enhanced absorption into the blood after oral administration) or enhance delivery to a desired biological compartment (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced water solubility or active transport across intestinal membranes compared to the parent compound.

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

[0039] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, 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; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0040] As used herein, the term "subject" means any animal (e.g., mammal), including, but not limited to, humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0041] In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder that can be treated with the compounds disclosed herein and / or according to the methods disclosed herein. In some embodiments, the subject has been identified or diagnosed as having a cancer with one or more PI3K alpha mutations. In some embodiments, the subject has a cancer that is positive for PI3K alpha mutations. In some embodiments, the subject is suspected of having a PI3K alpha gene-related cancer.

[0042] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a subject has one or more PI3Kα mutations using a sample from the subject (e.g., a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample)). Various techniques, such as next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR), can be used.

[0043] As used herein, the term "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying, or ameliorating such a condition before or after it has occurred. Treatment can target one or more effects or symptoms of a disease and / or underlying pathology. Treatment is intended to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even though the patient may still be suffering from the underlying disorder. For prophylactic benefit, pharmaceutical compounds and / or compositions can be administered to patients at risk of developing a particular disease or to patients who report one or more physiological symptoms of the disease, even though the disease may not have been diagnosed. Treatment can be any reduction, or can be, but is not limited to, the complete elimination of the disease or symptoms of the disease. Compared to comparable untreated controls, such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0044] As used herein, the term "therapeutic benefit" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0045] After their preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 95% or more by weight of the compound ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the present invention are greater than 99% pure.

[0046] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0047] As used herein, the term "isolated" or "substantially isolated" refers to a molecule (e.g., a polypeptide or polynucleotide) that has been engineered to exist at a higher concentration than in nature or that has been removed from its natural environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified if at least 10%, 20%, 40%, 50%, 70%, or 90% of the non-subject antibody material naturally associated with it has been removed. For example, a polynucleotide or polypeptide that naturally occurs in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated." Furthermore, recombinant DNA molecules contained in a vector are considered isolated for purposes of the present invention. Isolated RNA molecules include the products of in vivo or in vitro RNA replication of DNA and RNA molecules. Isolated nucleic acid molecules further include molecules produced synthetically. Furthermore, vector molecules contained in a recombinant host cell are also isolated. Therefore, not all "isolated" molecules need to be "purified."

[0048] As used herein, the term "purified," when used in reference to a molecule, means that the concentration of the purified molecule is increased relative to the molecules that accompany it in its natural environment or the environment in which it was produced, found, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally exclude water, buffers, and reagents that are added to maintain the integrity of the purified molecule or facilitate its purification. By this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~4 "Alkyl" is C1, C2, C3, C4, C 1~3 , C 1~2 , C 2~4 , C 3~4 and C 2~3 Alkyl groups are intended to be included.

[0050] As used herein, the term "aliphatic" or "aliphatic group" means a straight or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic.

[0051] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 Numerical ranges such as "1 to 10," whenever they appear herein, refer to each integer within the given range, e.g., "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also encompasses the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, "alkyl" refers to C 1~6It may also be an alkyl group. 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 alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, and saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in this specification, an alkyl group is any of the following: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R x )3, -OR x , -SR x , -OC(O)-R x , -N(R x )2, -C(O)R x , -C(O)OR x , -OC(O)N(R x )2, -C(O)N(R x )2, -N(R x )C(O)OR x , -N(R x )C(O)R x , -N(R x )C(O)N(R x )2, -N(R x )C(NR x )N(R x )2, -N(Rx )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, and each R x are independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. In a non-limiting embodiment, the substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0052] Unless otherwise specifically defined, the terms "aromatic" or "aryl" refer to a cyclic aromatic hydrocarbon group having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, H, halogen, —O—Ci-C alkyl, Ci-C alkyl, —Ci-C alkenyl, —O—Ci-C alkynyl, —Ci-C alkenyl, —Ci-C alkynyl, —OH, —O—P(O)(OH), —OC(O)Ci-C alkyl, —C(O)Ci-C alkyl, —OC(O)O—Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), —S(O)—Ci-C alkyl, —S(O)NHCi-C alkyl, and S(O)N(Ci-C alkyl). The substituents may themselves be optionally substituted. Furthermore, when containing two fused rings, aryl groups as defined herein may have a fully unsaturated ring and a fused unsaturated or partially saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

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

[0054] As used herein, the term "heteroaryl" or "hetero-aromatic" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 p-electrons shared in the cyclic array, and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1,2-dihydro-5H-pyrrolo[1,2-a]imidazole ... H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, o Xazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidyl nyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl."Heteroaryl" also means bicyclic ring systems having, in addition to carbon atoms, from 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S, wherein one ring system may be saturated or partially saturated.

[0055] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2)carbonyl. The term "NZ1Z2" as used herein refers to two groups, Z1 and Z2, attached to the parent molecular moiety through 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, acetylamino, and acetylmethylamino.

[0056] As used herein, the term "alkoxy" refers to an --O-alkyl group.

[0057] As used herein, the terms "cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic group that contains only carbon and hydrogen and may be saturated or partially unsaturated. Unless otherwise specified herein, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond or "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3~13Cycloalkyl). Numerical ranges such as "3 to 10," whenever they appear herein, refer to each integer within the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3~8 In some embodiments, "cycloalkyl" is a C 3~5 It may also be a cycloalkyl group. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~7 Examples of carbocyclyl groups include norbornyl (C7). 3~8 Examples of carbocyclyl groups are those listed above. 3~7 Carbocyclyl groups include cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, etc. 3~13 Examples of carbocyclyl groups are those listed above. 3~8Unless otherwise stated in this specification, cycloalkyl groups include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R 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, each R aare independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. The terms "cycloalkenyl" and "cycloalkynyl" reflect the above description of "cycloalkyl," with the prefix "alk" replaced with "alkene" or "alkyne," respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0058] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group having one or more skeletal atoms selected from atoms other than carbon, e.g., O, N, S, P, or combinations thereof. Unless otherwise specified herein, this term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Examples of heterocycloalkyl include 2-hydroxyaziridin-1-yl, 3-oxo-1-oxacyclobutan-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, and the like.

[0059] As used herein, the terms "heterocycle," "heterocyclic," or "heterocyclo" refer to a fully saturated or partially unsaturated cyclic group, e.g., a 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 15-membered spirocyclic or tricyclic ring system, having at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, where 0, 1, 2, or 3 atoms in each ring may be substituted by a substituent. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may be oxidized and the nitrogen heteroatom may be quaternized. The heterocyclic group may be bonded at any heteroatom or carbon atom in the ring or ring system. The heterocyclic group is optionally substituted. Examples of heterocyclic groups include epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, and azabicyclononanyl (e.g., octahydroindolizinyl). , azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl, diazaspirononanyl, oxazabioctoheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, and tetrahydro-2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide.

[0060] Detailed Description of the Invention The present invention is based in part on the discovery of novel tricyclic compounds and their derivatives as PI3K alpha inhibitors. These compounds are shown herein to selectively target, bind to, inhibit and / or modulate the activity of PI3K alpha. The compounds are orally available and can be used to treat various diseases and disorders associated with or related to PI3K alpha activity, such as various types of cancer.

[0061] In one aspect, the present invention generally provides a compound of structural formula (I): [ka] [In the formula, Ring A is 0 to 6 R a is a 5- or 6-membered aromatic ring substituted with R 1 is Z B -R B and R 2 is Z C -R C and V is C or N; W is C or N; X is N, CH or CR X and R X is Z X -R X’ and Z B , Z C and Z X each independently represents a covalent bond, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O), NRS(O), S(O)NR, or C, optionally independently substituted with a heteroatom selected from the group consisting of N, S, and O. 1~4 is a linking group selected from saturated or unsaturated divalent hydrocarbon groups, R B and R C Each of the 1~6a 5-10 membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from an aliphatic chain, N, O and S, each of which is selected from one or more R b , R c or R x are substituted appropriately with R X is deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR', or -N(R)S(O)2R; R a , R b , R c and R x Each of the H, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O)R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O)2NRR' or -N(R)S(O)2R, or C 1~6 an optionally substituted group selected from alkyl or a 4- to 6-membered carbocyclic ring; However, at least one R a is not H, which is substituted on ring A, Each of R and R' is independently H, unsubstituted or substituted C 1~4alkyl, or an unsubstituted or substituted 4- to 6-membered carbocyclic ring, or R and R', when attached to the same C or N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; i is 1, 2, 3, 4, 5, or 6] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0062] In certain embodiments of (I), ring A is selected from 1 to 4 R a and a five-membered aromatic ring substituted with a ): [ka] [In the formula, Y 1 , Y 2 and Y 3 are independently CH, N, NH, O, S, or C(O), with the proviso that Y 1 , Y 2 and Y 3 At least one of them is neither N nor NH, but Y 1 , Y 2 and Y 3 at least one of is C or CH] It has.

[0063] In certain embodiments of (I), ring A is selected from 1 to 4 R a and a six-membered aromatic ring substituted with b ): [ka] [In the formula, Y 1 , Y 2 , Y 3 and Y 4 are independently CH, N, NH, O, S, or C(O), with the proviso that Y 1 , Y 2 , Y 3 and Y 4 At least two of them are neither N nor NH, but Y 1 , Y 2 , Y3 and Y 4 at least two of which are C or CH] It has.

[0064] (I)~(I b In certain embodiments of B is 0 to 3 R b Ring B having 0-4 ring heteroatoms independently selected from N, O and S, substituted with R C is 0 to 3 R c and a ring C, 5-10 membered monocyclic or bicyclic aryl or heteroaryl ring having 0-4 ring heteroatoms independently selected from N, O, and S, substituted with c ): [ka] (In the formula, j is 0, 1, 2, 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, 5, or 6) It has.

[0065] (I)~(I c In certain embodiments of Z B is NH-C(O), and Z c is a single bond, and the structural formula (I d ): [ka] It has.

[0066] (I)~(I c In certain embodiments of Z B is C(O)-NH, and Z c is a single bond, and the structural formula (I e ): [ka] It has.

[0067] (I)~(I e In certain embodiments of ), V is C, W is N, and the bond between them is a single bond.

[0068] (I)~(I e In certain embodiments of ), V is N, W is C, and the bond between them is a single bond.

[0069] (I)~(I e In certain embodiments of ), V is C, W is C and the bond between them is a double bond.

[0070] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0071] In certain embodiments, Y 1 and Y 2 Each of R a is NH optionally substituted with

[0072] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0073] In certain embodiments, Y 1 and Y 2 is NH.

[0074] (I)~(I e In certain embodiments of), ring A is [ka] (In the formula, R a’ is H, optionally substituted C1~6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; R a” H, halo, optionally substituted C 1~6 Alkyl, NRR', CN, optionally substituted C 2~6 Alkynes, optionally substituted C 2~6 Substituted alkenes, optionally substituted C 1~6 alkoxyl, SO2R, NRSO2R'3, 4-6 membered carbocyclic or heterocyclic rings, provided that R a’ and R a” at least one of which is not H) is selected from.

[0075] In certain embodiments, R a” is selected from H, F, Cl, NH, OH, CH, CHF, CHF, CH, CHCHF, CHCHF, CHCF, CHFCF, CHCHOH, CH(OH)CH, CH(OH)CF, CHOH, CHCN, CHNH, CHN(CH), CHOCHF, CHOCF, NHCH, isopropyl, cyclopropyl, CCH, CHCH, CH-azetidine, CN, OCHF, SOCH, NHSOCH, CH-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0076] In certain embodiments, R a’’ are CH2CH2F, CH2CHF2, CH2CF3, CH2-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0077] CH2-Cyclopropyl, difluoro-propyl and trifluoro-propyl

[0078] (I)~(I e In certain embodiments of), ring A is [ka] (In the formula, Ra is H, Cl, F, CN, CH3 or CD3, R a’ are H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN, However, for each structure, R a and R a’ at least one of which is not H) is selected from.

[0079] In certain embodiments, R a’ is CH2CHF2 or CH2CF3.

[0080] In certain embodiments, R a is H.

[0081] In certain embodiments, R a is Cl, F, CN, CH3 or CD3.

[0082] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0083] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0084] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0085] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0086] In certain embodiments, Y 1 and Y 2 Each of the is CH.

[0087] (I)~(I e In certain embodiments of), ring A is [ka] (In the formula, each R a are independently selected from H, halo, CN, OH, C1-C4 alkyl, and C1-C4 alkoxy is selected from.

[0088] (I)~(I e In certain embodiments of a is not H.

[0089] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0090] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0091] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0092] (I)~(I e In certain embodiments of), ring A is [ka] is selected from.

[0093] (I)~(I e In certain embodiments of ), X is CH.

[0094] (I)~(I e In certain embodiments of X is.

[0095] (I)~(I e In certain embodiments of ), X is N.

[0096] (I)~(I e In certain embodiments of ), Ring B is a substituted or unsubstituted 5- or 6-membered monocyclic carbocyclyl or heterocyclic.

[0097] (I)~(I e In certain embodiments of ), ring B is a substituted or unsubstituted 5- or 6-membered monocyclic aryl or heteroaryl ring.

[0098] (I)~(I e In certain embodiments of ), Ring B is a substituted or unsubstituted 8-10 membered bicyclic carbocyclyl or heterocyclic.

[0099] (I)~(I e In certain embodiments of ), ring B is a substituted or unsubstituted 8-10 membered bicyclic aryl or heteroaryl ring.

[0100] Non-limiting examples of ring B are: [ka] Includes:

[0101] (I)~(I e In certain embodiments of), ring B is [ka] is selected from.

[0102] (I)~(I e In certain embodiments of), ring B is [ka] is selected from.

[0103] (I)~(I e In certain embodiments of), ring B is [ka] is selected from.

[0104] In certain embodiments, ring B is [ka] is.

[0105] (I)~(I e In certain embodiments of ), ring B is substituted or unsubstituted phenyl, pyridyl, pyridazinyl, or pyrazinyl.

[0106] In certain embodiments, Ring B is substituted or unsubstituted phenyl.

[0107] In certain embodiments, Ring B is substituted or unsubstituted pyridyl.

[0108] In certain embodiments, Ring B is substituted or unsubstituted pyridazinyl.

[0109] In certain embodiments, Ring B is substituted or unsubstituted pyrazinyl.

[0110] (I)~(I e In certain embodiments of ), Ring C is substituted or unsubstituted phenyl, pyridyl, pyridazinyl, or pyrazinyl.

[0111] In certain embodiments, Ring C is substituted or unsubstituted phenyl.

[0112] In certain embodiments, Ring C is substituted or unsubstituted pyridyl.

[0113] In certain embodiments, Ring C is substituted or unsubstituted pyridazinyl.

[0114] In certain embodiments, Ring C is substituted or unsubstituted pyrazinyl.

[0115] (I)~(I e In certain embodiments of ), each of ring B and ring C is independently substituted or unsubstituted phenyl.

[0116] Non-limiting examples of ring C are: [ka] Includes:

[0117] In certain embodiments, ring C is [ka] is.

[0118] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I f ): [ka] (wherein at least one R a is selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN It has.

[0119] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I g ): [ka] It has.

[0120] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I g’ ): [ka] (Wherein, ring A is [ka] (selected from It has.

[0121] In certain embodiments, ring A is [ka] (In the formula, R a’ is H, optionally substituted C 1~6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; R a” is H, halo, optionally substituted C 1~6 Alkyl, NRR', CN, optionally substituted C 2~6 Alkynes, optionally substituted C 2~6 Substituted alkenes, optionally substituted C 1~6 alkoxyl, SO2R, NRSO2R'3, 4-6 membered carbocyclic or heterocyclic rings, provided that R a’ and R a” at least one of which is not H) is selected from.

[0122] In certain embodiments, ring A is [ka] is.

[0123] In certain embodiments, R a”is selected from H, F, Cl, NH, OH, CH, CHF, CHF, CH, CHCHF, CHCHF, CHCF, CHFCF, CHCHOH, CH(OH)CH, CH(OH)CF, CHOH, CHCN, CHNH, CHN(CH), CHOCHF, CHOCF, NHCH, isopropyl, cyclopropyl, CCH, CHCH, CH-azetidine, CN, OCHF, SOCH, NHSOCH, CH-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0124] In certain embodiments, R a’’ are CH2CH2F, CH2CHF2, CH2CF3, CH2-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0125] In certain embodiments, ring A is [ka] (In the formula, R a is H, Cl, F, CN, CH3 or CD3, R a’ are H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN, However, for each structure, R a and R a’ at least one of which is not H) is selected from.

[0126] In certain embodiments, ring A is [ka] is.

[0127] In certain embodiments, ring A is [ka] is.

[0128] In certain embodiments, R a’ is selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3, and CH2CN. a’ is CH2CHF2 or CH2CF3.

[0129] In certain embodiments, R a is H. In certain embodiments, R a are Cl, F, CN, CH3 and CD3.

[0130] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I h ): [ka] It has.

[0131] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I i ): [ka] It has.

[0132] In certain embodiments, the compounds of the present invention are 1 In the following chirality: [ka] Shows.

[0133] In certain embodiments, the compounds of the present invention are 1 In the following chirality: [ka] Shows.

[0134] (I)~(I eIn certain embodiments, the compounds of the present invention have the structural formula (I j ): [ka] It has.

[0135] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I k ): [ka] It has.

[0136] In certain embodiments, X is CH.

[0137] (I)~(I e In certain embodiments, the compounds of the present invention are represented by structural formula I k’ : [ka] (Wherein, ring A is [ka] (selected from It has.

[0138] In certain embodiments, ring A is [ka] (In the formula, R a’ is H, optionally substituted C 1~6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; R a” is H, halo, optionally substituted C 1~6 Alkyl, NRR', CN, optionally substituted C 2~6 Alkynes, optionally substituted C 2~6 Substituted alkenes, optionally substituted C 1~6alkoxyl, SO2R, NRSO2R'3, 4-6 membered carbocyclic or heterocyclic rings, provided that R a’ and R a” at least one of which is not H) is selected from.

[0139] In certain embodiments, ring A is [ka] is.

[0140] In certain embodiments, R a” is selected from H, F, Cl, NH, OH, CH, CHF, CHF, CH, CHCHF, CHCHF, CHCF, CHFCF, CHCHOH, CH(OH)CH, CH(OH)CF, CHOH, CHCN, CHNH, CHN(CH), CHOCHF, CHOCF, NHCH, isopropyl, cyclopropyl, CCH, CHCH, CH-azetidine, CN, OCHF, SOCH, NHSOCH, CH-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0141] In certain embodiments, R a’’ are CH2CH2F, CH2CHF2, CH2CF3, CH2-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0142] In certain embodiments, ring A is [ka] (In the formula, R a is H, Cl, F, CN, CH3 or CD3, R a’ are H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN, However, for each structure, R a and R a’at least one of which is not H) is selected from.

[0143] In certain embodiments, ring A is [ka] is.

[0144] In certain embodiments, ring A is [ka] is.

[0145] In certain embodiments, R a’ is selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3, and CH2CN. a’ is CH2CHF2 or CH2CF3.

[0146] In certain embodiments, R a is H. In certain embodiments, R a are Cl, F, CN, CH3 and CD3.

[0147] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I l ): [ka] It has.

[0148] (I)~(I e In certain embodiments, the compounds of the present invention have the structural formula (I m ): [ka] It has.

[0149] (I)~(I e In certain embodiments of the present invention, the compound of formula (I) is R2 exhibits the following chirality at the carbon to which it is attached: [ka]

[0150] (I)~(I e In certain embodiments of the present invention, the compound of formula (I) is R 2 exhibits the following chirality at the carbon to which it is attached: [ka]

[0151] Non-limiting examples of compounds of the present invention are: [ka] [ka] [ka] (In the formula, Each R a are independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; Each R a’ are independently H or optionally substituted C 1~6 is alkyl, However, R a and R a’ at least one of which is not H) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0152] Non-limiting examples of compounds of the present invention are: [ka] [ka] (In the formula, Each Ra are independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; Each R a’ are independently H or optionally substituted C 1~6 is alkyl, However, R a and R a’ at least one of which is not H) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0153] In certain embodiments, R a and R a’ At least one of, if present, is CH2CH3, CD2CD3, CH2CHF2, CH2CF3 or CH2CN.

[0154] In certain embodiments, R a and R a’ At least one of, if present, is CH2CHF2 or CH2CF3.

[0155] In certain embodiments, the chirality is as follows: [ka]

[0156] In certain embodiments, the chirality is as follows: [ka]

[0157] Non-limiting examples of compounds of the present invention are: [ka] [ka] [ka] (In the formula, each R a are independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy, provided that at least one R a is not H) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0158] Non-limiting examples of compounds of the present invention are: [ka] [ka] [ka] (In the formula, each R a are independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy, provided that at least one R a is not H) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0159] In certain embodiments, the chirality is as follows: [ka]

[0160] In certain embodiments, the chirality is as follows: [ka]

[0161] In certain embodiments, the compounds of the present invention are 2 exhibits the following chirality at the carbon to which it is attached: [ka]

[0162] In certain embodiments, the compounds of the present invention are 2 exhibits the following chirality at the carbon to which it is attached: [ka]

[0163] Non-limiting examples of compounds of the present invention are: [ka] [ka] [ka] Also includes.

[0164] Non-limiting examples of compounds of the present invention also include those listed in Table 1 in the Examples section.

[0165] In certain embodiments, the compounds of the present invention have one or more deuterium atoms in place of hydrogen. In certain embodiments, the compounds of the present invention have one deuterium atom in place of a hydrogen atom.

[0166] In another aspect, the invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0167] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0168] In yet another aspect, the invention generally relates to unit dosage forms that include the pharmaceutical compositions disclosed herein.

[0169] In certain embodiments, the unit dosage form is in the form of a tablet or capsule.

[0170] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, salts or electrolytes such as sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0171] 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 certain embodiments, the compounds of the formula herein are administered transdermally (for example, using a transdermal patch).Other formulations can be conveniently provided in unit dosage form, for example, tablets and sustained-release capsules, and liposomes, and can be prepared by any method well known in the art of pharmacy.See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[0172] Such preparatory methods include the step of bringing into association the molecule to be administered with ingredients such as the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0173] 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) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (ii) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (iii) humectants, such as glycerol; (iv) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (v) solution retarders. The formulation may be mixed with (i) an absorbent, such as a sorbent, a sorbent, a sorbent-resistant sorbent, a sorbent-coated sorbent, a sorbent-resistant ...

[0174] 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 ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of these substances.In addition to such inert diluents, the composition may also contain additional agents such as wetting, emulsifying, suspending, sweetening, flavoring, or flavoring agents.

[0175] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.

[0176] In yet another aspect, the invention generally relates to a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0177] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Kα, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0178] In certain embodiments, the disease or disorder is a cell proliferative disorder.

[0179] In yet another aspect, the present invention generally relates to a method for treating or reducing cancer or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0180] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0181] Examples of cancers targeted in the present invention include, but are not limited to, head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer and rectal cancer), etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myeloma), sarcoma (e.g., osteosarcoma and soft tissue sarcoma), skin cancer, brain tumor, carcinoma, squamous cell carcinoma, adenocarcinoma, neuroma, melanoma, etc. Examples include lung cancer, pancreatic cancer, rectal cancer, colon cancer, colorectal cancer, and uterine cancer. In certain embodiments, the squamous cell carcinoma is cancer of the cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus. In one embodiment, the adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, or ovary. In certain embodiments, the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, leukemia, or uterine cancer.

[0182] In certain embodiments, the cancer is selected from the group consisting of ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, small cell and non-small cell lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, gastric cancer, bile duct cancer, hepatocellular carcinoma, thyroid cancer, and hematological malignancies.

[0183] In certain embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.

[0184] In certain embodiments, the subject has a mutated class IA PI3K p110α.

[0185] In certain embodiments, the subject has at least one of the following PI3K alpha mutations: H1047R, E542K, and E545K.

[0186] In certain embodiments, the subject does not have a PI3K alpha mutant protein.

[0187] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormonal therapy.

[0188] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder.

[0189] In yet another aspect, the invention relates generally to the use of the compounds disclosed herein for treating a disease or disorder.

[0190] The amount of active compound to be administered depends on the subject being treated, the severity of disorder or condition, route of administration, distribution of compound and the discretion of the prescribing physician.In some cases, the dosage level below the lower limit of the aforementioned range may be more than sufficient, while in other cases, even higher doses can be used without causing harmful side effects, and this higher dose is typically divided into several smaller doses for daily administration.

[0191] Any suitable route of administration may be used, e.g., oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalation, buccal, intraperitoneal, rectal, intrathoracic, and intrathecal. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the treatment and the nature of the active compound used.

[0192] In certain preferred embodiments, compound is orally administered.The pharmaceutical composition of the present invention suitable for oral administration can be provided as individual units such as capsules, sachets or tablets, each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in aqueous liquid or non-aqueous liquid; or as oil-in-water liquid emulsion or water-in-oil liquid emulsion, or packed into liposome, and as a bolus, etc.Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the compound absorption rate.

[0193] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with an appropriate binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored and can be formulated to achieve slow or controlled release of the active ingredient therein. Methods for formulating such slow 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 are described in several issued U.S. patents, some of which include, but are not limited to, U.S. Pat. Nos. 4,369,172 and 4,842,866, and the references cited therein. Coatings can be used for intestinal compound delivery (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is in the form of enteric-coated pellets, the enteric layer of which comprises hydroxypropylmethylcellulose acetate succinate.

[0194] For oral use tablets, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspension is administered orally, active ingredient is combined with emulsifying and suspending agent.If necessary, certain sweeteners and / or flavors and / or coloring agents can be added.

[0195] Compositions suitable for topical administration include lozenges, which comprise the ingredient in a flavored base, usually sucrose and gum arabic or tragacanth; and pastilles, which comprise the active ingredient in an inert base such as gelatin and glycerin, or sucrose and gum arabic.

[0196] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents.The preparations may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0197] Such injection solutions may be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injections, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0198] The compounds of the present invention may also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes may be used. The composition in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, etc. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0199] The pharmaceutical composition of this invention may be administered in the form of suppositories for rectal administration. 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, and therefore melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0200] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0201] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topical-transdermal patches and iontophoretic administration are also encompassed by this invention.

[0202] The therapeutic methods disclosed herein may be used in combination with or in addition to other treatments. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy.

[0203] Exemplary additional therapeutically active agents include, but are not limited to, drug compounds, small organic molecules such as, for example, compounds approved by the U.S. Food and Drug Administration (FDA) as set forth in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0204] In certain embodiments, compounds of the invention may be administered in combination with endocrine therapy, for example, agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0205] In some embodiments, the compounds of the 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 invention may be administered in combination with anti-HER2 agents such as trastuzumab or pertuzumab.

[0206] In certain embodiments, the methods disclosed herein are combined with one or more of immune checkpoint blockade, simultaneous T cell signaling, and tumor-targeted antibody therapy.

[0207] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0208] In certain embodiments, the method further comprises administering radiation therapy to the subject. In certain embodiments, the method further comprises administering targeted therapy to the subject. In certain embodiments, the method further comprises administering immunotherapy to the subject. In certain embodiments, the method further comprises administering hormone therapy to the subject.

[0209] As used herein, the term "chemotherapeutic agent" means a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), and rituximab (TYKERB®, GSK572016, GlaxoSmithKline). Kline], lonafarnib (SCH66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib [IRESSA®, AstraZeneca], alkylating agents such as AG1478, AG1571 (SU 5271; Sugen), thiotepa and CYTOXAN® cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine (t ethylenimines and methylamelamines, including methyltrimethylomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatins; kallistatins; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1);spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; enediyne antibiotics [e.g., calicheamicin, particularly calicheamicin gamma II and calicheamicin omega II (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores], aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilins, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomol Antibiotics such as folino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin, epirubicin, esonibicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamniprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calucelone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid ; Eniluracil; Amsacrine; Bestravsil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diazicon; Elformitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraeline; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS) Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor Free), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France);Examples of anti-inflammatory drugs include chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®), ibandronate, CPT-11, the topoisomerase inhibitor RFS2000, difluoromethylomithine (DMFO), retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0210] Examples of alternative (or additional) agents or treatments include immunotherapy (e.g., PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonists, cell signaling inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, etc.), mitotic inhibitors (e.g., paclitaxel, vincristine, etc.), and / or anti-cancer drugs (e.g., rituximab ... The therapeutic agents may include, but are not limited to, cyclosporine, 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.).

[0211] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds as being within its scope, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers and mixtures thereof are intended to be included in this invention.

[0212] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, when only two isomers are combined, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present invention. Those skilled in the art will readily understand that similar ratios are contemplated for more complex isomer mixtures.

[0213] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomer.

[0214] Isotopically labeled compounds are also within the scope of the present disclosure.As used herein, " isotopically labeled compounds " refers to the compounds disclosed herein, including pharmaceutical salts and prodrugs thereof, each of which is described herein, in which one or more atoms are replaced with atoms having atomic masses or mass numbers different from the atomic masses or mass numbers that are normally found in nature.The examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Contains Cl.

[0215] By isotopically labeling the compounds disclosed herein, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred due to their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can afford certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. The isotopically labeled compounds disclosed herein, including pharmaceutical salts, esters, and prodrugs thereof, may be prepared by any means known in the art.

[0216] Furthermore, the normally abundant hydrogen ( 1 Substitution of heavier isotopes, such as deuterium (H), can confer certain therapeutic advantages, for example, due to improved absorption, distribution, metabolism, and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. 12 C 13It may also benefit from substitution by C. (See WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431.)

[0217] 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, diastereomeric and other mixtures of such isomers, are within the scope of this disclosure.

[0218] After their preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 95% or more by weight of the compound ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the present invention are greater than 99% pure.

[0219] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0220] Any suitable route of administration may be used, e.g., parenteral, intravenous, subcutaneous, intramuscular, intracerebroventricular, internal, intraperitoneal, rectal, or oral administration. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the treatment and the nature of the active compound used.

[0221] Compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0222] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0223] The compounds of the present invention may also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes may be used. The composition in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, etc. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0224] The total daily dose of the compositions of the invention administered to a human or other mammalian host in single or divided doses may be, for example, in an amount of 0.0001 to 300 mg / kg body weight, more usually 1 to 300 mg / kg body weight per day. A dose of 0.0001 to 300 mg / kg body weight may also be given twice daily.

[0225] The materials, compositions, and components disclosed herein can be used for, with, in preparation for, or are products of the disclosed methods and compositions. When combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that although specific reference to various individual and collective combinations and permutations of each of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, when a method is disclosed and described, and several modifications that can be made to several molecules included in the method are discussed, unless specifically indicated to the contrary, any and all combinations and permutations of the method and possible modifications are specifically contemplated. Similarly, any subset or combination of these is specifically contemplated and disclosed. This concept applies to all aspects of this disclosure, including, but not limited to, steps in methods using the disclosed compositions. Thus, when there are various additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method step or combination of method steps of the disclosed method, and each such combination or subset of combinations should be considered specifically contemplated and disclosed. [Example]

[0226] The following examples are given for the purpose of illustrating the present invention, and are not intended to limit the scope or spirit of the present invention.

[0227] The compounds of the present invention, including those specifically disclosed hereinabove and hereinafter, can be prepared as described in the following schemes. Although the present invention has been described in detail using preferred embodiments, those skilled in the art should understand that the modifications, variations and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.

[0228] Table 1. Exemplary Compounds [Table 1] TIFF2025526507000075.tif250112 TIFF2025526507000076.tif250109 TIFF2025526507000077.tif250113 TIFF2025526507000078.tif232116 TIFF2025526507000079.tif250110 TIFF2025526507000080.tif243116 TIFF2025526507000081.tif250111 TIFF2025526507000082.tif241116 TIFF2025526507000083.tif250114 TIFF2025526507000084.tif250111 TIFF2025526507000085.tif250109 TIFF2025526507000086.tif238116 TIFF2025526507000087.tif250111 TIFF2025526507000088.tif253116 TIFF2025526507000089.tif250110 TIFF2025526507000090.tif250113 TIFF2025526507000091.tif250110 TIFF2025526507000092.tif250111 TIFF2025526507000093.tif237116 TIFF2025526507000094.tif250111 TIFF2025526507000095.tif97116

[0229] Representative synthesis procedure List of abbreviations [Table 2] TIFF2025526507000097.tif250130 TIFF2025526507000098.tif250130 TIFF2025526507000099.tif250130 TIFF2025526507000100.tif250130 TIFF2025526507000101.tif11138

[0230] Common LCMS methods: Shimadzu LCMS2020, reversed-phase column (Shim-Pack Scepter C18, 33 × 3.0 mm, 3 μm), A: HO / MeCN / FA = 90 / 10 / 0.05; B: elution with MeCN; detection: MS, ELS, UV (100 μL split to MS with in-line UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray-atmospheric pressure ionization.

[0231] General HPLC purification method: Apparatus: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281. Column: YMC-Triart C18, 250 x 20 mm, 5 µm; Welch Ultimate XB-C18, 250 x 21.2 mm, 5 µm. Detection wavelength: 220, 254 nM. Flow rate: 15 ml / min - 20 ml / min; Run time: 8 min; Column temperature: 25°C.

[0232] Representative chiral preparative SFC conditions and methods for the separation of racemic compounds: Preparative SFC conditions for Examples 29 and 30: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IB, 250 x 21.2 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B25% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 3 minutes Dissolution time: 2 hours

[0233] Preparative SFC conditions for Examples 36 and 37: Equipment: Waters Thar 80 preparative SFC Column: ChiralCel OD, 250 x 21.2 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B20% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 12 minutes Dissolution time: 2 hours

[0234] Preparative SFC conditions for Examples 39 and 40: Equipment: Waters Thar 80 preparative SFC Column: ChiralPak IC, 250 x 30 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B60% Flow rate: 50mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 3.2 minutes Dissolution time: 2 hours

[0235] Preparative SFC conditions for Examples 42 and 43: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 150×20mm ID, 5μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B30% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 8 minutes Dissolution time: 2 hours

[0236] Preparative SFC conditions for Examples 57 and 58: Equipment: Waters Thar 80 preparative SFC Column: ChiralPak IA, 250 x 21.2 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH (MeOH, neutral) Concentration gradient: B40% Flow rate: 30mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 15 minutes Dissolution time: 2 hours

[0237] Preparative SFC conditions for Examples 64 and 65: Preparative SFC separation method Equipment: Shimadzu PREP SOLUTION SFC Column: (R,R)-WHELK, 250 x 30 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B50% Flow rate: 60mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 10 minutes Dissolution time: 2 hours

[0238] Preparative SFC conditions for Examples 77 and 78: Equipment: Waters Thar 80 preparative SFC Column: (R,R)-WHELK, 250 x 30 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B40% Flow rate: 60mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 10 minutes Dissolution time: 3 hours

[0239] Preparative SFC conditions for Examples 87 and 88: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 150×20mm ID, 5μm Mobile phase: A is CO2 and B is MEOH + 0.1% NH3H2O Concentration gradient: B50% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 7 minutes Dissolution time: 4 hours

[0240] Preparative SFC conditions for Examples 125 and 126 Equipment: Waters Thar 80 preparative SFC Column: (R,R)-WHELK, 250 x 30 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B40% Flow rate: 60mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 15 minutes Dissolution time: 2 hours

[0241] Preparative SFC conditions for Examples 134 and 135: Equipment: Waters Thar 80 preparative SFC Column: ChiralPak C-IG, 250×30mm ID, 5μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B30% Flow rate: 60mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 15 minutes Dissolution time: 3 hours

[0242] Preparative SFC conditions for Examples 141-144: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 150×20mm ID, 5μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B10% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 20 minutes Dissolution time: 3 hours

[0243] Preparative SFC conditions for Examples 145 and 146: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 150×20mm ID, 5μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B10% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 10 minutes Dissolution time: 3 hours

[0244] Preparative SFC conditions for Examples 147 and 148: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak AS, 250 x 20 mm ID, 5 μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B15% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 10 minutes Dissolution time: 2 hours

[0245] Preparative SFC conditions for Examples 149 and 150: Equipment: Waters Thar 80 preparative SFC Column: ChiralCel OX, 250 x 20 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B30% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 13 minutes Dissolution time: 2 hours

[0246] Preparative SFC conditions for Examples 151 and 152: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak IH, 150×20mm ID, 5μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B15% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 10 minutes Dissolution time: 3 hours

[0247] Preparative SFC conditions for Examples 154 and 155: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak AS, 250 x 20 mm ID, 5 μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B15% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 10 minutes Dissolution time: 2 hours

[0248] Preparative SFC conditions for Examples 156 and 157: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralPak AS, 250 x 20 mm ID, 5 μm Mobile phase: A is CO2 and B is MEOH Concentration gradient: B10% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 15 minutes Dissolution time: 2 hours

[0249] Preparative SFC conditions for Examples 158 and 159: Equipment: Shimadzu PREP SOLUTION SFC Column: ChiralCel OX, 250 x 20 mm ID, 5 μm Mobile phase: A is CO2 and B is MeOH Concentration gradient: B20% Flow rate: 40mL / min Back pressure: 100bar Column temperature: 35℃ Wavelength: 220nm Cycle time: 15 minutes Dissolution time: 3 hours Synthesis Procedure:

[0250] [Example 1] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0251] Step A: To a solution of 3-amino-5,6,7,8-tetrahydro-2H-chromen-2-one (1.3 g, 7.87 mmol, 1.0 equiv.) in MeCN (15 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (2.1 g, 9.44 mmol, 1.2 equiv.) and pyridine (1.2 g, 15.74 mmol, 2.0 equiv.). The reaction mixture was stirred at 30 °C for 3 hours. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over Na SO , and concentrated to give a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether / EtOAc=5:1) to give 3-fluoro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-3-yl)-5-(trifluoromethyl)benzamide (2.7 g, 97%). 1 H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 2.58-2.48 (m, 4H), 1.86-1.76 (m, 4H). LCMS: m / z 354.1 ([MH] - ).

[0252] Step B: To a solution of 3-fluoro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-3-yl)-5-(trifluoromethyl)benzamide (2.7 g, 7.6 mmol, 1.0 equiv.) and 1-(4-methoxybenzyl)-1H-pyrrole-2,5-dione (3.6 g, 16.72 mmol, 2.2 equiv.) in decahydronaphthalene (65 mL), Ru / C (2.2 g, 5 wt.%) was added. The reaction mixture was heated to 190 °C and stirred for 12 h. The mixture was then filtered, the filtrate was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc 20:1) to give 3-fluoro-N-(2-(4-methoxybenzyl)-1,3-dioxo-2,3,6,7,8,9-hexahydro-1H-benzo[e]isoindol-4-yl)-5-(trifluoromethyl)benzamide (500 mg, 13%). LCMS: m / z 525.0 ([M-H] - ).

[0253] Step C: To a solution of 3-fluoro-N-(2-(4-methoxybenzyl)-1,3-dioxo-2,3,6,7,8,9-hexahydro-1H-benzo[e]isoindol-4-yl)-5-(trifluoromethyl)benzamide (300.0 mg, 0.57 mmol, 1.0 equiv.) in THF (5 mL) was added (2-chloro-5-fluorophenyl)magnesium bromide (2.9 mL, 0.5 M in THF, 1.43 mmol, 2.5 equiv.) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h. Water (10 mL) was then added to the mixture, which was then extracted with ethyl acetate (5 mL × 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc 5:1) to give N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-1-oxo-2,3,6,7,8,9-hexahydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (42.8 mg, 11%). LCMS: m / z 655.1 ([MH] - ).

[0254] Step D: To a solution of N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-1-oxo-2,3,6,7,8,9-hexahydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.076 mmol, 1.0 equiv) in toluene (1.5 mL) was added DDQ (69.0 mg, 0.304 mmol, 4.0 equiv) at 25 °C under a N atmosphere. The reaction mixture was heated to reflux and stirred for 12 h. Water (5 mL) was added to the mixture, which was then extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (10 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative TLC (eluted with petroleum ether / EtOAc = 5 / 1) to give N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (9 mg, 18%). LCMS: m / z 651.0 ([MH] - ).

[0255] Step E: To a solution of N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (9 mg, 0.014 mmol, 1.0 equiv) in TFA (0.3 mL) was added EtSiH (8.1 mg, 0.07 mmol, 5.0 equiv). The reaction mixture was heated to 90° C. and stirred for 5 hours. The reaction mixture was then purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1.1 mg, 15%) as a solid. 1H NMR (400 MHz, CD3OD): δ 9.22 (d, J = 8.4 Hz, 1H), 8.05 - 8.04 (m, 2H), 7.75 - 7.66 (m, 6H), 7.29-7.26 (m, 1H), 7.03-6.98 (m, 1H), 6.40 (s, 1H). LCMS: m / z 515.0 ([MH] - ).

[0256] [Example 2] N-[3-(2-chloro-5-fluorophenyl)-1,6-dioxo-1,2,3,7-tetrahydropyrrolo[3,4-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0257] Step A: To a solution of 1,2,3,4-tetrahydroisoquinolin-1-one (10 g, 67.9 mmol) in HSO (130 mL) at 0 °C, fuming HNO (3.4 mL, 67.9 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes. The reaction mixture was slowly poured into ice water (500 mL), and the mixture was subsequently filtered. The filter cake was azeotroped with toluene and evaporated to dryness in vacuo to give 7-nitro-1,2,3,4-tetrahydroisoquinolin-1-one (10.27 g, 53.4 mmol, 79%). 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 8.4, 2.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 3.44 (td, J = 6.6, 2.8 Hz, 2H), 3.07 (t, J = 6.6 Hz, 2H).

[0258] Step B: To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinolin-1-one (10 g, 52.0 mmol) in HSO (50 mL) was added NBS (11.1 g, 62.4 mmol) in portions. The reaction mixture was stirred at 60 °C for 1 h. The cooled mixture was diluted with ice water (500 mL) and filtered. The filter cake was azeotroped with toluene and dried to give 5-bromo-7-nitro-1,2,3,4-tetrahydroisoquinolin-1-one (13 g, 47.9 mmol, 92.2%). LCMS: m / z 271 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 5.6, 2.4 Hz, 2H), 8.43 (s, 1H), 3.47 (td, J = 6.6, 2.8 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H).

[0259] Step C: To a solution of 5-bromo-7-nitro-1,2,3,4-tetrahydroisoquinolin-1-one (10 g, 36.9 mmol) in DMF (150 mL) was added ethanedioic acid (2.62 mL, 55.3 mmol), acetic anhydride (5.20 mL, 55.3 mmol), Pd(OAc) (0.41 g, 1.845 mmol), Xant-Phos (2.13 g, 3.68 mmol), and DIEA-ethyldiisopropylamine (18.2 mL, 110 mmol). The reaction mixture was stirred at 100 °C under N for 6 h. The cooled reaction mixture was concentrated. The residue was purified by silica gel chromatography (30 g column) using 0-100% EtOAc / hexanes to give 7-nitro-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (2 g, 8.46 mmol, 23%). LCMS: m / z 237.0 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.88 (s, 1H), 8.73 (d, J = 2.6 Hz, 1H), 8.67 (d, J = 2.6 Hz, 1H), 8.46 (s, 1H), 3.40 (t, J = 6.2 Hz, 4H).

[0260] Step D: To a solution of 7-nitro-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (1 g, 4.23 mmol) in MeOH (50 mL) was added 2-isocyano-2-methylpropane (390 mg, 4.66 mmol), (4-methoxyphenyl)methanamine (640 mg, 4.65 mmol), and 2-chloro-5-fluorobenzene-1-carbaldehyde (0.74 g, 4.65 mmol). The reaction mixture was stirred at 20 °C under N for 12 h. The mixture was then concentrated and the residue was purified by silica gel chromatography (10 g column) using 0-80% EtOAc / hexanes to give N-[1-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl)amino]-2-oxoethyl]-N-[(4-methoxyphenyl)methyl]-7-nitro-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (2 g, 3.35 mmol, 79%). LCMS: m / z 597.1 [M+H] + .

[0261] Step E: To a solution of N-[1-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl)amino]-2-oxoethyl]-N-[(4-methoxyphenyl)methyl]-7-nitro-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (1 g, 1.67 mmol) in DMSO-d (50 mL) was added potassium 2-methylpropan-2-olate (470 mg, 4.18 mmol). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water and extracted with EA (200 mL × 3). The organic phase was dried over Na SO and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0-80% EtOAc / hexanes to give 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-4-nitro-2,3,6,7,8,9-hexahydro-1H-pyrrolo[4,3-f]isoquinoline-1,6-dione (440 mg, 0.860 mmol, 51%). LCMS: m / z 510.2 [M + H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.96 (s, 1H), 7.96 (dd, J = 10.5, 3.2 Hz, 1H), 7.80 (d, J = 6.2 Hz, 2H), 7.68 (d, J = 7.2 Hz, 1H), 7.16 - 7.09 (m, 1H), 7.00 (dd, J = 8.8, 5.2 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 4.54 (d, J = 15.2 Hz, 1H), 4.19 (d, J = 15.2 Hz, 1H), 3.65 (s, 3H).

[0262] Step F: To a solution of 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-4-nitro-2,3,6,7-tetrahydro-1H-pyrrolo[4,3-f]isoquinoline-1,6-dione (200 mg, 0.39 mmol) in MeOH (10 mL) was added 10% Pd / C (208 mg). The reaction mixture was stirred under H (15 Psi) at 20 °C for 1 h. The mixture was filtered and concentrated to give 4-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-2,3,6,7,8,9-hexahydro-1H-pyrrolo[4,3-f]isoquinoline-1,6-dione (90 mg, 0.187 mmol, 48%). LCMS: m / z 480.1 [M+H] + .

[0263] Step G: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-2,3,6,7-tetrahydro-1H-pyrrolo[4,3-f]isoquinoline-1,6-dione (90 mg, 0.188 mmol) in DCM (15 mL) was added 5-fluoro-3-(trifluoromethyl)benzoic acid (46.8 mg, 0.225 mmol), pyridine (74.2 mg, 0.938 mmol), and dichlorophosphinyl chloride (43.1 mg, 0.281 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water and extracted with DCM (30 mL × 3). The organic phase was dried over Na SO and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0–80% EtOAc / hexanes to give N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1,6-dioxo-1,2,3,7-tetrahydropyrrolo[4,3-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.030 mmol, 15%). LCMS: m / z 668 [MH] + .

[0264] Step H: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1,6-dioxo-1,2,3,7-tetrahydropyrrolo[4,3-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.022 mmol) in TFA (4 mL) was added triethylsilane (1 mL, 6.19 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo to give N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1,6-dioxo-1,2,3,7-tetrahydropyrrolo[3,4-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.021 mmol, 92%). LCMS: m / z 654.1 [M+H] + .

[0265] Step I: To a solution of N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1,6-dioxo-1,2,3,7-tetrahydropyrrolo[3,4-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.023 mmol) in TFA (4 mL) was added trifluoromethanesulfonic acid (3.44 mg, 0.023 mmol). The reaction mixture was stirred at 70° C. for 1 hour. The cooled reaction mixture was concentrated and the residue was purified by preparative TLC (EA) to give N-[3-(2-chloro-5-fluorophenyl)-1,6-dioxo-1,2,3,7-tetrahydropyrrolo[3,4-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7.3 mg, 0.014 mmol, 60%). LCMS: m / z 534 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.71 - 7.66 (m, 3H), 7.40 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 3.8 Hz, 1H), 7.00 (d, J = 5.2 Hz, 1H), 6.84 (d, J = 73.4 Hz, 1H), 6.30 (brs, 1H).

[0266] [Example 3] N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0267] Step A: To a solution of 1H-indazole-6-carbaldehyde (2.0 g, 13.7 mmol, 1.0 equiv.) and K2CO3 (3.8 g, 27.4 mmol, 2.0 equiv.) in DMF (15 mL) was added dropwise a solution of I2 (5.9 g, 23.3 mmol, 1.7 equiv.) in DMF (15 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. An aqueous solution of Na2SO4 (3.30 g) / K2CO3 (0.2 g) / HO (30 mL) was then added, and the solution was stirred for 1 h. The product was then precipitated by pouring the solution onto ice-water (300 mL) and collected by vacuum filtration to give 3-iodo-1H-indazole-6-carbaldehyde (2.3 g, 62%). LCMS: m / z 271.0 ([M-H] - ). 1 H NMR (300 MHz, DMSO-d6): δ 14.04 (brs, 1H), 10.14 (s, 1H), 8.19 (s, 1H), 7.78-7.54 (m, 2H).

[0268] Step B: To a solution of 3-iodo-1H-indazole-6-carbaldehyde (27.0 g, 99.2 mmol, 1.0 equiv) in HSO (98%, 300 mL) at 0 °C was added HNO (7.5 g, 119.1 mmol, 1.2 equiv) dropwise. The reaction mixture was stirred at room temperature for 3 h. The product was then precipitated by pouring the solution onto ice water (600 mL) and collected by vacuum filtration to give 3-iodo-5-nitro-1H-indazole-6-carbaldehyde (32.0 g, HPLC ca. 85%, 86%). LCMS: m / z 315.9 ([M-H] - ). 1 H NMR (300 MHz, DMSO-d6): δ 14.48 (brs, 1H), 10.29 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H).

[0269] Step C: To a solution of 3-iodo-5-nitro-1H-indazole-6-carbaldehyde (10.0 g, 31.5 mmol, 1.0 equiv) in HSO (98%, 100 mL) at 0 °C was added NBS (8.4 g, 47.3 mmol, 1.5 equiv). The reaction mixture was stirred at 30 °C for 5 h. The product was then precipitated by pouring the solution onto ice water (300 mL) and collected by vacuum filtration to give 7-bromo-3-iodo-5-nitro-1H-indazole-6-carbaldehyde (8.1 g, HPLC ∼78%, 51%). LCMS: m / z 393.8, 395.7 ([M-H] - ). 1 H NMR (300 MHz, DMSO-d6): δ 14.93 (brs, 1H), 10.24 (s, 1H), 8.28 (s, 1H).

[0270] Step D: To a solution of 7-bromo-3-iodo-5-nitro-1H-indazole-6-carbaldehyde (8.1 g, 20.5 mmol, 1.0 equiv.) in THF (100 mL) was added (2-chloro-5-fluorophenyl)magnesium bromide (204.6 mL, 0.5 M in THF, 102.3 mmol, 5.0 equiv.) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Water (150 mL) was then added to the mixture, which was then extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc 3:1) to give (7-bromo-3-iodo-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanol (10.0 g, 93%). LCMS: m / z 523.8, 525.7 ([M-H] - ). 1 H NMR (300 MHz, DMSO-d6): δ 14.40 (brs, 1H), 8.00 (s, 1H), 7.50 (dd, J = 9.0, 5.4 Hz, 1H), 7.38-7.00 (m, 2H), 6.82 (d, J = 6.0 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H).

[0271] Step E: To a solution of (7-bromo-3-iodo-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanol (10.0 g, 19.0 mmol, 1.0 equiv) in DCM (100 mL) at 25 °C was added DMP (12.1 g, 28.5 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether / EtOAc = 5:1) to give (7-bromo-3-iodo-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (7.1 g, 71%). LCMS: m / z 521.7, 523.8 ([M-H] - ).

[0272] Step F: To a solution of (7-bromo-3-iodo-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (500 mg, 0.95 mmol, 1.0 equiv) and Fe (266.1 mg, 4.8 mmol, 5.0 equiv) in EtOH (10 mL) at 50 °C, NH Cl (25.5 mg, 0.48 mmol, 0.5 equiv) in HO (5 mL) was added dropwise. The reaction mixture was heated to 90 °C and stirred for 1 h. Water (10 mL) and ethyl acetate (5 mL) were then added to the mixture, which was filtered. The filtrate was then extracted with ethyl acetate (15 mL × 2). The combined organic phase was washed with brine (10 mL), dried over Na SO , and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc 3:1) to give (5-amino-7-bromo-3-iodo-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (300 mg, 64%). LCMS: m / z 491.7, 493.8 ([M-H] - ).

[0273] Step G: A sealed vial was charged with (5-amino-7-bromo-3-iodo-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.4 mmol, 1.0 equiv.), Zn(CN) (142.3 mg, 1.2 mmol, 3.0 equiv.), Pd(PPh) (233.4 mg, 0.2 mmol, 0.5 equiv.), and DMAC (4 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. Water (10 mL) was added to the mixture, which was then extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (15 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc 1:1) to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (35 mg, 24%). LCMS: m / z 355.9 ([M-H] - ).

[0274] Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (35 mg, 0.1 mmol, 1.0 equiv.) in ACN (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (44.4 mg, 0.2 mmol, 2.0 equiv.) and pyridine (39 mg, 0.5 mmol, 5.0 equiv.). The reaction mixture was stirred at 30 °C for 4 h. The mixture was then diluted with water (5 mL) and extracted with ethyl acetate (3 mL × 2). The combined organic phase was washed with brine (3 mL), dried over Na SO , and concentrated to give a residue. The residue was purified by preparative TLC (eluted with petroleum ether: EtOAc = 1:1) to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 56%). LCMS: m / z 546.0 ([MH] - ).

[0275] Step I: To a solution of N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.05 mmol, 1.0 equiv) in TFA (1 mL) was added EtSiH (29.1 mg, 0.25 mmol, 5.0 equiv). The reaction mixture was heated to 80° C. and stirred for 2 hours. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.0 mg, 8%). LCMS: m / z 529.9 ([MH] - ). 1 H NMR (400 MHz, DMSO-d6): δ 15.15 (brs, 1H), 10.53 (s, 1H), 9.37 (brs, 1H), 8.10-7.90 (m, 2H), 7.90-7.62 (m, 2H), 7.31 (dd, J = 9.2, 5.2 Hz, 1H), 7.20-7.00 (m, 1H), 6.80-6.00 (m, 1H).

[0276] [Example 4] N-(8-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka] [ka]

[0277] Step A: To a solution of DMF (30.3 g, 415.2 mmol, 3.0 equiv) in CHCl3 (100 mL) was added PBr3 (101.2 g, 373.68 mmol, 2.7 equiv) dropwise at 0 °C for 1 h, followed by the addition of 7-chloro-3,4-dihydronaphthalen-1(2H)-one (25.0 g, 138.40 mmol, 1.0 equiv). The mixture was then stirred at room temperature for 24 h. The mixture was adjusted to pH 9 with solid NaHCO3 and partitioned with DCM (200 mL). The layers were separated. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether) to give 1-bromo-7-chloro-3,4-dihydronaphthalene-2-carbaldehyde (10.6 g, 28%). 1 H NMR (300 MHz, CDCl3): δ 10.24 (s, 1H), 7.87 (d, J = 2.0 Hz,1H), 7.32 (dd, J = 8.0 Hz 2H), 7.14 (d, J = 8.0 Hz, 1H), 2.83-2.78 (m, 2H), 2.64-2.59 (m, 2H).

[0278] Step B: To a solution of 1-bromo-7-chloro-3,4-dihydronaphthalene-2-carbaldehyde (12.2 g, 44.93 mmol, 1.0 equiv) in toluene (185 mL) was added DDQ (51.0 g, 224.65 mmol, 5.0 equiv) in an autoclave. The mixture was stirred at 110 °C for 48 h. The residue was partitioned between DCM (500 mL) and water (500 mL). The layers were separated. The aqueous layer was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1) to give 1-bromo-7-chloro-2-naphthaldehyde (5.5 g, 45%). LCMS: m / z 269.0 ([M+H] + ).

[0279] Step C: A solution of 1-bromo-7-chloro-2-naphthaldehyde (1.0 g, 3.71 mmol, 1.0 equiv) in DCE (50 mL) was treated with tosyl azide (1.46 g, 7.42 mmol, 2.0 equiv), 3,5-bis(trifluoromethyl)aniline (339.2 mg, 1.48 mmol, 0.4 equiv), [Cp * IrCl2]2 (294.8 mg, 0.37 mmol, 0.1 equiv.) and AgNTf (574.2 mg, 1.48 mmol, 0.4 equiv.) were added. The mixture was stirred under air at 80 °C for 6 h. The resulting precipitate was collected by filtration, washed with EtOAc (5 mL), and evaporated to dryness in vacuo to give N-(4-bromo-6-chloro-3-formylnaphthalen-2-yl)-4-methylbenzenesulfonamide (950 mg, 58%). 1 H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 10.39 (s, 1H), 8.29 (d, J = 2.0 Hz 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.75-7.70 (m, 3H), 7.34 (d, J = 8.2 Hz 2H), 2.32 (s, 3H).

[0280] Step D: To a solution of N-(4-bromo-6-chloro-3-formylnaphthalen-2-yl)-4-methylbenzenesulfonamide (1.36 g, 3.10 mmol, 1.0 equiv) in THF (13.6 mL) was added (2-chloro-5-fluorophenyl)magnesium bromide (31.0 mL, 0.5 mmol / mL, 5.0 equiv) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with HO (20 mL) and extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1) to give N-(4-bromo-6-chloro-3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (1.0 g, 57%). LCMS: m / z 565.8 ([M-H]- ).

[0281] Step E: To a solution of N-(4-bromo-6-chloro-3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (560 mg, 0.98 mmol, 1.0 equiv) in DCM (44 mL) at room temperature was added Dess-Martin periodinane (1.25 g, 2.94 mmol, 3.0 equiv). The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to give N-(4-bromo-6-chloro-3-(2-chloro-5-fluorobenzoyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (310 mg, 55%). LCMS: m / z 563.7 ([M-H] - ).

[0282] Step F: A solution of N-(4-bromo-6-chloro-3-(2-chloro-5-fluorobenzoyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (200 mg, 0.35 mmol, 1.0 equiv) in H2SO4 (6 mL) was added at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (10 mL). The resulting precipitate was collected by filtration, washed with water (5 mL), and evaporated to dryness to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to give (3-amino-1-bromo-7-chloronaphthalen-2-yl)(2-chloro-5-fluorophenyl)methanone (80 mg, 56%) as a yellow solid. LCMS: m / z 411.9 ([M+H] + ).

[0283] Step G: To a solution of (3-amino-1-bromo-7-chloronaphthalen-2-yl)(2-chloro-5-fluorophenyl)methanone (80 mg, 0.19 mmol, 1.0 equiv.) in DMAC (2 mL) in a microwave tube was added Zn(CN) (33.5 mg, 0.29 mmol, 1.5 equiv.) and Pd(pph) (65.9 mg, 0.06 mmol, 0.3 equiv.). The mixture was heated at 160 °C under microwave irradiation for 0.5 h. The residue was partitioned between EtOAc (5 mL) and water (5 mL). The layers were separated. The aqueous layer was extracted with EtOAc (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, and evaporated to dryness. The residue was purified by TLC to give 3-amino-7-chloro-2-(2-chloro-5-fluorobenzoyl)-1-naphthonitrile (37 mg, 54%). LCMS: m / z 359.0 ([M+H] + ).

[0284] Step H: To a solution of 7-chloro-2-(2-chloro-5-fluorobenzoyl)-1-naphthonitrile (37 mg, 0.10 mmol, 1.0 equiv) in MeCN (2 mL) was added KOH (1.7 mg, 0.03 mmol, 0.3 equiv) in HO (0.2 mL). The mixture was stirred at room temperature for 6 h. The residue was partitioned between EtOAc (2 mL) and water (2 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, and evaporated to dryness to give 4-amino-8-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2,3-dihydro-1H-benzo[e]isoindol-1-one (38 mg, crude). LCMS: m / z 374.9 ([M-H] - ).

[0285] Step I: To a solution of 4-amino-8-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2,3-dihydro-1H-benzo[e]isoindol-1-one (38 mg, crude) in MeCN (3 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (45.3 mg, 0.2 mmol, 2.0 equiv.) and pyridine (23.7 mg, 0.3 mmol, 3.0 equiv.). The mixture was stirred at 50° C. for 2 hours. The residue was partitioned between EtOAc (5 mL) and water (5 mL). The layers were separated. The aqueous layer was extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, and evaporated to dryness to give N-(8-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (58 mg, crude). LCMS: m / z 564.9 ([M-H] - ).

[0286] Step J: To a solution of N-(8-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (58 mg, crude) in TFA (3 mL) was added EtSiH (59.3 mg, 0.51 mmol, 5.0 equiv). The mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated to give a residue. The crude residue was purified by preparative HPLC to give N-(8-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (14 mg, 25%). LCMS: m / z 551.8 ([MH] - ). 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.37 (s, 1H), 9.18 (s, 1H), 8.18 (d, J = 9.2 Hz, 2H), 7.95 (s, 1H), 7.76-7.70 (m, 3H), 7.33 (d, J = 5.2 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 7.00-6.00 (br, 1.5H).

[0287] [Example 5] N-(3-(2-chloro-5-fluorophenyl)-7-methyl-1,6-dioxo-2,3,6,7-tetrahydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0288] Step A: To a solution of 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinoline-1,6(7H)-dione (450 mg, 0.879 mmol) in DMF (10 mL) was added KCO (364 mg, 2.64 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Iodomethane (125 mg, 0.879 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice water (50 mL) and extracted with EA (50 mL × 3). The organic phase was dried over NaSO and concentrated to give a residue that was purified by silica gel chromatography (5 g column) using 0-70% EtOAc / hexanes to give 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-7-methyl-4-nitro-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinoline-1,6(7H)-dione (95 mg, 0.181 mmol, 20%). LCMS: m / z 522.0 [M - H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.00 - 7.95 (m, 2H), 7.85 - 7.80 (m, 2H), 7.13 (td, J = 8.3, 3.2 Hz, 1H), 6.99 (dd, J = 8.8, 5.3 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 4.55 (d, J = 15.2 Hz, 1H), 4.19 (d, J = 15.2 Hz, 1H), 3.65 (s, 3H), 3.60 (s, 3H).

[0289] Step B: To a solution of 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-7-methyl-4-nitro-2,3,6,7-tetrahydro-1H-pyrrolo[4,3-f]isoquinoline-1,6-dione (60 mg, 0.115 mmol) in EtOH (10 mL) and water (3 mL) was added NH4Cl (12.3 mg, 0.229 mmol) and Fe (0.003 mL, 0.458 mmol). The reaction mixture was stirred at 75 °C for 1 h. The cooled mixture was filtered and concentrated. The residue was diluted with water (10 mL) and extracted with EA (10 mL × 3). The organic phase was dried over NaSO and concentrated to give 4-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-7-methyl-2,3,6,7-tetrahydro-1H-pyrrolo[4,3-f]isoquinoline-1,6-dione (50 mg, 0.101 mmol, 88%). LCMS: m / z 494 [M+H] + .

[0290] Step C: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-7-methyl-2,3,6,7-tetrahydro-1H-pyrrolo[4,3-f]isoquinoline-1,6-dione (40 mg, 0.081 mmol) and 5-fluoro-3-(trifluoromethyl)benzoic acid (20.22 mg, 0.097 mmol) in DCM (10 mL) was added pyridine (2 mL, 24.7 mmol). Dichlorophosphinyl chloride (24.8 mg, 0.162 mmol) was then added, and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water and extracted with DCM (30 mL × 3). The organic phase was dried over Na SO and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0-80% EtOAc / hexanes to give N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-7-methyl-1,6-dioxo-2,3-dihydro-1H-pyrrolo[4,3-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.044 mmol, 54%). LCMS: m / z 682.0 [MH] + .

[0291] Step D: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-7-methyl-1,6-dioxo-2,3-dihydro-1H-pyrrolo[4,3-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.037 mmol) in TFA (4 mL) was added triethylsilane (1 mL, 6.192 mmol). The reaction mixture was stirred at 20° C. for 1 hour. The mixture was concentrated in vacuo to give N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-7-methyl-1,6-dioxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.034 mmol, 92%), which was used in the next step without purification. LCMS: m / z 668.2 [M+H]+ .

[0292] Step E: To a solution of N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-7-methyl-1,6-dioxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.034 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (11.2 mg, 0.075 mmol). The reaction mixture was stirred at 70° C. for 1 hour. The cooled reaction mixture was concentrated and the residue was purified by preparative TLC (PE / EA=3:7) and then by preparative HPLC to give N-(3-(2-chloro-5-fluorophenyl)-7-methyl-1,6-dioxo-2,3,6,7-tetrahydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (13.8 mg, 0.025 mmol, 67%). LCMS: m / z 548.1 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.40 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.67 (m, 3H), 7.60 (d, J = 7.6 Hz, 1H), 7.28 (dd, J = 9.0, 5.0 Hz, 1H), 7.03 - 6.99 (m, 1H), 6.27 (s, 2H), 3.68 (s, 3H).

[0293] [Example 6] 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethyl)benzamido)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide [ka]

[0294] Step A: A sealed vial was charged with (5-amino-7-bromo-3-iodo-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (100 mg, 0.2 mmol, 1.0 equiv.), Zn(CN) (71.2 mg, 0.6 mmol, 3.0 equiv.), Pd(PPh) (116.7 mg, 0.1 mmol, 0.5 equiv.), and DMAC (2 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. Water (5 mL) was added to the mixture, which was then extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (5 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc = 1:1) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)-1H-indazole-3,7-dicarbonitrile (20 mg, 29%). LCMS: m / z 338.0 ([M-H] - ).

[0295] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-1H-indazole-3,7-dicarbonitrile (70.0 mg, 0.21 mmol, 1.0 equiv.) and KCO (28.5 mg, 0.21 mmol, 1.0 equiv.) in DMSO-d (0.5 mL) was added HO (30%, 71.4 mg, 0.63 mmol, 3.0 equiv.) at room temperature. Water (3 mL) was added to the mixture, which was then extracted with EtOAc (2 mL × 2). The combined organic phases were washed with brine (3 mL × 2), dried over NaSO, and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide (65 mg, crude). LCMS: m / z 374.0 ([M-H] - ).

[0296] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide (65 mg, 0.17 mmol, 1.0 equiv.) in ACN (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (78.4 mg, 0.35 mmol, 2.0 equiv.) and pyridine (41.1 mg, 0.52 mmol, 3.0 equiv.). The reaction mixture was stirred at 40° C. for 2 hours. The mixture was then diluted with water (5 mL) and extracted with ethyl acetate (3 mL × 2). The combined organic phase was washed with brine (3 mL) and aqueous NaCO (5 mL), dried over NaSO, and concentrated to give 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethyl)benzamido)-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide (110 mg, crude). LCMS: m / z 563.9 ([M-H] - ).

[0297] Step D: To a solution of 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethyl)benzamido)-6-hydroxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide (110 mg, 0.19 mmol, 1.0 equiv.) in TFA (5 mL) was added EtSiH (112.8 mg, 0.97 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethyl)benzamido)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide (10.5 mg, 9% yield over three steps). LCMS: m / z 547.9 ([MH] - ). 1H NMR (400 MHz, DMSO-d6): δ 14.35 (brs, 1H), 10.48 (s, 1H), 9.27 (brs, 1H), 8.32 (s, 1H), 8.20 - 7.87 (m, 2H), 7.87 - 7.65 (m, 2H), 7.48 (s, 1H), 7.31 (dd, J = 8.8, 5.2, 1H), 7.25 - 7.02 (m, 1H), 6.80 - 5.90 (m, 1H).

[0298] [Example 7] N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0299] Step A: To a solution of PBr3 (20 mL) in CHCl3 (300 mL) was added dropwise DMF (20 mL, 258.6 mmol) at 0 °C using N2. The reaction mixture was stirred at room temperature for approximately 2 h. 7-Fluoro-1,2,3,4-tetrahydronaphthalen-1-one (13.5 g, 82.3 mmol) was added, and the reaction mixture was stirred at 70 °C for 2 h. The cooled reaction mixture was diluted with DCM and saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% ethyl acetate in petroleum ether and dried to give the compound 1-bromo-7-fluoro-3,4-dihydronaphthalene-2-carbaldehyde (10.0 g, 39.2 mmol, 48%). LCMS: m / z 255 / 257 [M+H] + .

[0300] Step B: To a solution of 1-bromo-7-fluoro-3,4-dihydronaphthalene-2-carbaldehyde (16.0 g, 62.7 mmol) in toluene (300 mL) was added DDQ (35.6 g, 156.8 mmol). The reaction mixture was stirred at 100 °C for 3 days. The cooled reaction mixture was diluted with EA and saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-3% ethyl acetate in petroleum ether and dried to give compound 1-bromo-7-fluoronaphthalene-2-carbaldehyde (8.0 g, 31.6 mmol, 50.4%). LCMS: m / z 253 / 255 [M+H] + .

[0301] Step C: To a solution of (pentamethylcyclopentadienyl)iridium(III) chloride dimer (0.54 g, 0.68 mmol) in DCE (100 mL) was added 3,5-bis(trifluoromethyl)aniline (0.42 mL, 2.69 mmol), azido(4-methylphenyl)dioxo-λ 6 -sulfane (10.6 g, 53.7 mmol), 1-bromo-7-fluoronaphthalene-2-carbaldehyde (6.80 g, 26.9 mmol) and silver bis[dioxo(trifluoromethyl)-λ 6 -sulfanyl] azanide (1.04 g, 2.69 mmol) was added. The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-40% ethyl acetate in petroleum ether and dried to give compound N-(4-bromo-6-fluoro-3-formyl-2-naphthyl)-4-methylbenzenesulfonamide (3.5 g, 8.29 mmol, 31%). LCMS: m / z 422 / 424 [M+H] + .

[0302] Step D: Solution A: To a stirred mixture of lithium magnesium dichloridepropan-2-ide (10 mL, 1.3 mol / L) in THF (20 mL) was added dropwise 2-bromo-1-chloro-4-fluorobenzene (3 g, 14 mmol) at 0 °C under a N atmosphere. The mixture was stirred at 0 °C for an additional 30 min. To a stirred mixture of N-(4-bromo-6-fluoro-3-formyl-2-naphthyl)-4-methylbenzenesulfonamide (3.00 g, 7.1 mmol) in THF (30 mL) was added dropwise "Solution A" at 0 °C under a N atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA. The organic layer was separated, washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-15% ethyl acetate in petroleum ether and dried to give compound N-{4-bromo-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-6-fluoro-2-naphthyl}-4-methylbenzenesulfonamide (1.60 g, 2.90 mmol, 41%). LCMS: m / z 552 / 554 [M+H] + .

[0303] Step E: To a solution of N-{4-bromo-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-6-fluoro-2-naphthyl}-4-methylbenzenesulfonamide (1.40 g, 2.54 mmol) in DCM (30 mL) was added 1,1,1-triacetoxy-1,3-dihydro-1λ 5 -Benzo[d][1,2]iodoxol-3-one (0.87 mL, 2.79 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with DCM and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-40% ethyl acetate in petroleum ether and dried to give compound N-{4-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-naphthyl}-4-methylbenzenesulfonamide (1.00 g, 1.82 mmol, 72%). LCMS: m / z 550 / 552 [M+H] +.

[0304] Step F: To a solution of N-{4-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-2-naphthyl}-4-methylbenzenesulfonamide (1.20 g, 2.18 mmol) in NMP (15 mL) was added copper(I) cyanide (0.49 g, 5.50 mmol). The reaction mixture was stirred at 150 °C under N for 2 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over NaSO, and concentrated to give compound N-{3-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-6-fluoro-2-naphthyl}-4-methylbenzenesulfonamide (1.20 g, crude). The residue was used directly without purification. LCMS: m / z 497 [M+H] + .

[0305] Step G: To a solution of N-{3-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-6-fluoro-2-naphthyl}-4-methylbenzenesulfonamide (1.20 g, 2.42 mmol) in CHCN (8 mL) / HO (2 mL) was added LiOH (254 mg, 6.04 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over NaSO, and concentrated. The residue was dried to give compound N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (600 mg, 1.17 mmol, 48%). LCMS: m / z 513 [MH] - .

[0306] Step H: To a solution of N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (700 mg, 1.36 mmol) in HO (4 mL) was added HSO (10 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EA and saturated NaHCO solution. The organic layer was separated, washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 0–60% ethyl acetate in petroleum ether and dried to give compound 4-amino-3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-2,3-dihydro-1H-benzo[e]isoindol-1-one (450 mg, 1.25 mmol, 92%). LCMS: m / z 359[MH] - .

[0307] Step I: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-2,3-dihydro-1H-benzo[e]isoindol-1-one (200 mg, 0.55 mmol) in DCM (4 mL) was added 3-fluoro-5-(trifluoromethyl)benzoic acid (116 mg, 0.56 mmol), pyridine (1 mL), and POCl (0.52 mL, 5.55 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with EA and saturated NaHCO solution. The organic layer was separated, washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-60% ethyl acetate in petroleum ether and dried to give the compound N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.054 mmol, 10%) as a yellow solid. LCMS: m / z 549 [MH] - .

[0308] Step J: To a solution of N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.054 mmol) in TFA (4 mL) was added triethylsilane (1 mL, 6.20 mmol). The cooled reaction mixture was stirred at room temperature for 1 h. The reaction was diluted with EA and saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC and dried to give compound N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (8 mg, 0.015 mmol, 27%). LCMS: m / z 535 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.34 (s, 1H), 8.81 (dd, J = 10.8, 2.4 Hz, 1H), 8.24 (dd, J = 9.0, 5.8 Hz, 1H), 8.14 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.70 (s, 1H), 7.64 - 7.61 (m, 1H), 7.32 (dd, J = 8.8, 5.1 Hz, 1H), 7.15 - 7.11 (m, 1H), 6. 43 (brs, 1H). 6.15, (brs, 1H).

[0309] [Example 8] N-(3-bromo-6-(2-chloro-5-fluorophenyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka] [ka]

[0310] Step A: To a solution of methyl 6-amino-2-fluorobenzoate (10 g, 59.1 mmol) in toluene (100 mL) was added NBS (10.5 g, 59.1 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was filtered. The filtrate was concentrated. The residue was purified using silica gel column chromatography eluting with 0-5% ethyl acetate in petroleum ether to give methyl 2-amino-3-bromo-6-fluorobenzoate (9 g, 32.8 mmol, 55%). LCMS: m / z 248 [M+H] + .

[0311] Step B: To a solution of methyl 2-amino-3-bromo-6-fluorobenzoate (9 g, 36.3 mmol) in HO (9 mL) and dioxane (90 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (20.7 mL, 72.6 mmol), CsCO (23.6 g, 72.6 mmol) and bis[5-(diphenylphosphanyl)cyclopenta-1,3-dienyl]-λ 2 -Iron(II) palladium chloride (2.65 g, 3.63 mmol) was added. The reaction was stirred overnight at 90 °C under N2. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified using silica gel column chromatography eluting with 0-20% ethyl acetate in petroleum ether to give methyl 2-amino-6-fluoro-3-methylbenzoate (4.2 g, 22.8 mmol, 63%). LCMS: m / z 184 [M+H] + .

[0312] Step C: To a solution of methyl 2-amino-6-fluoro-3-methylbenzoate (2.8 g, 15.3 mmol) in AcOH (30 mL) was added AcO (4.31 mL, 45.9 mmol). The reaction was stirred at 60 °C for 3 h. The cooled reaction mixture was concentrated to remove half of the solvent. The residue was poured into ice water and quenched with saturated NaHCO solution. The mixture was subsequently extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated to give methyl 2-acetamido-6-fluoro-3-methylbenzoate (3.2 g, 14.2 mmol, 93%). LCMS: m / z 226 [M+H] + .

[0313] Step D: To a solution of methyl 2-acetamido-6-fluoro-3-methylbenzoate (1.8 g, 7.99 mmol) in concentrated HSO (18 mL) at 0 °C was added fuming HNO (0.459 mL, 10.4 mmol) dropwise. The reaction was stirred at 0 °C for 4 hours. The reaction was poured into ice water. The resulting mixture was filtered. The filter cake was washed with water, azeotroped with toluene, and dried to give methyl 2-acetamido-6-fluoro-3-methyl-5-nitrobenzoate (1.35 g, 4.77 mmol, 60%). LCMS: m / z 271 [M+H] + .

[0314] Step E: To a solution of methyl 6-(acetylamino)-2-fluoro-5-methyl-3-nitrobenzoate (1.8 g, 6.66 mmol) in MeOH (1 mL) was added SOCl2 (0.725 mL, 9.99 mmol). The reaction was stirred at 60 °C overnight. The cooled reaction mixture was concentrated to remove half of the solvent. The mixture was then filtered. The filter cake was washed with ice-cold MeOH and concentrated to give methyl 2-amino-6-fluoro-3-methyl-5-nitrobenzoate (1.35 g, 5.92 mmol, 89%). LCMS: m / z 229 [M+H] + .

[0315] Step F: To a solution of methyl 6-amino-2-fluoro-5-methyl-3-nitrobenzoate (920 mg, 4.03 mmol) in AcOH (10 mL) was added NaNO (612 mg, 8.87 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with EA. The organic layer was washed with saturated NaHCO solution, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 100% dichloroform to give compound methyl 6-fluoro-5-nitro-1H-indazole-7-carboxylate (450 mg, 1.65 mmol, 41%). LCMS: m / z 240 [M+H] + .

[0316] Step G: To a solution of methyl 6-fluoro-5-nitro-1H-indazole-7-carboxylate (670 mg, 2.801 mmol) in DMF (8 mL) was added NBS (1.09 g, 6.16 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with EA. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to give compound methyl 3-bromo-6-fluoro-5-nitro-1H-indazole-7-carboxylate (870 mg, 2.67 mmol, 95%). LCMS: m / z 318 [M+H] + .

[0317] Step H: To a solution of methyl 3-bromo-6-fluoro-5-nitro-1H-indazole-7-carboxylate (870 mg, 2.74 mmol) in MeOH (25 mL), THF (25 mL), and HO (25 mL) was added LiOH / HO (0.76 mL, 27.4 mmol) at 0 °C. The reaction was stirred overnight at room temperature. The reaction was concentrated to remove organics and acidified with 1 M HCl. The mixture was then filtered. The filter cake was dried to give compound 3-bromo-6-fluoro-5-nitro-1H-indazole-7-carboxylic acid (750 mg, 2.45 mmol, 90%). LCMS: m / z 304 [M+H] + .

[0318] Step I: To a solution of 3-bromo-6-fluoro-5-nitro-1H-indazole-7-carboxylic acid (750 mg, 2.47 mmol) in MeOH (15 mL), (4-methoxyphenyl)methanamine (0.322 mL, 2.47 mmol), 2-chloro-5-fluorobenzene-1-carbaldehyde (391 mg, 2.47 mmol), 2-chloro-5-fluorobenzene-1-carbaldehyde (391 mg, 2.47 mmol), and 2-isocyano-2-methylpropane (0.281 mL, 2.47 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give 3-bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-6-fluoro-N-(4-methoxybenzyl)-5-nitro-1H-indazole-7-carboxamide (1.2 g, 1.78 mmol, 72%). LCMS: m / z 664 [M+H] + .

[0319] Step J: To a solution of 3-bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-6-fluoro-N-(4-methoxybenzyl)-5-nitro-1H-indazole-7-carboxamide (1.1 g, 1.65 mmol) in DMA (10 mL) was added 1,1-bis(dimethylamino)-N-(2-methylprop-2-yl)methanimine (0.506 mL, 2.48 mmol). The reaction was stirred at 140 °C under N for 18 h. The cooled reaction mixture was poured into ice water and extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give 3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-5-nitro-6,7-dihydropyrrolo[3,4-g]indazol-8(1H)-one (430 mg, 0.673 mmol, 41%). LCMS: m / z 561 [M+H] + .

[0320] Step K: To a solution of 3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-5-nitro-6,7-dihydropyrrolo[3,4-g]indazol-8(1H)-one (420 mg, 0.748 mmol) in EtOH (3 mL) and HO (1 mL) was added NHCl (120 mg, 2.25 mmol) and Fe (251 mg, 4.49 mmol). The mixture was stirred at 80 °C for 3 h. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give 5-amino-3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-6,7-dihydropyrrolo[3,4-g]indazol-8(1H)-one (230 mg, 0.355 mmol, 47%). LCMS: m / z 531 [M+H] + .

[0321] Step L: To a solution of 5-amino-3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-6,7-dihydropyrrolo[3,4-g]indazol-8(1H)-one (70 mg, 0.132 mmol) in DCM (10 mL) was added pyridine (1 mL, 12.4 mmol). 5-Fluoro-3-(trifluoromethyl)benzoic acid (30.1 mg, 0.145 mmol) and POCl (40.4 mg, 0.264 mmol) were then added. The mixture was stirred at 25 °C for 1 h. The reaction was diluted with DCM and water. The organic layer was washed with brine, dried over Na SO , and concentrated. The residue was purified using preparative TLC eluting with 30% ethyl acetate in petroleum ether to give N-(3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5(trifluoromethyl)benzamide (30 mg, 0.037 mmol, 28%). LCMS: m / z 721 [M+H] + .

[0322] Step M: To a solution of N-(3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.069 mmol) in TFA (5 mL) was added triethylsilane (1.5 mL, 9.29 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo to give N-(3-bromo-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.071 mmol, crude). LCMS: m / z 705 [M+H] + .

[0323] Step N: To a solution of N-(3-bromo-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.071 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid (0.013 mL, 0.142 mmol). The reaction mixture was stirred at 70° C. for 1 hour. The cooled reaction mixture was concentrated. The residue was purified using preparative TLC (EA:PE = 2:1, Rf = 0.5) to give a crude product, which was purified by preparative HPLC (YMC-Actus Triart C18 150 x 20 mm x 5 um, 50%-95%, Phase A: HO (0.1% FA), Phase B: MeCN) to give N-(3-bromo-6-(2-chloro-5-fluorophenyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (16 mg, 0.027 mmol, 38%). LCMS: m / z 585 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.29 (s, 1H), 10.44 (s, 1H), 9.30 (s, 1H), 7.97 - 7.92 (m, 1H), 7.76 - 7.70 (m, 3H), 7.33 - 7.28 (m, 1H), 7.10 (s, 1H), 6.71 - 5.93 (m, 2H).

[0324] [Example 9] N-(6-(2-chloro-5-fluorophenyl)-3-cyano-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka] [ka]

[0325] Step A: To a solution of (7-bromo-3-iodo-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (1.0 g, 1.9 mmol, 1.0 equiv.) and AgCO (1.05 g, 3.8 mmol, 2.0 equiv.) in DMF (20 mL) was added CHCl (406.1 mg, 2.9 mmol, 1.5 equiv.) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. Water (30 mL) was added to the mixture, which was then extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified on silica gel (eluted with petroleum ether / EtOAc = 5:1) to give (7-bromo-3-iodo-1-methyl-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (400 mg, 39%). LCMS: m / z 537.8, 539.7 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.75-7.70 (m, 2H), 7.61-7.56 (m, 1H), 4.41 (s, 1H).

[0326] Step B: To a solution of (7-bromo-3-iodo-1-methyl-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (300 mg, 0.56 mmol, 1.0 equiv.) and Fe (156.2 mg, 2.8 mmol, 5.0 equiv.) in EtOH (10 mL) at 50 °C, NH Cl (15.0 mg, 0.28 mmol, 0.5 equiv.) in HO (1 mL) was added dropwise. The reaction mixture was heated to 90 °C and stirred for 1 h. Water (10 mL) and ethyl acetate (5 mL) were then added to the mixture, which was then filtered. The filtrate was then extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over NaSO, and concentrated to give (5-amino-7-bromo-3-iodo-1-methyl-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (220 mg, 77%) as a red oil. LCMS: m / z 507.8, 509.9 ([M+H]+ ).

[0327] Step C: A sealed vial was charged with (5-amino-7-bromo-3-iodo-1-methyl-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (50 mg, 0.1 mmol, 1.0 equiv), Zn(CN) (34.5 mg, 0.3 mmol, 3.0 equiv), Pd(PPh) (56.6 mg, 0.05 mmol, 0.5 equiv), and DMAC (1 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. Water (3 mL) was added to the mixture, which was then extracted with EtOAc (3 mL × 2). The combined organic phase was washed with brine (5 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative TLC (eluted with petroleum ether / EtOAc = 2:1) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)-1-methyl-1H-indazole-3,7-dicarbonitrile (6.8 mg, 19%) as a yellow oil. LCMS: m / z 354.0 ([M+H] + ).

[0328] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-1-methyl-1H-indazole-3,7-dicarbonitrile (30.0 mg, 0.09 mmol, 1.0 equiv.) in MeCN (2 mL) / HO (0.2 mL) was added KOH (9.5 mg, 0.18 mmol, 2.0 equiv.) at room temperature. The reaction mixture was stirred at 40 °C for 4 hours. Water (3 mL) was added to the mixture, and the mixture was extracted with EtOAc (3 mL × 2). The combined organic phases were washed with brine (3 mL × 2), dried over NaSO, and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (35 mg, crude) as a yellow oil. LCMS: m / z 370.0 ([M-H] - ).

[0329] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (35 mg, 0.1 mmol, 1.0 equiv.) in ACN (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (44.4 mg, 0.2 mmol, 2.0 equiv.) and pyridine (23.3 mg, 0.3 mmol, 3.0 equiv.). The reaction mixture was stirred at 50° C. for 2 hours. The mixture was then diluted with water (5 mL) and extracted with ethyl acetate (3 mL × 2). The combined organic phases were washed with brine (3 mL) and aqueous NaCO (5 mL), dried over NaSO, and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (70 mg, crude) as a red oil. LCMS: m / z 560.0 ([M-H] - ).

[0330] Step F: To a solution of N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (70 mg, 0.12 mmol, 1.0 equiv) in TFA (3 mL) was added EtSiH (69.8 mg, 0.6 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10.3 mg, 21% yield over three steps). LCMS: m / z 544.0 ([MH] - ). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (brs, 1H), 9.52 (brs, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.4, 1H), 7.77-7.72 (m, 2H), 7.31 (dd, J = 8.8, 5.2, 1H), 7.12-7.09 (m, 1H), 6.56-6.26 (m, 1H).

[0331] [Example 10] N-(7-(2-chloro-5-fluorophenyl)-2,9-dioxo-2,7,8,9-tetrahydro-1H-pyrrolo[3,4-h]quinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0332] Step A: To a stirred mixture of methyl 2-amino-5-nitrobenzoate (5 g, 25.5 mmol) in HOAc (50 mL) was added Br2 (1.57 mL, 30.6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of ice water (100 mL) at room temperature. The precipitated solid was collected by filtration and washed with water (3 x 20 mL) to give methyl 2-amino-3-bromo-5-nitrobenzoate (5 g, 18.2 mmol, 71%) as a yellow solid. LCMS: m / z 275 [M+H] + .

[0333] Step B: To a stirred mixture of methyl 2-amino-3-bromo-5-nitrobenzoate (4 g, 14.5 mmol) and 2-methylpropan-2-ylprop-2-enoate (2.53 mL, 17.5 mmol) in DMA (2 mL) was added Pd(PPh3)4 (3.36 g, 2.91 mmol) and TEA (6.06 mL, 43.6 mmol) at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The cooled mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (1:1) to give 2-methylpropan-2-yl(2Z)-3-[2-amino-3-(methoxycarbonyl)-5-nitrophenyl]prop-2-enoate (2 g, 6.21 mmol, 43%) as a yellow solid. LCMS: m / z 323 [M+H] + .

[0334] Step C: To a stirred mixture of 2-methylpropan-2-yl (2Z)-3-[2-amino-3-(methoxycarbonyl)-5-nitrophenyl]prop-2-enoate (2 g, 6.21 mmol) in dioxane (10 mL) was added concentrated HCl (5.17 mL, 62.1 mmol, 12 M) at room temperature. The resulting mixture was stirred at 100° C. overnight. The resulting mixture was concentrated under reduced pressure. This afforded 6-nitro-2-oxo-1H-quinoline-8-carboxylic acid (1 g, 4.27 mmol, 69%) as a yellow solid. LCMS: m / z 235 [M+H] + .

[0335] Step D: To a stirred mixture of 6-nitro-2-oxo-1H-quinoline-8-carboxylic acid (500 mg, 2.14 mmol) and 2-chloro-5-fluorobenzene-1-carbaldehyde (339 mg, 2.14 mmol) in MeOH (20 mL) was added (4-methoxyphenyl)methanamine (0.279 mL, 2.14 mmol) and 2-isocyano-2-methylpropane (0.243 mL, 2.14 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE: EtOAc (2:1) to give N-[1-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl)amino]-2-oxoethyl]-N-[(4-methoxyphenyl)methyl]-6-nitro-2-oxo-1H-quinoline-8-carboxamide (700 mg, 1.18 mmol, 55%) as a yellow solid. LCMS: m / z 595 [M+H] + .

[0336] Step E: To a stirred mixture of N-[1-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl)amino]-2-oxoethyl]-N-[(4-methoxyphenyl)methyl]-6-nitro-2-oxo-1H-quinoline-8-carboxamide (700 mg, 1.18 mmol) in DMSO-d6 (5 mL) was added potassium 2-methylpropan-2-olate (0.145 mL, 1.18 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (30 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE: EtOAc (1:1) to give 7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-6-nitro-2,7,8,9-tetrahydro-1H-pyrrolo[4,3-h]quinoline-2,9-dione (50 mg, 0.098 mmol, 8%) as a yellow solid. LCMS: m / z 510 [M+H] + .

[0337] Step F: To a stirred mixture of 7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-6-nitro-2,7,8,9-tetrahydro-1H-pyrrolo[4,3-h]quinoline-2,9-dione (100 mg, 0.196 mmol) and Fe (110 mg, 1.96 mmol) in EtOH (5 mL) and HO (1 mL) was added NH4Cl (105 mg, 1.96 mmol) at room temperature. The resulting mixture was stirred at 75 °C for 2 hours. The cooled reaction mixture was quenched at room temperature by the addition of water (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc:PE (1:1) to give 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-2,7,8,9-tetrahydro-1H-pyrrolo[4,3-h]quinoline-2,9-dione (60 mg, 0.125 mmol, 64%) as a yellow solid. LCMS: m / z 480 [M+H] + .

[0338] Step G: To a stirred mixture of 6-amino-7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-2,7,8,9-tetrahydro-1H-pyrrolo[4,3-h]quinoline-2,9-dione (50 mg, 0.104 mmol) and 3-fluoro-5-(trifluoromethyl)benzoic acid (26.0 mg, 0.125 mmol) in pyridine (2 mL) was added POCl (0.019 mL, 0.208 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE: EtOAc (1:1) to give N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-2,9-dioxo-1,7,8,9-tetrahydropyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.045 mmol, 43%) as a yellow solid. LCMS: m / z 670 [M+H] + .

[0339] Step H: To a stirred mixture of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-2,9-dioxo-1,7,8,9-tetrahydropyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.075 mmol) in TFA (1 mL) was added triethylsilane (0.25 mL, 1.55 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This gave N-[7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-2,9-dioxo-1,7,8,9-tetrahydropyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.031 mmol, 41%) as a yellow solid. LCMS: m / z 654 [M+H] + .

[0340] Step I: To a stirred mixture of N-[7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-2,9-dioxo-1,7,8,9-tetrahydropyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (15 mg, 0.023 mmol) in TFA (1 mL) was added trifluoromethanesulfonic acid (0.010 mL, 0.115 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 30 minutes. The cooled mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ANC in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This gave N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-1,7,8,9-tetrahydropyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (11.1 mg, 0.021 mmol, 91%) as a white solid. LCMS: m / z 534 [M + H] + .1H NMR (400 MHz, DMSO-d6) δ 10.52 (s,1H), 9.48 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.37 - 7.28 (m, 1H), 7.11 (s, 1H), 6.12 (s, 1H).

[0341] [Example 11] N-(7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-imidazo[1,2-a]pyrrolo[3,4-c]pyridin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0342] Step A: To a solution of 7-bromo-4-chloro-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (1 g, 2.02 mmol) in dioxane (10 mL) was added ethyl[di(prop-2-yl)]amine (1 mL, 6.05 mmol) and (2,4-dimethoxyphenyl)methanamine (0.45 mL, 3.02 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 18 hours. The cooled reaction mixture was poured into 100 mL of water and extracted with EA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with PE: EtOAc = 5: 1 to give 7-bromo-1-(2-chloro-5-fluorophenyl)-4-((3,4-dimethylbenzyl)amino)-2-(4-methoxybenzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (1 g, 1.68 mmol, 83%) as a green oil. LCMS: m / z 596 [M+H] + .

[0343] Step B: A solution of 7-bromo-1-(2-chloro-5-fluorophenyl)-4-((3,4-dimethylbenzyl)amino)-2-(4-methoxybenzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (780 mg, 1.31 mmol) in TFA (7 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was purified by silica gel chromatography eluting with PE:EA=4:1 to give 4-amino-7-bromo-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (480 mg, 1.01 mmol, 77%) as a white solid. LCMS: m / z 478 [M+H] + .

[0344] Step C: A mixture of 4-amino-7-bromo-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (480 mg, 1.01 mmol) in 2-chloroacetaldehyde (0.639 mL, 4.03 mmol) was stirred at 90° C. for 3 h. The cooled reaction mixture was poured into 20 mL of water and extracted with EA (20 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The crude product was purified by silica gel chromatography eluting with DCM:MeOH=10:1 to give 6-bromo-7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[3,2-a]pyridin-9-one (430 mg, 0.859 mmol, 85%) as a brown solid. LCMS: m / z 502 [M+H] + .

[0345] Step D: To a solution of 6-bromo-7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[3,2-a]pyridin-9-one (430 mg, 0.859 mmol) in dioxane (5 mL) was added CsCO (839 mg, 2.58 mmol), Pd(dba) (157 mg, 0.172 mmol), xantphos (99.4 mg, 0.172 mmol), and 3-fluoro-5-(trifluoromethyl)benzamide (266 mg, 1.29 mmol). The reaction mixture was stirred at 100 °C under N for 4 h. The cooled mixture was poured into 40 mL of water and extracted with EA (40 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography eluting with DCM:MeOH=10:1 to give N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[3,2-a]pyridin-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (230 mg, 0.358 mmol, 42%) as a yellow oil. LCMS: m / z 627 [M+H] + .

[0346] Step E: To a solution of N-[7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[3,2-a]pyridin-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.239 mmol) in TFA (2 mL) was added triethylsilane (0.2 mL) and trifluoromethanesulfonic acid (0.2 mL) at room temperature. The reaction mixture was stirred at 90 °C for 1 hour. The cooled reaction mixture was concentrated. The crude product was pre-purified by HPLC to give N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[3,2-a]pyridin-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (31.6 mg, 0.062 mmol, 26%). LCMS: m / z 507.0 [M + H] + . 1 H NMR (400 MHz, methanol-d₄) δ 8.39 (s, 1H), 8.25 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.60 (dd, J = 8.4, 5.1 Hz, 1H), 7.19–7.14 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H).

[0347] [Example 12] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0348] Step A: To a solution of PBr3 (19.5 mL, 207 mmol) in CHCl3 (85 mL) was added DMF (19.3 mL, 249 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. A solution of 6-chloro-1,2,3,4-tetrahydronaphthalen-1-one (15 g, 83.0 mmol) in CHCl3 (15 mL) was added at 0 °C. The reaction mixture was stirred at 70 °C for 18 h. The cooled mixture was diluted with water and extracted with EA (500 mL × 3). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (80 g column) using 0–80% EtOAc / hexane to give 1-bromo-6-chloro-3,4-dihydronaphthalene-2-carbaldehyde (10 g, 37.04 mmol, 45%) as a yellow solid, which was used directly in the next step.

[0349] Step B: To a solution of 1-bromo-6-chloro-3,4-dihydronaphthalene-2-carbaldehyde (10 g, 37.04 mmol) in toluene (100 mL) was added DDQ (25.47 g, 112.2 mmol). The reaction mixture was stirred at 100 °C for 48 h. The mixture was cooled, filtered through Celite, and washed with DCM. The filtrate was concentrated and purified by flash column chromatography on silica gel (0 to 30% EtOAc in hexanes) to give the intermediate 1-bromo-6-chloro-2-naphthaldehyde (5.0 g, 18.7 mmol, 51%) as a white solid, which was used directly in the next step.

[0350] Step C: A solution of 1-bromo-6-chloronaphthalene-2-carbaldehyde (1.2 g, 4.45 mmol) in DCE (12 mL) was treated with azido(4-methylphenyl)dioxo-λ 6 -sulfane (1.95 mL, 8.905 mmol), bis[iridium(3+)]bis(1,2,3,4,5-pentamethylcyclopenta-2,4-dien-1-ide)tetrachloride (0.18 g, 0.223 mmol), 3,5-bis(trifluoromethyl)aniline (0.139 mL, 0.890 mmol), and silver bis[dioxo(trifluoromethyl)-λ 6N-sulfanyl]azanide (0.35 g, 0.890 mmol) was added. The reaction was stirred at 100 °C for 18 h. The cooled reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-25%) to give N-(4-bromo-7-chloro-3-formylnaphthalen-2-yl)-4-methylbenzenesulfonamide (1.1 g, 2.51 mmol, 56%) as a white solid. LCMS: m / z 439.9 [M+H] + .

[0351] Step D: To a solution of N-(4-bromo-7-chloro-3-formyl-2-naphthyl)-4-methylbenzenesulfonamide (1.10 g, 2.51 mmol) in THF (10 mL) was slowly added bromo(2-chloro-5-fluorophenyl)magnesium (2.50 mL, 2.507 mmol, 1 M in THF). The reaction was stirred at 0 °C for 1.5 h. The reaction was quenched with ice-water and then extracted with EA. The combined extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with PE in EA (concentration gradient: 0 to 50%) to give N-(4-bromo-7-chloro-3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (800 mg, 1.40 mmol, 56%) as a yellow solid. LCMS: m / z 568.0 [M+H] + .

[0352] Step E: To a solution of N-(4-bromo-7-chloro-3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (700 mg, 1.23 mmol) in DCM (6 mL) was added Dess-Martin (1.56 g, 3.69 mmol). The reaction was stirred at room temperature for 18 h. The reaction was quenched with HO and then extracted with EA. The combined extracts were washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography eluting with EA in PE (gradient: 0-50%) to give N-{4-bromo-7-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (400 mg, 0.705 mmol, 57%) as a yellow solid. LCMS: m / z 566[M+H] + .

[0353] Step F: To a solution of N-{4-bromo-7-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (400 mg, 0.705 mmol) in NMP (4 mL) was added CuCN (84 mg, 1.41 mmol). The reaction was stirred at 150 °C for 18 h. The cooled reaction was quenched with ice water and then extracted with EA. The combined extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with PE in EA (gradient: 0 to 75%) to give N-(7-chloro-3-(2-chloro-5-fluorobenzoyl)-4-cyanonaphthalen-2-yl)-4-methylbenzenesulfonamide (250 mg, 0.487 mmol, 69%) as a yellow solid. LCMS: m / z 513.0 [M+H] + .

[0354] Step G: To a solution of N-(7-chloro-3-(2-chloro-5-fluorobenzoyl)-4-cyanonaphthalen-2-yl)-4-methylbenzenesulfonamide (250 mg, 0.487 mmol) in HO (0.5 mL) and acetonitrile (2.50 mL) was added potassium hydroxide (5.46 mg, 0.097 mmol). The reaction was stirred at room temperature for 3 h. The reaction was quenched with ice water and then extracted with EA. The combined extracts were washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography eluting with PE in EA (gradient: 0-75%) to give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (150 mg, 0.282 mmol, 58%) as a yellow solid. LCMS: m / z 528.9 [MH] - .

[0355] Step H: To a solution of N-[7-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (100 mg, 0.19 mmol) in TFA (3 mL) was added triethylsilane (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 30-100%) to give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (80 mg, 0.155 mmol, 83%) as a yellow solid. LCMS: m / z 417.1 [M+H] +

[0356] Step I: To a solution of N-[7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (80 mg, 0.155 mmol) in HO (0.50 mL) was added HSO (2 mL) at 0 °C. The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was poured into saturated NaHCO solution until pH = 8 and extracted with EtOAc (15 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (concentration gradient: 0-50%) to give 4-amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (40 mg, 0.11 mmol, 71%) as a yellow solid. LCMS: m / z 361.0 [M+H] +

[0357] Step J: To a solution of 4-amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (30 mg, 0.083 mmol) in pyridine (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoic acid (25.9 mg, 0.125 mmol) and dichlorophosphinyl chloride (0.012 mL, 0.125 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated, and the residue was purified by preparative HPLC to give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.1 mg, 0.004 mmol, 5%). LCMS: m / z 551.0 [M+H] + δ 9.20 (d, J = 9.2 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.75 - 7.61 (m, 4H), 7.27 (dd, J = 8.8, 4.8 Hz, 1H), 7.00 (dd, J = 11.2, 8.8 Hz, 1H), 6.67 - 6.07 (m, 2H).

[0358] [Example 13] N-(6-(2-chloro-5-fluorophenyl)-3-cyano-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0359] Step A: To a solution of (7-bromo-3-iodo-5-nitro-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (1.0 g, 1.9 mmol, 1.0 equiv.) and AgCO (1.05 g, 3.8 mmol, 2.0 equiv.) in DMF (20 mL) was added CHCl (406.1 mg, 2.9 mmol, 1.5 equiv.) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether / EtOAc=5:1) to give (7-bromo-3-iodo-2-methyl-5-nitro-2H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (380 mg, 37%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 7.80-.50 (m, 3H), 4.32 (s, 3H). LCMS: m / z 537.9, 539.8 ([M+H] + ).

[0360] Step B: To a solution of (7-bromo-3-iodo-2-methyl-5-nitro-2H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (500 mg, 0.93 mmol, 1.0 equiv.) and Fe (259 mg, 4.47 mmol, 5.0 equiv.) in EtOH (5 mL) was added dropwise NH4Cl (25.0 mg, 0.47 mmol, 0.5 equiv.) in HO (2.5 mL) at 50 °C. The reaction mixture was heated to 90 °C and stirred for 2 h. The mixture was then filtered, and the filtrate was concentrated and purified by column chromatography to give (5-amino-7-bromo-3-iodo-2-methyl-2H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (400 mg, 50%) as a red solid. LCMS: m / z 507.8, 509.9 ([M+H] + ).

[0361] Step C: A sealed vial was charged with (5-amino-7-bromo-3-iodo-2-methyl-2H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (150 mg, 0.295 mmol, 1.0 equiv.), Zn(CN) (104 mg, 0.885 mmol, 3.0 equiv.), Pd(PPh) (171 mg, 0.148 mmol, 0.5 equiv.), and DMAc (4 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. The mixture was diluted with water (approximately 5 mL) and extracted with EtOAc (approximately 5 mL × 2). The combined organic phase was washed with brine (approximately 5 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by column chromatography (eluted with petroleum ether / EtOAc) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-methyl-2H-indazole-3,7-dicarbonitrile (60 mg, 57%) as a yellow oil. LCMS: m / z 354.1 ([M+H] + ).

[0362] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-methyl-2H-indazole-3,7-dicarbonitrile (100 mg, 0.28 mmol, 1.0 equiv) in MeCN (5 mL) / HO (0.5 mL) was added KOH (5 mg, 0.085 mmol, 0.3 equiv) at room temperature. The reaction mixture was stirred at 30 °C for 2 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 2). The combined organic phases were washed with brine (5 mL × 2), dried over NaSO, and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (100 mg, crude) as a yellow oil. LCMS: m / z 369.8([M-H] - ).

[0363] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (100 mg, 0.269 mmol, 1.0 equiv.) in ACN (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (183 mg, 0.807 mmol, 3.0 equiv.) and pyridine (106 mg, 1.345 mmol, 5.0 equiv.). The reaction mixture was stirred at 50 °C overnight. The mixture was then diluted with water (approximately 5 mL) and extracted with ethyl acetate (approximately 3 mL × 2). The combined organic phases were washed with brine (5 mL) and aqueous NaCO (5 mL), dried over NaSO, and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (120 mg, crude) as a red oil. LCMS: m / z 560.0 ([M-H] - ).

[0364] Step F: To a solution of N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (120 mg, crude, approximately 0.214 mmol, 1.0 equiv) in TFA (2 mL) was added EtSiH (124 mg, 1.07 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, approx. 19% yield over three steps). LCMS: m / z 544.0 ([MH] - ). 1 H NMR (400 MHz, DMSO-d6): δ 10.58 (brs, 1H), 9.27 (brs, 1H), 8.10 - 7.20 (m, 5H), 7.10 (s, 1H), 6.80-5.80 (m, 1H), 4.45 (s, 3H).

[0365] [Example 14] N-(6-(2-chloro-5-fluorophenyl)-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0366] Step A: To a solution of (5-amino-7-bromo-3-iodo-1-methyl-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (100 mg, 0.2 mmol, 1.0 equiv) in MeOH (2.5 mL) was added PtO2 (25 mg). The reaction mixture was stirred at 40 °C under an atmosphere of hydrogen for 12 h. HPLC showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated to give (5-amino-7-bromo-1-methyl-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (65 mg, 85%) as a yellow oil. LCMS: m / z 382.0, 384.0 ([M+H] + ).

[0367] Step B: A sealed vial was charged with (5-amino-7-bromo-1-methyl-1H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (100 mg, 0.26 mmol, 1.0 equiv), Zn(CN) (45.8 mg, 0.39 mmol, 1.5 equiv), Pd(PPh) (92.4 mg, 0.08 mmol, 0.3 equiv), and DMAc (1.5 mL). The sealed vial was irradiated in a microwave at 160 °C for 0.5 h. Water (3 mL) was added to the mixture, which was then extracted with EtOAc (3 mL × 2). The combined organic phase was washed with brine (5 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative TLC (petroleum ether / EtOAc = 2:1) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)-1-methyl-1H-indazole-7-carbonitrile (38 mg, 44%) as a yellow oil. LCMS: m / z 329.1 ([M+H] + ).

[0368] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-1-methyl-1H-indazole-7-carbonitrile (120 mg, 0.37 mmol, 1.0 equiv) in MeCN (5 mL) / HO (0.5 mL) was added KOH (41.5 mg, 0.74 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 25 °C for 4 h. Water (5 mL) was added to the mixture and extracted with EtOAc (3 mL × 2). The combined organic phases were washed with brine (5 mL), dried over NaSO, and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-6,7-dihydropyrrolo[3,4-g]indazol-8(1H)-one (100 mg, 78%) as a yellow oil. LCMS: m / z 345.0 ([M-H] - ).

[0369] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-6,7-dihydropyrrolo[3,4-g]indazol-8(1H)-one (100 mg, 0.29 mmol, 1.0 equiv.) in ACN (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (131.4 mg, 0.58 mmol, 2.0 equiv.) and pyridine (68.8 mg, 0.87 mmol, 3.0 equiv.). The reaction mixture was stirred at 50° C. for 2 hours. The mixture was then diluted with water (10 mL) and extracted with EtOAc (5 mL × 2). The combined organic phases were washed with brine (10 mL) and aqueous NaCO (10 mL), dried over NaSO, and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (170 mg, crude) as a red oil. LCMS: m / z 535.0 ([M-H] - ).

[0370] Step E: To a solution of N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (170 mg, 0.29 mmol, 1.0 equiv) in TFA (5 mL) was added EtSiH (168.6 mg, 1.45 mmol, 5.0 equiv). The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (50% to 64% acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-1-methyl-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (7.0 mg, 5% yield over two steps) as a white solid. LCMS: m / z 519.0 ([MH] - ). 1 H NMR (400 MHz, DMSO-d6): δ ppm 10.36 (s, 1H), 9.28 (brs, 1H), 8.28 (s, 1H), 8.10 - 7.83 (m, 2H), 7.80 - 7.60 (m, 2H), 7.45 - 7.20 (m, 1H), 7.18 - 6.95 (m, 1H), 6.75 - 5.90 (m, 1H), 4.64 (s, 3H).

[0371] [Example 15] N-(7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-imidazo[1,5-a]pyrrolo[3,4-c]pyridin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka] [ka]

[0372] Step A: To a solution of 5-bromo-2-chloropyridine-3-carboxylic acid (2 g, 8.46 mmol), DIEA (2.73 g, 21.1 mmol), and HATU (3.86 g, 10.2 mmol) in anhydrous DMF (20 mL) was added (4-methoxyphenyl)methanamine (1.28 g, 9.30 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 hours, then diluted with EtOAc and washed with water. The organic layer was concentrated, and the residue was purified by silica gel column (PE:EA=10:1) to give 5-bromo-2-chloro-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide (2.8 g, 7.87 mmol, 93%) as a yellow solid. LCMS: m / z 357 [M+2+H] + .

[0373] Step B: To a solution of 5-bromo-N-[(2,4-dimethoxyphenyl)methyl]pyridine-3-carboxamide (2 g, 5.70 mmol) in THF (20 mL) was added NaH (510 mg, 8.54 mmol, 60% in mineral oil). The reaction mixture was stirred at room temperature for 30 minutes, and then 2-chloro-5-fluorobenzoyl chloride (1.65 g, 8.54 mmol) was added. The mixture was stirred at room temperature for 16 hours and then diluted with EA and water. The organic layer was separated and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (v / v=5 / 1) to give 5-bromo-N-[(2-chloro-5-fluorophenyl)carbonyl]-N-[(2,4-dimethoxyphenyl)methyl]pyridine-3-carboxamide (450 mg, 0.886 mmol, 16%) as a pale yellow solid. LCMS: m / z 513 [M+2+H] + .

[0374] Step C: To a solution of 5-bromo-2-chloro-N-[(2-chloro-5-fluorophenyl)carbonyl]-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide (22 g, 43.0 mmol) in THF (220 mL) was added LiHMDS (1 M, 64 mL) at −68° C. The reaction mixture was stirred at −68° C. for an additional 1 h. The mixture was quenched with 100 mL of saturated NH4Cl solution and extracted with 3×200 mL of ethyl acetate. The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE (v / v=1 / 2) to give 7-bromo-4-chloro-1-(2-chloro-5-fluorophenyl)-1-hydroxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (10 g, 19.5 mmol, 45.5%) as a pale yellow solid. LCMS: m / z 513 [M+2+H] + .

[0375] Step D: To a solution of 7-bromo-4-chloro-1-(2-chloro-5-fluorophenyl)-1-hydroxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (10 g, 19.5 mmol) in TFA (100 mL) was added triethylsilane (10 mL, 62.6 mmol). The reaction mixture was stirred at 70 °C for 3 hours and then concentrated in vacuo. The mixture was diluted with EA and HO and then adjusted to pH = 8 with saturated NaHCO solution. The organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE (v / v=1 / 2) to give 7-bromo-4-chloro-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (9 g, 18.1 mmol, 93%) as a white solid. LCMS: m / z 497 [M+2+H] + .

[0376] Step E: To a stirred mixture of 5-fluoro-3-(trifluoromethyl)benzene-1-carboxamide (208 mg, 1.01 mmol) in toluene (10 mL) was added 7-bromo-4-chloro-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (500 mg, 1.01 mmol), Pd(dba) (46.1 mg, 50 μmol), xantphos (58.3 mg, 0.101 mmol), and t-BuONa (145 mg, 1.51 mmol). The reaction mixture was stirred at 100 °C under N for 16 h. The cooled reaction mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with EA / PE = 0 to 30%) to give N-[4-chloro-1-(2-chloro-5-fluorophenyl)-1-hydroxy-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide (300 mg, 0.470 mmol, 47%) as a brown solid. LCMS: m / z 638 [M+H] + .

[0377] Step F: To a solution of N-[4-chloro-1-(2-chloro-5-fluorophenyl)-1-hydroxy-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide (300 mg, 0.470 mmol) in TFA (3 mL) was added EtSiH (0.76 mL, 4.70 mmol). The reaction mixture was stirred at 70 °C for 3 h and then concentrated in vacuo. The residue was diluted with EA and HO and then adjusted to pH = 8 with saturated NaHCO solution. The organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE (v / v=1 / 1) to give N-[4-chloro-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.241 mmol, 51%) as a brown solid. LCMS: m / z 622 [M+H] + .

[0378] Step G: A mixture of N-[4-chloro-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide (130 mg, 0.209 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (74.3 mg, 0.313 mmol), Pd(PPh)Cl (29.3 mg, 420 μmol), NaCO (55.4 mg, 0.522 mmol), EtOH (3 mL), and HO (0.3 mL) was stirred under nitrogen at 80 °C for 16 h. The cooled mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column eluting with ethyl acetate / petroleum ether (1 / 1) to obtain the compound 2-methylpropan-2-yl ({[1-(2-chloro-5-fluorophenyl)-7-({[3-fluoro-5-(trifluoromethyl)phenyl]carbonyl}amino)-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-4-yl]methyl}amino)methanoate (40 mg, 56 μmol, 27%) as a brown solid. LCMS: m / z 733 [M+H] + .

[0379] Step H: A solution of 2-methylpropan-2-yl ({[1-(2-chloro-5-fluorophenyl)-7-({[3-fluoro-5-(trifluoromethyl)phenyl]carbonyl}amino)-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-4-yl]methyl}amino)methanoate (15 mg, 21 μmol) in 4 M HCl in dioxane (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give N-[4-(aminomethyl)-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide (13 mg, 21 μmol, 100%) as a brown solid. LCMS: m / z 633 [M+H] + .

[0380] Step I: A solution of acetic anhydride (0.65 mL) and FA (0.25 mL) was stirred at 60° C. for 1 h, followed by N-[4-(aminomethyl)-1-(2-chloro-5-fluorophenyl)-1-hydroxy-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide (28 mg, 44 μmol) in FA (0.25 mL) and stirring at 60° C. for 2 h. After cooling to room temperature, the solvent was concentrated to dryness. The residue was diluted with EA and HO and then adjusted to pH=8 with saturated NaHCO solution. The organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE (v / v=1 / 1) to give N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[3,4-a]pyridin-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 39 μmol, 88%) as a brown solid. LCMS: m / z 643 [M+H] + .

[0381] Step J: To a solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[1,5-a]pyridin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 39 μmol) in TFA (1 mL) was added EtSiH (0.2 mL, 1.24 mmol) and CFSOOH (0.2 mL). The reaction mixture was stirred at 90 °C for 10 min. The cooled reaction mixture was concentrated and the crude material was purified by preparative HPLC to give N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[1,5-a]pyridin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (11 mg, 22 μmol, 56%). LCMS: m / z 507 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.69 (s, 1H), 8.60 (s, 1H), 7.94 (s, 1H), 7.75–7.62 (m, 3H), 7.28 (s, 1H), 7.04 (d, J = 6.2 Hz, 1H), 6.70 (s, 1H), 6.29 (s, 1H).

[0382] [Example 16] N-[3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka] [ka]

[0383] Step A: To a solution of 2-bromo-4-fluorobenzene-1-carbaldehyde (20 g, 98.5 mmol) in MeOH (120 mL) was added 2-amino-1,1-diethoxyethane (15.7 mL, 108 mmol). The reaction was stirred at room temperature for 2 hours. Sodium cyanoboranide (12.4 g, 197 mmol) was added, and the mixture was subsequently stirred at room temperature overnight. The reaction was quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 0-30%) to afford 1,1-diethoxy-2-{[(Z)-(2-bromo-4-fluorophenyl)methylidene]amino}ethane (17.5 g, 55.0 mmol, 56%) as a yellow oil. LCMS: m / z 318.19 [M+H] + .

[0384] Step B: To 1,1-diethoxy-2-{[(Z)-(2-bromo-4-fluorophenyl)methylidene]amino}ethane (17.5 g, 55.0 mmol) was slowly added chloranesulfonic acid (36.6 g, 314 mmol) at -10 °C. The reaction was stirred at 90 °C for 1 hour. The cooled reaction mixture was poured into ice water. The mixture was then adjusted to a pH value of 8-9 with 1N aqueous NaOH and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 0-30%) to give 8-bromo-6-fluoroisoquinoline (4.1 g, 18.1 mmol, 33%) as a yellow solid. LCMS: m / z 226.05 [M+H] + .

[0385] Step C: To a solution of 8-bromo-6-fluoroisoquinoline (2.1 g, 9.29 mmol) in THF (5 mL) was added dropwise LDA (4.68 mL, 35.4 mmol) at −78 °C under N. The reaction mixture was stirred at −78 °C for 1 h. 2-Chloro-5-fluorobenzene-1-carbaldehyde (2.95 g, 18.6 mmol) was added, and the reaction was stirred at −78 °C for an additional 1 h. The reaction was quenched with saturated NH4Cl solution. The mixture was then extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 0–30%) to afford (8-bromo-6-fluoroisoquinolin-7-yl)(2-chloro-5-fluorophenyl)methanol (3.2 g, 8.320 mmol, 90%) as a yellow solid. LCMS: m / z 384.60 [M+H] + .

[0386] Step D: To a solution of (8-bromo-6-fluoroisoquinolin-7-yl)(2-chloro-5-fluorophenyl)methanol (3 g, 7.80 mmol) in THF (5 mL) was added 1,1,1-triacetoxy-1,3-dihydro-1λ 5 -benzo[d][1,2]iodoxol-3-one (2.43 mL, 7.80 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was diluted with DCM and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 0-30%) to give the compound (8-bromo-6-fluoroisoquinolin-7-yl)(2-chloro-5-fluorophenyl)methanone (2.1 g, 5.49 mmol, 70%) as a yellow oil. LCMS: m / z 382.59 [M+H] + .

[0387] Step E: To a solution of (8-bromo-6-fluoroisoquinolin-7-yl)(2-chloro-5-fluorophenyl)methanone (2.3 g, 6.01 mmol) in NMP (5 mL) was added CuCN (1.08 g, 12.0 mmol). The reaction was stirred at 120 °C under N for 2 h using a sealed tube. The cooled reaction mixture was diluted with water. The mixture was then extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 0-50%) to afford 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoroisoquinoline-8-carbonitrile (400 mg, 1.22 mmol, 20%) as a yellow solid. LCMS: m / z 328.70 [M+H] + .

[0388] Step F: To a solution of 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoroisoquinoline-8-carbonitrile (270 mg, 0.821 mmol) in DMSO-d (5 mL) was added (2,4-dimethoxyphenyl)methanamine (0.185 mL, 1.23 mmol) and ethyl[di(prop-2-yl)]amine (0.407 mL, 2.46 mmol). The reaction was stirred at 130 °C for 10 min. The cooled reaction mixture was diluted with EA and water. The organic layer was washed with brine, dried over Na SO and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 0-50%) to give the compound 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}isoquinoline-8-carbonitrile (140 mg, 0.294 mmol, 36%) as a red solid. LCMS: m / z 475.90 [M+H] + .

[0389] Step G: To a solution of 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}isoquinoline-8-carbonitrile (210 mg, 0.441 mmol) in acetonitrile (5 mL) and HO (0.5 mL) was added KOH (49.5 mg, 0.883 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with water and EA. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 0-80%) to give 3-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-hydroxy-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-1-one (130 mg, 0.263 mmol, 60%) as a white solid. LCMS: m / z ESI 493.92 [M+H] + .

[0390] Step H: To a solution of 3-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-3-hydroxy-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-1-one (120 mg, 0.243 mmol) in TFA (3 mL) at room temperature, triethylsilane (0.5 mL) was added. The reaction was stirred at 50 °C for 1 h. The cooled reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 0-12%) to give 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-1-one (79 mg, 0.241 mmol, 99%) as a white solid. LCMS: m / z 327.74 [M+H] + .

[0391] Step I: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-1-one (20 mg, 0.061 mmol) in Py (2 mL) was added 5-fluoro-3-(trifluoromethyl)benzoic acid (12.7 mg, 0.061 mmol) and POCl (0.012 mL, 0.130 mmol) at 0 °C. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with water and DCM. The organic layer was washed with brine, dried over NaSO, and concentrated to give N-[3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-4-yl]-5-fluoro-N-{[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-(trifluoromethyl)benzamide (40 mg, 0.034 mmol, 56%) as a yellow solid. LCMS: m / z 707.94 [M+H] + .

[0392] Step J: To a solution of N-[3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-4-yl]-5-fluoro-N-{[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-(trifluoromethyl)benzamide (10 mg, 0.014 mmol) in THF (2 mL) and HO (2 mL) was added KOH (0.014 mL, 0.028 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with HO. The mixture was subsequently extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative TLC and then by preparative HPLC (C18, 0-50% acetonitrile in HO with HCOOH) to give N-[3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-h]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.5 mg, 0.005 mmol, 34%). LCMS: m / z 517.84 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 10.45 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 8.11 (s, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.33 - 7.24 (m, 1H), 7.03 (d, J = 6.6 Hz, 1H), 6.44 (s, 2H).

[0393] [Example 17] N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-[1,2,4]triazolo[1,5-a]pyrrolo[3,4-c]pyridin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0394] Step A: To a solution of 7-bromo-4-chloro-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (3.5 g, 7.05 mmol) in dioxane (35 mL) was added DIEA ethyldiisopropylamine (3.49 mL, 21.2 mmol) and (2,4-dimethoxyphenyl)methanamine (1.59 mL, 10.6 mmol) in a sealed tube. The reaction mixture was stirred at 100° C. for 18 hours. The cooled reaction mixture was diluted with EA (200 mL) and water (250 mL). The organic layer was separated, further washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1% to 50%) to give the compound 7-bromo-1-(2-chloro-5-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (4.5 g, 7.18 mmol, 100%) as a white solid. LCMS: m / z 628.1 [M+H]+

[0395] Step B: A solution of 7-bromo-1-(2-chloro-5-fluorophenyl)-4-[(2,4-dimethoxyphenyl)amino]-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (4.5 g, 7.34 mmol) in TFA (50 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and diluted with EA and saturated NaHCO3 solution. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1% to 100%) and dried to give the compound 4-amino-7-bromo-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (3.2 g, 6.71 mmol, 91%) as a yellow solid. LCMS: m / z 478.0 [M+H] +

[0396] Step C: To a solution of 4-amino-7-bromo-1-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (1.00 g, 2.09 mmol) in 2-propanol (50 mL) was added DMF-DMA (0.562 mL, 4.19 mmol). The reaction was stirred at 90° C. for 3 hours. The cooled reaction mixture was diluted with DCM / MeOH (10 / 1) (200 mL) and water (200 mL). The organic layer was separated and concentrated in vacuo to give crude compound 7-bromo-1-(2-chloro-5-fluorophenyl)-4-{[(E)-(dimethylamino)methylidene]amino}-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (1.1 g, 2.07 mmol, 99%) as a yellow solid. LCMS: m / z 533.1 [M+2+H] +

[0397] Step D: To a solution of 7-bromo-1-(2-chloro-5-fluorophenyl)-4-{[(E)-(dimethylamino)methylidene]amino}-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (1.20 g, 2.25 mmol) in propan-2-ol (20 mL) was added azanol hydrochloride (0.31 g, 4.51 mmol). The reaction was stirred at 70 °C for 18 h. The cooled reaction mixture was diluted with DCM (100 mL) and water (100 mL). The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA (1% to 50%) in DCM to give the compound 7-bromo-1-(2-chloro-5-fluorophenyl)-4-{[(E)-(hydroxyamino)methylidene]amino}-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (1.1 g, 2.116 mmol, 94%) as a white solid. LCMS: m / z 521.0 [M+2+H] +

[0398] Step E: To a solution of 7-bromo-1-(2-chloro-5-fluorophenyl)-4-{[(E)-(hydroxyamino)methylidene]amino}-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (350 mg, 0.673 mmol) in THF (5 mL) was added TFAA (0.103 mL, 0.741 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was diluted with DCM and saturated NaHCO solution. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with water and 0.1% HCOOH in CAN (1% to 100%) to give the compound 6-bromo-7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-8,9-dihydro-7H-[1,2,4]triazolo[1,5-a]pyrrolo[3,4-c]pyridin-9-one (70 mg, 0.140 mmol, 21%) as a white solid. LCMS: m / z 500.9 [M+H] +

[0399] Step F: To a stirred mixture of 6-bromo-7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-8,9-dihydro-7H-[1,2,4]triazolo[1,5-a]pyrrolo[3,4-c]pyridin-9-one (50 mg, 0.100 mmol) in dioxane (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (30.9 mg, 0.149 mmol), Xant-PHOS (11.53 mg, 0.020 mmol), CsCO (97.41 mg, 0.299 mmol), and Pd(dba) (18.25 mg, 0.020 mmol). The reaction mixture was stirred at 100 °C under N for 18 h. The cooled reaction mixture was quenched by adding saturated aqueous NH4Cl, extracted with EA, and the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to give N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-[1,2,4]triazolo[1,5-a]pyrrolo[4,3-c]pyridin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.037 mmol, 37%) as a yellow oil. LCMS: m / z 642.1 [MH] - .

[0400] Step G: To a solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-[1,2,4]triazolo[1,5-a]pyrrolo[4,3-c]pyridin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.078 mmol) in TFA (5 mL) was added triethylsilane (0.050 mL, 0.311 mmol) and trifluoromethanesulfonic acid (0.028 mL, 0.311 mmol). The reaction was stirred at 90° C. for 1 hour. The cooled reaction mixture was concentrated. The residue was purified by preparative HPLC (C18, 0-70% acetonitrile in HO) to give the compound N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-[1,2,4]triazolo[1,5-a]pyrrolo[3,4-c]pyridin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (3.0 mg, 0.006 mmol, 8%). LCMS: m / z 508.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.11 (s, 1H), 8.61 (s, 1H), 7.75–7.66 (m, 1H), 7.38–7.22 (m, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.70 (s, 1H), 6.45 (s, 1H).

[0401] [Example 18] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka] [ka]

[0402] Step A: To a solution of 3-bromo-2-fluorobenzoic acid (10 g, 45.6 mmol) in concentrated HSO (100 mL) was added concentrated HNO (3.16 g, 50.226 mmol) dropwise at 0°C to 25°C. The reaction mixture was stirred at 25°C for 16 hours. TLC showed the reaction was complete. The cooled reaction mixture was poured into ice water (300 mL) and then filtered. The filter cake was purified by silica gel column chromatography eluting with PE in EA (concentration gradient: 0 to 100%) to give 3-bromo-2-fluoro-5-nitrobenzoic acid (9.78 g, 37.2 mmol, 81%) as a white solid.

[0403] Step B: To a solution of 3-bromo-2-fluoro-5-nitrobenzoic acid (2.6 g, 9.85 mmol) in MeOH (50 mL) was added HSO (2 mL) at 25 °C. The reaction mixture was stirred at 90 °C under N for 1.5 h. TLC showed the reaction was complete. The cooled reaction mixture was concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (gradient: 0-100%) to give methyl 3-bromo-2-fluoro-5-nitrobenzoate (2.6 g, 9.35 mmol, 95%) as a white solid.

[0404] Step C: A suspension of methyl 3-bromo-2-fluoro-5-nitrobenzoate (2.8 g, 10.071 mmol) and iron(0) (0.358 mL, 50.3 mmol) in AcOH (35 mL) was stirred at 50 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was poured into saturated aqueous NaHCO (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give methyl 5-amino-3-bromo-2-fluorobenzoate (2.0 g, 8.06 mmol, 80%) as a yellow solid. LCMS: m / z 248.11 [M+H] +

[0405] Step D: To a stirred mixture of methyl 5-amino-3-bromo-2-fluorobenzoate (2.5 g, 10.1 mmol) in HO (20 mL) was added propane-1,2,3-triol (2.75 g, 30.2 mmol) and sodium 3-nitrobenzenesulfonate (6.81 g, 30.2 mmol) in concentrated HSO (25 mL). The reaction mixture was stirred at 120 °C under air atmosphere for 5 h. The cooled mixture was used in the next step without further purification. LCMS: m / z 270.12 [M+H] +

[0406] Step E: A solution of Step D in MeOH (30 mL) was stirred at 85° C. for 2 hours. The reaction mixture was poured into water (40 mL) and extracted with DCM (40 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give methyl 7-bromo-6-fluoroquinoline-5-carboxylate (800 mg, 2.82 mmol, 28%) as a white solid. LCMS: m / z 284.02 [M+H] +

[0407] Step F: To a solution of methyl 7-bromo-6-fluoroquinoline-5-carboxylate (1.4 g, 4.93 mmol) in THF (10 mL) was added a solution of LiOH·HO (622 mg, 14.8 mmol) in HO (3 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into HCl (20 mL, 0.2 mmol / mL) and extracted with DCM (20 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give 7-bromo-6-fluoroquinoline-5-carboxylic acid (1.0 g, 3.70 mmol, 75%) as a white solid. LCMS: m / z 270.04 [M+H] +

[0408] Step G: To a solution of 7-bromo-6-fluoroquinoline-5-carboxylic acid (2.7 g, 9.998 mmol), 2-chloro-5-fluorobenzene-1-carbaldehyde (1.55 g, 9.79 mmol), and PMBNH (1.34 g, 9.79 mmol) in MeOH (30 mL) was added t-BuNC (0.81 g, 9.789 mmol). The mixture was stirred at 25 °C for 18 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give 7-bromo-N-[1-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl)amino]-2-oxoethyl]-6-fluoro-N-[(4-methoxyphenyl)methyl]quinoline-5-carboxamide (4 g, 6.34 mmol, 63%) as a yellow solid. LCMS: m / z 630.12 [M+H] +

[0409] Step H: To a solution of 7-bromo-N-[1-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl)amino]-2-oxoethyl]-6-fluoro-N-[(4-methoxyphenyl)methyl]quinoline-5-carboxamide (5 g, 7.925 mmol) in CHCN (50 mL) was added 1,1-bis(dimethylamino)-N-(2-methylprop-2-yl)methanimine (4.07 g, 23.7 mmol). The mixture was stirred at 85 °C for 2 hours. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give 4-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-1-one (2 g, 3.790 mmol, 48%) as a yellow oil. LCMS: m / z 527.12 [M+H] +

[0410] Step I: To a solution of 4-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one (526 mg, 1.0 mmol) in TFA (10 mL) was added triethylsilane (0.34 mL, 2.1 mmol). The mixture was stirred at 75 °C for 1.5 hours. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous solution (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give 4-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one (434 mg, 0.85 mmol, 85%) as a yellow oil. LCMS: m / z 511.12 [M+H] +

[0411] Step J: To a stirred mixture of 4-bromo-3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-1-one (1 g, 1.954 mmol), 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (0.53 g, 2.540 mmol), Xant-PHOS (0.11 g, 0.195 mmol), and Pd(dba) (0.11 g, 0.195 mmol) in dioxane (20 mL) was added CsCO (1.91 g, 5.86 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The reaction mixture was concentrated. The residue was poured into saturated aqueous HCl (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (0.8 g, 1.25 mmol, 64%) as a yellow oil. LCMS: m / z 654.12 [M+H] +

[0412] Step K: To a solution of N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.031 mmol) and trifluoromethanesulfonic acid (0.014 mL, 0.157 mmol) in TFA (15 mL) was added triethylsilane (0.034 mL, 0.21 mmol). The mixture was stirred at 80° C. for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give N-[3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7 mg, 0.014 mmol, 43%). LCMS: m / z 518.12 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 9.82 (d, J = 8.3 Hz, 1H), 9.10 (d, J = 4.4 Hz, 1H), 8.97 (s, 1H), 8.61 - 8.28 (m, 1H), 7.87 - 7.74 (m, 1H), 7.52 (t, J = 9.8 Hz, 2H), 7.46 (s, 1H), 7.36 (s, 1H), 7.04 (s, 1H), 6.78 (s, 1H), 6.63 (s, 1H), 6.40 (s, 1H).

[0413] [Example 19] N-(3-(2-chloro-5-fluorophenyl)-6-cyano-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka] [ka]

[0414] Step A: To a solution of phosphorus tribromide (10.4 mL, 111 mmol) in CHCl3 (230 mL) was added DMF (10.3 mL, 133 mmol) dropwise at 0 °C. The mixture was subsequently stirred at this temperature for 2 h. A solution of 5-bromo-1,2,3,4-tetrahydronaphthalen-1-one (10 g, 44.3 mmol) in CHCl3 (230 mL) was added at 0 °C. The resulting mixture was stirred at 70 °C for 18 h. The solution was cooled, diluted with DCM, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0–30% EA in PE) to give 1,5-dibromo-3,4-dihydronaphthalene-2-carbaldehyde (8.8 g, 27.5 mmol, 62%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 8.0, 0.7 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 2.98 - 2.90 (m, 2H), 2.55 (dd, J = 9.0, 7.2 Hz, 2H).

[0415] Step B: To a stirred mixture of 1,5-dibromo-3,4-dihydronaphthalene-2-carbaldehyde (6.6 g, 20.8 mmol) in toluene (80 mL) was added DDQ (14.2 g, 62.7 mmol). The reaction mixture was stirred at reflux under O for 18 h. The reaction mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated and purified by flash column chromatography on silica gel (0-30% EA in PE) to give 1,5-dibromonaphthalene-2-carbaldehyde (4.7 g, 14.8 mmol, 71%) as a white solid. LCMS: m / z 315 [M+H] + .

[0416] Step C: To a stirred mixture of 1,5-dibromonaphthalene-2-carbaldehyde (3.6 g, 11.5 mmol) in 1,2-dichloroethane (40 mL), tosyl azide (376 mg, 1.91 mmol), bis[iridium(3+)]bis(1,2,3,4,5-pentamethylcyclopenta-2,4-dien-1-ide) tetrachloride (0.27 g, 0.34 mmol), silver bis[dioxo(trifluoromethyl)-λ 6 [-sulfanyl]azanide (0.44 g, 1.15 mmol) and 3,5-bis(trifluoromethyl)aniline (0.18 mL, 1.15 mmol) were added. The reaction mixture was stirred at 100° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with EA (3 mL) and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel to give N-(4,8-dibromo-3-formyl-2-naphthyl)-4-methylbenzenesulfonamide (800 mg, 1.66 mmol, 14%) as a yellow oil. LCMS: m / z 484 [M+H] + .

[0417] Step D: To a stirred mixture of lithium magnesium dichloridepropan-2-ide (6.37 mL, 8.28 mmol) in THF (8 mL) was added dropwise 2-bromo-1-chloro-4-fluorobenzene (1.73 g, 8.28 mmol) at 0° C. under a N atmosphere. The reaction mixture was stirred at 0° C. for an additional 30 minutes. To a stirred mixture of N-(4,8-dibromo-3-formyl-2-naphthyl)-4-methylbenzenesulfonamide (800 mg, 1.656 mmol) in THF (8 mL) was added dropwise solution A at 0° C. under a N atmosphere. The resulting mixture was stirred at room temperature for an additional hour. The reaction was quenched with saturated aqueous NH4Cl at room temperature. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography eluting with 0-60% ethyl acetate in petroleum ether and dried to give the compound N-{4,8-dibromo-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesulfonamide (600 mg, 0.98 mmol, 59%) as a yellow solid. LCMS: m / z 614 [M+H] + .

[0418] Step E: A solution of N-{4,8-dibromo-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesulfonamide (600 mg, 0.98 mmol) in DCM (10 mL) was treated with 1,1,1-triacetoxy-1,3-dihydro-1λ at room temperature under N 5-benzo[2,1-d][1,2]iodoxol-3-one (828 mg, 1.95 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was treated with HO (100 mL) and extracted with EA (3 × 300 mL). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified using silica gel column chromatography eluting with 0–50% ethyl acetate in petroleum ether and dried to give the compound N-{4,8-dibromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (250 mg, 0.409 mmol, 25%) as a yellow oil.

[0419] Step F: To a solution of N-{4,8-dibromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (200 mg, 0.33 mmol) in NMP (2 mL) was added CuCN (87.9 mg, 0.98 mmol) at room temperature under N. The reaction mixture was stirred at 120 °C for 1 h. The mixture was treated with HO (100 mL) and extracted with EA (3 × 300 mL). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography (eluted with 0–70% ethyl acetate in petroleum ether) to give N-{8-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-2-naphthyl}-4-methylbenzenesulfonamide (80 mg, 0.14 mmol, 44%) as a yellow oil. LCMS: m / z 557 / 559 [M+H] + .

[0420] Step G: To a stirred mixture of N-{8-bromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-2-naphthyl}-4-methylbenzenesulfonamide (80 mg, 0.14 mmol) in acetonitrile (4 mL) was slowly added a solution of KOH (40.2 mg, 0.72 mmol) in HO (1 mL). The reaction mixture was stirred at room temperature for an additional 2 h. The reaction mixture was diluted with water and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with a solvent mixture consisting of PE and EA (3:1) to give N-[6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (60 mg, 0.104 mmol, 73%) as a yellow oil. LCMS: m / z 575 / 577 [M+H] + .

[0421] Step H: To a solution of N-(6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-4-methylbenzenesulfonamide (60 mg, 0.11 mmol) in TFA (2 mL) at room temperature was added triethylsilane (0.2 mL). The mixture was stirred at 70° C. for an additional 1 h. The cooled reaction mixture was concentrated. The crude reaction mixture was then purified by silica gel column chromatography eluting with a solvent mixture consisting of PE and EA (3:1) to give N-(6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl)-4-methylbenzenesulfonamide (50 mg, 0.09 mmol, 81%) as a yellow solid. LCMS: m / z 559 / 561 [M+H] + .

[0422] Step I: To a stirred mixture of N-[6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (50 mg, 0.09 mmol) in HO (1 mL) was added concentrated HSO (4 mL) at 0 °C. The mixture was stirred at room temperature -60 °C for 2 hours. The reaction mixture was cooled to room temperature and poured into ice water. 2 M aqueous sodium hydroxide solution (15 mL) was added. The mixture was then extracted with ethyl acetate (50 mL). The resulting organic phase was washed successively with water (20 mL) and then brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (45 mg, 0.11 mmol, 100%), which was used directly in the next step. LCMS: m / z 405 / 407 [M+H] + .

[0423] Step J: To a solution of 5-bromo-6-chloro-1,2,3,4-tetrahydronaphthalen-1-one (200 mg, 0.771 mmol) and 4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (45 mg, 0.11 mmol) in pyridine (2 mL), POCl (0.02 mL, 0.22 mmol) was added dropwise. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (15 mL), washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (PE:EA=1:1) to give N-[6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (38 mg, 0.06 mmol, 57%) as a yellow solid.

[0424] Step K: To a reaction mixture of N-[6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (38 mg, 0.06 mmol) in dry DMF (2 mL) was added Zn(CN) (15 mg, 0.13 mmol), Pd(dba) (5.84 mg, 0.01 mmol), and bis(cyclopentyldiphenylphosphane)iron(0) (7.2 mg, 0.01 mmol). The reaction mixture was stirred at 120 °C under N for 18 h. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography followed by preparative HPLC purification to give N-[3-(2-chloro-5-fluorophenyl)-6-cyano-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (4.5 mg, 0.01 mmol, 13%). LCMS: m / z 542 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.55 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.69–7.66 (m, 3H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.03–7.01 (m, 1H), 6.40 (s, 2H).

[0425] [Example 20] Synthesis of N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-thiazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0426] Step A: To a solution of methyl 2-amino-6-fluorobenzoate (15 g, 87.6 mmol) in ACN (100 mL) was added NBS (17.2 g, 96.4 mmol) and AcOH (5 mL) at 0°C to 25°C. The reaction mixture was stirred at 25°C for 16 h. TLC showed the reaction was complete. The cooled reaction mixture was poured into water (300 mL) and extracted with EA (400 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (concentration gradient: 0 to 100%) to give methyl 2-amino-5-bromo-6-fluorocyclohexa-2,4-diene-1-carboxylate (10 g, 39.9 mmol, 46%) as a white solid.

[0427] Step B: To a solution of methyl 6-amino-3-bromo-2-fluorobenzoate (10 g, 39.9 mmol) in AcOH (100 mL) was added Br2 (7.03 g, 43.9 mmol) and potassium thiocyanate (9.72 g, 99.9 mmol) at 0°C to 25°C. The reaction mixture was stirred at 25°C under N2 for 18 h. TLC showed the reaction was complete. The cooled reaction mixture was concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (gradient: 0 to 100%) to give methyl 2-amino-6-bromo-5-fluoro-4,5-dihydrocyclohexa[1,2-d][1,3]thiazole-4-carboxylate (2.6 g, 8.46 mmol, 21%) as a white solid.

[0428] Step C: A suspension of methyl 2-amino-6-bromo-5-fluoro-4,5-dihydrocyclohexa[1,2-d][1,3]thiazole-4-carboxylate (3 g, 9.77 mmol) and 3-methyl-1-(nitrosooxidanyl)butane (3.27 mL, 24.4 mmol) in THF (35 mL) was stirred at 50 °C for 18 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0 to 100%) to give methyl 6-bromo-5-fluoro-4,5-dihydrocyclohexa[1,2-d][1,3]thiazole-4-carboxylate (1.6 g, 5.477 mmol, 56%) as a yellow solid. LCMS: m / z 290.11 [M+H] +

[0429] Step D: To a solution of methyl 6-bromo-5-fluoro-4,5-dihydrocyclohexa[1,2-d][1,3]thiazole-4-carboxylate (1 g, 3.42 mmol) in THF (10 mL) was added a solution of LiOH·HO (0.43 g, 10.3 mmol) in HO (3 mL). The mixture was stirred at 45 °C for 1 h. The reaction mixture was poured into HCl (20 mL, 0.2 mmol / mL) and extracted with EA (20 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0–100%) to give 6-bromo-5-fluoro-4,5-dihydrocyclohexa[1,2-d][1,3]thiazole-4-carboxylic acid (0.8 g, 2.87 mmol, 84%) as a white solid. LCMS: m / z 276.14 [M+H] +

[0430] Step E: To a solution of 6-bromo-5-fluorobenzo[d]thiazole-4-carboxylic acid (2.7 g, 9.79 mmol), 2-chloro-5-fluorobenzene-1-carbaldehyde (1.55 g, 9.79 mmol), and PMBNH (1.34 g, 9.79 mmol) in MeOH (30 mL) was added t-BuNC (0.81 g, 9.79 mmol). The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give 6-bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-5-fluoro-N-(4-methoxybenzyl)benzo[d]thiazole-4-carboxamide (4 g, 6.32 mmol, 63%) as a yellow solid. LCMS: m / z 636.12 [M+H] +

[0431] Step F: To a solution of 6-bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-5-fluoro-N-(4-methoxybenzyl)benzo[d]thiazole-4-carboxamide (1 g, 1.57 mmol) in DMA (5 mL) was added 1,1-bis(dimethylamino)-N-(2-methylprop-2-yl)methanimine (0.81 g, 4.71 mmol). The reaction mixture was stirred at 140° C. for 3 h. The cooled reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give 5-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H-[1,3]thiazolo[4,5-e]isoindol-8-one (0.1 g, 0.187 mmol, 12%) as a yellow oil. LCMS: m / z 533.12 [M+H] +

[0432] Step G: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H-[1,3]thiazolo[4,5-e]isoindol-8-one (0.3 g, 0.562 mmol) in TFA (10 mL) was added triethylsilane (0.227 mL, 1.41 mmol). The reaction mixture was stirred at 75 °C for 1.5 h. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous solution (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give 5-bromo-6-(2-chloro-5-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H-[1,3]thiazolo[4,5-e]isoindol-8-one (0.23 g, 0.444 mmol, 79%) as a yellow solid. LCMS: m / z 517.12 [M+H] +

[0433] Step H: To a stirred mixture of 5-bromo-6-(2-chloro-5-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H-[1,3]thiazolo[4,5-e]isoindol-8-one (0.2 g, 0.386 mmol) in dioxane (20 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (0.10 g, 0.502 mmol), xant-PHOS (0.02 g, 0.039 mmol), Pd(dba) (0.02 g, 0.039 mmol), and CsCO (0.38 g, 1.16 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous HCl (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (gradient: 0-100%) to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-[1,3]thiazolo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (0.15 g, 0.227 mmol, 59%) as a yellow solid. LCMS: m / z 660.12 [M+H] +

[0434] Step I: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-[1,3]thiazolo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.015 mmol) and trifluoromethanesulfonic acid (0.007 mL, 0.076 mmol) in TFA (5 mL) was added triethylsilane (8.81 mg, 0.076 mmol). The mixture was stirred at 80° C. for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-[1,3]thiazolo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (4.5 mg, 0.009 mmol, 57%). LCMS: m / z 524.12 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.51 (s, 1H), 8.29 (s, 1H), 7.71–7.66 (m, 3H), 7.27 (s, 1H), 7.00 (t, J = 8.4 Hz, 1H), 6.43 (s, 1H).

[0435] [Example 21] 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide [ka]

[0436] Step A: To a solution of 3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-5-nitro-6,7-dihydropyrrolo[3,4-g]indazol-8(1H)-one (500 mg, 0.89 mmol) in DMA (10 mL) was added Zn(CN) (314 mg, 2.67 mmol), bis(cyclopentyldiphenylphosphane)iron(0) (100 mg, 0.18 mmol), and tris[(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one]bis[palladium(0)] (81.5 mg, 0.09 mmol) under N. The reaction mixture was stirred at 150 °C for 4 h under N. The cooled reaction was diluted with EA and water. The organic layer was separated, further washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give the compound 6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-5-nitro-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (400 mg, 0.49 mmol, crude) as a yellow solid. LCMS: m / z 508 [M+H] + .

[0437] Step B: To a solution of 6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-5-nitro-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (400 mg, 0.788 mmol) in EtOH (15 mL) and HO (5 mL) was added NHCl (127 mg, 2.36 mmol) and Fe (264 mg, 4.73 mmol). The mixture was stirred at 80 °C for 3 h. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (260 mg, 0.54 mmol, 69%) as a yellow solid. LCMS: m / z 478 [M+H] + .

[0438] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazole-3-carbonitrile (150 mg, 0.31 mmol) in DCM (5 mL) was added pyridine (2.5 mL, 31.4 mmol). 3-Chloro-5-fluorobenzoic acid (60 mg, 0.35 mmol) and dichlorophosphinyl chloride (0.06 mL, 0.628 mmol) were then added. The mixture was stirred at 25 °C for 1 h. The reaction was diluted with DCM and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using preparative TLC eluting with 30% ethyl acetate in petroleum ether to give 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide (50 mg, 0.05 mmol, 15%) as a yellow solid. LCMS: m / z 634 [M+H] + .

[0439] Step D: To a solution of 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide (50 mg, 0.08 mmol) in TFA (5 mL) was added triethylsilane (0.014 mL, 7.88 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo to give 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide (50 mg, 0.07 mmol, crude) as a yellow liquid. LCMS: m / z 618[M+H] + .

[0440] Step E: To a solution of 3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-7-(4-methoxybenzyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide (50 mg, 0.07 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid (0.014 mL, 0.16 mmol). The reaction mixture was stirred at 75° C. for 1 hour. The cooled reaction mixture was concentrated. The residue was purified by preparative HPLC (YMC-Actus Triart C18 150 x 20 mm x 5 μm, 40%-95%, Phase A: HO (0.1% FA), Phase B: MeCN) to give the compound 3-chloro-N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluorobenzamide (25 mg, 0.05 mmol, 64%). LCMS: m / z 498 [M + H] + . 1H NMR (400 MHz, methanol-d4) δ 7.99 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.39 (s, 1H), 7.33–7.31 (m, 2H), 7.08–7.03 (m, 1H), 6.69–6.09 (m, 2H).

[0441] [Example 22] N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide [ka]

[0442] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazole-3-carbonitrile (100 mg, 0.21 mmol) and 4-benzo[d][1,2]thiazole-3-carboxylic acid (41.3 mg, 0.23 mmol) in Py (3 mL) was added POCl (0.04 mL, 0.42 mmol) at 0 °C with stirring under N. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to remove most of the solvent. The residue was poured into water (6 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product N-[6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide (110 mg, 0.17 mmol, 82%) as a light brown solid, which was used without further purification. LC / MS (ESI) m / z: 637 [MH] +

[0443] Step B: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide (120 mg, 0.19 mmol) and triethylsilane (0.46 mL, 2.82 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (0.08 mL, 0.94 mmol) with stirring at 0° C. The reaction mixture was stirred at 70° C. for 2 hours. The cooled reaction mixture was concentrated. The residue was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide (11 mg, 0.022 mmol, 12%). LC / MS (ESI) m / z: 503 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 15.20 (s, 1H), 10.39 (s, 1H), 9.41 (s, 1H), 8.66 (d, J = 7.6 Hz, 1H), 8.37 - 8.11 (m, 2H), 7.68 - 7.60 (m, 2H), 7.23 (d, J = 5.6 Hz, 1H), 7.00 (s, 1H), 6.41 (brs, 2H).

[0444] [Example 23] N-[6-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0445] Step A: To a solution of phosphorus tribromide (13 mL, 138 mmol) in CHCl3 (280 mL) was added DMF (13 mL, 166 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. Then, 5-chloro-1,2,3,4-tetrahydronaphthalen-1-one (10 g, 55.3 mmol) in CHCl3 (50 mL) was added dropwise at 0 °C. The mixture was then stirred at 70 °C for 2 h. The cooled mixture was added to ice water (400 mL). The mixture was concentrated in vacuo to remove CHCl3. The mixture was extracted with EA (500 mL × 3). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (20 g column) using 0-80% EtOAc / hexanes to give 1-bromo-5-chloro-3,4-dihydronaphthalene-2-carbaldehyde (8 g, 29.4 mmol, 53%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 2.93 (t, J = 8.2 Hz, 2H), 2.55 (t, J = 8.2 Hz, 2H).

[0446] Step B: To a solution of 1-bromo-5-chloro-3,4-dihydronaphthalene-2-carbaldehyde (2 g, 7.36 mmol) in toluene (20 mL) was added 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (5.02 g, 22.1 mmol). The reaction mixture was stirred at 110 °C for 12 h. The mixture was filtered, diluted with saturated Na2CO3 (200 mL), and extracted with EA (200 mL × 3). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (10 g column) using 0–5% EtOAc / hexane to give 1-bromo-5-chloronaphthalene-2-carbaldehyde (1.05 g, 3.89 mmol, 53%) as a pale solid. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.00 (dd, J = 10.8, 8.2 Hz, 2H), 7.81 (t, J = 8.2 Hz, 1H).

[0447] Step C: To a solution of 1-bromo-5-chloronaphthalene-2-carbaldehyde (800 mg, 2.96 mmol) in 1,2-dichloroethane (35 mL), tosyl azide (146 mg, 0.742 mmol), bis[iridium(3+)]bis(1,2,3,4,5-pentamethylcyclopenta-2,4-dien-1-ide) tetrachloride (59.1 mg, 0.074 mmol), silver bis[dioxo(trifluoromethyl)-λ 6 N-sulfanyl]azanide (115.2 mg, 0.297 mmol) and 3,5-bis(trifluoromethyl)aniline (68 mg, 0.297 mmol) were added. The mixture was stirred at 100° C. for 18 h. To the cooled mixture was added EA (20 mL) and stirred at 20° C. for 10 min. The mixture was then filtered and the filter cake was concentrated to give N-(4-bromo-8-chloro-3-formyl-2-naphthyl)-4-methylbenzenesulfonamide (760 mg, 1.73 mmol, 58%) as a yellow solid. LCMS: m / z 439.9 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.52 (s, 1H), 8.42 (d, J = 8.6 Hz, 1H), 8.04 (s, 1H), 8.00 (dd, J = 7.6, 0.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.73 (dd, J = 8.6, 7.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 2.40 (s, 3H).

[0448] Step D: To a solution of N-(4-bromo-8-chloro-3-formyl-2-naphthyl)-4-methylbenzenesulfonamide (760 mg, 1.73 mmol) in THF (20 mL) at 0 °C was added (2-chloro-5-fluorophenyl)magnesium chloride (1.30 g, 6.93 mmol). The reaction mixture was stirred from 0 °C to room temperature for 1 h. The mixture was quenched with MeOH and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0-30% EtOAc / hexane to afford N-{4-bromo-8-chloro-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesulfonamide (790 mg, 1.38 mmol, 80%) as a white solid. LCMS: m / z 568 [MH] + .

[0449] Step E: To a solution of N-{4-bromo-8-chloro-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesulfonamide (790 mg, 1.38 mmol) in DCM (50 mL) was added Dess-Martin (1.17 g, 2.77 mmol). The mixture was then stirred at 20 °C for 12 h. The reaction mixture was filtered. The filtrate was concentrated to give a residue, which was purified by silica gel chromatography (3 g column) using 0-30% EtOAc / hexane to give N-{4-bromo-8-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (300 mg, 0.529 mmol, 38%) as a white solid. LCMS: m / z 566 [M+H] + .

[0450] Step F: To a solution of N-{4-bromo-8-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (250 mg, 0.441 mmol) in NMP (10 mL) was added CuCN (59.2 mg, 0.661 mmol). The reaction mixture was stirred at 150 °C for 1 h. The cooled mixture was diluted with water and extracted with EA (50 mL × 3). The organic phase was dried over NaSO and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0–30% EtOAc / hexane to give N-{8-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-2-naphthyl}-4-methylbenzenesulfonamide (190 mg, 0.370 mmol, 84%) as a brown solid. LCMS: m / z 513 [M+H] + .

[0451] Step G: To a solution of N-{8-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-2-naphthyl}-4-methylbenzenesulfonamide (170 mg, 0.331 mmol) in CHCN (15 mL) and water (4 mL) was added KOH (74.3 mg, 1.32 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (30 mL) and concentrated in vacuo to remove CHCN, which was then extracted with EA (30 mL × 3). The organic phase was dried over NaSO and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0–50% EtOAc / hexanes to give N-[6-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (110 mg, 0.207 mmol, 62%) as a brown solid. LCMS: m / z 528.9 [MH] + .

[0452] Step H: To a solution of N-[6-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (110 mg, 0.207 mmol) in TFA (4 mL) was added triethylsilane (1 mL, 6.19 mmol). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo to give N-[6-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (110 mg, 0.203 mmol, 98%) as a brown oil. LCMS: m / z 515 [M+H] + .

[0453] Step I: To a solution of N-[6-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (100 mg, 0.194 mmol) in water (0.5 mL) was added H2SO4 (2 mL, 0.019 mmol). The reaction mixture was stirred at 40 °C for 2 h. The cooled reaction mixture was diluted with water, the pH adjusted to 8 with NaOH, and extracted with EA (30 mL × 3). The organic phase was washed with brine, dried over Na2SO4, and concentrated to give 4-amino-6-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (70 mg, 0.194 mmol, 99%) as a red solid. LCMS: m / z 361 [M+H] + .

[0454] Step J: To a solution of 4-amino-6-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (30 mg, 0.083 mmol) in DCM (5 mL) was added pyridine (2 mL, 24.7 mmol). Then, 3-fluoro-5-(trifluoromethyl)benzoic acid (20.7 mg, 0.100 mmol) and dichlorophosphinyl chloride (25 mg, 0.166 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative TLC (PE / EA=7:3) and then by preparative HPLC to give N-[6-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (6.4 mg, 0.012 mmol, 14%) as a white solid. LCMS: m / z 551 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.25 (d, J = 8.2 Hz, 1H), 8.43 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 9.4 Hz, 4H), 7.31–7.25 (m, 1H), 7.01 (t, J = 8.2 Hz, 1H), 6.37 (s, 2H).

[0455] [Example 24] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0456] Step A: To a solution of N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (500 mg, 0.784 mmol) in DCM (10 mL) was added m-CPBA (537 mg, 2.35 mmol) at 0°C to 25°C. The reaction mixture was stirred at 25°C for 16 h. TLC showed the reaction was complete. The cooled reaction mixture was washed with aqueous NaSO (60 mL), dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (concentration gradient: 0-100%) to give 3-(2-chloro-5-fluorophenyl)-4-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline 6-oxide (400 mg, 0.597 mmol, 76%) as a white solid. LCMS: m / z 770.11 [M+H] +

[0457] Step B: To a solution of 3-(2-chloro-5-fluorophenyl)-4-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline 6-oxide (400 mg, 0.597 mmol) in DCM (10 mL) was added POCl (2 mL) and DMF (1 mL) at 25 °C. The reaction mixture was stirred at 30 °C under N for 3 hours. TLC showed the reaction was complete. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (concentration gradient: 0-100%) to give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (200 mg, 0.291 mmol, 49%) as a white solid.

[0458] Step C: To a solution of N-[7-chloro-3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.030 mmol) and trifluoromethanesulfonic acid (0.014 mL, 0.157 mmol) in TFA (15 mL) was added triethylsilane (0.034 mL, 0.21 mmol). The mixture was stirred at 80° C. for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.9 mg, 0.005 mmol, 18%). LCMS: m / z 552.12 [M + H] + . 1H NMR (400 MHz, methanol-d4) δ 9.53 (d, J = 9.0 Hz, 1H), 8.51 (s, 1H), 8.06 (s, 1H), 7.73–7.68 (m, 4H), 7.34–7.24 (m, 1H), 7.02 (t, J = 8.2 Hz, 1H), 6.41 (s, 1H).

[0459] [Example 25] N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-oxazolo[5,4-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0460] To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, crude, 0.04 mmol, 1.0 equiv) in triethyl orthoformate (0.5 mL) under N at 25 °C, P-TsOH (3.8 mg, 0.02 mmol, 0.5 equiv) was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (acetonitrile in water with 0.1% FA) to give N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-oxazolo[5,4-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (0.8 mg) as a white solid. LCMS: m / z 505.9 ([M-H] - ).

[0461] [Example 26] N-[3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-b]imidazo[2,3-f]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0462] Step A: To a solution of 4,6-dichloropyridine-2-carboxylic acid (16 mL, 130 mmol) in DCM (250 mL) was added DIEA-ethyldiisopropylamine (54 mL, 326 mmol), HATU (74 g, 195 mmol), and (4-methoxyphenyl)methanamine (26 mL, 195 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (750 mL) and water (1000 mL). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The resulting solid was washed three times with water and dried under vacuum to give crude 4,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridine-2-carboxamide (40 g, 128.551 mmol, 99%) as a yellow solid. LCMS: m / z 313.0 [M+2+H] +

[0463] Step B: To a solution of 2-chloro-5-fluorobenzoic acid (17 g, 97.4 mmol) in DCM (170 mL) was added oxalyl chloride (12.5 mL, 146 mmol) and DMF (0.753 mL, 9.739 mmol) at 0 °C. The reaction was stirred at room temperature for 1 hour. The raw material was completely reacted by TLC detection. The reaction was concentrated in vacuo to give crude 2-chloro-5-fluorobenzoyl chloride (18.6 g, 96.3 mmol, 98%).

[0464] To a solution of 4,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridine-2-carboxamide (15 g, 48.207 mmol) in THF (200 mL) was added NaH (2.89 g, 72.3 mmol, 60% in mineral oil) at 0° C. The reaction was stirred at 0° C. for 1 h. Then a solution of 2-chloro-5-fluorobenzoyl chloride (18.6 g, 96.4 mmol) in THF (200 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with EA (500 mL) and water (500 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with EA and 2% DCM in PE (1% to 50%) to give the compound 4,6-dichloro-N-[(2-chloro-5-fluorophenyl)carbonyl]-N-[(4-methoxyphenyl)methyl]pyridine-2-carboxamide (11 g, 19.7 mmol, 41%) as a yellow solid.

[0465] Step C: To a solution of 4,6-dichloro-N-[(2-chloro-5-fluorophenyl)carbonyl]-N-[(4-methoxyphenyl)methyl]pyridine-2-carboxamide (11 g, 23.5 mmol) in THF (110 mL) was added LiHMDS (35.3 mL, 1.0 M in THF) at −68° C. The reaction mixture was stirred at −68° C. for an additional 1 h. The reaction mixture was quenched with 100 mL of saturated NH4Cl solution and extracted with 200 mL x 3 portions of ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE (v / v=1 / 2) to give 2,4-dichloro-5-(2-chloro-5-fluorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (4.2 g, 8.98 mmol, 38%) as a pale yellow solid. LCMS: m / z 467.0 [M+H] +

[0466] Step D: To a solution of 2,4-dichloro-5-(2-chloro-5-fluorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (4.2 g, 8.980 mmol) in TFA (50 mL) was added triethylsilane (5.22 g, 44.901 mmol). The reaction mixture was stirred at 70 °C for an additional hour. The cooled reaction mixture was concentrated. The residue was quenched with 100 mL of saturated NaHCO3 solution and extracted with 200 mL x 3 ethyl acetate portions. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE (v / v=1 / 1) to give 2,4-dichloro-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-one (3 g, 6.64 mmol, 74%) as a yellow solid. LCMS: m / z 451.0 [M+H] +

[0467] Step E: To a solution of (2,4-dimethoxyphenyl)methanamine (0.33 mL, 2.21 mmol) in dioxane (10 mL) in a sealed tube was added DIEA ethyldiisopropylamine (1.10 mL, 6.64 mmol) and (2,4-dimethoxyphenyl)methanamine (0.33 mL, 2.21 mmol). The reaction mixture was stirred at 160 °C for 3 h. The cooled reaction mixture was diluted with EA (200 mL) and water (200 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate (1% to 30%) in petroleum ether to give the crude product. The crude product was purified using silica gel column chromatography eluting with water and 0.1% HCOOH (50%-75%) in CAN to give the compound 4-chloro-5-(2-chloro-5-fluorophenyl)-2-{[(2,4-dimethoxyphenyl)methyl]amino}-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (300 mg, 0.515 mmol, 23%) as a white solid. LCMS: m / z 582.2 [M+H] +

[0468] Step F: A solution of 4-chloro-5-(2-chloro-5-fluorophenyl)-2-{[(2,4-dimethoxyphenyl)methyl]amino}-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (330 mg, 0.567 mmol) in TFA (10 mL, 135 mmol) was stirred at room temperature for 3 hours. The reaction was concentrated in vacuo. The residue was diluted with EA and saturated NaHCO3 solution. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (10% to 50%) and dried to give the compound 2-amino-4-chloro-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (230 mg, 0.532 mmol, 93.9%) as a yellow solid. LCMS: m / z 432.0 [M+H]+

[0469] Step G: A solution of 2-amino-4-chloro-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (233 mg, 0.539 mmol) in 2-chloroacetaldehyde (10 mL, 157.5 mmol) was stirred at 90° C. for 3 h. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1% to 100%) and dried to give the compound 4-chloro-3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[4,3-b]imidazo[2,1-f]pyridin-1-one (190 mg, 0.416 mmol, 77%) as a yellow solid. LCMS: m / z 456.0 [M+H] +

[0470] Step H: To a solution of 4-chloro-3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-pyrrolo[3,4-b]imidazo[2,3-f]pyridin-1-one (100 mg, 0.219 mmol) in dioxane (10 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (90.8 mg, 0.438 mmol), CsCO (286 mg, 0.877 mmol), Xantphos (63.4 mg, 0.110 mmol), and Pd(dba) (100 mg, 0.110 mmol). The reaction was stirred at 120 °C under N for 6 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 0-50%) to obtain the compound N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-b]imidazo[2,3-f]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (65 mg, 0.101 mmol, 46%) as a brown oil. LCMS: m / z 627.1 [M+H] +

[0471] Step I: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-b]imidazo[2,3-f]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (65 mg, 0.101 mmol) in TFA (5 mL) was added triethylsilane (0.114 mL, 0.708 mmol) and trifluoromethanesulfonic acid (0.063 mL, 0.708 mmol). The reaction was stirred at 90° C. for 1 hour. The cooled reaction mixture was concentrated. The residue was purified by preparative HPLC (C18, 0-70% acetonitrile in HO) to give the compound N-[3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-b]imidazo[2,3-f]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.02 mmol, 20%). LCMS: m / z 507.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.93 (s, 1H), 8.68 (s, 1H), 8.16 (s, 1H), 8.00 (s, 2H), 7.71 (d, J = 9.4 Hz, 1H), 7.58 (s, 1H), 7.37 (dd, J = 9.8, 4.6 Hz, 1H), 7.19 - 6.85 (m, 2H), 6.29 (s, 1H).

[0472] [Example 27] N-[6-(2-chloro-5-fluorophenyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0473] Step A: To a solution of 6-fluoro-7-(methoxycarbonyl)-1H-indazole-5-carboxylate (1.60 g, 6.75 mmol) in MeOH (10 mL) / HO (10 mL) / THF (10 mL) was added LiOH (0.67 mL, 23.8 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EA (10 mL) and HCl (2 mol / L, 10 mL). The organic layer was separated, washed with brine, dried over NaSO, and concentrated. The residue was dried to give the compound 7-carboxy-6-fluoro-1H-indazole-5-carboxylic acid (1.00 g, 4.48 mmol, 66%) as a yellow solid. LCMS: m / z 224 [M−H] - .

[0474] Step B: To a solution of 2-isocyano-2-methylpropane (0.36 mL, 3.14 mmol) in MeOH (15 mL) was added 7-carboxy-6-fluoro-1H-indazole-5-carboxylic acid (700 mg, 3.14 mmol), 2-chloro-5-fluorobenzene-1-carbaldehyde (498 mg, 3.14 mmol), and (4-methoxyphenyl)methanamine (0.41 mL, 3.14 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with 0-15% ethyl acetate in petroleum ether and dried to give the compound 7-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-6,6-dimethyl-1,4-dioxo-2,5-diazahept-1-yl]-6-fluoro-1H-indazole-5-carboxylate (1.30 g, 2.23 mmol, 71%) as a yellow solid. LCMS: m / z 586 [M+H] + .

[0475] Step C: To a solution of 7-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-6,6-dimethyl-1,4-dioxo-2,5-diazahept-1-yl]-6-fluoro-1H-indazole-5-carboxylate (500 mg, 0.86 mmol) in DMA (10 mL) was added 1,1-bis(dimethylamino)-N-(2-methylprop-2-yl)methanimine (212 mg, 1.29 mmol). The reaction mixture was stirred at 140 °C overnight. The reaction mixture was diluted with EA and water. The organic layer was washed with brine, dried over Na SO , and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether and dried to give the compound 6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazole-5-carboxylate (300 mg, 0.65 mmol, 73%) as a yellow oil. LCMS: m / z 483 [M+H] + .

[0476] Step D: To a solution of 6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazole-5-carboxylate (35 mg, 0.073 mmol) in EtOH (5 mL) was added Fe (40 mg, 0.728 mmol) and NHCl (39 mg, 0.728 mmol). The reaction mixture was stirred at 80 °C for 3 h. The cooled reaction was diluted with EA and water. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was dried to give the compound 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-8-one (30 mg, 0.066 mmol, 91%) as a yellow solid. LCMS: m / z 453 [M+H] + .

[0477] Step E: To a solution of 5-fluoro-3-(trifluoromethyl)benzoic acid (14 mg, 0.066 mmol) in pyridine (2 mL, 24.73 mmol), POCl (0.1 mL, 1.07 mmol) and 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-8-one (30 mg, 0.066 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was diluted with EA and saturated NaHCO solution. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was dried to give the compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-N-{[3-fluoro-5-(trifluoromethyl)phenyl]carbonyl}-3-(trifluoromethyl)benzamide (crude 30 mg, 0.047 mmol, 70%) as a yellow solid. LCMS: m / z 799 [M+H] + .

[0478] Step F: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-N-{[3-fluoro-5-(trifluoromethyl)phenyl]carbonyl}-3-(trifluoromethyl)benzamide (crude 30 mg, 0.036 mmol) in THF (2 mL) was added KOH (0.5 mL, 1.00 mmol) and HO (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was diluted with EA and saturated NaHCO solution. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative TLC and dried to give the compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 43%) as a yellow solid. LCMS: m / z 643 [M+H] + .

[0479] Step G: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (0.5 mL) was added EtSiH (0.5 mL, 3.01 mmol) and trifluoromethanesulfonic acid (0.05 mL, 0.57 mmol). The reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC and dried to give the compound N-[6-(2-chloro-5-fluorophenyl)-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (2 mg, 0.004 mmol, 25%). LCMS: m / z 507 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.92 (s, 1H), 10.40 (s, 1H), 9.20 (s, 1H), 8.29 (s, 1H), 8.05 - 7.83 (m, 2H), 7.83 - 7.63 (m, 2H), 7.31 (s, 1H), 7.10 (s, 1H), 6.47 - 6.20 (m, 2H).

[0480] [Example 28] N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[3,4-e]pyridin-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0481] Step A: To a stirred mixture of 2,4-dichloro-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (1 g, 2.21 mmol) in HO (2 mL) and EtOH (20 mL) was added potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (790 mg, 3.32 mmol), pd(pph3)2Cl2 (310 mg, 0.443 mmol), and Na2CO3 (590 mg, 5.54 mmol). The reaction mixture was stirred at 80 °C under N2 for 16 h. The cooled mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column eluting with ethyl acetate / petroleum ether (1 / 1) to obtain the compound 2-methylpropan-2-yl ({[4-chloro-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-2-yl]methyl}amino) methanoate (330 mg, 0.604 mmol, 27%) as a brown solid. LCMS: m / z 546 [M+H] + .

[0482] Step B: To a stirred mixture of 2-methylpropan-2-yl ({[4-chloro-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-2-yl]methyl}amino)methanoate (300 mg, 0.549 mmol) in dioxane (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-1-carboxamide (125 mg, 0.604 mmol), Pd(OAc) (12.0 mg, 55.1 μmol), dppf (60.9 mg, 110 μmol), and t-BuONa (132 mg, 1.37 mmol). The reaction mixture was stirred at 100° C. for 16 hours. The cooled mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with EA / PE = 0 to 50%) to give 2-methylpropan-2-yl ({[5-(2-chloro-5-fluorophenyl)-4-({[3-fluoro-5-(trifluoromethyl)phenyl]carbonyl}amino)-6-[(4-methoxyphenyl)methyl]-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-2-yl]methyl}amino)methanoate (100 mg, 0.139 mmol, 25%) as a brown solid. LCMS: m / z 717 [M+H] + .

[0483] Step C: A solution of 2-methylpropan-2-yl ({[5-(2-chloro-5-fluorophenyl)-4-({[3-fluoro-5-(trifluoromethyl)phenyl]carbonyl}amino)-6-[(4-methoxyphenyl)methyl]-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-2-yl]methyl}amino)methanoate (45 mg, 63 μmol) in HCl (2 mL, 4 M in dioxane) was stirred at room temperature for 2 hours. The mixture was concentrated to give N-[2-(aminomethyl)-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (38 mg, 62 μmol, 98%) as a brown solid. LCMS: m / z 617 [M+H] + .

[0484] Step D: A solution of acetic anhydride (0.65 mL) and FA (0.25 mL) was stirred at 60° C. for 1 h. N-[2-(aminomethyl)-5-(2-chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 65 μmol) in FA (0.25 mL) was stirred at 60° C. for 2 h. After cooling to room temperature, the solvent was concentrated and the mixture was adjusted to pH=8. The mixture was then extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give N-[6-(2-chloro-5-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-b]imidazo[4,3-f]pyridin-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 64 μmol, 98%) as crude product, which was used directly in the next step. LCMS: m / z 627 [M+H] + .

[0485] Step E: To a solution of N-[6-(2-chloro-5-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-b]imidazo[4,3-f]pyridin-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 64 μmol) in TFA (2 mL) was added TfOH (0.2 mL). The mixture was stirred at 70 °C for 30 minutes and then concentrated. The crude product was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-b]imidazo[4,3-f]pyridin-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.2 mg, 4 μmol, 7%). LCMS: m / z 507 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.42 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.71 (d, J = 9.8 Hz, 1H), 7.63–7.61 (m, 2H), 7.30 (s, 1H), 7.06–7.01 (m, 1H), 6.84 (s, 1H), 6.41 (s, 1H).

[0486] [Example 29] (S)—N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 30 (R)—N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0487] N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (75 mg, 0.14 mmol) was purified by preparative SFC to give (S)—N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 0.05 mmol, 33%). LCMS: m / z 532 [M + H] + . 1 H NMR (400 MHz, DMSO-d) δ 15.22 (s, 1H), 10.53 (s, 1H), 9.38 (s, 1H), 8.06–7.88 (m, 2H), 7.82–7.63 (m, 2H), 7.34–7.30 (m, 1H), 7.10 (s, 1H), 6.80–5.66 (m, 2H), and (R)-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (27.6 mg, 0.05 mmol, 36.8%) were obtained. LCMS: m / z 532 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 15.23 (s, 1H), 10.54 (s, 1H), 9.39 (s, 1H), 8.06 - 7.92 (m, 2H), 7.78 - 7.69 (m, 2H), 7.33 - 7.30 (m, 1H), 7.10 (s, 1H), 6.69 - 5.98 (m, 2H).

[0488] [Example 31] N-(3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 32 N-(3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0489] Step A: To a solution of N-[7-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (300 mg, 0.436 mmol) in dioxane (10 mL) was added sodium tert-butoxide (146.7 mg, 1.31 mmol), MeOH (1 mL, 24.7 mmol), and t-BuBrettPhos Palladacycle 3rd generation (74.6 mg, 0.087 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 18 h. TLC indicated the reaction was complete. The cooled reaction mixture was washed with water (60 mL) and extracted with DCM (60 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (concentration gradient: 0-100%) to give N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.015 mmol, 3%) as a white solid. LCMS: m / z 688.11 [M+H] +

[0490] Step B: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.088 mmol) and trifluoromethanesulfonic acid (0.014 mL, 0.157 mmol) in TFA (15 mL) was added triethylsilane (0.034 mL, 0.21 mmol). The mixture was stirred at 80 °C for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.055 mmol, 62%). LCMS: m / z 548.12 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.34 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.70–7.65 (m, 3H), 7.28 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.00 (s, 1H), 6.69–6.07 (m, 1H), 4.09 (s, 3H).

[0491] Step C: To a solution of N-[3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.018 mmol) in dioxane (15 mL) was added concentrated HCl (0.5 mL, 3.01 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.8 mg, 0.005 mmol, 29%). LCMS: m / z 534.12 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 12.11 (s, 1H), 10.64 (s, 1H), 9.32 (s, 1H), 8.97 (d, J = 9.8 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.33 - 7.29 (m, 1H), 7.09 - 7.08 (m, 1H), 6.68 (d, J = 9.7 Hz, 2H), 6.01 (s, 1H).

[0492] [Example 33] N-[6-(2-chloro-5-fluorophenyl)-3-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0493] Step A: To a solution of 4-bromo-6-fluoro-1H-indazole (7.5 g, 34.8 mmol) in DMF (110 mL) was added NaH (1 g, 41.8 mmol, 60% in mineral oil) in portions at 0 °C. The reaction mixture was stirred for 10 min, and then CHCl (3.25 mL, 52.3 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The reaction mixture was quenched with H2O and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 0-10%) to give compound 4-bromo-6-fluoro-1-methylindazole (4.5 g, 19.6 mmol, 56%) as a white solid. LCMS: m / z 229 [M+H] + .

[0494] Step B: To a solution of 4-bromo-6-fluoro-1-methylindazole (4.5 g, 19.6 mmol) in THF (70 mL) was added LDA (5.2 mL, 39.2 mmol) at −78° C. The mixture was stirred at −78° C. for 30 minutes, and then 2-chloro-5-fluorobenzene-1-carbaldehyde (6.23 g, 39.2 mmol) was added. The reaction mixture was stirred at −78° C. for an additional 2 hours. LCMS showed the reaction was complete. The reaction was diluted with an aqueous solution of NH4Cl and EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 5-10%) to obtain the compound (4-bromo-6-fluoro-1-methylindazol-5-yl)(2-chloro-5-fluorophenyl)methanol (1.5 g, 3.87 mmol, 20%) as a white solid. LCMS: m / z 387 [M+H] + .

[0495] Step C: To a solution of (4-bromo-6-fluoro-1-methylindazol-5-yl)(2-chloro-5-fluorophenyl)methanol (1.5 g, 3.87 mmol) in DCM (15 mL) was added Dess-Martin periodinane (3.28 g, 7.74 mmol). The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction was diluted with DCM and HO. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient: 15-20%) to give the compound (4-bromo-6-fluoro-1-methylindazol-5-yl)(2-chloro-5-fluorocyclohexa-1,5-dienyl)methanone (1.2 g, 3.10 mmol, 80%) as a white solid. LCMS: m / z 385 [M+H] + .

[0496] Step D: To a solution of (4-bromo-6-fluoro-1-methylindazol-5-yl)(2-chloro-5-fluorophenyl)methanone (600 mg, 1.56 mmol) in DMA (10 mL) was added dppf (172 mg, 0.311 mmol), Zn(CN) (201 mg, 1.71 mmol), zinc(0) (20.4 mg, 0.311 mmol), and Pd(dba) (142 mg, 0.156 mmol). The reaction mixture was stirred at 100 °C for 18 h. LCMS showed the reaction was complete. The cooled reaction mixture was diluted with EA and saturated sodium chloride. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 10-15%) to give the compound 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-1-methylindazole-4-carbonitrile (300 mg, 0.904 mmol, 58%) as a white solid. LCMS: m / z 332 [M+H] + .

[0497] Step E: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-1-methylindazole-4-carbonitrile (150 mg, 0.452 mmol) in DMSO-d (5 mL) was added DIEA (116 mg, 0.904 mmol) and (2,4-dimethoxyphenyl)methanamine (75.6 mg, 0.452 mmol). The reaction mixture was stirred at 130 °C under N for 5 h. LCMS showed the reaction was complete. The cooled reaction mixture was diluted with EA and saturated sodium chloride. The organic layer was washed with brine, dried over NaSO, and concentrated. The reaction mixture was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 15-20%) to give the compound 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-1-methylindazole-4-carbonitrile (75 mg, 0.157 mmol, 35%) as an orange solid. LCMS: m / z 479 [M+H] + .

[0498] Step F: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}-1-methylindazole-4-carbonitrile (150 mg, 0.313 mmol) in MeOH (5 mL) and HO (0.5 mL) was added sodium hydroxide (25.1 mg, 0.626 mmol). The reaction was stirred at room temperature for 10 minutes. LCMS showed the reaction was complete. The reaction was diluted with EA and HO. The organic layer was washed with brine, dried over NaSO, and concentrated to give the compound 6-(2-chloro-5-fluorophenyl)-5-{[(2,4-dimethoxyphenyl)methyl]amino}-6-hydroxy-3-methyl-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (140 mg, 0.282 mmol, 90%) as a brown solid. LCMS: m / z 497 [M+H] + .

[0499] Step G: To a solution of 6-(2-chloro-5-fluorophenyl)-5-{[(2,4-dimethoxyphenyl)methyl]amino}-6-hydroxy-3-methyl-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (130 mg, 0.262 mmol) in TFA (4 mL) was added EtSiH (0.4 mL, 2.48 mmol). The reaction was stirred at 70 °C for 30 min. LCMS showed the reaction was complete. The cooled reaction was concentrated and diluted with EA and NaHCO. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with MeOH:DCM (concentration gradient: 5-10%) to obtain the compound 5-amino-6-(2-chloro-5-fluorophenyl)-3-methyl-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (70 mg, 0.212 mmol, 81%) as a yellow solid. LCMS: m / z 331 [M+H] + .

[0500] Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-methyl-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (20 mg, 60 μmol) in pyridine (2 mL) was added 5-fluoro-3-(trifluoromethyl)benzoic acid (12.6 mg, 60 μmol) and POCl (0.011 mL, 0.120 mmol). The reaction mixture was stirred at room temperature for 10 minutes. LCMS showed the reaction was complete. The reaction was quenched with H O and extracted with EA. The organic layer was washed with brine, dried over Na SO , and concentrated. The crude material was purified by preparative HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (6.2 mg, 12 μmol, 20%). LCMS: m / z 521 [M + H] + . 1H NMR (400 MHz, methanol-d4) δ 8.47 (s, 1H), 7.80 (s, 1H), 7.80–7.64 (m, 3H), 7.26 (dd, J = 8.8, 5.0 Hz, 1H), 7.01–6.98 (m, 1H), 6.38 (s, 1H), 4.17 (s, 3H).

[0501] [Example 34] N-(6-(2-chloro-5-fluorophenyl)-3-methoxy-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0502] Step A: To a solution of 3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-5-nitro-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-8-one (500 mg, 0.890 mmol) in dioxane (8 mL) was added sodium 2-methylpropan-2-olate (171 mg, 1.78 mmol), MeOH (0.18 mL, 4.45 mmol), and t-BuBrettPhos-Pd-G3 (84.5 mg, 0.089 mmol). The reaction mixture was stirred overnight at 90 °C under N2. The cooled reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [concentration gradient: 0-15%] to give the compound 6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-5-nitro-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-8-one (150 mg, 0.292 mmol, 33%) as a yellow solid. LCMS: m / z 513 [M+H] +

[0503] Step B: To a solution of 6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-5-nitro-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-8-one (150 mg, 0.292 mmol) in EtOH (10 mL) and HO (5 mL) was added Fe (163 mg, 2.92 mmol) and NHCl (78.2 mg, 1.46 mmol). The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was filtered and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give the compound 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-8-one (150 mg, crude) as a yellow solid. LCMS: m / z 483 [M+H] +

[0504] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-8-one (50 mg, 0.104 mmol) in CH3CN (2 mL) was added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (70.3 mg, 0.311 mmol). The reaction mixture was stirred at 50 °C for 2 h. The cooled reaction mixture was dissolved in HO and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [concentration gradient: 0-15%] to obtain the compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (40 mg, 0.059 mmol, 57%) as a yellow solid. LCMS: m / z 673 [M+H] +

[0505] Step D: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.045 mmol) in TFA (2 mL) and TfOH (0.1 mL) was added triethylsilane (31.1 mg, 0.267 mmol). The reaction mixture was stirred at 60° C. for 2 hours. The cooled reaction mixture was concentrated. The residue was purified by preparative HPLC to give the compound N-[6-(2-chloro-5-fluorophenyl)-3-methoxy-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (4.9 mg, 0.009 mmol, 20%). LCMS: m / z 537 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.31 (s, 1H), 9.12 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.76 - 7.61 (m, 3H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.13 (s, 1H), 4.05 (s, 3H).

[0506] [Example 35] N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide [ka]

[0507] Step A: To a stirred solution of 8-bromo-6-fluoroquinoline (5 g, 22.1 mmol) in THF (8 mL) was slowly added LDA (16.5 mL, 33.1 mmol, 2 M) at −65° C. After stirring at −65° C. for 30 minutes, a solution of 2-chloro-5-fluorobenzene-1-carbaldehyde (4.5 g, 28.7 mmol) in THF (15 mL) was added dropwise to the mixture. After stirring at −65° C. for 1 hour, the mixture was poured into ice water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-80%, EtOAc in PE) to give (8-bromo-6-fluoroquinolin-7-yl)(2-chloro-5-fluorophenyl)methanol (7.5 g, 19.5 mmol, 88%) as a brown solid. LCMS: m / z 384 [M+H] + .

[0508] Step B: To a stirred solution of (8-bromo-6-fluoroquinolin-7-yl)(2-chloro-5-fluorophenyl)methanol (7.2 g, 18.7 mmol) in DCM (100 mL) at 0 °C, Dess-Martin (11.1 g, 28.1 mmol) was slowly added. After stirring at room temperature for 3 h, the mixture was poured into NaHCO (aq, 100 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–40%, EtOAc in PE) to give (8-bromo-6-fluoroquinolin-7-yl)(2-chloro-5-fluorophenyl)methanone (6.1 g, 15.9 mmol, 85%) as a white solid. LCMS: m / z 382 [M+H] + .

[0509] Step C: To a stirred solution of (8-bromo-6-fluoroquinolin-7-yl)(2-chloro-5-fluorophenyl)methanone (6.1 g, 15.9 mmol) in NMP (60 mL) was added CuCN (2.8 g, 31.8 mmol) at room temperature. After stirring at 120 °C under N for 2 h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated to zero. The cooled mixture was filtered. The filter cake was washed with EtOAc (10 mL × 3) to give 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoroquinoline-8-carbonitrile (3.4 g, 10.3 mmol, 65%) as an off-white solid. LCMS: m / z 328 [M+H] + .

[0510] Step D: To a stirred solution of 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoroquinoline-8-carbonitrile (200 mg, 0.61 mmol) in DMSO-d6 (3 mL) at room temperature, DIPEA (0.3 mL, 1.8 mmol) and (2,4-dimethoxyphenyl)methanamine (0.1 mL, 0.73 mmol) were added. After stirring at 130 °C for 1 h, the cooled mixture was purified by preparative HPLC (C18, 40-90% MeCN in HO with 0.1% FA) to afford 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}quinoline-8-carbonitrile (150 mg, 0.31 mmol, 51%) as a brown solid. LCMS: m / z 476 [M+H] + .

[0511] Step E: To a stirred solution of 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino}quinoline-8-carbonitrile (150 mg, 0.31 mmol) in MeCN (8 mL) / HO (2 mL) was added potassium hydroxide (176 mg, 3.1 mmol) at room temperature. After stirring at room temperature for 20 minutes, 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 NaSO, filtered, and concentrated to give 7-(2-chloro-5-fluorophenyl)-6-{[(2,4-dimethoxyphenyl)methyl]amino}-7-hydroxy-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-9-one (100 mg, 0.21 mmol, 65%) as a yellow solid. LCMS: m / z 494 [M+H] + .

[0512] Step F: To a stirred solution of 7-(2-chloro-5-fluorophenyl)-6-{[(2,4-dimethoxyphenyl)methyl]amino}-7-hydroxy-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-9-one (100 mg, 0.21 mmol) in TFA (3 mL, 39.1 mmol), EtSiH (1 mL, 0.4 mmol) was slowly added. After stirring at 70 °C for 2 h, the mixture was concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 6-amino-7-(2-chloro-5-fluorophenyl)-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-9-one (75 mg, 0.35 mmol, 86%) as a yellow solid. LCMS: m / z 328 [M+H] + .

[0513] Step G: To a stirred solution of 6-amino-7-(2-chloro-5-fluorophenyl)-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-9-one (75 mg, 0.33 mmol) in MeCN (5 mL) was slowly added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (0.103 mL, 0.671 mmol) and pyridine (0.136 mL, 1.67 mmol). After stirring at 50° C. for 2 hours, the mixture was poured into water (100 mL) and extracted with EtOAc (60 mL×2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-6-yl]-3-fluoro-N-{[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-5-(trifluoromethyl)benzamide (100 mg, 0.14 mmol, 66%) as a white solid. LCMS: m / z 328 [M+H] + .

[0514] Step H: To a stirred solution of N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-6-yl]-3-fluoro-N-{[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-5-(trifluoromethyl)benzamide (100 mg, 0.14 mmol) in THF (5 mL) was added KOH (23 mg, 0.42 mmol) slowly at 0 °C. After stirring at room temperature for 30 min, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give crude N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.047 mmol, 33%) as a white solid. LCMS: m / z 534 [M+H] + .

[0515] Step I: To a stirred solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.047 mmol) in TFA (3 mL, 39 mmol) was added EtSiH (1 mL, 0.4 mmol) slowly. After stirring at 90 °C for 6 h, the cooled reaction mixture was concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN in HO with 0.1% TFA) to give N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (4 mg, 0.008 mmol, 16%) as a white solid. LCMS: m / z 518 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.29 - 9.14 (m, 2H), 8.73 (d, J = 7.8 Hz, 1H), 8.22 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.70 (s, 1H), 7.33 (dd, J = 8.8, 5.2 Hz, 1H), 7.14 - 7.08 (m, 1H), 6.50 (brs, 1H) 6.23 (brs, 1H).

[0516] [Example 36] (R)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide and Example 37 (S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide [ka]

[0517] 3-Chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide (55 mg, 0.11 mmol) was purified by preparative SFC to give (R)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide (15.5 mg, 0.03 mmol, 28.2%). LCMS: m / z 498 [M + H] + . 1 H NMR (400 MHz, methanol-d₄) δ 7.98 (s, 1H), 7.45–7.40 (m, 1H), 7.38 (s, 1H), 7.34–7.27 (m, 2H), 7.08–7.01 (m, 1H), 6.67–6.06 (m, 2H), and (S)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide (15.1 mg, 0.03 mmol, 27.5%) were obtained. LCMS: m / z 498 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.98 (s, 1H), 7.46–7.41 (m, 1H), 7.38 (s, 1H), 7.34–7.28 (m, 2H), 7.08–7.02 (m, 1H), 6.69–6.19 (m, 2H).

[0518] [Example 38] N-(7-(2-chloro-5-fluorophenyl)-1-methyl-2,9-dioxo-2,7,8,9-tetrahydro-1H-pyrrolo[3,4-h]quinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka] Example 38

[0519] [Example 39] (R)—N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide and Example 40 (S)—N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide [ka]

[0520] N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide (70 mg, 0.139 mmol) was separated by preparative SFC to give (R)-N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide (26.8 mg, 0.053 mmol). LCMS: m / z 503 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 15.22 (s, 1H), 10.40 (s, 1H), 9.41 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.24 (dd, J = 8.4, 5.2 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 6.41 (brs, 1H). and (S)-N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-1,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]benzo[d][1,2]thiazole-3-carboxamide (24.2 mg, 0.048 mmol). LCMS: m / z 503 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 15.22 (s, 1H), 10.40 (s, 1H), 9.41 (s, 1H), 8.67 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.69 (dd, J = 11.2, 4.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.24 (dd, J = 8.8, 5.2 Hz, 1H), 7.01 (td, J = 8.4, 2.8 Hz, 1H), 6.47 (brs, 1H).

[0521] [Example 41] N-(7-amino-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0522] Step A: To a solution of 3-(2-chloro-5-fluorophenyl)-4-({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline 6-oxide (200 mg, 0.299 mmol), TosCl (170.72 mg, 0.896 mmol) in DCM (10 mL) was added NHOH (1 mL, 29.8 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. TLC showed the reaction was complete. The cooled reaction mixture was washed with water (60 mL) and extracted with DCM (60 mL). The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (concentration gradient: 0-100%) to give N-[7-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.090 mmol, 30%) as a white solid. LCMS: m / z 669.11 [M+H] +

[0523] Step B: To a solution of N-[7-amino-3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.092 mmol) and trifluoromethanesulfonic acid (0.014 mL, 0.157 mmol) in TFA (15 mL) was added triethylsilane (0.034 mL, 0.21 mmol). The mixture was stirred at 80° C. for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give N-(7-amino-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.055 mmol, 62%). LCMS: m / z 532.12 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 10.66 (s, 1H), 9.32 (s, 1H), 9.15 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.96 - 7.66 (m, 2H), 7.65 (s, 1H), 7.45 (dd, J = 8.8, 5.2 Hz, 1H), 7.25 - 7.23 (m, 1H), 7.06 (d, J = 9.1 Hz, 1H), 6.85 (s, 3H), 6.17 (s, 1H).

[0524] [Example 42] (S)—N-(6-(2-chloro-5-fluorophenyl)-3-cyano-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 43 (R)—N-(6-(2-chloro-5-fluorophenyl)-3-cyano-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide [ka]

[0525] N-(6-(2-chloro-5-fluorophenyl)-3-cyano-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (90 mg) was separated by preparative SFC to give Example 42 (32.1 mg). LCMS: m / z 546 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.27 (s, 1H), 8.04 - 7.91 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.12 - 7.09 (m, 1H), 6.40 (s, 1H), 6.23 (s, 1H), 4.46 (s, 3H). 33.5 mg of Example 43 was obtained. LCMS: m / z 546 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.26 (s, 1H), 8.04 - 7.87 (m, 2H), 7.75 (d, J = 9.3 Hz, 1H), 7.70 (s, 1H), 7.32 (dd, J = 8.9, 5.1 Hz, 1H), 7.12 - 7.09 (m, 1H), 6.43 (s, 1H), 6.26 (s, 1H), 4.46 (s, 3H). [Example 44]

[0526] N-[6-(2-chloro-5-fluorophenyl)-2,3-dimethyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0527] [ka]

[0528] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5-fluorophenyl)methanone (900 mg, 1.671 mmol) in dioxane (10 mL) and HO (2 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.430 mL, 1.504 mmol), KCO (577 mg, 4.178 mmol), and Pd(dppf)Cl (122 mg, 0.167 mmol). The reaction mixture was stirred at 90 °C under a N atmosphere for 3 h. The cooled reaction was diluted with EA and water. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient 0-40%) to give the compound (7-bromo-2,3-dimethyl-5-nitroindazol-6-yl)(2-chloro-5-fluorophenyl)methanone (530 mg, 1.24 mmol, 74%) as a yellow solid. LCMS: m / z 426 [M+H] + .

[0529] Step B: To a solution of (7-bromo-2,3-dimethyl-5-nitroindazol-6-yl)(2-chloro-5-fluorophenyl)methanone (540 mg, 1.266 mmol) in ethanol (10 mL) and HO (2 mL) was added NH4Cl (338 mg, 6.33 mmol) and Fe (353 mg, 6.33 mmol) at room temperature. The reaction mixture was degassed with N2 and stirred at 90 °C under N2 atmosphere for 2 h. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with PE in EA (concentration gradient: 0-80%) to give (5-amino-7-bromo-2,3-dimethylindazol-6-yl)(2-chloro-5-fluorophenyl)methanone (400 mg, 1.008 mmol, 80%) as a red solid. LCMS: m / z 397 [M+H] + .

[0530] Step C: To a solution of (5-amino-7-bromo-2,3-dimethylindazol-6-yl)(2-chloro-5-fluorophenyl)methanone (370 mg, 0.933 mmol) in DMA (8 mL) was added Zn(CN) (328 mg, 2.799 mmol) and Pd(PPh) (538 mg, 0.466 mmol). The reaction mixture was stirred at 150 °C under a N atmosphere for 1 h. The cooled reaction mixture was diluted with EA and water. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (concentration gradient 0–80%) to give the compound 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2,3-dimethylindazole-7-carbonitrile (200 mg, 0.583 mmol, 62%) as a green solid. LCMS: m / z 343 [M+H] + .

[0531] Step D: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2,3-dimethylindazole-7-carbonitrile (200 mg, 0.583 mmol) in ACN (5 mL) and HO (1 mL) was added KOH (164 mg, 2.91 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,3-dimethyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (140 mg, 0.388 mmol, 66%) as a yellow solid. LCMS: m / z 361 [M+H] + .

[0532] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,3-dimethyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (140 mg, 0.388 mmol) in ACN (5 mL) was...

Claims

1. Structural formula I: 【Chemistry 1】 [In the formula, Ring A has 0 to 6 R ａ It is a 5- or 6-membered aromatic ring that is substituted with R １ is Z Ｂ -R Ｂ And, R ２ is Z Ｃ -R Ｃ And, V is either C or N, W is either C or N, X is N, CH or CR Ｘ And, R Ｘ is Z Ｘ -R Ｘ’ and Z Ｂ Z Ｃ and Z Ｘ Each of these is independently covalent, O, S, NR, NRC(O), C(O)NR, C(O), C(O)O, OC(O), S(O) ２ NRS(O) ２ , S(O) ２ NR, or C, in which one or more carbon atoms are appropriately and independently substituted with heteroatoms selected from the group consisting of N, S, and O. １～４ A linking group selected from saturated or unsaturated divalent hydrocarbon groups, R Ｂ and R Ｃ Each of them is independent, C １～６ An aliphatic chain, a 5-10 membered monocyclic, bicyclic, or bridging carbocyclyl, heterocyclic, aryl, or heteroaryl ring having 0-4 ring heteroatoms independently selected from N, O, and S, each having one or more R ｂ , R ｃ or R ｘ It is replaced as appropriate, R Ｘ These are deuterium, oxo, halogen, -CN, and -NO. ２ , -OR, -SR, -NRR', -S(O) ２ R, -S(O) ２ NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O )R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O) ２ NRR', or -N(R)S(O) ２ It is R, R ａ , R ｂ , R ｃ and R ｘ Each of them is independent, H, deuterium, oxo, halogen, -CN, -NO ２ , -OR, -SR, -NRR', -S(O) ２ R, -S(O) ２ NRR', -S(O)R, -S(O)NRR', -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N(R)OR, -OC(O )R, -OC(O)NRR', -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR', -N(R)C(NR)NRR', -N(R)S(O) ２ NRR' or -N(R)S(O) ２ R, or C １～６ The group is appropriately substituted, selected from alkyl groups or 4-6 membered carbocyclic rings. However, at least one R ａ H is not such that ring A is substituted, R and R' can independently be H, unsubstituted, or substituted C. １～４ Selected from alkyl or unsubstituted or substituted 4- to 6-membered carbocyclic rings, or if R and R' are bonded to the same C or N atom, together they form an unsubstituted or substituted 4- to 6-membered heterocyclic ring. i is 1, 2, 3, 4, 5, or 6. A compound having the same property or a pharmaceutically acceptable form or isotopic derivative thereof.

2. Ring A has 1 to 4 R ａ It is a five-membered aromatic ring that is substituted with, and its structural formula is I ａ : 【Chemistry 2】 [In the formula, Y １ , Y ２ and Y ３ Each of them is independently CH, N, NH, O, S, or C(O), where Y １ , Y ２ and Y ３ At least one of them is Y, not N or NH. １ , Y ２ and Y ３ At least one of them is C or CH. The compound according to claim 1, having the following characteristics.

3. R Ｂ However, there are 0 to 3 R ｂ A ring B having 0 to 4 ring heteroatoms independently selected from N, O, and S, which are substituted with a 5 to 10-membered monocyclic or bicyclic carbocyclyl, heterocyclic, aryl, or heteroaryl ring, R Ｃ However, there are 0 to 3 R ｃ A ring C having 0 to 4 ring heteroatoms independently selected from N, O, and S, substituted with a 5 to 10-membered monocyclic or bicyclic aryl or heteroaryl ring, with structural formula I ｃ : 【Transformation 3】 (In the formula, j is 0, 1, 2, 3, 4, 5, or 6. k is 0, 1, 2, 3, 4, 5, or 6. The compound according to claim 1, having the following characteristics.

4. Z Ｂ NH-C(O) and Z ｃ It is a single bond, structural formula I ｄ : 【Chemistry 4】 The compound according to claim 3, having the following characteristics.

5. Z Ｂ is C(O)-NH, Z ｃ It is a single bond, structural formula I ｅ : 【Transformation 5】 The compound according to claim 3, having the following characteristics.

6. The compound according to any one of claims 1 to 5, wherein V is C, W is C, and the bond between them is a double bond.

7. Ring A is 【Transformation 6】 A compound according to any one of claims 1 to 5, selected from the above.

8. Ring A is 【Transformation 7】 (In the formula, R ａ These are H, Cl, F, CN, CH ３ or CD ３ And, R ａ’ H, CH ２ CH ３ CD ２ CD ３ ,CH ２ CHF ２ ,CH ２ CF ３ and CH ２ It is CN, However, for each structure, R ａ and R ａ’ (At least one of them is not H) A compound according to claim 7, selected from the above.

9. Ring A is 【Transformation 8】 【Chemistry 9】 (In the formula, each R ａ These are independently H, halo, CN, OH, C １ ~C ４ Alkyl and C １ ~C ４ (Selected from alkoxy) A compound according to any one of claims 1 to 5, selected from the above.

10. Ring A is 【Chemistry 10】 A compound according to claim 1, selected from the following.

11. The compound according to any one of claims 1 to 5 and 10, wherein X is CH.

12. X is CR Ｘ The compound according to any one of claims 1 to 5 and 10.

13. The compound according to any one of claims 1 to 5 and 10, wherein X is N.

14. Ring B is 【Chemistry 11】 【Chemistry 12】 A compound according to any one of claims 1 to 5 and 10, selected from among them.

15. Ring B is 【Chemistry 13】 A compound according to any one of claims 1 to 5 and 10, selected from among them.

16. Ring C is 【Chemistry 14】 A compound according to any one of claims 1 to 5 and 10, selected from among them. 【Request Item 17】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 (In the formula, Each R ａ is independently selected from H, halo, CN, OH, optionally substituted C １ ~C ４ alkyl, optionally substituted C １ ~C ４ alkoxy, Each R ａ’ These are independently H or C which are appropriately substituted. １～６ It is alkyl, However, R ａ and R ａ’ (At least one of them is not H) A compound having a structural formula selected from the following. 【Request Item 18】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 (In the formula, Each R ａ is independently selected from H, halo, CN, OH, optionally substituted C １ ~C ４ alkyl, optionally substituted C １ ~C ４ alkoxy, Each R ａ’ These are independently H or C which are appropriately substituted. １～６ It is alkyl, However, R ａ and R ａ’ At least one of them is not H, Each R ａ” This is H, halo, and C as appropriate. １～６ Alkyl, NRR', CN, and appropriately substituted C ２～６ Alkynes, appropriately substituted C ２～６ Substituted alkenes, appropriately substituted C １～６ Alkoxyl, SO ２ R, NRSO ２ R' ３ (It is a 4-6 member carbon-cyclic or heterocyclic structure.) A compound having a structural formula selected from the following.

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

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, 10, and 17 to 19, and a pharmaceutically acceptable excipient, carrier, or diluent.

21. Use of a compound according to any one of claims 1 to 5, 10, and 17 to 19, and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a pharmaceutical for the treatment of cancer.

22. The use according to claim 21, 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, cholangiocarcinoma, urothelial carcinoma of the bladder, gastric cancer, cholangiocarcinoma, hepatocellular carcinoma, thyroid cancer, and hematological malignancies.

23. The use according to claim 21, wherein the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and glioblastoma.

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