TRICYCLIC ARYL DERIVATIVES, AND COMPOSITIONS AND METHODS

THEREOF

Priority Claims and Related Applications

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

Technical Fields of the Invention

[0002] The invention generally relates to novel compounds and therapeutic uses thereof.

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

Background of the Invention

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

[0004] The PI3K family is divided into three different classes: Class I, Class II, and Class III, based on their primary structure, regulation, and lipid substrate specificity. (Kalaany etal. 2009 Nature 458 (7239): 725-31; Leevers etal. (1999) Current Opinion in Cell Biology 11 (2): 219—

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SUBSTITUTE SHEET (RULE 26) 25.) Class I PI3Ks (pl 10a, pl 10p, pl 105 and pl lOy) are activated by tyrosine kinases or G protein-coupled receptors to produce phosphatidylinositol-3,4,5-triphosphate (PIP 3).

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

[0005] The class IA PI3K pl 10a (PI3Ka) is mutated in many human cancers. Angiogenesis has been shown to selectively require the PI3Ka isoform in the control of endothelial cell migration. Mutations in the gene encoding PI3Ka (PIK3CA) or PI3Ka up-regulation occurs in many human cancers such as ovarian cancer, cervical cancer, breast cancer, colorectal cancer, endometrial cancer, gastric carcinomas, hepatocellular carcinoma, small and non-small cell lung cancer, thyroid carcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas. In cancer, PI3Ka mutations are often hotspot point mutations in the helical or kinase domain, such as E542K, E545K and H1047R. (Graupera et al. 2008 Nature 453: 662-6; Campbell et al. 2004 Cancer Res 64, 7678-7681; Levine et al. 2005 Clin Cancer Res 1 L 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 Then 3, 772-775; Li et al. 2006 Breast Cancer Res Treat %, 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 el u/. 2005 Ear J "Cancer 41 , 1649- 1654, Oda e/ aZ. 2005 Cancer Res. 65, 10669-10673; Byun el al. 1093 Ini J Cancer 104, 318- 327; Lee et al 2005 Oncogene 24, 1477-1480; Tang eG?/. 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; S uj obert et al 1997 Blood 106, 1063-1066, Hickey and.

Cotter 2006 J Biol Chern 281, 2441-2450; Hartmann et al. 2005 Acta Neuropathol (Ber!) 109, 639-642.)

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

Summary of the Invention

[0007] The invention provides novel tricyclic compounds and derivatives thereof as PI3Ka inhibitors, which are shown herein to exhibit favorable potency and selectivity profiles over known PI3Ka inhibitors. These novel compounds selectively target, bind to, inhibit and/or

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SUBSTITUTE SHEET (RULE 26) modulate the activity of PI3Ka. The compounds are also orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for treating various diseases and disorders associated with or related to PI3Ka activities, such as various types of cancer.

[0008] In one aspect, the invention generally relates to a compound having the structural formula (I) or a pharmaceutically acceptable form or an isotope derivative thereof, wherein

Ring A is a 5- or 6-membered aromatic ring, substituted with 0-6 R ^a s;

R ¹ is Z ^B -R ^B ;

R ² is Z ^c -R ^c ;

V is C or N;

W is C or N;

X is N, CH or CR ^X ;

R ^x is Z ^x -R ^x ; each of Z ^B , Z ^c and Z ^x is independently a covalent bond, 0, S, NR, NRC(O), C(0)NR, C(O), C(O)O, OC(O), S(O) ₂ , NRS(O)2, S(O)2NR, or a linking group selected from CM saturated or unsaturated bivalent hydrocarbon radicals, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S and 0; each of R ^B and R ^c independently a Ci-6 aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, 0 and S, optionally substituted with one or more R ^b , R ^c or R ^x , respectively

R ^x is 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(0)NRR’, -C(O)N(R)OR, -OC(O)R, -

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SUBSTITUTE SHEET (RULE 26) 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; each of R ^a , R ^b , R ^c and R ^x is independently

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 an optionally substituted group selected from Ci-6 alkyl or 4- to 6-membered carbocyclic ring, provided that at least one R ^a is not H such that Ring A is substituted; each of R and R’ is independently selected from H, unsubstituted or substituted CM alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same C or N atom, together form an unsubstituted or substituted 4- to 6- membered heterocyclic ring; and z is 1, 2, 3, 4, 5 or 6.

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

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

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

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

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

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

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SUBSTITUTE SHEET (RULE 26) [0015] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0016] In yet another aspect, the invention generally relates to use of a compound disclosed herein for treating a disease or disorder, such as various types of cancer.

Definitions

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2006.

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

[0019] The term “comprising”, when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term “consisting essentially of’, when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

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

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SUBSTITUTE SHEET (RULE 26) 0021] In this specification and the appended claims, the singular forms "a, " " II

[ an, and "the" include plural reference, unless the context clearly dictates otherwise.

[0022] As used herein, the terms “administration” of or “administering” a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, using any suitable formulation or route of administration, as discussed herein.

[0023] As used herein, the term “co-administer” refers to the presence of two pharmacological agents in a subject’s body (e.g., in the blood) at the same time. The two pharmacological agents can be administered concurrently or sequentially.

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

[0025] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below.

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

[0027] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. Such amount may be administered as a single dosage or according to a regimen. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is

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SUBSTITUTE SHEET (RULE 26) administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

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

[0029] As used herein, a “PI3Ka-associated” disease or disorder refers to diseases or disorders associated with or mediated by PI3Ka or having one or more PI3Ka mutations. Examples of PI3Ka-associated diseases or disorders include various cancer types. A PI3Ka- associated disease or disorder may also refer allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diabetic complications, or acute coronary syndrome.

[0030] As used herein, the term “contacting” refers to the bringing together of indicated moi eties in vitro or in vivo. For example, “contacting” a cell with a compound disclosed herein includes the administration of the compound to a subject in need thereof, as well as, for example, introducing the compound into a sample containing a cellular or purified preparation. In some embodiments, a cell in which inhibition of PI3Ka activity is desired is contacted with an effective amount of a compound disclosed herein or pharmaceutically acceptable form thereof to negatively modulate the activity of PI3Ka. By negatively modulating the activity of PI3Ko> the methods disclosed herein are designed to inhibit undesired cellular proliferation resulting from enhanced PI3Ka activity within the cell. The cells may be contacted in a. single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of PI3Ka. The ability of compounds to bind. PI3Ka may be monitored in vitro using methods known in the art. The inhibitory activity of exemplary ⁷ compounds in cells may be monitored, for example, by measuring the inhibition of PI3Ka activity using methods known in the art.

[0031] As used herein, the terms “unsubstituted or substituted” and “optionally substituted are used interchangeably and refer to where a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (z.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional

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SUBSTITUTE SHEET (RULE 26) groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, - COOH, -CH ₂ CN, -O-Ci-Ce alkyl, Ci-C ₆ alkyl, -OCi-C ₆ alkenyl, -OCi-C ₆ alkynyl, -Ci-C ₆ alkenyl, -Ci-C ₆ alkynyl, -OH, -OP(O)(OH) ₂ , -OC(O)Ci-C ₆ alkyl, -C(O)Ci-C ₆ alkyl, -OC(O)OCi- C ₆ alkyl, NH ₂ , NH(CI-C ₆ alkyl), N(CI-C ₆ alkyl) ₂ , -NHC(O)CI-C ₆ alkyl, -C(O)NHCI-C ₆ alkyl, - S(O) ₂ -C1-C ₆ alkyl, -S(O)NHCI-C ₆ alkyl, and S(O)N(CI-C ₆ alkyl) ₂ .

[0032] As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

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

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SUBSTITUTE SHEET (RULE 26) lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

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

[0035] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of

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SUBSTITUTE SHEET (RULE 26) esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0036] In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0037] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

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

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SUBSTITUTE SHEET (RULE 26) compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0039] As used herein, the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

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

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

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SUBSTITUTE SHEET (RULE 26) [0042] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the subject has one or mote PI3Ka mutations using a sample (e g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject. Various techniques may be employed, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).

[0043] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

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

[0045] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater

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SUBSTITUTE SHEET (RULE 26) than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

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

[0047] As used herein, the term an “isolated” or “substantially isolated” molecule (such as a polypeptide or polynucleotide) is one that has been manipulated to exist in a higher concentration than in nature or has been removed from its native environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of non-subject-antibody materials with which it is associated in nature have been removed. For example, a polynucleotide or a polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated." Further, recombinant DNA molecules contained in a vector are considered isolated for the purposes of the present invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include synthetically produced molecules.

Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

[0048] As used herein, the term “purified” when used in reference to a molecule, it means that the concentration of the molecule being purified has been increased relative to molecules associated with it in its natural environment, or environment in which it was produced, found or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids and sugars but generally do not include water, buffers, and reagents added to maintain the integrity or facilitate the purification of the molecule being purified. According to this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

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

13

SUBSTITUTE SHEET (RULE 26) [0050] As used herein, the term “aliphatic” or “aliphatic group” refers to a linear or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic.

[0051] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., Ci-io alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a Ci-6 alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, - ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2 -methylbutyl, 3- m ethylbutyl, 2 -methylpentyl, 3 -methylpentyl, 4-m ethylpentyl, 2-methylhexyl, 3 -methylhexyl, 4- methylhexyl, 5 -methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R ^x )3 , -OR ^X , -SR ^X , -OC(O)-R ^X , -N(R ^X ) ₂ , - C(O)R ^X , -C(O)OR ^X , -OC(O)N(R ^X ) ₂ , -C(O)N(R ^X ) ₂ , -N(R ^X )C(O)OR ^X , -N(R ^X )C(O)R ^X , - N(R ^X )C(O)N(R ^X ) ₂ , -N(R ^X )C(NR ^X )N(R ^X ) ₂ , -N(R ^X )S(O)IN(R ^X ) ₂ (where t is 1 or 2), -P(=O)(R ^X )(R ^X ), or -O-P(=O)(OR ^X ) ₂ wherein each R ^x is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl,

14

SUBSTITUTE SHEET (RULE 26) trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 3- hydroxypropyl, benzyl, and phenethyl.

[0052] Unless otherwise specifically defined, the term “aromatic” or “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, H, halogen, -O-Ci-Ce alkyl, Ci-Ce alkyl, -Ci-Ce alkenyl, -OCi-Ce alkynyl, -Ci-Ce alkenyl, -Ci-C ₆ alkynyl, -OH, -OP(O)(OH) ₂ , -OC(O)Ci-C ₆ alkyl, -C(O)Ci-C ₆ alkyl, -OC(O)OCi- Cealkyl, NH ₂ , NH(CI-C ₆ alkyl), N(CI-C ₆ alkyl) ₂ , -S(O) ₂ -Ci-C ₆ alkyl, -S(O)NHCi-C ₆ alkyl, and S(O)N(Ci-Ce alkyl) ₂ . The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthal enyl, and tetrahydrobenzoannul enyl.

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

[0054] As used herein, the terms “heteroaryl” or “hetero-aromatic” refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 p electrons shared in a. cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyk benzthiazolyl, benztriazolyl, benztetrazolyl. benzisoxazolyl, benzi.sothiaz.o1yl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyk chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole, furanyl, furazanyl, iniidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indo.ILr.iny I , indolyl, 3H~indolyl, isobenzofuranyl, isochromanyl, isomdazolyl, isoindolinyl, isoindoiyl, isoquinolinyi, isothiazolyl, isoxazolyl, methylenedioxyphenyL naphthyridinyk octahydroisoquinolinyL oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyk oxazolidinyl, oxazolyk oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl , phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,

15

SUBSTITUTE SHEET (RULE 26) pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, telrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyL 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, ihianthrenyL thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thi enoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xan thenyl. “Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, (), and S in which one ring system may be saturated or partially saturated.

[0055] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyal kyL cyano, cyanoalkyl, formyl, haloalkoxy, haloaikyk halogen, hydroxy, hydroxyalkyl. mercapto, nitro, -NZj.Z?„ and (NZsZ?.)carbonyt The term "NZiZ?." as used herein, means two groups, Zi and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Zi and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkyl carbonyl, and formyl. Representative examples of NZ-Zj include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

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

[0057] As used herein, the terms “cycloalkyl” and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups

16

SUBSTITUTE SHEET (RULE 26) include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moi eties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 carbocyclyl groups include norbornyl (C7). Examples of C3-8 carbocyclyl groups include the aforementioned C3.7 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-lH indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R ^a )3 , -OR ^a , - SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)Ra, -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , - N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , -N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t N(R ^a ) ₂ (where t is 1 or 2), - P(=O)(R ^a )(R ^a ), or -O-P(=O)(OR ^a ) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0058] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., 0, N, S, P or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of

17

SUBSTITUTE SHEET (RULE 26) heterocycloalkyl include 2-hydroxy-aziridin-l-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2-dimethyl- tetrahydrofuran-3-yl, 3 -carboxy -morpholin-4-yl, l-cyclopropyl-4-methyl-piperazin-2-yl. 2- pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H- [1,4] oxazine, etc.

[0059] As used herein, the terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fully saturated or partially unsaturated cyclic groups, for example, 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered spirocyclic or tricyclic ring systems, which have at least one heteroatom (selected from the group consisting of N, 0, and S) in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. A heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrroiidinonyl, piperidinyl, piperazinyl. imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyi, trithianyl, dioxolanyl, oxazohdinyl, oxazoli di nonyl, decahydroquinolinyL piperidony k 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyL azepany I , oxazepanyl, azabi cy c-1 ohexany I s, azabicy cloheptany I , azabi cy clooc (any 1 s, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- IH,3H,5H- oxazolo[3,4-c]ox.azolyl, tetrahydro- VFL3TI- spiro[cyclopropane-l ,2'-pyrrolizine], hexahydro- 1 H -pyrrol izinyl, hexahydro-1 H-pyrrolo[2,l- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls. oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, and tetrahydro- 2H-thiopyranyl I -oxide and tetrahydro-2H- thiopyranyl 1 , 1 -dioxide.

Detailed Description of the Invention

[0060] The invention is based in part on the discovery of novel tricyclic compounds and derivatives thereof as PI3Ka inhibitors. These compounds are shown herein to selectively target, bind to, inhibit and/or modulate the activity of PI3Ka. The compounds are orally available and

18

SUBSTITUTE SHEET (RULE 26) can be used for treating various diseases and disorders associated with or related to PI3Ka activities, such as various types of cancer.

[0061] In one aspect, the invention generally relates to a compound having the structural formula (I) or a pharmaceutically acceptable form or an isotope derivative thereof, wherein

Ring A is a 5- or 6-membered aromatic ring, substituted with 0-6 R ^a s;

R ¹ is Z ^B -R ^B ;

R ² is Z ^c -R ^c ;

V is C or N;

W is C or N;

X is N, CH or CR ^X ;

R ^x is Z ^x -R ^x ; each of Z ^B , Z ^c and Z ^x is independently a covalent bond, 0, S, NR, NRC(O), C(0)NR, C(O), C(O)O, OC(O), S(O) ₂ , NRS(O)2, S(O)2NR, or a linking group selected from CM saturated or unsaturated bivalent hydrocarbon radicals, wherein one or more carbons are optionally and independently substituted with a heteroatom selected from the group consisting of N, S and 0; each of R ^B and R ^c independently a Ci-6 aliphatic chain, a 5- to 10-membered monocyclic, bicyclic or bridged carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, 0 and S, optionally substituted with one or more R ^b , R ^c or R ^x , respectively

R ^x is 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(0)NRR’, -C(O)N(R)OR, -OC(O)R, - 0C(0)NRR’, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NRR’, -N(R)C(NR)NRR’, - N(R)S(0) ₂ NRR’, or -N(R)S(O) ₂ R;

19

SUBSTITUTE SHEET (RULE 26) each of R ^a , R ^b , R ^c and R ^x is independently

H, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O) ₂ R, -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) ₂ NRR’ or -N(R)S(O) ₂ R; or an optionally substituted group selected from C1-6 alkyl or 4- to 6-membered carbocyclic ring, provided that at least one R ^a is not H such that Ring A is substituted; each of R and R’ is independently selected from H, unsubstituted or substituted C1-4 alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same C or N atom, together form an unsubstituted or substituted 4- to 6- membered heterocyclic ring; and i is 1, 2, 3, 4, 5 or 6.

[0062] In certain embodiments of (I), Ring A is a 5-membered aromatic ring, substituted with 1-4 R ^a s, having the structural formula (I _a ): wherein each of Y ¹ , Y ² and Y ³ is independently CH, N, NH, 0, S or C(O), provided that at least one of Y ¹ , Y ² and Y ³ is not N orNH and at least one of Y ¹ , Y ² and Y ³ is C or CH.

[0063] In certain embodiments of (I), Ring A is a 6-membered aromatic ring, substituted with 1-4 R ^a s, having the structural formula (lb):

20

SUBSTITUTE SHEET (RULE 26) wherein each of Y ¹ , Y ² , Y ³ and Y ⁴ is independently CH, N, NH, O, S or C(O), provided that at least two of Y ¹ , Y ² , Y ³ and Y ⁴ is not N or NH and at least two of Y ¹ , Y ² , Y ³ and Y ⁴ is C or CH. [0064] In certain embodiments of (I)-(Ib), R ^B is Ring B, a 5- to 10-membered monocyclic or bicyclic carbocyclyl, heterocyclic, aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, substituted with 0-3 R ^b ’s; and R ^c is Ring C, a 5- to 10- membered monocyclic or bicyclic aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, O and S, substituted with 0-3 R ^c ’s, having the structural formula (Ic): wherein j is 0, 1, 2, 3, 4, 5 or 6; and

£ is 0, 1, 2, 3, 4, 5 or 6.

[0065] In certain embodiments of (I)-(Ic), Z ^B is NH-C(O) and Z ^c is a single bond, having the structural formula (Id):

[0066] In certain embodiments of (I)-(Ic), Z ^B is C(O)-NH and Z ^c is a single bond, having the structural formula (I _e ):

21

SUBSTITUTE SHEET (RULE 26)

[0067] In certain embodiments of (I)-(Ie), V is C and W is N, and the bond therebetween is a single bond.

[0068] In certain embodiments of (I)-(I _e ), V is N and W is C, and the bond therebetween is a single bond.

[0069] In certain embodiments of (I)-(Ie), V is C and W is C, and the bond therebetween is a double bond.

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

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

[0072] In certain embodiments of (I)-(Ie), Ring A is selected from:

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

[0074] In certain embodiments of (I)-(Ie), Ring A is selected from: wherein

22

SUBSTITUTE SHEET (RULE 26) R ^a is H, optionally substituted Ci-6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; and

R ^a is selected from H, halo, optionally substituted Ci-6 alkyl, NRR’, CN, optionally substituted C ₂ -6 alkyne, optionally substituted C ₂ -6 substituted alkene, optionally substituted Ci-6 alkoxyl, SO ₂ R, NRSO ₂ R’ ₃ , 4- to 6-membered carbocyclic or heterocyclic, provided that for at least one of R ^a and R ^a is not H.

[0075] In certain embodiments, R ^a is selected from H, F, Cl, NH ₂ , OH, CH ₃ , CHF ₂ , CH ₂ F, C ₂ H ₅ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ , CHFCF ₃ , CH ₂ CH ₂ OH, CH(OH)CH ₃ , CH(OH)CF ₃ , CH ₂ OH, CH ₂ CN, CH ₂ NH ₂ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OCHF ₂ , CH ₂ OCF ₃ , NHCH ₃ , isopropyl, cyclopropyl, CCH, CHCH ₂ , CH ₂ -azetidine, CN, OCHF ₂ , SO ₂ CH ₃ , NHSO ₂ CH ₃ , CH ₂ - cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0076] In certain embodiments, R ^a is CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ , CH ₂ -cyclopropyl, difluoro-propyl and trifluoro-propyl.

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

[0078] In certain embodiments of (I)-(Ie), Ring A is selected from: wherein

R ^a is H, Cl, F, CN, CH ₃ or CD ₃ ; and

R ^a is H, CH ₂ CH ₃ , CD ₂ CD ₃ , CH ₂ CHF ₂ , CH ₂ CF ₃ and CH ₂ CN, provided that for each structure at least one of R ^a and R ^a is not H.

[0079] In certain embodiments, R ^a is CH ₂ CHF ₂ or CH ₂ CF ₃ .

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

[0081] In certain embodiments, R ^a is Cl, F, CN, CH ₃ or CD ₃ .

[0082] In certain embodiments of (I)-(Ie), Ring A is selected from:

[0083] In certain embodiments of (I)-(I _e ), Ring A is selected from:

23

SUBSTITUTE SHEET (RULE 26)

[0084] In certain embodiments of (I)-(I _e ), Ring A is selected from:

[0085] In certain embodiments of (I)-(Ie), Ring A is selected from:

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

[0087] In certain embodiments of (I)-(Ie), Ring A is selected from: wherein each R ^a is independently selected from H, halo, CN, OH, C1-C4 alkyl and C1-C4 alkoxy.

[0088] In certain embodiments of (I)-(Ie), R ^a is not H.

[0089] In certain embodiments of (I)-(Ie), Ring A is selected from:

24

SUBSTITUTE SHEET (RULE 26)

[0090] In certain embodiments of (I)-(Ie), Ring A is selected from:

[0091] In certain embodiments of (I)-(Ie), Ring A is selected from:

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

25

SUBSTITUTE SHEET (RULE 26)

[0093] In certain embodiments of (I)-(Ie), X is CH.

[0094] In certain embodiments of (I)-(I _e ), X is CR ^X .

[0095] In certain embodiments of (I)-(Ie), X is N.

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

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

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

26

SUBSTITUTE SHEET (RULE 26) [0099] In certain embodiments of (I)-(Ie), Ring B is a substituted or unsubstituted 8- to 10- membered bicyclic aryl or heteroaryl ring.

[00100] Non-limiting examples of Ring B include:

[00101] In certain embodiments of (I)-(Ie), Ring B is selected from:

27

SUBSTITUTE SHEET (RULE 26) [00102] In certain embodiments of (I)-(Ie), Ring B is selected from:

[00103] In certain embodiments of (I)-(Ie), Ring B is selected from:

[00104] In certain embodiments, Ring B is:

[00105] In certain embodiments of (I)-(Ie), Ring B is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

[00106] In certain embodiments, Ring B is a substituted or unsubstituted phenyl.

[00107] In certain embodiments, Ring B is a substituted or unsubstituted pyridyl.

[00108] In certain embodiments, Ring B is a substituted or unsubstituted pyridazinyl.

[00109] In certain embodiments, Ring B is a substituted or unsubstituted pyrazinyl.

[00110] In certain embodiments of (I)-(Ie), Ring C is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

[00111] In certain embodiments, Ring C is a substituted or unsubstituted phenyl.

[00112] In certain embodiments, Ring C is a substituted or unsubstituted pyridyl.

[00113] In certain embodiments, Ring C is a substituted or unsubstituted pyridazinyl.

[00114] In certain embodiments, Ring C is a substituted or unsubstituted pyrazinyl.

[00115] In certain embodiments of (I)-(I _e ), each of Ring B and Ring C is independently a substituted or unsubstituted phenyl.

[00116] Non-limiting examples of Ring C include:

28

SUBSTITUTE SHEET (RULE 26)

[00117] In certain embodiments, Ring C is:

[00118] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (If): wherein at least one R ^a is selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN.

[00119] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (I _g ):

29

SUBSTITUTE SHEET (RULE 26)

[00120] In certain embodiments of (I)-(I _e ), a compound of the invention has the structural formula (I _g ’): wherein Ring A is selected from:

[00121] In certain embodiments, Ring A is selected from:

30

SUBSTITUTE SHEET (RULE 26) wherein

R ^a is H, optionally substituted Ci-6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; and

R ^a is selected from H, halo, optionally substituted Ci-6 alkyl, NRR’, CN, optionally substituted C2-6 alkyne, optionally substituted C2-6 substituted alkene, optionally substituted Ci-6 alkoxyl, SO2R, NRSChR’s, 4- to 6-membered carbocyclic or heterocyclic, provided that for at least one of R ^a and R ^a is not H.

[00122] In certain embodiments, Ring A is:

[00123] In certain embodiments, R ^a is selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C ₂ H ₅ , CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH ₃ , CH(OH)CF ₃ , CH2OH, CH2CN, CH2NH2, CH ₂ N(CH ₃ ) ₂ , CH2OCHF2, CH2OCF3, NHCH3, isopropyl, cyclopropyl, CCH, CHCH ₂ , CH ₂ -azetidine, CN, OCHF ₂ , SO2CH3, NHSO2CH3, CH ₂ - cyclopropyl, difluoro-propyl and trifluoro-propyl.

[00124] In certain embodiments, R ^a is CH2CH2F, CH2CHF2, CH2CF3, QT-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[00125] In certain embodiments, Ring A is selected from: wherein

R ^a is H, Cl, F, CN, CH ₃ or CD ₃ ; and

R ^a is H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH ₂ CN, provided that for each structure at least one of R ^a and R ^a is not H.

31

SUBSTITUTE SHEET (RULE 26) [00126] In certain embodiments, Ring A is

[00127] In certain embodiments, Ring A is:

[00128] In certain embodiments, R ^a is selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN. In certain embodiments, R ^a is CH2CHF2 or CH2CF3.

[00129] In certain embodiments, R ^a is H. In certain embodiments, R ^a is Cl, F, CN, CHs and

CDs.

[00130] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ih):

[00131] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (1):

32

SUBSTITUTE SHEET (RULE 26)

[00132] In certain embodiments, a compound of the invention exhibits the following chirality in R ¹ :

[00133] In certain embodiments, a compound of the invention exhibits the following chirality in R ¹ :

[00134] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ij):

33

SUBSTITUTE SHEET (RULE 26)

[00135] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ik):

[00136] In certain embodiments, X is CH.

[00137] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula Ik’: wherein Ring A is selected from:

34

SUBSTITUTE SHEET (RULE 26)

[00138] In certain embodiments, Ring A is selected from: wherein

R ^a is H, optionally substituted Ci-6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; and

R ^a is selected from H, halo, optionally substituted Ci-6 alkyl, NRR’, CN, optionally substituted C2-6 alkyne, optionally substituted C2-6 substituted alkene, optionally substituted Ci-6 alkoxyl, SO2R, NRSChR^, 4- to 6-membered carbocyclic or heterocyclic, provided that for at least one of R ^a and R ^a is not H.

[00139] In certain embodiments, Ring A is:

[00140] In certain embodiments, R ^a is selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C2H5, CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH ₃ , CH(OH)CF ₃ , CH2OH, CH2CN, CH2NH2, CH ₂ N(CH ₃ ) ₂ , CH2OCHF2, CH2OCF3, NHCHs, isopropyl, cyclopropyl, CCH, CHCH ₂ , CH ₂ -azetidine, CN, OCHF ₂ , SO2CH3, NHSO2CH3, CH ₂ - cyclopropyl, difluoro-propyl and trifluoro-propyl.

[00141] In certain embodiments, R ^a is CH2CH2F, CH2CHF2, CH2CF3, QT-cyclopropyl, difluoro-propyl and trifluoro-propyl.

35

SUBSTITUTE SHEET (RULE 26) [00142] In certain embodiments, Ring A is selected from: wherein

R ^a is H, Cl, F, CN, CH ₃ or CD ₃ ; and

R ^a ’ is H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH ₂ CN, provided that for each structure at least one of R ^a and R ^a is not H.

[00143] In certain embodiments, Ring A is

[00144] In certain embodiments, Ring A is:

[00145] In certain embodiments, R ^a is selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN In certain embodiments, R ^a is CH2CHF2 or CH2CF3.

[00146] In certain embodiments, R ^a is H. In certain embodiments, R ^a is Cl, F, CN, CH3 and

CD ₃ .

[00147] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ii):

36

SUBSTITUTE SHEET (RULE 26) (II)

[00148] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (I _m ):

[00149] In certain embodiments of (I)-(Ie), a compound of the invention exhibits the following chirality at the carbon to which R ² is bond:

[00150] In certain embodiments of (I)-(I _e ), a compound of the invention exhibits the following chirality at the carbon to which R ² is bond:

[00151] Non-limiting examples of compounds of the invention include:

37

SUBSTITUTE SHEET (RULE 26)

38

SUBSTITUTE SHEET (RULE 26) wherein each R ^a is independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy; and each R ^a is independently H or an optionally substituted Ci-e alkyl, provided that at least one of R ^a and R ^a is not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

[00152] Non-limiting examples of compounds of the invention include:

39

SUBSTITUTE SHEET (RULE 26)

40

SUBSTITUTE SHEET (RULE 26) wherein

41

SUBSTITUTE SHEET (RULE 26) each R ^a is independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy; and each R ^a is independently H or an optionally substituted Ci-e alkyl, provided that at least one of R ^a and R ^a is not H, or a pharmaceutically acceptable form or an isotope derivative thereof. [00153] In certain embodiments, at least one of R ^a and R ^a , if present, is CH2CH3, CD2CD3, CH2CHF2, CH2CF3 or CH ₂ CN.

[00154] In certain embodiments, at least one of R ^a and R ^a , if present, is CH2CHF2 or CH2CF3.

[00155] In certain embodiments, the chirality is as followings:

[00156] In certain embodiments, the chirality is as followings:

[00157] Non-limiting examples of compounds of the invention also include:

42

SUBSTITUTE SHEET (RULE 26)

43

SUBSTITUTE SHEET (RULE 26)

44

SUBSTITUTE SHEET (RULE 26) wherein each R ^a is independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, provided that at least one R ^a is not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

[00158] Non-limiting examples of compounds of the invention also include:

45

SUBSTITUTE SHEET (RULE 26)

46

SUBSTITUTE SHEET (RULE 26)

47

SUBSTITUTE SHEET (RULE 26) wherein each R ^a is independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, provided that at least one R ^a is not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

[00159] In certain embodiments, the chirality is as followings:

[00160] In certain embodiments, the chirality is as followings:

[00161] In certain embodiments, a compound of the invention exhibits the following chirality at the carbon to which R ² is bond:

[00162] In certain embodiments, a compound of the invention exhibits the following chirality at the carbon to which R ² is bond:

[00163] Non-limiting examples of compounds of the invention also include:

48

SUBSTITUTE SHEET (RULE 26)

49

SUBSTITUTE SHEET (RULE 26)

50

SUBSTITUTE SHEET (RULE 26)

51

SUBSTITUTE SHEET (RULE 26) [00164] Non-limiting examples of compounds of the invention also include those listed in Table 1 in the Examples section.

[00165] In certain embodiments, a compound of invention has one or more deuterium atoms in place of hydrogen. In certain embodiments, a compound of invention has one deuterium atom in place of a hydrogen atom.

[00166] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[00167] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[00168] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[00169] In certain embodiments, the unit dosage form is in the form of a tablet or capsule. [00170] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[00171] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch). Other formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

52

SUBSTITUTE SHEET (RULE 26) [00172] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary shaping the product.

[00173] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[00174] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, symps, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert

53

SUBSTITUTE SHEET (RULE 26) diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[00175] 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.

[00176] In yet another aspect, the invention generally relates to a method for inhibiting PI3Ka activity in a cell, comprising contacting the cell with a compound disclosed herein.

[00177] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Ka, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[00178] In certain embodiments, the disease or disorder is a cellular proliferative disease. [00179] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[00180] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[00181] Examples of cancers targeted in the present invention include, but are not particularly limited to, head and neck cancer, digestive organ cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer, and rectal cancer), etc.), lung cancer (e.g., 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, a carcinoma, squamous carcinoma, adenocarcinoma, neuroma, melanoma and the like. Examples include lung cancer, pancreatic cancer, rectal cancer, colon cancer colorectal cancer and uterine cancer. In certain embodiments, squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus. In one embodiment, adenocarcinoma is a cancer of prostate, small intestine, endometrium, uterine cervix, large

54

SUBSTITUTE SHEET (RULE 26) intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary. In certain embodiments, tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer leukemia, or uterine cancer.

[00182] In certain embodiments, the cancer is selected from the group consisting of ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, small and non-small cell lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, gastric carcinomas, bile duct cancer, hepatocellular carcinoma, thyroid carcinoma, and a hematologic malignancy.

[00183] In certain embodiments, the cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas. [00184] In certain embodiments, the subject has a mutated class IA PI3K pl 10a.

[00185] In certain embodiments, the subject has at least one of the following PI3Ka mutations: H1047R, E542K, and E545K.

[00186] In certain embodiments, the subject does not have a PI3Ka mutant protein.

[00187] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[00188] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[00189] In yet another aspect, the invention generally relates to use of a compound disclosed herein for treating a disease or disorder.

[00190] The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the route of administration, the disposition of the compound and the discretion of the prescribing physician. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day. [00191] Any appropriate route of administration can be employed, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalational, buccal, intraperintoneal, rectal, intrapleural, and intrathecal administration. Most suitable means of administration for a particular patient will depend on the nature and severity of

55

SUBSTITUTE SHEET (RULE 26) the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[00192] In certain preferred embodiments, the compound is administered orally. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[00193] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[00194] In the case of tablets for oral use, carriers that are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

56

SUBSTITUTE SHEET (RULE 26) [00195] Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[00196] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[00197] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[00198] Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers,

57

SUBSTITUTE SHEET (RULE 26) preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[00199] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[00200] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

[00201] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[00202] Methods of treatment disclosed herein may be employed in combination with or in addition to other therapies. In certain embodiments, the subject being treated is further

58

SUBSTITUTE SHEET (RULE 26) administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[00203] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds, e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as provided in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[00204] In certain embodiments, a compound of the invention may be administered in combination with endocrine therapy, e.g., agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[00205] In some embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine. In other embodiments, a compound of the invention may be administered in combination with an anti-HER2 agent, e.g., trastuzumab or pertuzumab. [00206] In certain embodiments, the method disclosed herein is in combination with one or more of immune check point blockade, co-signaling of I cells, and tumor targeting antibody therapies.

[00207] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[00208] In certain embodiments, the method further comprises administering a radiotherapy to the subject. In certain embodiments, the method further comprises administering a targeted therapy to the subject. In certain embodiments, the method further comprises administering an immunotherapy to the subject. In certain embodiments, the method further comprises administering hormonal therapy to the subject.

[00209] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis),

59

SUBSTITUTE SHEET (RULE 26) Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophy cins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L- norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone,

60

SUBSTITUTE SHEET (RULE 26) dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[00210] Examples of the second (or further) agent or therapy may include, but are not limited to, immunotherapies (e.g. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonist, cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab and the like), mitosis inhibitors (e.g., paclitaxel, vincristine, vinblastine and the like), alkylating agents (e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and the like), anti-metabolites (e.g., methotrexate, 5-FU and the like), intercalating anticancer agents, (e.g., actinomycin, anthracycline, bleomycin, mitomycin-C and the like), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide and

61

SUBSTITUTE SHEET (RULE 26) the like), immunotherapic agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[00211] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cisand trans-i somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[00212] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures. [00213] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[00214] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically -labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ C1, respectively.

[00215] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and/or substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C)

62

SUBSTITUTE SHEET (RULE 26) labeled compounds are particularly preferred for their ease of preparation and detectability.

Further, substitution with heavier isotopes such as deuterium ( ² H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[00216] Further, substitution of normally abundant hydrogen ( ¹ H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and/or excretion (ADME) properties, creating drugs with improved efficacy, safety, and/or tolerability. Benefits may also be obtained from replacement of normally abundant ¹² C with ¹³ C. (See, WO 2007/005643, WO 2007/005644, WO 2007/016361, and WO 2007/016431.)

[00217] Stereoisomers (e.g., cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

[00218] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[00219] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates. [00220] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[00221] Compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like),

63

SUBSTITUTE SHEET (RULE 26) carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00222] These compositions can also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[00223] Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[00224] Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily and more usually 1 to 300 mg/kg body weight. The dose, from 0.0001 to 300 mg/kg body, may be given twice a day.

[00225] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and

64

SUBSTITUTE SHEET (RULE 26) discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

Examples

[00226] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[00227] Compounds of the invention, including those specifically disclosed herein above and herein below, may be prepared as described in the following schemes. Although the present invention has been described in detail with preferred embodiments, those of ordinary skill in the art should understand that modifications, variations, and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.

Table 1. Exemplary Compounds

65

SUBSTITUTE SHEET (RULE 26)

66

SUBSTITUTE SHEET (RULE 26)

67

SUBSTITUTE SHEET (RULE 26)

68

SUBSTITUTE SHEET (RULE 26)

69

SUBSTITUTE SHEET (RULE 26)

70

SUBSTITUTE SHEET (RULE 26)

71

SUBSTITUTE SHEET (RULE 26)

72

SUBSTITUTE SHEET (RULE 26)

73

SUBSTITUTE SHEET (RULE 26)

74

SUBSTITUTE SHEET (RULE 26)

75

SUBSTITUTE SHEET (RULE 26)

76

SUBSTITUTE SHEET (RULE 26)

77

SUBSTITUTE SHEET (RULE 26)

78

SUBSTITUTE SHEET (RULE 26)

19

SUBSTITUTE SHEET (RULE 26)

80

SUBSTITUTE SHEET (RULE 26)

81

SUBSTITUTE SHEET (RULE 26)

82

SUBSTITUTE SHEET (RULE 26)

83

SUBSTITUTE SHEET (RULE 26)

84

SUBSTITUTE SHEET (RULE 26)

85

SUBSTITUTE SHEET (RULE 26)

86

SUBSTITUTE SHEET (RULE 26)

87

SUBSTITUTE SHEET (RULE 26)

88

SUBSTITUTE SHEET (RULE 26)

89

SUBSTITUTE SHEET (RULE 26)

Exemplary Synthetic Procedures

List of Abbreviations aq: aqueous

Ac = Acetyl

AcO = Acetate

AciO = Acetic anhydride

AIBN a,a'-Azoisobyronitrile

All = Allyl

Alloc = Allyloxycarbonyl

Am = Amyl (Pentyl)

Ar = Aryl

B2Pin2 = bis(pinacolato)diboron

90

SUBSTITUTE SHEET (RULE 26) 9-BBN = 9-Borabicyclononane

BHT = tert-Butylhydroxytoluene

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

BMS = Borane-methylsulphide complex

Bn = Benzyl

Boc = tert-Butoxy carbonyl

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

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

BuOH = Butanol

Bz = Benzoyl

Bzl = Benzyl

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

2-(2’ -amino- 1 , 1 ’biphenyl)Jpalladium(II)

CBS = Corey -Bashki-Shibat

Cbz = Benzyloxycarbonyl

CbzCl = Benzyl chloroformate ox

Cod = Cyclooctadiene

Cp = Cyclopentadienyl

CSA = Camphorsulphonic acid

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

DAST = Diethylaminosulphur trifluoride dba = Dibenzylideneacetone

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

DCC = 1,3 -Dicyclohexylcarbodiimide

DCM = Dichloromethane

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

DEAD = Diethyl azodicarboxylate

DHP = Dihydropiran

91

SUBSTITUTE SHEET (RULE 26) DHQD = Dihydroquinidine

DIBAL = Diisobutylaluminium hydride

DIBAL-H = Diisobutylaluminium hydride

DIG = Diisopropylcarbodiimide

DIPEA = Diisopropylethylamine

DMA = N,N-Dimethylacetamide

DMAC = N,N-Dimethylacetamide

DMAP = 4-Dimethylaminopyridine

DME = 1,2-Dimethoxy ethane

DMF = N,N-Dimethylformamide

DMP = Dess-Martin periodinane

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

DMS = Dimethylsulphide

DMSO = Dimethylsulphoxide

DPA = Diisopropylamine

DPP A = Diphenylphosphoryl azide

Ddpb = l,4-bis(diphenylphosphino)butane

Dppe = l,2-bis(diphenylphosphino)ethane

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

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

EA = Ethyl acetate

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

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

Eq = equivalent

ESI or ES = Electrospray ionization

Et = ethyl

Et2O = Diethyl ether

EtOAc = Ethyl acetate

FMOC = 9-Fluorenylmethoxycarbonyl

92

SUBSTITUTE SHEET (RULE 26) HATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- bjpyridinium 3 -oxide hexafluorophosphate

HMDS = Hexamethyldisilazane

HMPA = Hexamethylphosphoramide

HOAt = 7-Aza-l-hydroxybenzotriazole

HOBt = 1 -Hydroxybenzotriazole

HPLC = high pressure liquid chromatography

IP A = Isopropyl alcohol

Im = Imidazole

KHMDS Potassium bis(trimethylsilyl)amide

KOAc Potassium acetate

LAH = Lithium aluminium hydride

LDA = Lithium diisopropyl ami de

LHMDS = Lithium bis(trimethylsilyl)amide

MCPBA = meta-chloroperoxybenzoic acid Me = Methyl

MeCN = Acetonitrile

MeOH = Methanol

MOM = Methoxymethyl

Mg = magnesium

MS = Molecular sieves

Ms = Methanesulphonyl

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

NaHMDS = Sodium bis(trimethylsilyl)amide NaCNBHs = Sodium cyanoborohydride NBS = N-Bromosuccinimide

NCS = N-Chlorosuccinimide

NIS = N-Iodosuccinimide

NMM = N-Methylmorpholine

93

SUBSTITUTE SHEET (RULE 26) NMO = N-Methylmorpholine-N-oxide

NMP = N-Methylpyrrolidone

NMR = Nuclear magnetic resonance

Ns = p-Nitrophenyl sulphonyl

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

Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium

PDC = Pyridinium dichlorochromate

PCC = Pyridinium chlorochromate

PE = Petroleum ether

Ph = Phenyl

Piv = Pivaloyl, 2,2-dimethylacetyl

PMB = p-Methoxybenzyl

PPA = Polyphosphoric acid

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

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

PTC = Phase transfer catalyst

PTS A = p-Toluenesulphonic acid

Pv = Pivaloyl, 2,2-dimethylacetyl

Py = Pyridine

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

RT = room temperature

SFC = supercritical fluid chromatography

Prep-SFC = Preparative SFC

SEM = 2-(Trimethylsilyl)ethoxymethyl

TBAF = Tetrabutylammonium fluoride

TBDMS = tert-Butyldimethylsilyl

TBDPS = tert-Butyldiphenyl silyl

TBHP = tert-Butylhydroperoxyde

94

SUBSTITUTE SHEET (RULE 26) TBS = tert-Butyldimethylsilyl

TEA = Tri ethylamine

TES = Triethylsilyl

Tf = Trifluoromethanesulfonyl

TfO = Trifluoromethanesulfonate

Tf2O = Trifluoromethanesulfonyl anhydride

TfOH = Trifluoromethanesulfonic acid

TFA = Trifluoroacetic acid

TFAA = Trifluoroacetic anhydride

Thexyl = 2,3-dimethyl-2-butyl

THF = Tetrahydrofurane

THP = Tetrahydropyranyl

TIPS = Triisopropylsilyl

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

TMG = Tetramethylguanidine

TMS = Trimethylsilyl

Tol = p-Toluyl

TPAP = Tetra-n-propylammonium perruthenate

TPS = Tripropylsilyl

Tr = Trityl, triphenylmethyl

Troc = 2,2,2-Trichloroethoxycarbonyl

Trt = Trityl, triphenylmethyl

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

UV = ultraviolet

Z = Benzyloxycarbony

UV: ultra violet

General LCMS Method:

95

SUBSTITUTE SHEET (RULE 26) [00228] Shimadzu LCMS2020, Reverse-phase column (Shim-Pack Scepter Cl 8, 33 x 3.0 mm, 3um), elution with A: H2O/MeCN/FA = 90/10/0.05; B: MeCN; Detection: MS, ELS, UV (100 pL split to MS with in-line UV detector); MS ionization method: Electrospray (positive and negative ion). ES-API = electrospray-atmospheric pressure ionization.

General HPLC Purification Method:

[00229] IInnssttrruummeenntt = Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281. Column = YMC-Triart C18, 250*20 mm, 5um; Welch Ultimate XB-C18, 250*21.2 mm, 5um.

Detection wavelength = 220, 254 nM. Flow rate = 15ml/min-20ml/min; Run time = 8 min;

Column temperature = 25 °C.

Exemplary chiral prep-SFC conditions and methods for racemic compounds separation:

[00230] Prep-SFC conditions for Example 29 and 30:

Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralPak IB, 250x21.2mm I D., 5 pm

Mobile phase: A for CO2 and B for MeOH

Gradient: B 25%

Flow rate: 40mL/min

Back pressure: 100 bar

Column temperature: 35°C

Wavelength: 220 nm

Cycle-time: 3 min

Eluted time: 2 H

[00231] Prep-SFC conditions for Example 36 and 37 :

Instrument: Waters Thar 80 preparative SFC Column: ChiralCel OD, 250x21.2mm I D., 5pm Mobile phase: A for CO2 and B for MeOH Gradient: B 20 %

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35°C

96

SUBSTITUTE SHEET (RULE 26) Wavelength: 220 nm

Cycle-time: 12 min

Eluted time: 2 H

[00232] Prep-SFC conditions for Example 39 and 40:

Instrument: Waters Thar 80 preparative SFC Column: ChiralPak IC, 250x30 mm I D., 5 pm Mobile phase: A for CO2 and B for MeOH Gradient: B 60%

Flow rate: 50 mL/min

Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm Cycle-time: 3.2 min Eluted time: 2 H

[00233] Prep-SFC conditions for Example 42 and 43:

Instrument: SHIMADZU PREP SOLUTION SEC

Column: ChiralPak IH, 150><20mm I.D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 30%

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35°C

Wavelength: 220nm

Cycle-time: 8 min

Eluted time: 2 H

[00234] Prep-SFC conditions for Example 57 and 58:

Instrument: Waters Thar 80 preparative SEC

Column: ChiralPak IA, 250x21.2 mm I D., 5 pm

Mobile phase: A for CO2 and B for MeOH (MeOH, neutral)

Gradient: B 40 %

Flow rate: 30 mL/min

97

SUBSTITUTE SHEET (RULE 26) Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm

Cycle-time: 15 min Eluted time: 2 H

[00235] Prep-SFC conditions for Example 64 and 65:

Preparative SFC separation method

Instrument: SHIMADZU PREP SOLUTION SFC

Column: (R,R)-WHELK, 250x30mm I D., 5 pm

Mobile phase: A for CO2 and B for MeOH

Gradient: B 50%

Flow rate: 60 mL/min

Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm

Cycle-time: 10 min Eluted time: 2 H

[00236] Prep-SFC conditions for Example 77 and 78:

Instrument: Waters Thar 80 preparative SFC Column: (R,R)-WHELK, 250x30 mm I D., 5 pm Mobile phase: A for CO2 and B for MeOH Gradient: B 40%

Flow rate: 60 mL/min

Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm

Cycle-time: 10 min Eluted time: 3 H

[00237] Prep-SFC conditions for Example 87 and 88:

Instrument: SHIMADZU PREP SOLUTION SEC

Column: ChiralPak IH, 150><20mm I.D., 5pm

98

SUBSTITUTE SHEET (RULE 26) Mobile phase: A for CO2 and B for MEOH+0.1%NH ₃ H ₂ O

Gradient: B 50%

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35°C

Wavelength: 220nm

Cycle-time: 7min

Eluted time: 4 H

[00238] Prep-SFC conditions for Example 125 and 126

Instrument: Waters Thar 80 preparative SFC Column: (R,R)-WHELK, 250x30 mm I D., 5 pm Mobile phase: A for CO ₂ and B for MeOH Gradient: B 40%

Flow rate: 60 mL/min

Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm

Cycle-time: 15 min Eluted time: 2 H

[00239] Prep-SFC conditions for Example 134 and 135:

Instrum ent: Waters Thar 80 preparative SFC

Column: ChiralPak C-IG, 250x30mm I D., 5pm

Mobile phase: A for CO2 and B for MeOH

Gradient: B 30%

Flow rate:60mL/min

Back pressure: 100 bar Column temperature: 35°C Wavelength: 220 nm

Cycle-time: 15 min Eluted time: 3H

[00240] Prep-SFC conditions for Examples 141 - 144:

99

SUBSTITUTE SHEET (RULE 26) Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralPak IH, 150><20mm I.D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 10%

Flow rate: 40mL /min

Back pressure: 100 bar Column temperature: 35°C Wavelength: 220nm

Cycle-time: 20 min Eluted time: 3 H

[00241] Prep-SFC conditions for Example 145 and 146:

Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralPak IH, 150x20mm I.D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 10%

Flow rate: 40mL /min

Back pressure: 100 bar Column temperature: 35°C Wavelength: 220nm

Cycle-time: 10 min Eluted time: 3 H

[00242] Prep-SFC conditions for Example 147 and 148:

Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralPak AS, 250x20mm I D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 15%

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35°C

Wavelength: 220nm

Cycle-time: lOmin

100

SUBSTITUTE SHEET (RULE 26) Eluted time: 2H

[00243] Prep-SFC conditions for Example 149 and 150:

Instrument: Waters Thar 80 preparative SFC Column: ChiralCel OX, 250x20mm I D., 5pm Mobile phase: A for CO2 and B for MeOH Gradient: B 30 %

Flow rate: 40mL /min

Back pressure: 100 bar Column temperature: 35°C Wavelength: 220 nm

Cycle-time: 13 min Eluted time: 2 H

[00244] Prep-SFC conditions for Example 151 and 152:

Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralPak IH, 150x20mm I.D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 15%

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35°C

Wavelength: 220nm

Cycle-time: lOmin

Eluted time: 3H

[00245] Prep-SFC conditions for Example 154 and 155:

Instrument: SHIMADZU PREP SOLUTION SFC

Column: ChiralPak AS, 250x20mm I D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 15%

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35°C

101

SUBSTITUTE SHEET (RULE 26) Wavelength: 220nm

Cycle-time: lOmin

Eluted time: 2H

[00246] Prep-SFC conditions for Example 156 and 157:

Instrument: SHIMADZU PREP SOLUTION SEC

Column: ChiralPak AS, 250x20mm I D., 5pm

Mobile phase: A for CO2 and B for MEOH

Gradient: B 10%

Flow rate: 40mL /min

Back pressure: 100 bar

Column temperature: 35°C

Wavelength: 220nm

Cycle-time: 15min

Eluted time: 2H

[00247] Prep-SFC conditions for Example 158 and 159:

Instrument: SHIMADZU PREP SOLUTION SEC

Column: ChiralCel OX, 250x20mm I D., 5pm

Mobile phase: A for CO2 and B for MeOH Gradient: B 20 %

Flow rate: 40mL /min

Back pressure: 100 bar Column temperature: 35°C Wavelength: 220 nm

Cycle-time: 15 min Eluted time: 3 H

Synthetic procedure:

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

102

SUBSTITUTE SHEET (RULE 26)

[00248] 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 eq) in MeCN (15 mL) were added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (2.1 g, 9.44 mmol, 1.2 eq) and Pyridine (1.2 g, 15.74 mmol, 2.0 eq). The reaction mixture was stirred at 30 °C for 3 h. Then the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SC>4 and concentrated to give a residue. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc = 5: 1) to give 3-fluoro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen- 3-yl)-5-(trifluoromethyl)benzamide (2.7 g, 97%). 'H NMR (400 MHz, CDCh): 5 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 ([M-H]").

[00249] 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 eq) and l-(4-methoxybenzyl)-lH-pyrrole-2,5-

103

SUBSTITUTE SHEET (RULE 26) dione (3.6 g, 16.72 mmol, 2.2 eq) in decahydronaphthalene (65 mL) was added Ru/C (2.2 g, 5% wt). The reaction mixture was heated to 190 °C and stirred for 12 h. Then the mixture was filtered, and the filtrate was concentrated, added water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over NaiSCU and concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether / EtOAc = 20: 1) to give 3-fluoro-N-(2-(4-methoxybenzyl)-l,3-dioxo-2,3,6,7,8,9- hexahydro-lH-benzo[e]isoindol-4-yl)-5-(trifluoromethyl)benza mide (500 mg, 13%). LCMS: m/z 525.0 ([M-H]").

[00250] Step C: To a solution of 3-fluoro-N-(2-(4-methoxybenzyl)-l,3-dioxo-2,3,6,7,8,9- hexahydro-lH-benzo[e]isoindol-4-yl)-5-(trifluoromethyl)benza mide (300.0 mg, 0.57 mmol, 1.0 eq) 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 eq) dropwise at 0 °C. The reaction mixture was stirred at rt for 12 h. Then the mixture was added water (10 mL), extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether / EtOAc = 5: 1) to give N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl) -l-oxo-2,3,6,7,8,9- hexahydro-lH-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromet hyl)benzamide (42.8 mg, 11%). LCMS: m/z 655.1 ([M-H]").

[00251] Step D: To a solution ofN-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4- methoxybenzyl)-l-oxo-2,3,6,7,8,9-hexahydro-lH-benzo[e]isoind ol-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.076 mmol, 1.0 eq) in Toluene (1.5 mL) was added DDQ (69.0 mg, 0.304 mmol, 4.0 eq) at 25 °C under N2 atmosphere. The reaction mixture was heated to reflux and stirred for 12 h. The mixture was added water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated to give a residue. The residue was purified by Pre-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-lH-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromet hyl)benzamide (9 mg, 18%). LCMS: m/z 651.0 ([M-H]").

[00252] Step E: To a solution of N-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4- methoxybenzyl)-l-oxo-2,3-dihydro-lH-benzo[e]isoindol-4-yl)-3 -fluoro-5- (trifluoromethyl)benzamide (9 mg, 0.014 mmol, 1.0 eq) in TFA (0.3 mL) was added EtsSiH (8.1

104

SUBSTITUTE SHEET (RULE 26) mg, 0.07 mmol, 5.0 eq). The reaction mixture was heated to 90 °C and stirred for 5 h. Then the reaction mixture was by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(3-(2-chloro- 5-fluorophenyl)-l-oxo-2,3-dihydro-lH-benzo[e]isoindol-4-yl)- 3-fluoro-5- (trifluoromethyl)benzamide (1.1 mg, 15%) as solid. ^X H NMR (400 MHz, CD3OD): 5 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 ([M-H]’).

Example 2 N-[3-(2-chloro-5-fluorophenyl)-l,6-dioxo-l,2,3,7-tetrahydrop yrrolo[3,4- f|isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[00253] Step A: To a solution of 1,2,3,4-tetrahydroisoquinolin-l-one (10 g, 67.9 mmol) in H2SO4 (130 mL) was added dropwise fuming HNO3 (3.4 mL, 67.9 mmol) at 0 °C. The reaction mixture was stirred for 30 min. The reaction mixture was poured slowly into ice water (500 mL) and the following mixture was filtered. The filter cake was azeotroped with toluene and dried vacuum to give 7-nitro-l,2,3,4-tetrahydroisoquinolin-l-one (10.27 g, 53.4 mmol, 79%). NMR (400 MHz, DMSO-d6) 5 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).

105

SUBSTITUTE SHEET (RULE 26) [00254] Step B: To a solution of 7-nitro- 1,2,3, 4-tetrahydroisoquinolin-l -one (10 g, 52.0 mmol) in H2SO4 (50 mL) was added NBS (1 LI g, 62.4 mmol) batchwise. The reaction mixture was stirred at 60 °C for 1 hours. 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-l,2,3,4- tetrahydroisoquinolin-l-one (13 g, 47.9 mmol, 92.2 %). LCMS: m/z 271 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 6 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).

[00255] Step C: To a solution of 5-bromo-7-nitro-l,2,3,4-tetrahydroisoquinolin-l-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)2 (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 N2 for 6 hours. The cooled reaction mixture was concentrated. The residue was purified by silica gel chromatography (30 g column) using 0 - 100% EtOAc/hexane to afford 7- nitro-l-oxo-l,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) 5 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).

[00256] Step D: To a solution of 7-nitro-l-oxo-l,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-l- carbaldehyde (0.74 g, 4.65 mmol). The reaction mixture was stirred at 20 °C under N2 for 12 hours. The following mixture was concentrated and the residue was purified by silica gel chromatography (10 g column) using 0 - 80% EtOAc/hexane to afford N-[l-(2-chl oro-5- fluorophenyl)-2-[(2-methylprop-2-yl)amino]-2-oxoethyl]-N-[(4 -methoxyphenyl)methyl]-7-nitro- l-oxo-l,2,3,4-tetrahydroisoquinoline-5-carboxamide (2 g, 3.35 mmol, 79%). LCMS: m/z 597.1 [M + H] ⁺

[00257] Step E: To a solution ofN-[l-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2- yl)amino]-2-oxoethyl]-N-[(4-methoxyphenyl)methyl]-7-ni tro-l-oxo-1, 2,3,4- tetrahydroisoquinoline-5-carboxamide (1 g, 1.67 mmol) in DMSO-d6 (50 mL) was added potassium 2-methylpropan-2-olate (470 mg, 4.18 mmol). The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water, extracted with EA (200 mL x 3). The organic phase was dried over NaiSOr and concentrated. The residue was purified by

106

SUBSTITUTE SHEET (RULE 26) silica gel chromatography (5 g column) using 0 - 80% EtOAc/hexane to afford 3-(2-chloro-5- fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-4-nitro- 2,3,6,7,8,9-hexahydro-lH- pyrrolo[4,3-f]isoquinoline-l, 6-dione (440 mg, 0.860 mmol, 51%). LCMS: m/z 510.2 [M + H] ⁺ TI NMR (400 MHz, DMSO-d6) 5 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).

[00258] Step F: To a solution of 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl)methyl]-4-nitro-2,3,6,7-tetrahydro-lH-pyrrolo[ 4,3-f]isoquinoline-l, 6-dione (200 mg, 0.39 mmol) in MeOH (10 mL) was added 10% of Pd/C (208 mg). The reaction mixture was stirred at 20 °C under Hi (15 Psi) for 1 hour. The mixture was filtered and concentrated to give 4- amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphe nyl) methyl]-2,3,6,7,8,9- hexahydro-lH-pyrrolo[4,3-f]isoquinoline-l, 6-dione (90 mg, 0.187 mmol, 48%). LCMS: m/z 480.1 [M + H] ⁺

[00259] Step G: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl) methyl]-2, 3, 6, 7-tetrahydro-lH-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 hour. The reaction mixture was diluted with water, extracted with DCM (30 mL x 3). The organic phase was dried over NaiSCL and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0 - 80% EtOAc/hexane to afford N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl)methyl]-l, 6-dioxo-l, 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 [M - H] ⁺ [00260] Step H: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl) methyl]-!, 6-dioxo-l, 2,3, 7-tetrahydropyrrolo[4,3-f]isoquinolin-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (15 mg, 0.022 mmol) in TLA (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 under vacuum to give N-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-l, 6-dioxo-l, 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] ⁺

107

SUBSTITUTE SHEET (RULE 26) [00261] Step I: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-l,6-dioxo-l,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 prep-TLC (EA) to give N-[3-(2-chloro-5-fluorophenyl)-l,6-dioxo-l,2,3,7-tetrahydrop yrrolo[3,4- f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7.3 mg, 0.014 mmol, 60%). LCMS: m/z 534 [M + H] ^{+ X} H NMR (400 MHz, CDCh) 5 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).

Example 3 N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-tetrahy dropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

108

SUBSTITUTE SHEET (RULE 26)

[00262] Step A: A solution of l/7-indazole-6-carbaldehyde (2.0 g, 13.7 mmol, 1.0 eq) and K2CO3 (3.8 g, 27.4 mmol, 2.0 eq) in DMF (15 mL) was added dropwise a solution of I2 (5.9 g, 23.3 mmol, 1.7 eq) in DMF (15 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. An aqueous solution consisting of Xa A/O : (3.30 g) / K2CO3 (0.2 g) / II2O (30 ml,) was then added, and the solution was stirred for 1 h. The product was then precipitated by pouring the solution over ice-water (300 mL) and collected by vacuum filtration to give 3-iodo-l 77-in dazole- 6-carbaldehyde (2.3 g, 62%). LCMS: m/z 271.0 ([M-H]"). 'H NMR (300 MHz, DMSO-d6): 5 14.04 (brs, 1H), 10.14 (s, 1H), 8.19 (s, 1H), 7.78-7.54 (m, 2H).

[00263] Step B: To a solution of 3-iodo-177-indazole-6-carbaldehyde (27.0 g, 99.2 mmol, 1.0 eq) in H2SO4 (98%, 300 mL) was added dropwise HNO3 (7.5 g, 119.1 mmol, 1.2 eq) at 0 °C. The reaction mixture was stirred at RT for 3 h. The product was then precipitated by pouring the solution over ice-water (600 mL) and collected by vacuum filtration to give 3-iodo-5-nitro-lZ7- indazole-6-carbaldehyde (32.0 g, HPLC~85%, 86%). LCMS: m/z 315.9 ([M-H]"). ^NMR (300 MHz, DMSO-d6): 5 14.48 (brs, 1H), 10.29 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H).

[00264] Step C: To a solution of 3-iodo-5-nitro-l/7-indazole-6-carbaldehyde (10.0 g, 31.5 mmol, 1.0 eq) in H2SO4 (98%, 100 mL) was added NBS (8.4 g, 47.3 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at 30 °C for 5 h. The product was then precipitated by pouring the solution over ice-water (300 mL) and collected by vacuum filtration to give 7-bromo-3-iodo-5- nitro-l/7-indazole-6-carbaldehyde (8.1 g, HPLC -78%, 51%). LCMS: m/z 393.8, 395.7 ([M-H]"). !H NMR (300 MHz, DMSO-d6): 5 14.93 (brs, 1H), 10.24 (s, 1H), 8.28 (s, 1H).

109

SUBSTITUTE SHEET (RULE 26) [00265] Step D: To a solution of 7-bromo-3-iodo-5-nitro-l/f-indazole-6-carbaldehyde (8.1 g,

20.5 mmol, 1.0 eq) 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 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Then the mixture was added water (150 mL), extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with brine (200 mL), dried over NaiSCU and concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether / EtOAc = 3: 1) to give (7-bromo-3-iodo-5-nitro-l//-indazol-6- yl)(2-chloro-5-fluorophenyl)methanol (10.0 g, 93%). LCMS: m/z 523.8, 525.7 ([M-H]"). ^X H NMR (300 MHz, DMSO-d6): 5 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).

[00266] Step E: To a solution of (7-bromo-3-iodo-5-nitro-l//-indazol-6-yl)(2-chloro-5- fhiorophenyl)methanol (10.0 g, 19.0 mmol, 1.0 eq) in DCM (100 mL) was added DMP (12.1 g,

28.5 mmol, 1.5 eq) at 25 °C. The reaction mixture was stirred at rt for 2 h. Then the mixture was 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-lH-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (7.1 g, 71%). LCMS: m/z 521.7, 523.8 ([M-H]").

[00267] Step F: To a solution of (7-bromo-3-iodo-5-nitro-lH-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (500 mg, 0.95 mmol, 1.0 eq) and Fe (266.1 mg, 4.8 mmol, 5.0 eq) in EtOH (10 mL) was added NH4CI (25.5 mg, 0.48 mmol, 0.5 eq) in H2O (5 mL) dropwise at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Then the mixture was added water (10 mL) and ethyl acetate (5 mL), filtered, then the filtrate was extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SC>4 and concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether/ EtOAc = 3: 1) to give (5-amino-7-bromo-3-iodo-lH-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (300 mg, 64%). LCMS: m/z 491.7, 493.8 ([M-H]").

[00268] Step G: A sealed vial was charged with (5-amino-7-bromo-3-iodo-lH-indazol-6- yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.4 mmol, 1.0 eq), Zn(CN)2 (142.3 mg, 1.2 mmol, 3.0 eq), Pd(PPh3)4 (233.4 mg, 0.2 mmol, 0.5 eq) and DMAC (4 mL). The sealed vial was irradiated in the microwave at 160 °C for 0.5 h. The mixture was added water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (15 mL x 2), dried over Na2SO4 and concentrated to give a residue. The residue was purified by

110

SUBSTITUTE SHEET (RULE 26) silica gel (eluted with petroleum ether/ EtOAc = 1 : 1) to give 5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-8-oxo-l,6,7,8-tetrahydropyrrolo[3,4- g]indazole-3-carbonitrile (35 mg, 24%). LCMS: m/z 355.9 ([M-H]").

[00269] 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 eq) in ACN (2 mL) were added 3-fluoro-5-(trifluoromethyl) benzoyl chloride (44.4 mg, 0.2 mmol, 2.0 eq) and Pyridine (39 mg, 0.5 mmol, 5.0 eq). The reaction mixture was stirred at 30 °C for 4 h Then the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL x 2). The combined organic phases were washed with brine (3 mL), dried over NaiSCU and concentrated to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether: EtOAc =1 : 1) to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-8-oxo-l, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (30 mg, 56%). LCMS: m/z 546.0 ([M-H]").

[00270] Step I: To a solution ofN-(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 eq) in TEA (1 mL) was added EtsSiH (29.1 mg, 0.25 mmol, 5.0 eq). The reaction mixture was heated to 80 °C and stirred for 2 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l, 6,7, 8-tetrahydropyrrolo[3,4-g]indazol-5- yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.0 mg, 8%). LCMS: m/z 529.9 ([M-H]'). ¹ H NMR (400 MHz, DMSO-d6): 5 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).

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

111

SUBSTITUTE SHEET (RULE 26)

[00271] Step A: To a solution of DMF (30.3 g, 415.2 mmol, 3.0 eq) in CHCh (100 mL) was added PBn (101.2 g, 373.68 mmol, 2.7 eq) dropwise at 0 °C for 1 h, then the 7-chloro-3,4- dihydronaphthalen-l(2H)-one (25.0 g, 138.40 mmol, 1.0 eq) was added. Then the mixture was stirred at room temperature for 24 h. The mixture was adjusted to pH 9 with solid NaHCOs and partitioned with DCM (200 mL). The layers were separated. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4 and evaporated to dryness. The residue was purified by silica gel column

112

SUBSTITUTE SHEET (RULE 26) chromatography (petroleum ether) to give l-bromo-7-chloro-3,4-dihydronaphthalene-2- carbaldehyde (10.6 g, 28%). ^ NMR (300 MHz, CDCh): 6 10.24 (s, 1H), 7.87 (d, J= 2.0 Hz,lH), 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). [00272] Step B: To a solution of l-bromo-7-chl oro-3, 4-dihydronaphthalene-2-carbaldehy de (12.2 g, 44.93 mmol, 1.0 eq) in toluene (185 mL) was added DDQ (51.0 g, 224.65 mmol, 5.0 eq) in 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 x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SC>4 and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 50/1) to give l-bromo-7-chl oro-2 - naphthaldehyde (5.5 g, 45%). LCMS: m/z 269.0 ([M +H] ⁺ ).

[00273] Step C: To a solution of l-bromo-7-chloro-2-naphthaldehyde (1.0 g, 3.71 mmol, 1.0 eq) in DCE (50 mL) was added tosyl azide (1.46 g, 7.42 mmol, 2.0 eq), 3,5- bis(trifluoromethyl)aniline (339.2 mg, 1.48 mmol, 0.4 eq), [Cp*IrCh]2 (294.8 mg, 0.37 mmol, 0.1 eq), AgNTf (574.2 mg, 1.48 mmol, 0.4 eq) at room temperature. The mixture was stirred at 80°C under air for 6 h. The precipitate formed was collected by filtration, washed with EtOAc (5 mL), dried in vacuo to give N-(4-bromo-6-chl oro-3 -formylnaphthal en-2-yl)-4- methylbenzenesulfonamide (950 mg, 58%). 'H NMR (400 MHz, DMSO-d6): 5 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).

[00274] 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 eq) in THE (13.6 mL) was added (2-chloro- 5-fluorophenyl)magnesium bromide (31.0 mL, 0.5 mmol/mL, 5.0 eq) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic phase was washed with brine (50 mL), dried over Na2SO4, 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-methylbenzen esulfonamide (1.0 g, 57%).

LCMS: m/z 565.8 ([M -H]").

113

SUBSTITUTE SHEET (RULE 26) [00275] Step E: To a solution of N-(4-bromo-6-chloro-3-((2-chloro-5- fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzen esulfonamide (560 mg, 0.98 mmol, 1.0 eq) in DCM (44 mL) was added Dess-Martin periodinane (1.25 g, 2.94 mmol, 3.0 eq) at room temperature. The mixture was stirred at room temperature for 12 h. 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-methylbenzenesulfo namide (310 mg, 55%). LCMS: m/z 563.7 ([M -H]").

[00276] Step F: To a solution of N-(4-bromo-6-chl oro-3 -(2 -chi oro-5 - fluorobenzoyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (200 mg, 0.35 mmol, 1.0 eq) in H2SO4 (6 mL) at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was poured into ice water (10 mL). The precipitate formed was collected by filtration, washed with water (5 mL), dried in vacuo 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)metha none (80 mg, 56%) as a yellow solid. LCMS: m/z 411.9 ([M +H] ⁺ ).

[00277] Step G: To a solution of (3-amino-l-bromo-7-chloronaphthalen-2-yl)(2-chloro-5- fluorophenyl)methanone (80 mg, 0.19 mmol, 1.0 eq) in DMAC (2 mL) was added Zn(CN)2 (33.5 mg, 0.29 mmol, 1.5 eq) and Pd(pph3)4 (65.9 mg, 0.06 mmol, 0.3 eq) in microwave tube. The mixture was heated under microwave irradiation at 160°C 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 x 3). The combined organic layers were washed with brine (10 mL), dried over Na2$O4 and evaporated to dryness. The residue was purified by TLC to give 3-amino- 7-chloro-2-(2-chloro-5-fluorobenzoyl)-l -naphthonitrile (37 mg, 54%). LCMS: m/z 359.0 ([M +H] ⁺ ).

[00278] Step H: To a solution of 7-chloro-2-(2-chloro-5-fluorobenzoyl)-l-naphthonitrile (37 mg, 0.10 mmol, 1.0 eq) in MeCN (2 mL) was added KOH (1.7 mg, 0.03 mmol, 0.3 eq) in H2O (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 x 3). The combined organic layers were washed with brine (5 mL), dried over NaiSO4 and evaporated to dryness to give 4-amino-8-chl oro-3 -(2-chloro-5-

114

SUBSTITUTE SHEET (RULE 26) fluorophenyl)-3-hydroxy-2,3-dihydro-lH-benzo[e]isoindol-l-on e (38 mg, curde). LCMS: m/z 374.9 ([M-H]").

[00279] Step I: To a solution of 4-amino-8-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-

2.3-dihydro-lH-benzo[e]isoindol-l-one (38 mg, curde) in MeCN (3 mL) was added 3-fluoro-5- (trifluoromethyl)benzoyl chloride (45.3 mg, 0.2 mmol, 2.0 eq) and pyridine (23.7 mg, 0.3 mmol, 3.0 eq). The mixture was stirred at 50°C for 2 h. 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 x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and evaporated to dryness to give N-(8-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo-

2.3-dihydro-lH-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluo romethyl)benzamide (58 mg, curde). LCMS: m/z 564.9 ([M-H]").

[00280] Step J: To a solution of N-(8-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo-

2,3-dihydro-lH-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluo romethyl)benzamide (58 mg, curde) in TEA (3 mL) was added EtaSiH (59.3 mg, 0.51 mmol, 5.0 eq). The mixture was stirred at room temperature for 2 h. The mixture was fdtered, and the fdtrate was concentrated to give a residue. The crude residue was purified by Prep-HPLC to give N-(8-chloro-3-(2-chloro-5-fluorophenyl)- 1 -oxo-2, 3-dihydro-lH-benzo[e]isoindol-4-yl)-3-fluoro-5-(trifluoromet hyl)benzamide (14 mg, 25%). LCMS: m/z 551.8 ([M-H]"). *H NMR (400 MHz, DMSO-d6): 5 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).

Example 5 N-(3-(2-chloro-5-fluorophenyl)-7-methyl-l,6-dioxo-2,3,6,7-te trahydro-lH- pyirolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl) benzamide

115

SUBSTITUTE SHEET (RULE 26)

[00281] Step A: To a solution of 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4- methoxybenzyl)-4-nitro-2,3-dihydro-lH-pyrrolo[3,4-f]isoquino line-l,6(7H)-dione (450 mg, 0.879 mmol) in DMF (10 mL) was added K2CO3 (364 mg, 2.64 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. lodomethane (125 mg, 0.879 mmol) was added and the reaction mixture was stirred at rt for 1 hour. The mixture was poured into ice water (50 mL), extracted with EA (50 mL x 3). The organic phase was dried over Na2SO4 and concentrated to give a residue, which was purified by silica gel chromatography (5 g column) using 0 - 70% EtOAc/hexane to 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-7- methyl-4- nitro-2,3-dihydro-lH-pyrrolo[3,4-f]isoquinoline-l,6(7H)-dion e (95 mg, 0.181 mmol, 20%). LCMS: m/z 522.0 [M - H] ⁺ 'H NMR (400 MHz, DMSO-d6) 5 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).

[00282] 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-lH -pyrrolo[4,3-f]isoquinoline-l,6- di one (60 mg, 0.115 mmol) in EtOH (10 mL) and water (3 mL) was added NH4CI (12.3 mg, 0.229 mmol) and Fe (0.003 mL, 0.458 mmol). The reaction mixture was stirred at 75 °C for 1 hour. The cooled mixture was filtered and concentrated. The residue was diluted with water (10 mL) and extracted with EA (10 mL x 3). The organic phase was dried over ISfeSCL and concentrated to give 4-amino-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl)methyl]-7-methyl-2,3,6,7-tetrahydro-lH-pyrrolo [4,3-f]isoquinoline-l,6-dione (50 mg, 0.101 mmol, 88%). LCMS: m/z 494 [M + H] ⁺ .

[00283] 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-lH-pyrrolo [4,3-f]isoquinoline-l,6-dione (40 mg, 0.081 mmol) and 5-fluoro-3-(trifluoromethyl)benzoic acid (20.22 mg, 0.097 mmol)

116

SUBSTITUTE SHEET (RULE 26) in DCM (10 mL) was added pyridine (2 mL, 24.7 mmol). Then dichlorophosphinyl chloride (24.8 mg, 0.162 mmol) was added and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water, extracted with DCM (30 mL x 3). The organic phase was dried over NaiSCU and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0 - 80% EtOAc/hexane to afford N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy- 2-[(4-methoxyphenyl)methyl]-7-methyl-l,6-dioxo-2,3-dihydro-l H-pyrrolo[4,3-f]isoquinolin-4- yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.044 mmol, 54%). LCMS: m/z 682.0 [M - H] ⁺ . [00284] Step D: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl)methyl]-7-methyl-l,6-dioxo-2,3-dihydro-lH-pyrr olo[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 under vacuum to give N-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-7-methyl-l,6-dioxo-2,3-dihydro-lH-pyrr olo[3,4-f]isoquinolin-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.034 mmol, 92%). It was used for nest step without purification. LCMS: m/z 668,2 [M + H] ⁺

[00285] Step E: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-7-methyl-l,6-dioxo-2,3-dihydro-lH-pyrr olo[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 prep-TLC (PE/EA=3: 7) and then by prep-HPLC to give N-(3-(2-chloro-5-fluorophenyl)-7- methyl-l,6-dioxo-2,3,6,7-tetrahydro-lH-pyrrolo[3,4-f]isoquin olin-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide (13.8 mg, 0.025 mmol, 67%). LCMS: m/z 548.1 [M + H] ⁺ 'H NMR (400 MHz, Methanol-d4) 5 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).

Example 6 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethyl)b enzamido)-8-oxo- l,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide

117

SUBSTITUTE SHEET (RULE 26)

[00286] Step A: A sealed vial was charged with (5-amino-7-bromo-3-iodo-lH-indazol-6- yl)(2-chloro-5-fluorophenyl)methanone (100 mg, 0.2 mmol, 1.0 eq), Zn(CN)2 (71.2 mg, 0.6 mmol, 3.0 eq), Pd(PPhs)4 (116.7 mg, 0.1 mmol, 0.5 eq) and DMAC (2 mL). The sealed vial was irradiated in the microwave at 160 °C for 0.5 h. The mixture was added water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine (5 mL x 2), dried over TsfeSCL and concentrated to give a residue. The residue was purified by silica gel (eluted with petroleum ether/ EtOAc = 1 : 1) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)-lH- indazole-3,7-dicarbonitrile (20 mg, 29%). LCMS: m/z 338.0 ([M-H]").

[00287] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-lH-indazole-3,7- dicarbonitrile (70.0 mg, 0.21 mmol, 1.0 eq) and K2CO3 (28.5 mg, 0.21 mmol, 1.0 eq) in DMSO- d6 (0.5 mL) was added H2O2 (30%, 71.4 mg, 0.63 mmol, 3.0 eq) at room temperature. The mixture was added water (3 mL) and extracted with EtOAc (2 mL x 2). The combined organic phases were washed with brine (3 mL x 2), dried over Na2SO4 and concentrated to give 5-amino- 6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-l,6,7,8-tetrahyd ropyrrolo[3,4-g]indazole-3- carboxamide (65 mg, crude). LCMS: m/z 374.0 ([M-H]").

[00288] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo- l,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide (65 mg, 0.17 mmol, 1.0 eq) in ACN (2 mL) were added 3-fluoro-5-(trifluoromethyl) benzoyl chloride (78.4 mg, 0.35 mmol, 2.0 eq) and Pyridine (41.1 mg, 0.52 mmol, 3.0 eq). The reaction mixture was stirred at 40 °C for 2 h. Then the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL x 2). The combined organic phases were washed with brine (3 mL) and aqueous solution ISfeCCh (5 mL),

118

SUBSTITUTE SHEET (RULE 26) dried over NazSCU and concentrated to give 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5- (trifluoromethyl)benzamido)-6-hydroxy-8-oxo-l,6,7,8-tetrahyd ropyrrolo[3,4-g]indazole-3- carboxamide (110 mg, crude). LCMS: m/z 563.9 ([M-H]").

[00289] Step D: To a solution of 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5- (trifluoromethyl)benzamido)-6-hydroxy-8-oxo-l,6,7,8-tetrahyd ropyrrolo[3,4-g]indazole-3- carboxamide (110 mg, 0.19 mmol, 1.0 eq) in TFA (5 mL) was added EtgSiH (112.8 mg, 0.97 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5- (trifluoromethyl)benzamido)-8-oxo-l,6,7,8-tetrahydropyrrolo[ 3,4-g]indazole-3-carboxamide (10.5 mg, three steps yield 9%). LCMS: m/z 547.9 ([M-H]").

!H NMR (400 MHz, DMSO-d6): 5 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).

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

119

SUBSTITUTE SHEET (RULE 26)

[00290] Step A: To a solution of PBn (20 mL) in CHCh (300 mL) were added DMF (20 mL, 258.6 mmol) dropswile at 0 °C with N2. The reaction mixture was stirred at rt about 2 hours. 7- fluoro-l,2,3,4-tetrahydronaphthalen-l-one (13.5 g, 82.3 mmol) was added, and the reaction mixture was stirred at 70 °C for 2 hours. The cooled reaction mixture was diluted with DCM and saturated NaHCOa solution. The organic layer was separated, washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10 % ethyl acetate in petroleum ether, and dried to afford compound l-bromo-7-fluoro-3,4-dihydronaphthalene-2-carbaldehyde (10.0 g, 39.2 mmol, 48%). LCMS: m/z 255/257 [M + H] ⁺ .

[00291] Step B: To a solution of l-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 NaHCCh solution. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-3% ethyl acetate in petroleum ether and dried to afford compound l-bromo-7-fluoronaphthalene-2-carbaldehyde (8.0 g, 31.6 mmol, 50.4 %). LCMS: m/z 253/255 [M + H] ⁺ .

[00292] Step C: To a solution of (Pentamethylcyclopentadienyl)iridium(III) chloride dimer (0.54 g, 0.68 mmol) in DCE (100 mL) were added 3,5-bis(trifluoromethyl)aniline (0.42 mL, 2.69 mmol), azido(4-methylphenyl)dioxo-X ⁶ -sulfane (10.6 g, 53.7 mmol), l-bromo-7- fluoronaphthalene-2-carbaldehyde (6.80 g, 26.9 mmol) and silver bis[dioxo(trifluoromethyl)-X6- sulfanyl]azanide (1.04 g, 2.69 mmol). 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

120

SUBSTITUTE SHEET (RULE 26) chromatography eluting with 0-40 % ethyl acetate in petroleum ether, and dried to afford compound N-(4-bromo-6-fluoro-3-formyl-2-naphthyl)-4-methylbenzenesulf onamide (3.5 g, 8.29 mmol, 31%). LCMS: m/z 422/424 [M + H] ⁺ .

[00293] Step D: Solution A : To a stirred mixture of lithium magnesium dichloride propan-2- ide (10 mL, 1.3 mol/L) in THF (20 mL) was added dropwise 2-bromo-l-chloro-4-fluorobenzene (3 g, 14 mmol) at 0 °C under N2 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 the “Solution A ” dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred at rt for an additional Ih. The reaction was quenched with water at rt. The resulting mixture was extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-15 % ethyl acetate in petroleum ether, and dried to afford compound N-[4-bromo-3-[(2-chloro-5- fluorophenyl)(hydroxy)methyl]-6-fluoro-2-naphthyl}-4-methylb enzenesulfonamide (1.60 g, 2.90 mmol, 41%). LCMS: m/z 552/554 [M + H] ⁺ .

[00294] Step E: To a solution of N-{4-bromo-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]- 6-fluoro-2-naphthyl}-4-m ethylbenzenesulfonamide (1.40 g, 2.54 mmol) in DCM (30 mL) were added l,l,l-triacetoxy-l,3-dihydro-lX5-benzo[d][l,2]iodoxol-3-one (0.87 mL, 2.79 mmol). 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 Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-40 % ethyl acetate in petroleum ether and dried to afford compound N-[4-bromo-3-[(2-chloro- 5-fluorophenyl)carbonyl]-6-fluoro-2-naphthyl]-4-methylbenzen esulfonamide (1.00 g, 1.82 mmol, 72%). LCMS: m/z 550/552 [M + H] ⁺ .

[00295] 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) were added cyanocopper (I) (0.49 g, 5.50 mmol). The reaction mixture was stirred at 150 °C under N2 for 2 hr. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated to afford compound N-{3-[(2- chloro-5-fluorophenyl)carbonyl]-4-cyano-6-fluoro-2-naphthyl} -4-methylbenzenesulfonamide

121

SUBSTITUTE SHEET (RULE 26) (1.20 g, cmde). The residue was not purified and will be used directly. LCMS: m/z 497 [M + H] ⁺ .

[00296] 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 CFLCN (8 mL)/H20 (2 mL) were added LiOH (254 mg, 6.04 mmol). The reaction mixture was stirred at rt for 3 hr. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over IsfeSCU and concentrated. The residue was dried to afford compound N- [3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-l-oxo-2,3-di hydro-lH-benzo[e]isoindol-4-yl]- 4-methylbenzenesulfonamide (600 mg, 1.17mmol, 48%). LCMS: m/z 513 [M - H]".

[00297] Step H: To a solution of N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-l-oxo-

2.3-dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulf onamide (700 mg, 1.36 mmol) in H2O (4 mL) were added H2SO4 (10 mL). The reaction mixture was stirred at rt for 1 hr. The reaction was diluted with EA and saturated NaHCOa solution. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-60% ethyl acetate in petroleum ether and dried to afford compound 4-amino-3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-2,3-d ihydro- lH-benzo[e]isoindol-l-one (450 mg, 1.25 mmol, 92%). LCMS: m/z 359 [M- H]".

[00298] Step I: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-

2.3-dihydro-lH-benzo[e]isoindol-l-one (200 mg, 0.55 mmol) in DCM (4 mL) were added 3- fluoro-5-(trifluoromethyl)benzoic acid (116 mg, 0.56 mmol), pyridine (1 mL) and POCI3 (0.52 mL, 5.55 mmol). The reaction mixture was stirred at rt for 2 hours. The reaction was diluted with EA and saturated NaHCCL solution. The organic layer was separated, washed with brine, dried over NazSCU and concentrated. The residue was purified using silica gel column chromatography eluting with 0-60% ethyl acetate in petroleum ether and dried to afford compound N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-l-oxo-2,3- dihydro-lH- benzo[e]isoindol-4-yl]-3-fhioro-5-(trifluoromethyl)benzamide (30 mg, 0.054 mmol, 10%) as yellow solid. LCMS: m/z 549 [M - H]".

[00299] Step J: To a solution of N-[3-(2-chloro-5-fluorophenyl)-8-fluoro-3-hydroxy-l-oxo-

2.3-dihydro-lH-benzo[e]isoindol-4-yl]-3-fluoro-5-(trifluo romethyl)benzamide (30 mg, 0.054 mmol) in TFA (4 mL) were added tri ethyl silane (1 mL, 6.20 mmol). The cooled reaction mixture was stirred at rt for 1 hr. The reaction was diluted with EA and saturated

122

SUBSTITUTE SHEET (RULE 26) NaHCOg solution. The organic layer was separated, washed with brine, dried over NaiSCU and concentrated. The residue was purified by prep-HPLC and dried to afford compound N-[3-(2- chloro-5-fluorophenyl)-8-fluoro-l-oxo-2,3-dihydro-lH-benzo[e ]isoindol-4-yl]-3-fluoro-5-

(trifluoromethyl)benzamide (8 mg, 0.015 mmol, 27%). LCMS: m/z 535 [M + H] ⁺ . ^! H NMR (400

MHz, DMSO-d6) 5 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).

Example 8 7V-(3-bromo-6-(2-chloro-5-fluorophenyl)-8-oxo-l,6,7,8-tetrah ydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

123

SUBSTITUTE SHEET (RULE 26)

[00300] 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 hr. 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 afford methyl 2-amino-3-bromo-6-fluorobenzoate (9 g, 32.8 mmol, 55%). LCMS: m/z 248 [M + H] ⁺ .

[00301] Step B: To a solution of methyl 2-amino-3-bromo-6-fluorobenzoate (9 g, 36.3 mmol) in H2O (9 mL) and dioxane (90 mL) were added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (20.7 mL, 72.6 mmol), CS2CO3 (23.6 g, 72.6 mmol), and bis[5-(diphenylphosphanyl)cyclopenta- l,3-dienyl]-X2-iron(II) palladium chloride (2.65 g, 3.63 mmol). The reaction was stirred at 90 °C under N2 overnight. 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 afford methyl 2-amino-6-fluoro-3-methylbenzoate (4.2 g, 22.8 mmol, 63%). LCMS: m/z 184 [M + H] ⁺ .

[00302] 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 AC2O (4.31 mL, 45.9 mmol). The reaction was stirred at 60 °C for 3 hr. The cooled reaction mixture was concentrated to remove half solvent. The residue was poured into ice water and quenched with saturated NaHCCh solution. The following mixture was extracted with EA. The organic layer was washed with brine, dried over NaiSCU and concentrated to afford methyl 2-acetamido-6-fluoro-3-methylbenzoate (3.2 g, 14.2 mmol, 93%). LCMS: m/z 226 [M + H] ⁺ .

[00303] Step D: To a solution of methyl 2-acetamido-6-fluoro-3-methylbenzoate (1.8 g, 7.99 mmol) in con.LLSCL (18 mL) was added dropwise fuming HNCL (0.459 mL, 10.4 mmol) at 0 °C. The reaction was stirred at 0 °C for 4 hr. The reaction was poured into ice water. The resulting

124

SUBSTITUTE SHEET (RULE 26) mixture was filtered. The filter cake was washed with water, azeotroped with toluene and dried to afford methyl 2-acetamido-6-fluoro-3-methyl-5-nitrobenzoate (1.35 g, 4.77 mmol, 60%). LCMS: m/z 271 [M + H] ⁺ .

[00304] 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 SOCh (0.725 mL, 9.99 mmol). The reaction was stirred at 60 °C overnight. The cooled reaction mixture was concentrated to remove half solvent. The following mixture was filtered. The filter cake was washed with ice MeOH and concentrated to afford methyl 2-amino-6-fluoro-3-methyl-5-nitrobenzoate (1.35 g, 5.92 mmol, 89%). LCMS: m/z 229 [M + H] ⁺ .

[00305] 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 NaNOz (612 mg, 8.87 mmol). The reaction mixture was stirred at room temperature for 3 hr. The reaction was poured into ice water and extracted with EA The organic layer was washed with saturated NaHCOa solution, dried over NagSO-i and concentrated. The residue was purified using silica gel column chromatography eluting with 100% dichloroform to afford compound methyl 6-fluoro-5-nitro-17/-indazole-7-carboxylate (450 mg, 1.65 mmol, 41%). LCMS: m/z 240 [M + H] ⁺ .

[00306] Step G: To a solution of methyl 6-fluoro-5-nitro-l/f-indazole-7-carboxylate (670 mg, 2.801 mmol) in DMF (8 mL) was added MBS (1.09 g, 6.16 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction was poured into ice water and extracted with EA The organic layer was washed with saturated NaHCOg solution and brine, dried over Na ₂ SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound methyl 3-bromo-6-fluoro-5- nitro-17/-indazole-7-carboxylate (870 mg, 2.67 mmol, 95%). LCMS: m/z 318 [M + H] ⁺ .

[00307] Step H: To a solution of methyl 3-bromo-6-fluoro-5-nitro-l/Z-indazole-7-carboxylate (870 mg, 2.74 mmol) in MeOH (25 mL), THF (25 mL) and H ₂ O (25 mL) was added LiOH/H ₂ O (0.76 mL, 27.4 mmol) at 0 °C. The reaction was stirred at room temperature overnight. The reaction was concentrated to remove organic and acided with IM HC1. The following mixture was filtered. The filter cake was dried to afford compound 3-bromo-6-fluoro-5-nitro-17/- indazole-7-carboxylic acid (750 mg, 2.45 mmol, 90%). LCMS: m/z 304 [M + H]“.

[00308] Step I: To a solution of 3-bromo-6-fluoro-5-nitro-17/-indazole-7-carboxylic acid (750 mg, 2.47 mmol) in MeOH (15 mL) were added (4-methoxyphenyl)methanamine (0.322 mL, 2.47

125

SUBSTITUTE SHEET (RULE 26) mmol), 2-chloro-5-fluorobenzene-l-carbaldehyde (391 mg, 2.47 mmol) 2-chloro-5- fluorobenzene-l-carbaldehyde (391 mg, 2.47 mmol) and 2-isocyano-2-methylpropane (0.281 mL, 2.47 mmol). 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 afford 3-bromo-7V-(2-(tert-butylamino)-l- (2-chloro-5-fluorophenyl)-2-oxoethyl)-6-fluoro-A-(4-methoxyb enzyl)-5-nitro-l//-indazole-7- carboxamide (1.2 g, 1.78 mmol, 72%). LCMS: m/z 664 [M + H]“.

[00309] Step J: To a solution of 3-bromo-A-(2-(tert-butylamino)-l-(2-chloro-5- fluorophenyl)-2-oxoethyl)-6-fluoro-/V-(4-methoxybenzyl)-5-ni tro-l/7-indazole-7-carboxamide (1.1 g, 1.65 mmol) in DMA (10 mL) was added l,l-bis(dimethylamino)-N-(2-methylprop-2- yl)methanimine (0.506 mL, 2.48 mmol). The reaction was stirred under N2 at 140 °C for 18 hr. The cooled reaction mixture was poured into ice 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 0-30% ethyl acetate in petroleum ether to afford 3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybe nzyl)-5-nitro-6,7- dihydropyrrolo[3,4-g]indazol-8(lf/)-one (430 mg, 0,673 mmol, 41%). LCMS: m/z 561 [M + H] ⁺ .

[00310] 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(l/ /)-one (420 mg, 0.748 mmol) in EtOH (3 mL) and FLO (1 mL) was added NH4CI (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 afford 5-amino-3-bromo-6-(2-chloro-5- fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-6,7-dihydropyrro lo[3,4-g]indazol-8(l//)-one (230 mg, 0.355 mmol, 47%). LCMS: m/z 531 [M + H] ⁺ .

[00311] 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(17/)-on e (70 mg, 0.132 mmol) in DCM (10 mL) was added pyridine (1 mL, 12.4 mmol). Then 5-fluoro-3-(trifluoromethyl)benzoic acid (30.1 mg, 0.145 mmol) and POCL (40.4 mg, 0.264 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was diluted with DCM and water. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using prep-TLC

126

SUBSTITUTE SHEET (RULE 26) eluting with 30% ethyl acetate in petroleum ether to afford A-(3-bromo-6-(2-chloro-5- fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-8-oxo-l,6,7,8-te trahydropyrrolo[3,4-g]indazol-5- yl)-3-fluoro-5 (trifluoromethyl)benzamide (30 mg, 0.037 mmol, 28%). LCMS: m/z 721 [M + H] ⁺ .

[00312] Step M: To a solution of 7V-(3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4- methoxybenzyl)-8-oxo-l,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 tri ethyl silane (1.5 mL, 9.29 mmol) and the mixture was stirred at 25 °C for 1 hour. The reaction was concentrated under vacuo to afford A-(3-bromo-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-8 -oxo- l,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (50 mg, 0.071 mmol, crude). LCMS: m/z 705 [M + H] ⁺ .

[00313] Step N: To a solution of 7V-(3-bromo-6-(2-chloro-5-fluorophenyl)-7-(4- methoxybenzyl)-8-oxo-l,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 prep- TLC (EA: PE=2: 1, Rf=0.5) to afford a crude, which was purified by prep-HPLC (YMC -Actus Triart C18 150*20mm*5um, 50%-95%, phase A :H2O(0.1%FA), phase B :MeCN ) to afford N- (3-bromo-6-(2-chloro-5-fluorophenyl)-8-oxo-l,6,7,8-tetrahydr opyrrolo[3,4-g]indazol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (16 mg, 0.027 mmol, 38%). LCMS: m/z 585 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 8 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).

Example 9 N-(6-(2-chloro-5-fluorophenyl)-3-cyano-l-methyl-8-oxo-l, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

127

SUBSTITUTE SHEET (RULE 26)

[00314] Step A: A solution of (7-bromo-3-iodo-5-nitro-lH-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1.0 g, 1.9 mmol, 1.0 eq) and Ag2COs (1.05 g, 3.8 mmol, 2.0 eq) in DMF (20 mL) was added CH3I (406.1 mg, 2.9 mmol, 1.5 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was added water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over Na2SC>4 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-l-methyl-5-nitro-lH-indazol-6-yl)(2-chloro-5 - fluorophenyl)methanone (400 mg, 39%). LCMS: m/z 537.8, 539.7 ([M+H] ⁺ ). ^ NMR (400 MHz, DMSO-d6): 5 8.42 (s, 1H), 7.75-7.70 (m, 2H), 7.61-7.56 (m, 1H), 4.41 (s, 1H).

[00315] Step B: To a solution of (7-bromo-3-iodo-l-methyl-5-nitro-lH-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (300 mg, 0.56 mmol, 1.0 eq) and Fe (156.2 mg, 2.8 mmol, 5.0 eq) in EtOH (10 mL) was added NH4CI (15.0 mg, 0.28 mmol, 0.5 eq) in H2O (1 mL) dropwise at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Then the mixture was added water (10 mL) and ethyl acetate (5 mL), filtered, then the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SC>4 and concentrated to give (5-amino-7-bromo-3-iodo-l-methyl-lH-indazol-6-yl)(2-chloro-5 - fluorophenyl)methanone (220 mg, 77%) as a red oil. LCMS: m/z 507.8, 509.9 ([M+H] ⁺ ).

[00316] Step C: A sealed vial was charged with (5-amino-7-bromo-3-iodo-l-methyl-lH- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (50 mg, 0.1 mmol, 1.0 eq), Zn(CN)2 (34.5 mg,

128

SUBSTITUTE SHEET (RULE 26) 0.3 mmol, 3.0 eq), Pd(PPh3)4 (56.6 mg, 0.05 mmol, 0.5 eq) and DMAC (1 mL). The sealed vial was irradiated in the microwave at 160 °C for 0.5 h. The mixture was added water (3 mL) and extracted with EtOAc (3 mL x 2). The combined organic phases were washed with brine (5 mL x 2), dried over Na2SO4 and concentrated to give a residue. The residue was purified by Pre-TLC (eluted with petroleum ether/ EtOAc = 2: 1) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)-l- methyl-lH-indazole-3,7-dicarbonitrile (6.8 mg, 19%) as a yellow oil. LCMS: m/z 354.0 ([M+H] ⁺ ).

[00317] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-l -methyl- 1H- indazole-3,7-dicarbonitrile (30.0 mg, 0.09 mmol, 1.0 eq) in MeCN (2 mL) / ELO (0.2 mL) was added KOH (9.5 mg, 0.18 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 40 °C for 4 h. The mixture was added water (3 mL) and extracted with EtOAc (3 mL x 2). The combined organic phases were washed with brine (3 mL x 2), dried over Na2SO4 and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-8-oxo -l, 6,7,8- tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (35 mg, crude) as a yellow oil. LCMS: m/z 370.0 ([M-H]-).

[00318] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-8- oxo-l,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (35 mg, 0.1 mmol, 1.0 eq) in ACN (2 mL) were added 3 -fluoro-5 -(trifluoromethyl) benzoyl chloride (44.4 mg, 0.2 mmol, 2.0 eq) and Pyridine (23.3 mg, 0.3 mmol, 3.0 eq). The reaction mixture was stirred at 50 °C for 2 h. Then the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL x 2). The combined organic phases were washed with brine (3 mL) and aqueous solution ISfeCCh (5 mL), dried over Na2SC>4 and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy- l-methyl-8-oxo-l,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]").

[00319] Step F: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-l- methyl-8-oxo-l,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3 -fluoro-5- (trifluoromethyl)benzamide (70 mg, 0.12 mmol, 1.0 eq) in TFA (3 mL) was added EtaSiH (69.8 mg, 0.6 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(6-(2-chloro-5-fluorophenyl)-3-cyano-l-methyl- 8-oxo-l,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro -5-(trifluoromethyl)benzamide (10.3

129

SUBSTITUTE SHEET (RULE 26) mg, three steps yield 21%). LCMS: m/z 544.0 ([M-H]"). 'H NMR (400 MHz, DMSO-d6): 5

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).

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

130

SUBSTITUTE SHEET (RULE 26) [00320] Step A: To a stirred mixture of methyl 2-amino-5-nitrobenzoate (5 g, 25.5 mmol) in HO Ac (50 mL) was added Bn (1.57 mL, 30.6 mmol) at room temperature. The resulting mixture was stirred for 4 h at room temperature. The reaction was quenched by the addition of ice water (100 mL) at room temperature. The precipitated solids were 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] ⁺ .

[00321] Step B: To a stirred mixture of methyl 2-amino-3-bromo-5-nitrobenzoate (4 g, 14.5 mmol) and 2-methylpropan-2-yl prop-2-enoate (2.53 mL, 17.5 mmol) in DMA (2 mL) was added Pd(PPhs)4 (3.36 g, 2.91 mmol) and TEA (6.06 mL, 43.6 mmol) at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The cooled mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (1: 1) to afford 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] ⁺ .

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 con.HCl (5.17 mL, 62.1 mmol, 12M) at room temperature. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. This resulted in 6-nitro-2-oxo-lH- quinoline-8-carboxylic acid (1 g, 4.27 mmol, 69%) as a yellow solid. LCMS: m/z 235 [M + H] ⁺ .

[00322] Step D: To a stirred mixture of 6-nitro-2-oxo-lH-quinoline-8-carboxylic acid (500 mg, 2.14 mmol) and 2-chloro-5-fluorobenzene-l-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, eluted with PE: EtOAc (2: 1) to afford N-[l-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl) amino]-2-oxoethyl]-N-[(4- methoxyphenyl) methyl]-6-nitro-2-oxo-lH-quinoline-8-carboxamide (700 mg, 1.18 mmol, 55%) as a yellow solid. LCMS: m/z 595 [M + H] ⁺ .

[00323] Step E: To a stirred mixture of N-[l-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2- yl) amino]-2-oxoethyl]-N-[(4-methoxyphenyl) methyl]-6-nitro-2-oxo-lH-quinoline-8-

131

SUBSTITUTE SHEET (RULE 26) carboxamide (700 mg, 1.18 mmol) in DMSO-d6 (5 mL) was added potassium 2-methylpropan- 2-olate (0.145 mL, 1.18 mmol) in portions 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, eluted with PE: EtOAc (1 : 1) to afford 7-(2-chloro-5-fluorophenyl)- 7-hydroxy-8-[(4-methoxyphenyl) methyl]-6-nitro-2,7,8,9-tetrahydro-lH-pyrrolo[4,3-h] quinoline-2, 9-dione (50 mg, 0.098 mmol, 8%) as a yellow solid. LCMS: m/z 510 [M + H] ⁺ . [00324] 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-lH-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 FLO (1 mL) was added NH4CI (105 mg, 1.96 mmol) at room temperature. The resulting mixture was stirred for 2 h at 75 °C. The cooled reaction mixtyre was quenched by the addition of water (10 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc: PE (1: 1) to afford 6-amino-7-(2-chloro-5-fluorophenyl)-7- hydroxy-8-[(4-methoxyphenyl) methyl]-2,7,8,9-tetrahydro-lH-pyrrolo[4,3-h] quinoline-2, 9- dione (60 mg, 0.125 mmol, 64%) as a yellow solid. LCMS: m/z 480 [M + H] ⁺ .

[00325] 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-lH-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 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EtOAc (1 : 1) to afford N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl ) methyl]-2,9- dioxo-l,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] ⁺ .

[00326] Step H: To a stirred mixture of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4- methoxyphenyl) methyl]-2,9-dioxo-l,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

132

SUBSTITUTE SHEET (RULE 26) h. The resulting mixture was concentrated under reduced pressure. This resulted in N-[7-(2- chloro-5-fluorophenyl)-8-[(4-methoxyphenyl) methyl]-2,9-dioxo-l,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] ⁺ .

[00327] Step I: To a stirred mixture of N-[7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl) methyl]-2,9-dioxo-l,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 min. The cooled resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ANC in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-[7-(2-chloro-5-fluorophenyl)-2,9-dioxo-l,7,8,9-tetrahydrop yrrolo[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) 8 10.52 (s,lH), 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).

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

133

SUBSTITUTE SHEET (RULE 26)

[00328] Step A: To a solution of 7-bromo-4-chloro-l-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-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 rt. 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 100 mL EA. The combined organic layers were washed with brine, dried overNa2SC>4 and concentrated. The residue was purified by silica gel chromatography eluted with PE: EtOAc=5: 1 to give 7-bromo-l-(2-chloro-5-fluorophenyl)-4-((3,4-dimethylbenzyl)a mino)-2-(4- m ethoxybenzyl)- l,2-dihydro-3H-pyrrolo[3,4-c]pyri din-3 -one (1 g, 1.68 mmol, 83%) as a green oil. LCMS: m/z 596 [M + H] ⁺ .

[00329] Step B: A solution of 7-bromo-l-(2-chloro-5-fluorophenyl)-4-((3,4- dimethylbenzyl)amino)-2-(4-methoxybenzyl)-l,2-dihydro-3H-pyr rolo[3,4-c]pyri din-3 -one (780 mg, 1.31 mmol) in TFA (7 mL) was stirred at rt for 1 hour. The reaction mixture was concentrated. The residue was purified by silica gel chromatography eluted with PE: EA=4: 1 to give 4-amino-7-bromo-l-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphe nyl)methyl]-2,3-dihydro- lH-pyrrolo[4,3-c]pyridin-3-one (480 mg, 1.01 mmol, 77%) as a white solid. LCMS: m/z 478 [M + H] ⁺ .

[00330] Step C: A mixture of 4-amino-7-bromo-l-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-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 20 mL EA. The combined organic layers was washed with brine, dried over Na2SC>4 and concentrated. The crude product was purified by silica gel chromatography eluted with DCM: MeOH=10: 1 to give 6-bromo-7-(2- chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)methyl]-8,9-dihyd ro-7H-pyrrolo[4,3-

134

5UB5TITUTE SHEET (RULE 26) c]imidazo[3,2-a]pyridin-9-one (430 mg, 0.859 mmol, 85%) as a brown solid. LCMS: m/z 502 [M + H] ⁺ .

[00331] 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 CS2CO3 (839 mg, 2.58 mmol), Pd2(dba)s (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 N2 for 4 h. The cooled mixture was poured into 40 mL of water and extracted with 40 mL EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted 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)be nzamide (230 mg, 0.358 mmol, 42%) as a yellow oil. LCMS: m/z 627 [M + H] ⁺ .

[00332] 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]imi dazo[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 rt. 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 purification 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-fluor o-5-(trifluoromethyl)benzamide (31.6 mg, 0.062 mmol, 26%). LCMS: m/z 507.0 [M + H] ⁺ . ^X H NMR (400 MHz, Methanol-d4) 5 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, 1 = 8.4, 5.1 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H).

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

135

SUBSTITUTE SHEET (RULE 26)

[00333] Step A: To a solution of PBn (19.5 mL, 207 mmol) in CHCL (85 mL) was added

DMT (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-l,2,3,4-tetrahydronaphthalen-l-one (15 g, 83.0 mmol) in CHCL (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, extracted with EA (500 mL x 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 afford l-bromo-6-chl oro-3, 4-dihydronaphthalene-2- carbaldehyde (10 g, 37.04 mmol, 45%) as a yellow solid, and was used directly for the next step. [00334] Step B: To a solution of l-bromo-6-chl oro-3, 4-dihydronaphthalene-2-carbaldehy de (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 hr. The mixture was cooled and filtered through celite and washed with DCM. The filtrate was concentrated and purified by flash column chromatography on silica gel (0-30% EtOAc in hexane) to provide intermediate l-bromo-6-chloro-2- naphthaldehyde (5.0 g, 18.7 mmol, 51%) as a white solid, and was used directly for the next step.

136

SUBSTITUTE SHEET (RULE 26) [00335] Step C: To a solution of l-bromo-6-chloronaphthalene-2-carbaldehyde (1.2 g, 4.45 mmol) in DCE (12 mL) were added azido(4-methylphenyl)dioxo-X ⁶ -sulfane (1.95 mL, 8.905 mmol), bis[iridium(3+)] bis(l,2,3,4,5-pentamethylcyclopenta-2,4-dien-l-ide) tetrachloride (0.18 g, 0.223 mmol), 3,5-bis(trifhioromethyl)aniline (0.139 mL, 0.890 mmol) and silver bis[dioxo(trifluoromethyl)-X6-sulfanyl]azanide (0.35 g, 0.890 mmol). The reaction was stirred at 100 °C for 18 hr. 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 MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-25%) 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] ⁺ . [00336] Step D: To a solution of N-(4-bromo-7-chloro-3-formyl-2-naphthyl)-4- m ethylbenzenesulfonamide (1.10 g, 2.51 mmol) in THF (10 mL) were added slowly bromo(2- chloro-5-fluorophenyl)magnesium (2.50 mL, 2.507 mmol, 1 M in THF). The reaction was stirred at 0 °C for 1.5hr. The reaction was quenched with ice-water then extracted with EA. The combined extracts were washed by brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography eluted with PE in EA (gradient: 0-50%) to give N-(4- bromo-7-chloro-3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)n aphthalen-2-yl)-4- methylbenzenesulfonamide (800 mg, 1.40 mmol, 56%) as a yellow solid. LCMS: m/z 568.0 [M+H] ⁺ .

[00337] Step E: To a solution of N-(4-bromo-7-chloro-3-((2-chloro-5- fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzen esulfonamide (700 mg, 1.23 mmol) in DCM (6 mL) were added Dess-Martin (1.56 g, 3.69 mmol). The reaction was stirred at room temperature for 18 hr. The reaction was quenched with H2O then extracted with EA. The combined extracts were washed by brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EA in PE (gradient: 0-50%) to give N-{4- bromo-7-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-2-napht hyl}-4- methylbenzenesulfonamide (400 mg, 0.705 mmol, 57%) as a yellow solid. LCMS: m/z 566 [M+H] ⁺ .

[00338] Step F: To a solution of N-{4-bromo-7-chloro-3-[(2-chloro-5- fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamid e (400 mg, 0.705

137

SUBSTITUTE SHEET (RULE 26) mmol) in NMP (4 mL) were added CuCN (84 mg, 1.41 mmol). The reaction was stirred at 150 °C for 18 hr. The cooled reaction was quenched with ice-water then extracted with EA. The combined extracts were washed by brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with PE in EA (gradient: 0-75%) 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] ⁺ .

[00339] 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 H2O (0.5 mL) and acetonitrile (2.50 mL) were added potassium hydroxide (5.46 mg, 0.097 mmol). The reaction was stirred at room temperature for 3 hr. The reaction was quenched with ice-water then extracted with EA. The combined extracts were washed by brine, dried over NaiSCU and concentrated. The residue was purified by silica gel chromatography eluted with PE in EA (gradient: 0-75%) to give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo-2,3- dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (150 mg, 0.282 mmol, 58%) as yellow solid. LCMS: m/z 528.9 [M-H]".

[00340] Step H: To a solution of N-[7-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo- 2,3-dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulfona mide (100 mg, 0.19 mmol) in TFA (3 mL) were added triethylsilane (0.5 mL). The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 30-100%) give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH - benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (80 mg, 0.155 mmol, 83%) as a yellow solid. LCMS: m/z 417.1 [M+H] ⁺

[00341] Step I: To a solution of N-[7-chloro-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro- lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (80 mg, 0.155 mmol) in H2O (0.50 mL) was added H2SO4 (2 mL) at 0 °C. The reaction mixture was stirred at 40 °C for 2 hr. The reaction mixture was poured into saturated NaHCOg solution until the PH = 8 and extracted with EtOAc (15 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-50%)

138

SUBSTITUTE SHEET (RULE 26) give 4-amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-lH- benzo[e]isoindol-l-one (40 mg, 0.11 mmol, 71%) as a yellow solid. LCMS: m/z 361.0 [M+H] ⁺

[00342] Step J: To a solution of 4-amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro- lH-benzo[e]isoindol-l-one (30 mg, 0.083 mmol) in pyridine (2 mL) were 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 hr. The reaction was concentrated and the residue was purified by prep-HPLC to afford N-[7-chl oro-3 -(2-chloro- 5-fluorophenyl)-l-oxo-2,3-dihydro-lH-benzo[e]isoindol-4-yl]- 5-fluoro-3-

(trifhioromethyl)benzamide (2.1 mg, 0.004 mmol, 5%). LCMS: m/z 551.0 [M+H] ⁺ . 5 9.20 (d, J- 92 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).

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-(trifluorom ethyl)benzamide

139

SUBSTITUTE SHEET (RULE 26) [00343] Step A: A solution of (7-bromo-3-iodo-5-nitro-lH-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1.0 g, 1.9 mmol, 1.0 eq) and Ag2COs (1.05 g, 3.8 mmol, 2.0 eq) in DMF (20 mL) was added CH3I (406.1 mg, 2.9 mmol, 1.5 eq) 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 x 2). The combined organic phases were washed with brine (20 mL x 2), dried over NazSCf 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. ^! H NMR (400 MHz, DMSO-d6): 5 8.56 (s, 1H), 7.80-.50 (m, 3H), 4.32 (s, 3H). LCMS: m/z 537.9, 539.8 ([M+H] ⁺ ). [00344] 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 eq) and Fe (259 mg, 4.47 mmol, 5.0 eq) in EtOH (5 mL) was added NH4CI (25.0 mg, 0.47 mmol, 0.5 eq) in H2O (2.5 mL) dropwise at 50 °C. The reaction mixture was heated to 90 °C and stirred for 2 h. Then the mixture was filtered, then the filtrate was concentrated, and purified by column to give (5-amino-7-bromo-3- iodo-2-methyl-2H-indazol-6-yl)(2-chloro-5-fluorophenyl)metha none (400 mg, 50 %) as a red solid. LCMS: m/z 507.8, 509.9 ([M+H] ⁺ ).

[00345] 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 eq), Zn(CN)2 (104 mg, 0.885 mmol, 3.0 eq), Pd(PPli3)4 (171mg, 0.148mmol, 0.5 eq) and DMAc (4 mL). The sealed vial was irradiated in the microwave at 160 °C for 0.5 h. The mixture was diluted with water (~5 mL) and extracted with EtOAc (~5 mL x 2). The combined organic phases were washed with brine (~5 mL x 2), dried over NaiSCU and concentrated to give a residue. The residue was purified by column (eluted with petroleum ether/EtOAc) to give 5-amino-6-(2- chloro-5-fluorobenzoyl)-2-methyl-2H-indazole-3,7-dicarbonitr ile (60 mg, 57%) as a yellow oil. LCMS: m/z 354.1 ([M+H] ⁺ ).

[00346] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-methyl-2H- indazole-3,7-dicarbonitrile (lOOmg, 0.28 mmol, 1.0 eq) in MeCN (5 mL) / H2O (0.5 mL) was added KOH (5 mg, 0.085 mmol, 0.3 eq) 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 x 2). The combined organic phases were washed with brine (5 mL x 2), dried over Na2$O4 and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo -2, 6,7,8-

140

SUBSTITUTE SHEET (RULE 26) tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (100 mg, crude) as a yellow oil. LCMS: m/z 369.8 ([M-H]").

[00347] 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 (lOOmg, 0.269mmol, 1.0 eq) in ACN (2 mL) was added 3 -fluoro-5 -(trifluoromethyl) benzoyl chloride (183mg, 0.807mmol, 3.0 eq) and Pyridine (106mg, 1.345mmol, 5.0 eq). The reaction mixture was stirred at 50 °C for overnight. Then the mixture was diluted with water (~5 mL) and extracted with ethyl acetate (~3 mL x 2). The combined organic phases were washed with brine (5 mL) and aqueous solution NaiCCh (5 mL), dried over NaiSCU 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]").

[00348] Step F: To a solution ofN-(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, ~ 0.214 mmol, 1.0 eq) in TFA (2 mL) was added EpSiH (124 mg, 1.07 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(6-(2-chloro-5-fluorophenyl)-3- cyano-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol -5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (30 mg, three steps yield ~ 19%). LCMS: m/z 544.0 ([M-H]"). ^J H NMR (400 MHz, DMSO-d6): 5 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).

Example 14 N-(6-(2-chloro-5-fluorophenyl)-l-methyl-8-oxo-l, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

141

SUBSTITUTE SHEET (RULE 26)

[00349] Step A: To a solution of (5-amino-7-bromo-3-iodo-l-methyl-lH-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (100 mg, 0.2 mmol, 1.0 eq) in MeOH (2.5 mL) was added PtCh (25 mg). The reaction mixture was stirred under the atmosphere of hydrogen at 40 °C for 12 h. HPLC showed the completion of the reaction. The mixture was filtered and the filtrate was concentrated to give (5-amino-7-bromo-l-methyl-lH-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (65 mg, 85%) as yellow oil. LCMS: m/z 382.0, 384.0 ([M+H] ⁺ ).

[00350] Step B: A sealed vial was charged with (5-amino-7-bromo-l-methyl-lH-indazol-6- yl)(2-chloro-5-fluorophenyl)methanone (100 mg, 0.26 mmol, 1.0 eq), Zn(CN)2 (45.8 mg, 0.39 mmol, 1.5 eq), Pd(PPhs)4 (92.4 mg, 0.08 mmol, 0.3 eq) and DMAc (1.5 mL). The sealed vial was irradiated in the microwave at 160 °C for 0.5 h. The mixture was added water (3 mL) and extracted with EtOAc (3 mL x 2). The combined organic phases were washed with brine (5 mL x 2), dried over Na2SOi and concentrated to give a residue. The residue was purified by Pre-TLC (Petroleum ether / EtOAc = 2: 1) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)-l-methyl-lH- indazole-7-carbonitrile (38 mg, 44%) as a yellow oil. LCMS: m/z 329.1 ([M+H] ⁺ ).

[00351] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-l -methyl- 1H- indazole-7-carbonitrile (120 mg, 0.37 mmol, 1.0 eq) in MeCN (5 mL) / H2O (0.5 mL) was added KOH (41.5 mg, 0.74 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 25 °C for 4 h. The mixture was added water (5 mL) and extracted with EtOAc (3 mL x 2). The combined organic phases were washed with brine (5 mL), dried over Na2SO4 and concentrated to

142

SUBSTITUTE SHEET (RULE 26) give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-6,7-d ihydropyrrolo[3,4- g]indazol-8(lH)-one (100 mg, 78%) as a yellow oil. LCMS: m/z 345.0 ([M-H]").

[00352] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl- 6,7-dihydropyrrolo[3,4-g]indazol-8(lH)-one (100 mg, 0.29 mmol, 1.0 eq) in ACN (5 mL) were added 3 -fluoro-5 -(trifluoromethyl) benzoyl chloride (131.4 mg, 0.58 mmol, 2.0 eq) and Pyridine (68.8 mg, 0.87 mmol, 3.0 eq). The reaction mixture was stirred at 50 °C for 2 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine (10 mL) and aqueous solution Na2COs (10 mL), dried over Na2SO4 and concentrated to give N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-8- oxo-l,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]").

[00353] Step E: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-8-oxo- l,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (170 mg, 0.29 mmol, 1.0 eq) in TFA (5 mL) was added EpSiH (168.6 mg, 1.45 mmol, 5.0 eq). The reaction mixture was stirred at 50 °C for 2 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water 50% to 64%) to give N-(6-(2-chloro-5-fluorophenyl)-l-methyl-8-oxo-l,6,7,8-tetrah ydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (7.0 mg, 5% yield for two steps) as a white solid. LCMS: m/z 519.0 ([M-H]"). ¹ H NMR (400 MHz, DMSO-d6): d 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).

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

143

SUBSTITUTE SHEET (RULE 26)

[00354] 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 rt. The resulting mixture was stirred for 2h, 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-carboxa mide (2.8 g, 7.87 mmol, 93%) as a yellow solid. LCMS: m/z 357 [M+2+H] .

[00355] 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

144

SUBSTITUTE SHEET (RULE 26) mineral oil). The reaction mixture was stirred at rt for 30min, then 2-chloro-5-fluorobenzoyl chloride (1.65 g, 8.54 mmol) was added. The mixture was stirred at rt for 16h, and then diluted with EA and water. The organic layer was separated and concentrated. The residue was purified by silica gel column chromatography eluted with ethylacetate/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 light yellow solid. LCMS: m/z 513 [M+2+H] ⁺ .

[00356] 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 THE (220 mL) was added LiHMDS (IM, 64 mL) at -68 °C. The reaction mixture was stirred at -68 °C for additional 1 h. The mixture was quenched by 100 mL of saturated NH4CI solution and extracted with 200 mL x 3 of ethyl acetate. The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography eluted with EA/PE (v/v = 1/2) to give 7-bromo-4- chloro- 1 - (2 -chi oro-5 -fluorophenyl)- 1 -hy droxy-2- [(4-methoxyphenyl)m ethyl] -2, 3 -dihydro- 1 H- pyrrolo[4,3-c]pyridin-3-one (10 g, 19.5 mmol, 45.5%) as a light yellow solid. LCMS: m/z 513 [M+2+H] ⁺ .

[00357] Step D: To a solution of 7-bromo-4-chloro-l-(2-chloro-5-fluorophenyl)-l-hydroxy-2- [(4-methoxyphenyl)methyl]-2,3-dihydro-lH-pyrrolo[4,3-c]pyrid in-3-one (10 g, 19.5 mmol) in TEA (100 mL) was added tri ethyl silane (10 mL, 62.6 mmol). The reaction mixture was stirred at 70 °C for 3 h, then concentrated under vacuum. The mixture was diluted with EA and H2O, then adjust pH=8 with saturated NaHCOs solution. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluted with EAZPE (v/v = 1/2) to give 7-bromo-4-chloro-l-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-pyrrolo[4,3-c]pyridin-3 -one (9 g, 18.1 mmol, 93%) as a white solid. LCMS: m/z 497 [M+2+H] ⁺ .

[00358] Step E: To a stirred mixture of 5-fluoro-3-(trifluoromethyl)benzene-l-carboxamide (208 mg, 1.01 mmol) in toluene (10 mL) was added 7-bromo-4-chloro-l-(2-chloro-5- fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-pyr rolo[4,3-c]pyridin-3-one (500 mg, 1.01 mmol), Pd2(dba)3 (46.1 mg, 50 pmol), xantphos (58.3 mg, 0.101 mmol) and /-BuONa (145 mg, 1.51 mmol). The reaction mixture was stirred at 100 °C under N2 for 16h. The cooled reaction mixture was evaporated to dryness. The residue was purified by column

145

SUBSTITUTE SHEET (RULE 26) chromatography on silica gel (eluted with EA/PE = 0-30%) to afford N-[4-chloro-l-(2-chloro-5- fluorophenyl)-l-hydroxy-2-[(4-methoxyphenyl)methyl]-3-oxo-2, 3-dihydro-lH-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] ⁺ .

[00359] Step F: To a solution ofN-[4-chloro-l-(2-chloro-5-fluorophenyl)-l-hydroxy-2-[(4- methoxyphenyl)methyl]-3-oxo-2,3-dihydro-lH-pyrrolo[4,3-c]pyr idin-7-yl]-3-fluoro-5- (trifluoromethyl)benzamide (300 mg, 0.470 mmol) in TFA (3 mL) was added EtaSiH (0.76 mL, 4.70 mmol). The reaction mixture was stirred at 70 °C for 3 h, and then concentrated under vacuum. The residue was diluted with EA and FEO, then adjusted pH=8 with saturated NaHCOa solution. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluted with EA/PE (v/v = 1/1) to give N-[4-chloro- l-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-3-ox o-2,3-dihydro-lH-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] ⁺ .

[00360] Step G: A mixture ofN-[4-chloro-l-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-3-oxo-2,3-dihydro-lH-pyrrolo[4,3-c]pyr idin-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(PPha)2C12 (29.3 mg, 420 pmol), Na2COa (55.4 mg, 0.522 mmol), EtOH (3 mL) and H2O (0.3 mL) was stirred at 80 °C under N2 for 16h under nitrogen. The cooled mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with ethyl acetate/petroleum ether (1/1) to afford compound 2-methylpropan-2-yl ({[l-(2-chloro-5- fluorophenyl)-7-( { [3 -fluoro-5 -(trifluoromethyl)phenyl] carbonyl } amino)-2- [(4- methoxyphenyl)methyl]-3-oxo-2,3-dihydro-lH-pyrrolo[4,3-c]pyr idin-4- yl]methyl}amino)methanoate (40 mg, 56 pmol, 27%) as a brown solid. LCMS: m/z 733 [M+H] ⁺ . [00361] Step H: A solution of 2-methylpropan-2-yl ({[l-(2-chloro-5-fhiorophenyl)-7-({[3- fluoro-5-(trifluoromethyl)phenyl]carbonyl]amino)-2-[(4-metho xyphenyl)methyl]-3-oxo-2,3- dihydro-lH-pyrrolo[4,3-c]pyridin-4-yl]methyl}amino)methanoat e (15 mg, 21 pmol) in 4M HC1 in dioxane (2 mL) was stirred at rt for 2h. The mixture was concentrated to afforded N-[4- (aminomethyl)- 1 -(2-chl oro-5 -fluorophenyl)-2- [(4-methoxyphenyl)methyl] -3 -oxo-2, 3 -dihydro-

146

SUBSTITUTE SHEET (RULE 26) lH-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)b enzamide (13 mg, 21 pmol, 100%) as a brown solid. LCMS: m/z 633 [M+H] ⁺ .

[00362] Step I: A solution of acetic anhydride (0.65 mL) and FA (0.25 mL) was stirred at 60 °C for Ih, then N-[4-(aminomethyl)-l-(2-chloro-5-fluorophenyl)-l-hydroxy-2-[ (4- methoxyphenyl)methyl]-3-oxo-2,3-dihydro-lH-pyrrolo[4,3-c]pyr idin-7-yl]-3-fluoro-5- (trifluoromethyl)benzamide (28 mg, 44 pmol) in FA (0.25 mL) was stirred at 60 °C for 2h. After cooled to room temperature, the solvent was concentrated to dryness. The residue was diluted with EA and H2O, then adjust pH=8 with saturated NaHCOs solution. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluted 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-pyr rolo[4,3-c]imidazo[3,4- a]pyridin-6-yl]-3-fluoro-5-(trifluoromethyl)benzamide (25 mg, 39 pmol, 88%) as a brown solid. LCMS: m/z 643 [M+H] ⁺ .

[00363] Step J: To a solution ofN-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4- methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imi dazo[l,5-a]pyridin-6-yl]-5- fluoro-3-(trifluoromethyl)benzamide (25 mg, 39 pmol) in TFA (1 mL) was added EtgSiH (0.2 mL, 1.24 mmol) and CF3SO2OH (0.2 mL). The reaction mixture was stirred at 90 °C for lOmin. The cooled reaction mixture was concentrated and the crude was prep-HPLC to afforded N-[7- (2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c ]imidazo[l,5-a]pyridin-6-yl]-5- fluoro-3-(trifluoromethyl)benzamide (11 mg, 22 pmol, 56%). LCMS: m/z 507 [M+H] ⁺ . 'H NMR (400 MHz, Methanol-d4) 5 8.69 (s, IH), 8.60 (s, IH), 7.94 (s, IH), 7.75 - 7.62 (m, 3H), 7.28 (s, IH), 7.04 (d, J= 62 Hz, IH), 6.70 (s, IH), 6.29 (s, IH).

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

147

SUBSTITUTE SHEET (RULE 26)

[00364] Step A: To a solution of 2-bromo-4-fluorobenzene-l-carbaldehyde (20 g, 98.5 mmol) in MeOH (120 mL) was added 2-amino-l,l -diethoxy ethane (15.7 mL, 108 mmol). The reaction was stirred at room temperature for 2 hr. Sodium cyanoboranuide (12.4 g, 197 mmol) was added and the following mixture was stirred at room temperature overnight. The reaction was quenched with water and concentrated in vacuo. The residue was diluted water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford 1,1 -di ethoxy-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] ⁺ .

[00365] Step B: To l,l-diethoxy-2-{[(Z)-(2-bromo-4- fluorophenyl)methylidene]amino}ethane (17.5 g, 55.0 mmol) was added slowly chloranesulfonic acid (36.6 g, 314 mmol) at -10 °C. The reaction was stirred at 90 °C for 1 hr. The cooled reaction

148

5UB5TITUTE SHEET (RULE 26) mixture was poured into ice-water. The following mixture was adjusted to pH value 8-9 with aq.1 N NaOH solution, extracted with DCM. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford 8-bromo-6- fluoroisoquinoline (4.1 g, 18.1 mmol, 33%) as a yellow solid. LCMS: m/z 226.05 [M+H] ⁺ .

[00366] 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 N2. The reaction mixture was stirred at -78 °C for 1 h. 2-chloro-5-fluorobenzene-l-carbaldehyde (2.95 g, 18.6 mmol) was added and the reaction was stirred at -78 °C for additional 1 hr. The reaction was quenched with saturated NH4CI solution. The following mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0- 30%) to afford (8-bromo-6-fluoroisoquinolin-7-yl)(2-chloro-5-fluorophenyl)m ethanol (3.2 g, 8.320 mmol, 90%) as a yellow solid. LCMS: m/z 384.60 [M+H] ⁺ .

[00367] 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 l,l,l-triacetoxy-l,3- dihydro-lX5-benzo[d][l,2]iodoxol-3-one (2.43 mL, 7.80 mmol). 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 eluted with ethyl acetate in petroleum ether (gradient: 0- 30%) to afford 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] ⁺ . [00368] 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 for 2 hr using a sealed tube under N2. The cooled reaction mixture was diluted with water. The following mixture was extracted with EA. The organic layer was washed with brine, dried over ISfeSCL and concentrated. The residue was purified using silica gel column chromatography eluted 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] ⁺ .

149

SUBSTITUTE SHEET (RULE 26) [00369] Step F: To a solution of 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoroisoquinoline- 8-carbonitrile (270 mg, 0.821 mmol) in DMSO-d6 (5 mL) were 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 Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-50%) to afford 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] ⁺ .

[00370] 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 H2O (0.5 mL) was added KOH (49.5 mg, 0.883 mmol). The reaction was stirred at room temperature for 1 hr. The reaction was diluted with water and EA The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-80%) to afford 3-(2-chloro-5-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-hydroxy-2,3-dihydro-lH-pyrro lo[4,3-h]isoquinolin-l-one (130 mg, 0.263 mmol, 60%) as a white solid. LCMS: m/z ESI 493.92 [M+H] ⁺ .

[00371] Step H: To a solution of 3-(2-chloro-5-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-hydroxy-2,3-dihydro-lH-pyrro lo[4,3-h]isoquinolin-l-one (120 mg, 0.243 mmol) in TEA (3 mL) was added triethylsilane (0.5 mL) at it The reaction was stirred at 50 °C for 1 hr. 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 eluted with ethyl acetate in petroleum ether (gradient: 0- 12%) to afford 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-lH-pyrrolo[4 ,3-h]isoquinolin- l-one (79 mg, 0.241 mmol, 99%) as a white solid. LCMS: m/z 327.74 [M+H] ⁺ .

[00372] Step I: To a solution of 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-lH- pyrrolo[4,3-h]isoquinolin-l-one (20 mg, 0.061 mmol) in Py (2 mL) at 0 °C were added 5-fluoro- 3-(trifhioromethyl)benzoic acid (12.7 mg, 0.061 mmol) and POCL (0.012 mL, 0.130 mmol). The reaction was stirred at room temperature for 1 hr. The reaction was diluted with water and DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated to

150

SUBSTITUTE SHEET (RULE 26) afford N-[3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-pyrrolo[ 4,3-h]isoquinolin-4-yl]-5- fluoro-N-{ [5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-(trifluorome thyl)benzamide (40 mg, 0.034 mmol, 56%) as a yellow solid. LCMS: m/z 707.94 [M+H] ⁺ .

[00373] Step J: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH- pyrrolo[4,3-h]isoquinolin-4-yl]-5-fluoro-N-{[5-fluoro-3-(tri fluoromethyl)phenyl]carbonyl}-3- (trifluoromethyl)benzamide (10 mg, 0.014 mmol) in THF (2 mL) and H2O (2 mL) was added KOH (0.014 mL, 0.028 mmol). The reaction mixture was stirred at rt for 1 h and then diluted with H2O. The following mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC and then by prep-HPLC (C18, 0~50 % acetonitrile in H2O with HCOOH) to afford N-[3-(2-chloro-5- fluorophenyl)-l-oxo-2,3-dihydro-lH-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] ⁺ . ^L H NMR (400 MHz, Methanol-d4) 5 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).

Example 17 N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-[l,2,4]t riazolo[l,5- a]pyrrolo[3,4-c]pyridin-6-yl]-5-fliioro-3-(trifliioromethyl) benzamide

151

SUBSTITUTE SHEET (RULE 26)

[00374] Step A: To a solution of 7-bromo-4-chloro-l-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-pyrrolo[4,3-c]pyridin-3 -one (3.5 g, 7.05 mmol) in dioxane (35 mL) were 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 hr. The cooled reaction mixture was diluted with EA (200 mL) and water (250 mL). The organic layer was separated, washed with further brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~50%) to afford compound 7-bromo-l-(2-chloro-5-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}-2-[(4-methoxyphenyl)methyl]-2, 3-dihydro-lH-pyrrolo[4,3- c]pyri din-3 -one (4.5 g, 7.18 mmol, 100%) as a white solid. LCMS: m/z 628.1 [M+H] ⁺ [00375] Step B: A solution of 7-bromo-l-(2-chloro-5-fluorophenyl)-4-[(2,4- dimethoxyphenyl)amino]-2-[(4-methoxyphenyl)methyl]-2,3-dihyd ro-lH-pyrrolo[4,3-c]pyridin- 3-one (4.5 g, 7.34 mmol) in TFA (50 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, diluted with EA and saturated NaHCCb solution. The organic layer was separated, washed with further brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~100%) dried to afford compound 4-amino-7-bromo-l-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-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] ⁺

[00376] Step C: To a solution of 4-amino-7-bromo-l-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-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 hr. 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 afford crude

152

SUBSTITUTE SHEET (RULE 26) compound 7-bromo-l-(2-chloro-5-fluorophenyl)-4-{[(E)-(dimethylamino)m ethylidene]amino}- 2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-pyrrolo[4,3-c]pyr idin-3-one (1.1 g, 2.07 mmol, 99%) as a yellow solid. LCMS: m/z 533.1 [M+2+H] ⁺

[00377] Step D: To a solution of 7-bromo-l-(2-chloro-5-fluorophenyl)-4-{[(E)- (dimethylamino)methylidene]amino}-2-[(4-methoxyphenyl)methyl ]-2,3-dihydro-lH- 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 hr. The cooled reaction mixture was diluted with DCM (100 mL) and water (100 mL). The organic layer was separated, washed with further brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in DCM (l%~50%) to afford compound 7- bromo-l-(2-chloro-5-fluorophenyl)-4-{[(E)-(hydroxyamino)meth ylidene]amino}-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-pyrrolo[4,3-c]pyridin-3 -one (LI g, 2.116 mmol, 94%) as a white solid. LCMS: m/z 521.0 [M+2+H] ⁺

[00378] Step E: To a solution of 7-bromo-l-(2-chloro-5-fluorophenyl)-4-{[(E)- (hydroxyamino)methylidene]amino}-2-[(4-methoxyphenyl)methyl] -2,3-dihydro-lH-pyrrolo[4,3- c]pyridin-3-one (350 mg, 0.673 mmol) in THE (5 mL) was added TFAA (0.103 mL, 0.741 mmol). The reaction was stirred at room temperature for 3 hr. The reaction was diluted with DCM and saturated NaHCCb solution. The organic layer was separated, washed with further brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with water and 0.1% HCOOH in ACN (l%~100%) to afford compound 6-bromo-7-(2-chloro-5-fluorophenyl)-8-[(4-methoxyphenyl)meth yl]-8,9-dihydro-7H- [l,2,4]triazolo[l,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] ⁺

[00379] Step F: To a stirred mixture of 6-bromo-7-(2-chloro-5-fluorophenyl)-8-[(4- methoxyphenyl)methyl]-8,9-dihydro-7H-[l,2,4]triazolo[l,5-a]p yrrolo[3,4-c]pyridin-9-one (50 mg, 0.100 mmol) in dioxane (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l- carboxamide (30.9 mg, 0.149 mmol), Xant-PHOS (11.53 mg, 0.020 mmol), CS2CO3 (97.41 mg, 0.299 mmol) and Pd2(dba)3 (18.25 mg, 0.020 mmol). The reaction mixture was stirred at 100 °C under N2 for 18 hr. The cooled reaction mixture was quenched by adding sat. aq. NH4CI solution, extracted with EA, 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-

153

SUBSTITUTE SHEET (RULE 26) chloro-5-fluorophenyl)-7-hydroxy-8-[(4-methoxyphenyl)methyl] -9-oxo-8,9-dihydro-7H- [l,2,4]triazolo[l,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 [M-H]".

[00380] Step G: To a solution ofN-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-8-[(4- methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-[l,2,4]triazolo[l ,5-a]pyrrolo[4,3-c]pyridin-6-yl]- 5-fluoro-3-(trifluoromethyl)benzamide (50 mg, 0.078 mmol) in TFA (5 mL) were 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 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in FLO) to afford compound N-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro-7H-[l,2,4]t riazolo[l,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] ^{+ J} H NMR (400 MHz, Methanol-d4) 5 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).

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

154

SUBSTITUTE SHEET (RULE 26)

[00381] Step A: To a solution of 3-bromo-2-fluorobenzoic acid (10 g, 45.6 mmol) in con.fTSCh (100 mL) was added dropwise con. HNO3 (3.16 g, 50.226 mmol) at 0 °C -

25 °C. The reaction mixture was stirred at 25 °C for 16h. TLC indicated the reaction was completed. The cooled reaction mixture was poured into ice water (300 ml) and then filtered. The filter cake was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0-100%) to give 3-bromo-2-fluoro-5-nitrobenzoic acid (9.78 g, 37.2 mmol, 81%) as a white solid.

[00382] 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 H2SO4 (2 mL) at 25 °C. The reaction mixture was stirred at 90 °C for 1.5h under N2. TLC indicated the reaction was completed. The cooled reaction mixture was concentrated. The residue was purified by a silica gel column chromatography eluted 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.

[00383] Step C: A suspension of methyl 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 3h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was poured into saturated aqueous NaHCCh (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) 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] ⁺

155

SUBSTITUTE SHEET (RULE 26) [00384] Step D: To a stirred mixture of methyl 5-amino-3-bromo-2-fluorobenzoate (2.5 g, 10.1 mmol) in H2O (20 mL) was added propane- 1,2, 3 -tri ol (2.75 g, 30.2 mmol) and sodium 3- nitrobenzenesulfonate (6.81 g, 30.2 mmol) in con.lTSCU (25 mL). The reaction mixture was stirred at 120 °C under air atmosphere for 5h. The cooled resulting mixture was used next step without other purified. LCMS: m/z 270.12 [M + H] ⁺

[00385] Step E: The solution of step D in MeOH (30 mL) was stirred at 85 °C for 2hr. The reaction mixture was poured into water (40 mL) and extracted with DCM (40 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) 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] ⁺

[00386] 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 LiOHLLO (622 mg, 14.8 mmol) in H2O (3 mL). The mixture was stirred at 25 °C for 3hr. The reaction mixture was poured into HC1 (20 mL, 0.2 mmol/mL) and extracted with DCM (20 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) 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] ⁺

[00387] Step G: To a solution of 7-bromo-6-fluoroquinoline-5-carboxylic acid (2.7 g, 9.998 mmol), 2-chloro-5-fluorobenzene-l-carbaldehyde (1.55 g, 9.79 mmol), PMBNH2 (1.34 g, 9.79 mmol) in MeOH (30 mL) was added LBuNC (0.81 g, 9.789 mmol). The mixture was stirred at 25 °C for 18hr. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 7-bromo-N-[l-(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] ⁺

[00388] Step H: To a solution of 7-bromo-N-[l-(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 CH3CN (50 mL) was added l,l-bis(dimethylamino)-N-(2-methylprop-2-yl) methanimine (4.07 g, 23.7 mmol). The mixture was stirred at 85 °C for 2hr. The reaction mixture

156

SUBSTITUTE SHEET (RULE 26) was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSCh, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 4-bromo-3-(2-chloro-5- fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl) methyl]-2,3-dihydro-lH-pyrrolo[4,3-f]quinolin- 1-one (2 g, 3.790 mmol, 48%) as a yellow oil. LCMS: m/z 527.12 [M + H] ⁺ [00389] Step I: To a solution of 4-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4- methoxybenzyl)-2,3-dihydro-lH-pyrrolo[3,4-f]quinolin-l-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 1.5hr. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous water (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 4-bromo-3-(2-chloro-5- fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-lH-pyrrolo[3,4 -f]quinolin-l-one (434 mg, 0.85 mmol, 85%) as a yellow oil. LCMS: m/z 511.12 [M + H] ⁺

[00390] Step J: To a stirred mixture of 4-bromo-3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-pyrrolo[4,3-f]quinolin- l-one (1 g, 1.954 mmol), 3- fluoro-5-(trifluoromethyl)benzene-l-carboxamide (0.53 g, 2.540 mmol), Xant-PHOS (0.11 g, 0.195 mmol), Pd2(dba)s (0.11 g, 0.195 mmol) in dioxane (20 mL) was added CS2CO3 (1.91 g, 5.86 mmol). The reaction mixture was stirred at 85 °C under N2 for 16hr. The reaction mixture was concentrated. The residue was poured into saturated aqueous water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSCU, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) to give N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-l -oxo-2,3- dihydro-lH-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluor omethyl)benzamide (0.8 g, 1.25 mmol, 64%) as a yellow oil. LCMS: m/z 654.12 [M + H] ⁺

[00391] Step K: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]- 1 -oxo-2, 3 -dihydro- 1 H-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 prep-HPLC to give N-[3-(2-chloro-5-fluorophenyl)-l-

157

SUBSTITUTE SHEET (RULE 26) oxo-2, 3-dihydro-lH-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(triflu oromethyl)benzamide (7 mg, 0.014 mmol, 43%). LCMS: m/z 518.12 [M + H] ⁺ . ^J H NMR (400 MHz, CDC1 ₃ ) 6 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),

151 (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).

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

158

SUBSTITUTE SHEET (RULE 26)

[00392] Step A: To a solution of phosphorus tribromide (10.4 mL, 111 mmol) in CHCE (230 mL) was added DMF (10.3 mL, 133 mmol) dropwise at 0 °C. The following mixture was stirred at this temperature for 2 h. A solution of 5-bromo-l,2,3,4-tetrahydronaphthalen-l-one (10 g, 44.3 mmol) in CHCI3 (230 mL) was added at 0 °C. The resulting mixture was stirred at 70 °C for 18 h. The solution was cooled and diluted with DCM, washed with sat. NaHCCL and brine, dried over Na2SC>4 and concentrated. The residue was purified by flash column chromatography on silica gel (0-30% EA in PE) to give l,5-dibromo-3,4-dihydronaphthalene-2-carbaldehyde (8.8 g, 27.5 mmol, 62%) as a yellow oil. Tf NMR (400 MHz, DMSO-d6) 5 10.13 (s, 1H), 7.89 (d, J =

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, <7= 9.0, 7.2 Hz, 2H).

[00393] Step B: To a stirred mixture of l,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 O2 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 l,5-dibromonaphthalene-2-carbaldehyde (4.7 g, 14.8 mmol, 71%) as a white solid. LCMS: m/z 315 [M + H] ⁺ .

[00394] Step C: To a stirred mixture of l,5-dibromonaphthalene-2-carbaldehyde (3.6 g, 11.5 mmol) in 1,2-di chloroethane (40 mL) was added tosyl azide (376 mg, 1.91 mmol), bis[iridium(3+)] bis(l,2,3,4,5-pentamethylcyclopenta-2,4-dien-l-ide) tetrachloride (0.27 g, 0.34 mmol), silver bis[dioxo(trifluoromethyl)-X6-sulfanyl]azanide (0.44 g, 1.15 mmol) and 3,5- bis(trifluoromethyl)aniline (0.18 mL, 1.15 mmol). 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 pad of celite. The filtrate was concentrated in vacuo and the resulting residue

159

SUBSTITUTE SHEET (RULE 26) was purified by flash column chromatographyon 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] ⁺ .

[00395] Step D: A: To a stirred mixture of lithium magnesium dichloride propan-2-ide (6.37 mL, 8.28 mmol) in THF (8 mL) was added dropwise 2-Bromo-l-chloro-4-fluorobenzene (1.73 g, 8.28 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for additional 30 min. 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 the solution A at 0 °C under N2 atmosphere. The resulting mixture was stirred at it for an additional Ih. The reaction was quenched with NH4CI saturated aqueous solution at rt. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NazSCk 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 afford compound N-{4,8-dibromo-3-[(2-chloro-5- fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesul fonamide (600 mg, 0.98 mmol, 59%) as a yellow solid. LCMS: m/z 614 [M + H] ⁺

[00396] Step E: To a solution of N-{4,8-dibromo-3-[(2-chloro-5- fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesul fonamide (600 mg, 0.98 mmol) in DCM (10 mL) at rt under N2 was added l,l,l-triacetoxy-l,3-dihydro-lX5-benzo[2,l- d][l,2]iodoxol-3-one (828 mg, 1.95 mmol). The reaction mixture was stirred for 1 hour at rt. The mixture was treated with H2O (100 mL) and extracted with EA (3 x 300 mL). The combined organic phase was dried over anhydrous Na2SC>4 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 afford compound N-{4,8-dibromo-3-[(2-chloro-5- fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamid e (250 mg, 0.409 mmol, 25%) as a yellow oil.

[00397] Step F: To a solution of N-{4,8-dibromo-3-[(2-chloro-5-fluorophenyl)carbonyl]-2- naphthyl}-4-m ethylbenzenesulfonamide (200 mg, 0.33 mmol) in NMP (2 mL) at rt under N2 was added CuCN (87.9 mg, 0.98 mmol). The reaction mixture was stirred for 1 hour at 120 °C. The mixture was treated with H2O (100 mL) and extracted with EA (3 x 300 mL). The combined organic phase was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The

160

SUBSTITUTE SHEET (RULE 26) crude product was purified by column chromatography (eluting with 0-70% ethyl acetate in petroleum ether) followed 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] ⁺ .

[00398] 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 added slowly a solution of KOH (40.2 mg, 0.72 mmol) in H2O (1 mL). The reaction mixture was stirred at room temperature for an additional 2 h. The reaction mixture was diluted with water, extracted with DCM (3 x 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 composed of PE and EA (3: 1) to afford N- [6-bromo-3 -(2-chl oro-5 -fluorophenyl)-3 -hydroxy- 1 -oxo-2, 3 -dihydro- 1 H- benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (60 mg, 0.104 mmol, 73%) as yellow oil. LCMS: m/z 575/577 [M + H] ⁺ .

[00399] Step H: To a solution of N-(6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo- 2,3-dihydro-lH-benzo[e]isoindol-4-yl)-4-methylbenzenesulfona mide (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 additional 1 hour. The cooled reaction mixture was concentrated. The crude reaction mixture was then purified by silica gel column chromatography eluting with a solvent mixture composed of PE and EA (3: 1) to afford N-(6-bromo-3-(2-chloro-5-fluorophenyl)- 1-oxo- 2,3-dihydro-lH-benzo[e]isoindol-4-yl)-4-methylbenzenesulfona mide (50 mg, 0.09 mmol, 81%) as a yellow solid. LCMS: m/z 559/561 [M + H]".

[00400] Step I: To a stirred mixture of N-[6-bromo-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3- dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (50 mg, 0.09 mmol) in H2O (1 mL) were added concentrated H2SO4 (4 mL) at 0 °C. The mixture mixture was stirred rt 60 °C for 2 hrs. The reaction mixture was cooled to room temperature and poured into ice-water. 2M aqeous sodium hydroxide solution (15 mL) was added. The following mixture was extracted with ethyl acetate (50 mL). The organic phase obtained was washed with water (20 mL) then brine (20 mL) in turn, dried with anhydrous sodium sulfate and concentrated to give 4-amino-6- bromo-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-lH-benzo[e]iso indol-l-one (45 mg, 0.11 mmol, 100 %), which was directly used in the next step. LCMS: m/z 405/407 [M + H] ⁺ .

161

SUBSTITUTE SHEET (RULE 26) [00401] Step J: To a solution of 5-bromo-6-chloro-l,2,3,4-tetrahydronaphthalen-l-one (200 mg, 0.771 mmol) and 4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-lH- benzo[e]isoindol-l-one (45 mg, 0.11 mmol) in pyridine (2 mL) was added dropwise POCL (0.02 mL, 0.22 mmol). The following mixture was stirred at rt for 1 hour. The reaction mixture was diluted with EA (15 mL), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column (PE: EA=1 : 1) to give N-[6-bromo-3-(2-chloro-5-fluorophenyl)-l-oxo- 2,3-dihydro-lH-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluorom ethyl)benzamide (38 mg, 0.06 mmol, 57%) as a yellow solid.

[00402] Step K: To a reaction mixture of N-[6-bromo-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3- dihydro-lH-benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethy l)benzamide (38 mg, 0.06 mmol) in dry DMF (2 mL) was added Zn(CN)i (15 mg, 0.13 mmol), Pd2(dba)g (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 N2 for 18 hrs. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over NaiSCU and concentrated. The residue was purified by column chromatography followed by prep-HPLC purification to give N-[3-(2-chloro-5-fluorophenyl)-6-cyano-l-oxo-2,3-dihydro-lH- benzo[e]isoindol-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (4.5 mg, 0.01 mmol, 13%). LCMS: m/z 542 [M + H] ⁺ . Tl NMR (400 MHz, Methanol-d4) 5 9.55 (d, J= 8.4 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J= 1A 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).

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)be nzamide

162

SUBSTITUTE SHEET (RULE 26)

[00403] 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 - 25 °C. The reaction mixture was stirred at 25 °C for 16h. TLC indicated the reaction was completed. The cooled reaction mixture was poured into water (300 ml) and extracted with EA (400 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0 - 100%) to give methyl 2-amino-5- bromo-6-fluorocyclohexa-2,4-diene-l -carboxylate (10 g, 39.9 mmol, 46%) as a white solid. [00404] Step B: To a solution of methyl 6-amino-3-bromo-2-fluorobenzoate (10 g, 39.9 mmol) in AcOH (100 mL) was Bn (7.03 g, 43.9 mmol) and potassium thiocyanate (9.72 g, 99.9 mmol) at 0 °C - 25 °C. The reaction mixture was stirred at 25 °C under N2 for 18h. TLC indicated the reaction was completed. The cooled reaction mixture was concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0-100%) to give methyl 2-amino-6-bromo-5-fluoro-4,5-dihydrocyclohexa[l,2-d][l,3]thi azole-4-carboxylate (2.6 g, 8.46 mmol, 21%) as a white solid.

[00405] Step C: A suspension of methyl methyl methyl 2-amino-6-bromo-5-fluoro-4,5- dihydrocyclohexa[l,2-d][l,3]thiazole-4-carboxylate (3 g, 9.77 mmol) and 3-methyl-l- (nitrosooxidanyl)butane (3.27 mL, 24.4 mmol) in THF (35 mL) was stirred at 50 °C for 18h. The reaction mixture was concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give methyl 6-bromo-5-fluoro- 4,5-dihydrocyclohexa[l,2-d][l,3]thiazole-4-carboxylate (1.6 g, 5.477 mmol, 56%) as a yellow solid. LCMS: m/z 290.11 [M + H] ⁺

163

SUBSTITUTE SHEET (RULE 26) [00406] Step D: To a solution of methyl 6-bromo-5-fluoro-4,5-dihydrocyclohexa[l,2- d][l,3]thiazole-4-carboxylate (1 g, 3.42 mmol) in THF (10 mL) was added a solution of LiOHFLO (0.43 g, 10.3 mmol) in H2O (3 mL). The mixture was stirred at 45 °C for Ihr. The reaction mixture was poured into HC1 (20 mL, 0.2 mmol/mL) and extracted with EA (20 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0 -100%) give 6-bromo-5-fluoro-4,5-dihydrocyclohexa[l,2-d][l,3]thiazole-4- carboxylic acid (0.8 g, 2.87 mmol, 84%) as a white solid. LCMS: m/z 276.14 [M + H] ⁺

[00407] 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-l-carbaldehyde (1.55 g, 9.79 mmol), PMBNH2 (1.34 g, 9.79 mmol) in MeOH (30 mL) was added LBuNC (0.81 g, 9.79 mmol). The reaction mixture was stirred at 25 °C for 18hr. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 6-bromo-N-(2-(tert-butylamino)-l-(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] ⁺

[00408] Step F: To a solution of 6-bromo-N-(2-(tert-butylamino)-l-(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 l,l-bis(dimethylamino)-N-(2-methylprop-2-yl) methanimine (0.81 g, 4.71 mmol). The reaction mixture was stirred at 140 °C for 3hr, The cooled reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 5-bromo-6-(2-chloro- 5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)methyl]-7,8-di hydro-6H-[l,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] ⁺ [00409] Step G: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-7,8-dihydro-6H-[l,3]thiazolo[4,5-e]iso indol-8-one (0.3 g, 0.562 mmol) in TFA (10 mL) was added tri ethyl silane (0.227 mL, 1.41 mmol). The reaction mixture was stirred at 75 °C for 1.5hr. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous water (30 mL) and extracted with EtOAc (30 mL). The organic layer was

164

SUBSTITUTE SHEET (RULE 26) dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 5-bromo-6-(2-chloro-5- fluorophenyl)-7-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H-[l, 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] ⁺

[00410] Step H: To a stirred mixture of 5-bromo-6-(2-chloro-5-fluorophenyl)-7-[(4- methoxyphenyl)methyl]-7,8-dihydro-6H-[l,3]thiazolo[4,5-e]iso indol-8-one (0.2 g, 0.386 mmol) in dioxane (20 mL) was added 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (0.10 g, 0.502 mmol), xant-PHOS (0.02 g, 0.039 mmol), Pd2(dba)s (0.02 g, 0.039 mmol) and CS2CO3 (0.38 g, 1.16 mmol). The reaction mixture was stirred at 85 °C under N2 for 16hr. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-[l,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] ⁺ [00411] Step I: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-[l,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 prep-HPLC to give N-[6-(2-chloro-5-fluorophenyl)-8- oxo-7, 8-dihydro-6H-[l,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] ⁺ . ^NMR (400 MHz, Methanol-d4) 5 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).

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

165

SUBSTITUTE SHEET (RULE 26)

[00412] 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(l/ 7)-one (500 mg, 0.89 mmol) in DMA (10 mL) were added Zn(CN)2 (314 mg, 2.67 mmol), bis(cyclopentyldiphenylphosphane) iron(0) (100 mg, 0.18 mmol) and tris[(lE,4E)-l,5-diphenylpenta-l,4-dien-3-one] bis[palladium(0)] (81.5 mg, 0.09 mmol) under N2. The reaction mixture was stirred at 150 °C under N2 for 4 h. The cooled reaction was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford compound 6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-5- nitro-8-oxo-l, 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] ⁺ .

[00413] Step B: To a solution of 6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4- methoxybenzyl)-5-nitro-8-oxo-l,6,7,8-tetrahydropyrrolo[3,4-g ]indazole-3-carbonitrile (400 mg,

166

SUBSTITUTE SHEET (RULE 26) 0.788 mmol) in EtOH (15 mL) and FLO (5 mL) were added NH4CI (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 afford 5-amino-6-(2- chloro-5-fluorophenyl)-6-hydroxy-7-(4-methoxybenzyl)-8-oxo-l ,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] ⁺ . [00414] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-8-oxo-l,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). Then 3-chloro-5- fluorobenzoic acid (60 mg, 0.35 mmol) and dichlorophosphinyl chloride (0.06 mL, 0.628 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was diluted with DCM and water. The organic layer was washed with brine, dried over Na^SCU and concentrated. The residue was purified using prep-TLC eluting with 30% ethyl acetate in petroleum ether to afford 3-chloro-A-(6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-7- (4-methoxybenzyl)-8-oxo- l,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzam ide (50 mg, 0.05 mmol, 15%) as a yellow solid. LCMS: m/z 634 [M + H] ⁺ .

[00415] Step D: To a solution of 3-chloro-A-(6-(2-chloro-5-fluorophenyl)-3-cyano-6- hydroxy-7-(4-methoxybenzyl)-8-oxo-l,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 hour. The reaction was concentrated under vacuo to afford 3-chloro-7V-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l, 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] ⁺ .

[00416] Step E: To a solution of 3-chloro-A-(6-(2-chloro-5-fluorophenyl)-3-cyano-7-(4- methoxybenzyl)-8-oxo-l,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 prep-HPLC (YMC-Actus Triart C18 150*20mm*5um, 40%-95%, phase A :H2O(0.1%FA), phase B :MeCN ) to afford compound 3-chloro-7V-[6-(2- chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-tetrahydropyrro lo[4,3-g]indazol-5-yl]-5-

167

SUBSTITUTE SHEET (RULE 26) fluorobenzamide (25 mg, 0.05 mmol, 64%). LCMS: m/z 498 [M + H] ⁺ . 'H NMR (400 MHz, Methanol-d4) 5 7.99 (s, IH), 7.44 (d, J = 7.6 Hz, IH), 7.39 (s, IH), 7.33 - 7.31 (m, 2H), 7.08 - 7.03 (m, IH), 6.69 - 6.09 (m, 2H).

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

[00417] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl) methyl]-8-oxo-l,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 POCh (0.04 mL, 0.42 mmol) at 0 °C under N2 with stirring. The reaction mixture was stirred at rt for Ih. The reaction mixture was concentrated in vaccum to remove most of solvent. The residue was poured into water (6 mL) and extracted with EtOAc (10 mL*3). The organic layer was dried over Na2SC>4, 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][l,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[M-H]+

[00418] Step B: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-cyano-6-hydroxy-7-[(4- methoxyphenyl) methyl] -8-oxo-l,6,7,8-tetrahydropyrrolo[4,3-g] indazol-5-yl] benzofd] [1,2] thiazole-3 -carboxamide (120 mg, 0.19 mmol), triethylsilane (0.46 mL, 2.82 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (0.08 mL, 0.94 mmol) at 0 °C with stirring. The reaction mixture was stirred at 70 °C for 2h. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to obtain N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo- l,6,7,8-tetrahydropyrrolo[4,3-g] indazol-5-yl] benzofd] [1,2] thiazole-3 -carboxamide (11 mg, 0.022 mmol, 12%). LC/MS (ESI) m/z: 503 [M+H] ⁺ . ^NMR (400 MHz, DMSO-d6) 5 15.20 (s,

168

SUBSTITUTE SHEET (RULE 26) 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).

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

[00419] Step A: To a solution of phosphorus tribromide (13 mL, 138 mmol) in CHCh (280 mL) was added DMF (13 mL, 166 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hours. Then 5-chloro-l,2,3,4-tetrahydronaphthalen-l-one (10 g, 55.3 mmol) in CHCh (50 mL) was added dropwise at 0 °C. The following mixture was stirred at 70 °C for 2 hours. The cooled mixture was added into ice water (400 mL) and concentrated under vacuum to remove CHCh. The mixture was extracted with EA (500 mL x 3). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (20 g column)

169

SUBSTITUTE SHEET (RULE 26) using 0 - 80% EtOAc/hexane to afford l-bromo-5-chloro-3,4-dihydronaphthalene-2- carbaldehyde (8 g, 29.4 mmol, 53%) as a brown solid, 'H NMR (400 MHz, DMSO-d6) 5 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).

[00420] Step B: To a solution of l-bromo-5-chl oro-3, 4-dihydronaphthalene-2-carbaldehy de (2 g, 7.36 mmol) in toluene (20 mL) was added 4,5-dichloro-3,6-dioxocyclohexa-l,4-diene-l,2- dicarbonitrile (5.02 g, 22.1 mmol). The reaction mixture was stirred at 110 °C for 12 hours. The mixture was fdtered and was diluted with saturation NajCOs (200 mL), extracted with EA (200 mL x 3). The organic phase was dried over NaiSCU and concentrated. The residue was purified by silica gel chromatography (10 g column) using 0 - 5% EtOAc/hexane to afford l-bromo-5- chloronaphthalene-2-carbaldehyde (1.05 g, 3.89 mmol, 53%) as a pale solid. 'H NMR ('400 MHz, DMSO-d6) 5 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).

[00421] Step C: To a solution of l-bromo-5-chloronaphthalene-2-carbaldehyde (800 mg, 2.96 mmol) in 1,2-di chloroethane (35 mL) was added tosyl azide (146 mg, 0.742 mmol), bis[iridium(3+)] bis(l,2,3,4,5-pentamethylcyclopenta-2,4-dien-l-ide) tetrachloride

(59.1 mg, 0.074 mmol), silver bis[dioxo(trifluoromethyl)-X6-sulfanyl]azanide (115.2 mg, 0.297 mmol) and 3,5-bis(trifluoromethyl)aniline (68 mg, 0.297 mmol). The mixture was stirred at 100 °C for 18 hours. The cooled mixture was added EA (20 mL) and stirred at 20 °C for 10 min. The following mixture was 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] ⁺ NMR (400 MHz, DMSO-d6) 5 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).

[00422] Step D: To a solution of N-(4-bromo-8-chloro-3-formyl-2-naphthyl)-4- methylbenzenesulfonamide (760 mg, 1.73 mmol) in THE (20 mL) was added (2-chloro-5- fluorophenyl)magnesium chloride (1.30 g, 6.93 mmol) at 0 °C. The reaction mixture was stirred at 0 °C to rt for 1 hour. 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)met hyl]-2-naphthyl}-4-

170

SUBSTITUTE SHEET (RULE 26) methylbenzenesulfonamide (790 mg, 1.38 mmol, 80%) as a white solid. LCMS: m/z 568 [M - H] ⁺ .

[00423] Step E: To a solution of N-{4-bromo-8-chloro-3-[(2-chloro-5- fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesul fonamide (790 mg, 1.38 mmol) in DCM (50 mL) was added Dess-Martin (1.17 g, 2.77 mmol). The following mixture was stirred at 20 °C for 12 hours. The reaction mixture was filtered. The filtrate was concentrated to give the residue, which was purified by silica gel chromatography (3 g column) using 0 - 30% EtOAc/hexane to afford N-{4-bromo-8-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-2- naphthyl}-4-m ethylbenzenesulfonamide (300 mg, 0.529 mmol, 38%) as a white solid. LCMS: m/z 566 [M + H] ⁺

[00424] Step F: To a solution of N-{4-bromo-8-chloro-3-[(2-chloro-5- fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamid e (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 hour. The cooled mixture was diluted with water, extracted with EA (50 mL x 3). The organic phase was dried over NaiSO4 and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0 - 30% EtOAc/hexane to afford 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] ⁺

[00425] Step G: To a solution ofN-[8-chloro-3-[(2-chloro-5-fluorophenyl)carbonyl]-4- cyano-2-naphthyl}-4-methylbenzenesulfonamide (170 mg, 0.331 mmol) in CH3CN

(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 hour. The reaction mixture was diluted with water (30 mL) and concentrated under vacuum to remove CH3CN, which was extracted with EA (30 mL x 3). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0 - 50% EtOAc/hexane to afford N-[6-chloro-3-(2-chloro-5- fluorophenyl)-3-hydroxy-l-oxo-2,3-dihydro-lH-benzo[e]isoindo l-4-yl]-4- methylbenzenesulfonamide (110 mg, 0.207 mmol, 62%) as a brown solid. LCMS: m/z 528.9 [M - H] ⁺ . [00426] Step H: To a solution of N-[6-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo-

2,3-dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulf onamide (110 mg, 0.207 mmol) in IF A (4 mL) was added triethylsilane (1 mL, 6.19 mmol). The mixture was stirred at

171

SUBSTITUTE SHEET (RULE 26) 20 °C for 1 hour. The reaction mixture was concentrated under vacuum to give N-[6-chloro-3-(2- chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-benzo[e]isoindol -4-yl]-4- methylbenzenesulfonamide (110 mg, 0.203 mmol, 98%) as a brown oil. LCMS: m/z 515 [M +

H] ⁺ .

[00427] Step I: To a solution of N-[6-chloro-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro- lH-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 hours. The cooled reaction mixture was diluted with water and adjust pH to 8 with NaOH, extracted with EA (30 mL x 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-lH- benzo[e]isoindol-l-one (70 mg, 0.194 mmol, 99%) as a red solid. LCMS: m/z 361 [M + H] ⁺ [00428] Step J: To a solution of 4-amino-6-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro- lH-benzo[e]isoindol-l-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 prep-TLC (PE/EA=7:3) and then by prep-HPLC to give N-[6-chloro-3-(2-chloro-5- fluorophenyl)-l-oxo-2,3-dihydro-lH-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] ^{+ J} HNMR (400 MHz, Methanol-d4) 5 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).

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

172

SUBSTITUTE SHEET (RULE 26)

[00429] Step A: To a solution ofN-(3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4- methoxybenzyl)-l-oxo-2,3-dihydro-lH-pyrrolo[3,4-f]quinolin-4 -yl)-3-fluoro-5- (trifluoromethyl)benzamide (500 mg, 0.784 mmol) in DCM (10 mL) was added /n-CPBA (537 mg, 2.35 mmol) at 0 °C - 25 °C. The reaction mixture was stirred at 25 °C for 16h. TLC indicated the reaction was completed. The cooled reaction mixture was washed with aqueous NazSOs (60 mL), dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0-100%) to give 3-(2-chloro- 5 -fluorophenyl)-4-({ [5 -fluoro-3 -(trifluor omethyl)phenyl] carbonyl } amino)-3 -hydroxy-2- [(4- methoxyphenyl)methyl]-l-oxo-2,3-dihydro-lH-pyrrolo[4,3-f]qui noline 6-oxide (400 mg, 0.597 mmol, 76%) as a white solid. LCMS: m/z 770.11 [M + H] ⁺

[00430] Step B: To a solution of 3-(2-chloro-5-fluorophenyl)-4-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)-3-hydroxy-2-[(4-meth oxyphenyl)methyl]-l-oxo-2,3- dihydro-lH-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 for 3h under N2. TLC indicated the reaction was completed. The reaction mixture was concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0-100%) to give N-[7-chloro-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl)methyl]- 1 -oxo-2, 3 -dihydro- 1 H-pyrrolo[4, 3 -f] quinolin-4-yl]-5 -fluoro-3 - (trifluoromethyl)benzamide (200 mg, 0.291 mmol, 49%) as a white solid.

[00431] Step C: To a solution ofN-[7-chloro-3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]- 1 -oxo-2, 3 -dihydro- 1 H-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 prep-HPLC to give N-[7-chloro-3-(2-chloro-5-

173

SUBSTITUTE SHEET (RULE 26) fluorophenyl)-l-oxo-2,3-dihydro-lH-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] ⁺ . 'H NMR (400 MHz, Methanol-d4) 5 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).

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

[00432] To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-hydroxy-l-oxoisoind olin- 4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, crude, 0.04 mmol, 1.0 eq) in Triethyl orthoformate (0.5 mL) was added P-TsOH (3.8 mg, 0.02 mmol, 0.5 eq) at 25 °C under N2. The reaction mixture was stirred at 80 °C for 2 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water) to give N-(6-(2-chloro-5-fluorophenyl)-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]").

Example 26 N-[3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-pyrrolo[ 3,4- b]imidazo[2,3-f]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)be nzamide

174

SUBSTITUTE SHEET (RULE 26)

[00433] Step A: To a solution of 4,6-dichloropyridine-2-carboxylic acid (16 mL, 130 mmol) in DCM (250 mL) were 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 hr. 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 obtained solid was washed with water for three times, dried under vacuum to afford crude 4,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridine-2-carboxami de (40 g, 128.551 mmol, 99%) as a yellow solid. LCMS: m/z 313.0 [M+2+H] ⁺

[00434] Step B: To a solution of 2-chloro-5-fluorobenzoic acid (17 g, 97.4 mmol) in DCM (170 mL) were 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 hr. The raw materials have been completely reacted through TLC detection. The reaction was concentrated in vacuo to afford crude 2-chloro-5-fluorobenzoyl chloride (18.6 g, 96.3 mmol, 98%).

[00435] To a solution of 4,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridine-2-carboxami de (15 g, 48.207 mmol) in THF (200 mL) was added NaH (2.89 g, 72.3 mmol, 60% in mineral oil)

175

SUBSTITUTE SHEET (RULE 26) at 0 °C. The reaction was stirred at 0 °C for 1 hr. 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 rt for 2 hr. The reaction was diluted with EA (500 mL) and water (500 mL). The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE and 2% DCM (l%~50%) to afford 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. [00436] 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) at -68 °C was added LiHMDS (35.3 mL, 1.0 M in THF). The reaction mixture was stirred at -68 °C for additional 1 hours. The reaction mixture was quenched by 100 mL of saturated NH4CI solution and extracted with 200 mL x 3 of ethyl acetate. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography eluted 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 light yellow solid. LCMS: m/z 467.0 [M+H] ⁺

[00437] 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 tri ethylsilane (5.22 g, 44.901 mmol). The reaction mixture was stirred at 70 °C for additional 1 hours. The cooled reaction mixture was concentrated. The residue was quenched by 100 mL of saturated NaHCCh solution and extracted with 200 mL x 3 of ethyl acetate. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography eluted 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] [00438] Step E: To a solution of (2,4-dimethoxyphenyl)methanamine (0.33 mL, 2.21 mmol) in dioxane (10 mL) were added DIEA EthyldiisopropylaMine (1.10 mL, 6.64 mmol) and (2,4- dimethoxyphenyl)methanamine (0.33 mL, 2.21 mmol) in a sealed tube. The reaction mixture was stirred at 160 °C for 3 hr. The cooled reaction mixture was diluted with EA (200 mL) and water (200 mL). The organic layer was washed with brine, dried over JSfeSCL and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in

176

SUBSTITUTE SHEET (RULE 26) petroleum ether (l%~30%) to afford crude products. The crude product was purified using silica gel column chromatography eluting with water and 0.1% HCOOH in CAN (50%~75%) to afford compound 4-chloro-5-(2-chloro-5-fluorophenyl)-2-{[(2,4-dimethoxypheny l)methyl]amino}-6- [(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyrid in-7-one (300 mg, 0.515 mmol, 23%) as a white solid. LCMS: m/z 582.2 [M+H] ⁺

[00439] 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 hr. The reaction was concentrated in vacuo. The residue was diluted with EA and saturated NaHCCf 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%~50%) dried to afford compound 2-amino-4-chloro-5-(2- chloro-5-fluorophenyl)-6-[(4-methoxyphenyl)methyl]-6,7-dihyd ro-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] ⁺

[00440] 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 hr. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1%~100%) dried to afford compound 4-chloro-3-(2-chloro-5- fluorophenyl)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-pyr rolo[4,3-b]imidazo[2,l- f]pyridin-l-one (190 mg, 0.416 mmol, 77%) as a yellow solid. LCMS: m/z 456.0 [M+H] ⁺ [00441] Step H: To a solution of 4-chloro-3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-pyrrolo[3,4-b]imidazo[2 ,3-f]pyridin-l-one (100 mg, 0.219 mmol) in dioxane (10 mL) were added 3-fluoro-5-(trifluoromethyl)benzene-l- carboxamide (90.8 mg, 0.438 mmol), CS2CO3 (286 mg, 0.877 mmol), Xantphos (63.4 mg, 0.110 mmol) and Pd2(dba)3 (100 mg, 0.110 mmol). The reaction was stirred at 120 °C under N2 for 6 hr. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-50%) to afford compound N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl )methyl]-l-oxo-2,3-

177

SUBSTITUTE SHEET (RULE 26) dihydro-lH-pyrrolo[4,3-b]imidazo[2,3-f]pyridin-4-yl]-5-fluor o-3-(trifluoromethyl)benzamide (65 mg, 0.101 mmol, 46%) as a brown oil. LCMS: m/z 627.1 [M+H] ⁺

[00442] Step I: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-[(4- methoxyphenyl)methyl]-l-oxo-2,3-dihydro-lH-pyrrolo[4,3-b]imi dazo[2,3-f]pyridin-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (65 mg, 0.101 mmol) in TFA (5 mL) were 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 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in H2O) to afford compound N-[3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-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] ⁺ !H NMR (400 MHz, DMSO-d6) 6 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, 9.8, 4.6 Hz, 1H), 7.19 - 6.85 (m, 2H), 6.29 (s, 1H).

Example 27 N-[6-(2-chloro-5-fluorophenyl)-8-oxo-l,6,7,8-tetrahydropyrro lo[4,3- g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide

178

SUBSTITUTE SHEET (RULE 26) [00443] Step A: To a solution of 6-fluoro-7-(methoxycarbonyl)-lH-indazole-5-carboxylate (1.60 g, 6.75 mmol) in MeOH (10 mL) /H ₂ O (10 mL)/THF (10 mL) was added LiOH (0.67 mL, 23.8 mmol). The reaction mixture was stirred at rt for 4h. The reaction was diluted with EA (10 mL) and HC1 (2 mol/L, 10 mL) solution. The organic layer was separated, washed with brine, dried over Na ₂ SC>4 and concentrated. The residue was dried to afford compound 7-carboxy-6- fluoro-lH-indazole-5-carboxylate (1.00 g, 4.48 mmol, 66%) as yellow solid. LCMS: m/z 224 [M - H]-.

[00444] 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-lH-indazole-5-carboxylate (700 mg, 3.14 mmol), 2-chloro-5-fluorobenzene-l-carbaldehyde (498 mg, 3.14 mmol) and (4- methoxyphenyl)methanamine (0.41 mL, 3.14 mmol). The reaction mixture was stirred at rt overnight. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na ₂ SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-15 % ethyl acetate in petroleum ether and dried to afford compound 7-[3-(2-chloro-5-fhiorophenyl)-2-[(4-methoxyphenyl)methyl]-6 ,6-dimethyl-l,4- dioxo-2,5-diazahept-l-yl]-6-fluoro-lH-indazole-5-carboxylate (1.30 g, 2.23 mmol, 71%) as yellow solid. LCMS: m/z 586 [M + H] ⁺ .

[00445] Step C: To a solution of 7-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-6,6-dimethyl-l,4-dioxo-2,5-diazahept-l -yl]-6-fluoro-lH-indazole-5- carboxylate (500 mg, 0.86 mmol) in DMA (10 mL) was added l,l-bis(dimethylamino)-N-(2- methylprop-2-yl)methanimine (212 mg, 1.29 mmol). The reaction mixture was stirred at 140 °C overnight. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na ₂ SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50 % ethyl acetate in petroleum ether, and dried to afford compound 6-(2-chloro-5-fhiorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)me thyl]-8-oxo-l, 6,7,8- tetrahydropyrrolo[4,3-g]indazole-5-carboxylate (300 mg, 0.65 mmol, 73%) as yellow oil. LCMS: m/z 483 [M + H] ⁺ .

[00446] Step D: To a solution of 6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-8-oxo-l,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 NH4CI (39 mg, 0.728 mmol). The reaction mixture was stirred at 80 °C for 3h. The cooled reaction was diluted with

179

SUBSTITUTE SHEET (RULE 26) EA and water. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was dried to afford compound 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7- [(4-methoxyphenyl)methyl]-l,6,7,8-tetrahydropyrrolo[4,3-g]in dazol-8-one (30 mg, 0.066 mmol, 91%) as yellow solid. LCMS: m/z 453 [M + H] ⁺ .

[00447] Step E: To a solution of 5-fluoro-3-(trifluoromethyl)benzoic acid (14 mg, 0.066 mmol) in pyridine (2 mL, 24.73 mmol) was added POCI3 (0.1 mL, 1.07 mmol) and 5-amino-6- (2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl)meth yl]-l, 6,7,8- tetrahydropyrrolo[4,3-g]indazol-8-one (30 mg, 0.066 mmol). The reaction mixture was stirred at rt for 30 mins. The reaction was diluted with EA and saturated NaHCCb solution. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was dried to afford compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphenyl )methyl]-8- oxo-l,6,7,8-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-N -{[3-fluoro-5- (trifluoromethyl)phenyl]carbonyl}-3-(trifluoromethyl)benzami de (30 mg crude, 0.047 mmol, 70%) as yellow solid. LCMS: m/z 799 [M + H] ⁺ .

[00448] Step F: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-8-oxo-l,6,7,8-tetrahydropyrrolo[4,3-g] indazol-5-yl]-5-fluoro-N-{[3- fluoro-5-(trifluoromethyl)phenyl]carbonyl}-3-(trifluoromethy l)benzamide (30 mg crude, 0.036 mmol) in THF (2 mL) was added KOH (0.5 mL, 1.00 mmol) and H2O (0.5 mL). The reaction mixture was stirred at rt for Ih. The reaction was diluted with EA and saturated NaHCOa solution. The organic layer was washed with brine, dried over ISfeSCL and concentrated. The residue was purified by prep-TLC and dried to afford compound N-[6-(2-chloro-5-fluorophenyl)- 6-hydroxy-7-[(4-methoxyphenyl)methyl]-8-oxo-l,6,7,8-tetrahyd ropyrrolo[4,3-g]indazol-5-yl]-3- fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 43%) as yellow solid LCMS: m/z 643 [M + H] ⁺ .

[00449] Step G: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-8-oxo-l,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 EtaSiH (0.5 mL, 3.01 mmol) and trifluoromethanesulfonic acid (0.05 mL, 0.57 mmol). The reaction mixture was stirred at 70 °C for 2h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC and dried to afford compound N-[6-(2-chloro-5-fluorophenyl)-8-oxo-l, 6,7,8- tetrahydropyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluorom ethyl)benzamide (2 mg, 0.004

180

SUBSTITUTE SHEET (RULE 26) mmol, 25%). LCMS: m/z 507 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 6 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).

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

[00450] 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 H2O (2 mL) and EtOH (20 mL) was added potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (790 mg, 3.32 mmol), pd(pph3)2Ch (310 mg, 0.443 mmol) and Na2COa (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, extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column eluting with ethyl acetate/petroleum ether (1/1) to afford compound

181

5UB5TITUTE SHEET (RULE 26) 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)methano ate (330 mg, 0.604 mmol, 27%) as a brown solid. LCMS: m/z 546 [M+H] ⁺ .

[00451] 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-l -carboxamide (125 mg, 0.604 mmol), Pd(OAc)2 (12.0 mg, 55.1 pmol), dppf (60.9 mg, 110 pmol) and LBuONa (132 mg, 1.37 mmol). The reaction mixture was stirred at 100 °C for 16h. The cooled mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluted with EA/PE = 0-50%) to afford 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)m ethanoate (100 mg, 0.139 mmol, 25%) as a brown solid. LCMS: m/z 717 [M+H] ⁺ .

[00452] Step C: A solution of 2-methylpropan-2-yl ({[5-(2-chloro-5-fluorophenyl)-4-({[3- fluoro-5-(trifluoromethyl)phenyl]carbonyl}amino)-6-[(4-metho xyphenyl)methyl]-7-oxo-6,7- dihy dro-5H-pyrrolo[4, 3 -b]pyridin-2-yl]methyl}amino)m ethanoate (45 mg, 63 pmol) in HC1 (2 mL, 4M in dioxane) was stirred at rt for 2h. The mixture was concentrated to afforded N-[2- (aminomethyl)-5 -(2-chl oro-5 -fluorophenyl)-6- [(4-methoxyphenyl)methyl] -7-oxo-6, 7-dihydro- 5H-pyrrolo[4,3-b]pyridin-4-yl]-3-fluoro-5-(trifluoromethyl)b enzamide (38 mg, 62 pmol, 98%) as a brown solid. LCMS: m/z 617 [M+H] ⁺ .

[00453] Step D: A solution of acetic anhydride (0.65 mL) and FA (0.25 mL) was stirred at 60 °C for Ih. N-[2-(aminomethyl)-5-(2-chloro-5-fhjorophenyl)-6-[(4-methoxy phenyl)methyl]-7- oxo-6, 7-dihydro-5H-pyrrolo[4,3-b]pyridin-4-yl]-5-fluoro-3-(trifluo romethyl)benzamide (40 mg, 65 pmol) in FA (0.25 mL) was stirred at 60 °C for 2h. After cooled to rt, the solvent was concentrated, and the mixture was adjusted to pH=8. The following mixture was extracted with LA. 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-(triflu oromethyl)benzamide (40 mg, 64 pmol, 98%) as a crude product and used directly for next step. LCMS: m/z 627 [M+H] ⁺ .

182

SUBSTITUTE SHEET (RULE 26) [00454] 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]imi dazo[4,3-f]pyridin-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (40 mg, 64 pmol) in TFA (2 mL) was added TfOH (0.2 mL). The mixture was stirred at 70 °C for 30 min and then concentrated. The crude was purified by prep-HPLC to afforded 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)be nzamide (2.2 mg, 4 pmol, 7%).

LCMS: m/z 507 [M+H] ⁺ . ^NMR (400 MHz, Methanol-d4) 8 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).

Example 29 (5)-/V-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide and Example 30 (7?)-/V-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-t etrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[00455] 7V-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-tetrah ydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (75 mg, 0.14 mmol) was purified by prep-SFC to afford (S)-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (25 mg, 0.05 mmol, 33%). LCMS: m/z 532 [M + H] ⁺ . 'H NMR(400 MHz, DMSO-d6) 8 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-l,6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (27.6mg, 0.05 mmol, 36.8%). LCMS: m/z 532 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 8 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).

183

SUBSTITUTE SHEET (RULE 26) Example 31 N-(3-(2-chloro-5-fluorophenyl)-7-methoxy-l-oxo-2,3-dihydro-l H-pyrrolo[3,4- f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide and Example 32 N-(3-(2- chloro-5-fluorophenyl)-7-hydroxy-l-oxo-2,3-dihydro-lH-pyrrol o[3,4-f]quinolin-4-yl)-3- fluoro-5-(trifluoromethyl)benzamide

[00456] 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- 1 H-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 Gen. 3 (74.6 mg, 0.087 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 18h. TLC indicated the reaction was completed. The cooled reaction mixture was wished with water (60 mL) and extracted with DCM (60 mL). The organic layer was dried over MgSCU, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0 -100%) to give N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-7-methoxy-2-[(4- methoxyphenyl)methyl]- 1 -oxo-2, 3 -dihydro- 1 H-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] ⁺

[00457] 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- 1 H-pyrrolo[4, 3 -f] quinolin-4-yl]-5 -fluoro-3 - (trifluoromethyl)benzamide (60 mg, 0.088 mmol) and trifluoromethanesulfonic acid (0.014 mL,

184

SUBSTITUTE SHEET (RULE 26) 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 prep-HPLC to give N-[3-(2-chloro-5-fluorophenyl)-7- methoxy-l-oxo-2,3-dihydro-lH-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] ⁺ . NMR (400 MHz, Methanol-d4) 5 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).

[00458] Step C: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-7-methoxy-l-oxo-2,3- dihydro-lH-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluor omethyl)benzamide (10 mg, 0.018 mmol) in dioxane (15 mL) was added con.HCl (0.5 mL, 3.01 mmol). The mixture was stirred at 80 °C for 1 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by prep-HPLC to give N-[3-(2-chloro-5-fluorophenyl)-7-hydroxy-l-oxo- 2,3-dihydro-lH-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trif luoromethyl)benzamide (2.8 mg, 0.005 mmol, 29%). LCMS: m/z 534.12 [M + H] ⁺ . ^! H NMR (400 MHz, Methanol-d4) 5 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).

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

185

SUBSTITUTE SHEET (RULE 26)

[00459] Step A: To a solution of 4-bromo-6-fluoro-lH-indazole (7.5 g, 34.8 mmol) in DMF (110 mL) was added in batches NaH (1 g, 41.8 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred for lOmin, then CH3I (3.25 mL, 52.3 mmol) was added. The reaction mixture was stirred at rt for 3h. LCMS showed the reaction was completed. 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 (gradient: 0-10%) to afford compound 4-bromo-6- fluoro-1 -methylindazole (4.5 g, 19.6 mmol, 56%) as a white solid. LCMS: m/z 229 [M + H] ⁺ . [00460] Step B: To a solution of 4-bromo-6-fluoro-l -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 min, then 2-chloro-5-fluorobenzene-l-carbaldehyde (6.23 g, 39.2 mmol) was added. The reaction mixture was stirred at -78 °C for another 2 h. LCMS showed the reaction was completed. The reaction was diluted with aqueous solution of NH4CI and EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 5-10%) to afford compound (4-bromo-6-fluoro-l-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] ⁺ . [00461] Step C: To a solution of (4-bromo-6-fluoro-l-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 rt for 1 h. LCMS showed the reaction was completed. The reaction was diluted with DCM and H2O. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 15-20%) to afford compound (4-bromo-6-fluoro-l-methylindazol-5-yl)(2-chloro-5-fluorocyc lohexa-l,5- dienyl)methanone (1.2 g, 3.10 mmol, 80%) as a white solid. LCMS: m/z 385 [M+H] ⁺ .

186

SUBSTITUTE SHEET (RULE 26) [00462] Step D: To a solution of (4-bromo-6-fluoro-l-methylindazol-5-yl)(2-chloro-5- fluorophenyl)methanone (600 mg, 1.56 mmol) in DMA(10 mL) were added dppf (172 mg, 0.311 mmol), Zn(CN)2 (201 mg, 1.71 mmol), zinc (0) (20.4 mg, 0.311 mmol), and Pd2(dba)3 (142 mg, 0.156 mmol). The reaction mixture was stirred at 100 °C for 18 h. LCMS showed the reaction was completed. The cooled reaction mixture was diluted with EA and saturated sodium chloride. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether(gradient:10-15%) to afford compound 5-[(2-chloro-5-fluorophenyl)carbonyl]-6- fluoro-l-methylindazole-4-carbonitrile (300 mg, 0.904 mmol, 58%) as a white solid. LCMS: m/z 332 [M+H] ⁺ .

[00463] Step E: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-l- methylindazole-4-carbonitrile (150 mg, 0.452 mmol) in DMSO-d6 (5 mL) were added DIEA (116 mg, 0.904 mmol), (2,4-dimethoxyphenyl)methanamine (75.6 mg, 0.452 mmol). The reaction mixture was stirred at 130 °C for 5 h under N2. LCMS showed the reaction was completed. The cooled reaction mixture was diluted with EA and saturated sodium chloride. The organic layer was washed with brine, dried over Na2SOi and concentrated. The reaction was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether(gradi ent: 15-20%) to afford compound 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-l-methylindazole-4-carbonitril e (75 mg, 0.157 mmol, 35%) as an orange solid. LCMS: m/z 479 [M + H] ⁺ .

[00464] Step F: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-l-methylindazole-4-carbonitril e (150 mg, 0.313 mmol) in MeOH (5 mL) and H2O (0.5 mL) were added hydroxy sodium (25.1 mg, 0.626 mmol). The reaction was stirred at room temperature for 10 min. LCMS showed the reaction was completed. The reaction was diluted with EA and H2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 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] ⁺ .

[00465] 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) were added EtsSiH (0.4 mL, 2.48 mmol). The reaction

187

SUBSTITUTE SHEET (RULE 26) was stirred at 70 °C for 30 min. LCMS showed the reaction was completed. The cooled reaction was concentrated, diluted with EA and NaHCCf. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with (gradient: MeOH: DCM=5-10%) to afford 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] ⁺ .

Step H: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-methyl-7, [00466] 8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (20 mg, 60 pmol) in pyridine (2 mL) were added 5-fluoro-3-(trifluoromethyl)benzoic acid (12.6 mg, 60 pmol mol), POCI3 (0.011 mL, 0.120 mmol). The reaction mixture was stirred at room temperature for 10 min. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by prep-HPLC to afforded 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)b enzamide (6.2 mg, 12 pmol, 20%). LCMS: m/z 521 [M + H] ⁺ . ^NMR (400 MHz, Methanol-d4) 5 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).

Example 34 N-(6-(2-chloro-5-fluorophenyl)-3-methoxy-8-oxo-l, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00467] Step A: To a solution of 3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4- methoxyphenyl)methyl]-5-nitro-l,6,7,8-tetrahydropyrrolo[4,3- g]indazol-8-one (500 mg, 0.890

188

SUBSTITUTE SHEET (RULE 26) 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 /-BuBrettPhos-Pd-G3 (84.5 mg, 0.089 mmol). The reaction mixture was stirred at 90 °C under N2 overnight. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient : 0-15%] to afford compound 6-(2-chl oro-5- fluorophenyl)-6-hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl ]-5-nitro-l, 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] ⁺

[00468] Step B: To a solution of 6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4- methoxyphenyl)methyl]-5-nitro-l,6,7,8-tetrahydropyrrolo[4,3- g]indazol-8-one (150 mg, 0.292 mmol) in EtOH (10 mL) and H2O (5 mL) were added Fe (163 mg, 2.92 mmol) and NH4CI (78.2 mg, 1.46 mmol). The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was fdtered, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to afford compound 5-amino-6-(2-chloro-5-fluorophenyl)-6- hydroxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-l,6,7,8-tetrah ydropyrrolo[4,3-g]indazol-8- one (150 mg crude) as a yellow solid. LCMS: m/z 483 [M + H] ⁺

[00469] Step C: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy- 7-[(4-methoxyphenyl)methyl]-l,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 2h. The cooled reaction mixture was dissolved in H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient : 0-15%] to afford compound N-[6-(2-chloro-5- fluorophenyl)-6-hy droxy-3-methoxy-7-[(4-methoxyphenyl)methyl]-8-oxo-l, 6,7,8- tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluorom ethyl)benzamide (40 mg, 0.059 mmol, 57%) as a yellow solid. LCMS: m/z 673 [M + H] ⁺

[00470] Step D: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-methoxy-7-[(4- methoxyphenyl)methyl]-8-oxo-l,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 2 h. The

189

SUBSTITUTE SHEET (RULE 26) cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-methoxy-8-oxo-l,6,7,8-tetra hydropyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (4.9 mg, 0.009 mmol, 20%). LCMS: m/z

537 [M + H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 6 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).

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

190

SUBSTITUTE SHEET (RULE 26) [00471] Step A: To a stirred solution of 8-bromo-6-fluoroquinoline (5 g, 22.1 mmol) in THF (8 mL) was added LDA (16.5 mL, 33.1 mmol, 2M) slowly at -65 °C. After stirred at -65 °C for 30 min, a solution of 2-chloro-5-fluorobenzene-l-carbaldehyde (4.5 g, 28.7 mmol) in THF (15 mL) was added dropwise to the mixture. After stirred at -65 °C for Ih, 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 with NaiSCL, filtered and concentrated. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-80%, EtOAc in PE) to give (8-bromo-6-fluoroquinolin-7-yl)(2- chloro-5-fhiorophenyl)methanol (7.5 g, 19.5 mmol, 88%) as a brown solid. LCMS: m/z 384 [M+H] ⁺ .

[00472] 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) was added Dess-Martin (11.1 g, 28.1 mmol) slowly at 0 °C . After stirred at rt for 3h, the mixture was poured into NaHCOa (aq, 100 mL) and extracted with DCM (20 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-40%, 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] ⁺ . [00473] 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 rt . After stirred at 120 °C under N2 for 2h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated until there were no more drops. The cooled mixture was filtered. The filter cake was washed by 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] ⁺ .

[00474] 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) was added DIPEA (0.3 mL, 1.8 mmol) and (2,4-dimethoxyphenyl)methanamine (0.1 mL, 0.73 mmol) at rt . After stirred at 130 °C for Ih, the cooled mixture was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % FA) to give 7-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4-

191

SUBSTITUTE SHEET (RULE 26) dimethoxyphenyl)methyl]amino}quinoline-8-carbonitrile (150 mg, 0.31 mmol, 51%) as a brown solid. LCMS: m/z 476 [M+H] ⁺ .

[00475] 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)/ H2O (2 mL) was added potassium hydroxide (176 mg, 3.1 mmol) at rt. After stirred at rt for 20 min, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with IsfeSCL, 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] ⁺ .

[00476] Step F: To a stirred solution of 7-(2-chloro-5-fluorophenyl)-6-{[(2,4- dimethoxyphenyl)methyl]amino}-7-hydroxy-8,9-dihydro-7H-pyrro lo[4,3-h]quinolin-9-one (100 mg, 0.21 mmol) in TFA (3 mL, 39.1 mmol) was added EtsSiH (1 mL, 0.4 mmol) slowly. After stirred at 70 °C for 2h, 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] ⁺ .

[00477] 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 added 5-fluoro-3- (trifluoromethyl)benzoyl chloride (0.103 mL, 0.671 mmol) and pyridine (0.136 mL, 1.67 mmol) slowly. After stirred at 50 °C for 2h, the mixture was poured into water (100 mL) and extracted with EtOAc (60 mL*2). The combined organic phase was washed with brine, dried with Na2$O4, 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-flu oro-3- (trifluoromethyl)phenyl]carbonyl}-5-(trifluoromethyl)benzami de (100 mg, 0.14 mmol, 66%) as a white solid. LCMS: m/z 328 [M+H] ⁺ .

[00478] Step H: To a stirred solution ofN-[7-(2-chloro-5-fluorophenyl)-9-oxo-8,9-dihydro- 7H-pyrrolo[4,3-h]quinolin-6-yl]-3-fluoro-N-{[5-fluoro-3-(tri fluoromethyl)phenyl]carbonyl}-5- (trifluoromethyl)benzamide (100 mg, 0.14 mmol) in THE (5 mL) at 0 °C was added KOH (23 mg, 0.42 mmol) slowly. After stirred at rt 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,

192

SUBSTITUTE SHEET (RULE 26) dried with NaaSO-i, 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-(triflu oromethyl)benzamide (25 mg, 0.047 mmol, 33%) as a white solid. LCMS: m/z 534 [M+H] ⁺ .

[00479] 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-(trifluor omethyl)benzamide (25 mg, 0.047 mmol) in TFA (3 mL, 39 mmol) was added Eta Si H (1 mL, 0.4 mmol) slowly. After stirred at 90 °C for 6h, the cooled reaction mixture was concentrated. The residue was purified by prep- HPLC (C18, 40 ~ 90 % MeCN in H2O with 0.1 % TFA) to give N-[7-(2-chloro-5-fluorophenyl)- 9-oxo-8, 9-dihy dro-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] ⁺ . 'H NMR (400 MHz, DMSO- d6) 5 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).

Example 36 (l?)-3-chloro-A ^L (6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide and Example 37 (5)-3-chloro-/V- (6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-tetrahydr opyirolo[3,4-g]indazol-5-yl)-5- fluorobenzamide

[00480] 3-chloro-7V-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluorobenzamide(55 mg, 0.11 mmol) was purified by prep-SFC to afford (R)-3-chloro-N-(6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l, 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] ⁺ . 'H NMR (400 MHz, Methanol-d4) 5 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-

193

SUBSTITUTE SHEET (RULE 26) chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-tetrahydropyrro lo[3,4-g]indazol-5-yl)-5- fluorobenzamide (15.1 mg, 0.03 mmol, 27.5%). LCMS: m/z 498 [M + H] ⁺ . ^J H NMR (400 MHz, Methanol-d4) 5 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).

Example 38 N-(7-(2-chloro-5-fluorophenyl)-l-methyl-2,9-dioxo-2,7,8,9-te trahydro-lH- pyrrolo[3,4-h]quinolin-6-yl)-3-fluoro-5-(trifluoromethyl)ben zamide

Example 39 (R)-N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l,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- tetrahydropyrrole [4,3-g] indazol-5-yl] benzo[d] [1,2] thiazole-3-carboxamide

[00481] N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-tetrahy dropyrrolo[4,3-g] indazol-5-yl] benzofd] [1,2] thiazole-3 -carboxamide (70 mg, 0.139 mmol) was separated by prep-SFC to give (R)-N-[6-(2-chloro-5-fluorophenyl)-3-cyano-8-oxo-l, 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] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 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

194

SUBSTITUTE SHEET (RULE 26) 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-l,6,7,8-tet rahydropyrrolo[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] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 15.22 (s, 1H), 10.40 (s, 1H), 9.41 (s, 1H), 8.67 (d, J = 7.6 Hz, 1H), 8.33 (d, .7= 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).

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

[00482] Step A: To a solution of 3-(2-chloro-5-fluorophenyl)-4-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)-3-hydroxy-2-[(4-meth oxyphenyl)methyl]-l-oxo-2,3- dihydro-lH-pyrrolo[4,3-f]quinoline 6-oxide (200 mg, 0.299 mmol), TosCI (170.72 mg, 0.896 mmol) in DCM (10 mL) was added NH4OH (1 mL, 29.8 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for lb. TLC indicated the reaction was completed. The cooled reaction mixture was washed with water (60 mL) and extracted with DCM (60 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0-100%) to give N-[7-amino-3-(2- chloro-5-fluorophenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl] -l-oxo-2,3-dihydro-lH- pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)ben zamide (60 mg, 0.090 mmol, 30%) as a white solid. LCMS: m/z 669.11 [M + H] ⁺

[00483] Step B: To a solution of N-[7-amino-3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]- 1 -oxo-2, 3 -dihydro- 1 H-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 prep-HPLC to give N-(7-amino-3-(2-chloro-5-

195

5UB5TITUTE SHEET (RULE 26) fluorophenyl)-l-oxo-2,3-dihydro-lH-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] ⁺ . ^J H NMR (400 MHz, Methanol-d4) 5 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).

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-(trifluorom ethyl)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-(trifluorom ethyl)benzamide

[00484] 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-(trifluorom ethyl)benzamide (90 mg) was separated by prep-SFC to give Example 42 32.1 mg, LCMS: m/z 546 [M+H] ⁺ . ^! H NMR (400 MHz, DMSO-d6) 5 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). And Example 43 33.5 mg, LCMS: m/z 546 [M+H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 5 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 N-[6-(2-chloro-5-fluorophenyl)-2,3-dimethyl-8-oxo-7,8-dihydr o-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide

196

SUBSTITUTE SHEET (RULE 26)

[00485] 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 H2O (2 mL) was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (0.430 mL, 1.504 mmol), K2CO3 (577 mg, 4.178 mmol) and Pd(dppf)C12 (122 mg, 0.167 mmol). The reaction mixture was stirred at 90 °C under N2 atmosphere for 3 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 eluted with ethyl acetate in petroleum ether (0-40% gradient) to afford 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]+. [00486] 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 H2O (2 mL) was added NH4C1 (338 mg, 6.33 mmol) and Fe (353 mg, 6.33 mmol) at rt. The reaction mixture was

197

SUBSTITUTE SHEET (RULE 26) 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 eluted with PE in EA (gradient: 0-80%) to afford (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]+.

[00487] 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)2 (328 mg, 2.799 mmol) and Pd(PPh3)4 (538 mg, 0.466 mmol). The reaction mixture was stirred at 150 °C under N2 atmosphere for 1 h. The cooled reaction mixture was diluted with EA and water. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (0-80% gradient) to afford 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]+.

[00488] 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 H2O (1 mL) was added KOH (164 mg, 2.91 mmol) at 25 °C. The reaction mixture was stirred at 25 oC for 0.5 h. The reaction mixture was diluted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 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]+.

[00489] 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 added Py (0.094 mL, 1.164 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (105 mg, 0.466 mmol) at rt. The reaction mixture was stirred at rt for 10 min. The reaction solution was diluted with water and EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,3-dimethyl-8-oxo- 7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (180 mg, 0.261 mmol, 67%) as a green solid, which was used in next step without further purification. LCMS: m/z 551 [M + H]+.

198

SUBSTITUTE SHEET (RULE 26) [00490] Step F: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2,3-dimethyl-8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluo romethyl)benzamide (180 mg, 0.261 mmol) in triethylsilane (5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at it The reaction mixture was stirred at 70 °C for 5 hr. The cooled reaction mixture was concentrated.

The residue was purified by prep-HPLC to afford 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 (28.6 mg, 0.053 mmol, 20%). LCMS: m/z 535 [M + H]+. 1H NMR (400 MHz, DMSO-d6) 6 10.28 (s, 1H), 8.93 (brs, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.75 - 7.72 (m, 2H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.22 (brs, 1H), 4.16 (s, 3H), 2.67 (s, 3H).

Example 45 N-(3-(aminomethyl)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-ox o-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00491] To a solution of N-[5-(5-chloro-2-fluorophenyl)-3-cyano-2-methyl-7-oxo-6,7- dihydro-5H-pyrrolo[4,3-f]indazol-4-yl]-5-fluoro-3-(trifluoro methyl)benzamide (25 mg, 46 pmol) in MeOH (2 mL) was added Raney Ni (5 mg). The reaction mixture was stirred at 40 °C under Hi using a Hi balloon for 2h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC to afforded N-[3-(aminomethyl)-5-(5-chloro-2- fluorophenyl)-2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]in dazol-4-yl]-5-fluoro-3- (trifluoromethyl)benzamide (6 mg, 11 pmol, 24%). LCMS: m/z 548 [M-H]". 'H NMR (400 MHz,

Methanol-d4) 5 8.40 (s, 1H), 8.04 (s, 1H), 7.72 (d, J= 6.2 Hz, 2H), 7.65 (d, J= 8.8 Hz, 1H), 7.26 (dd, J= 8.8, 5.0 Hz, 1H), 6.99 (t, J= 7.0 Hz, 1H), 6.36 (s, 1H), 4.63 (s, 2H), 4.37 (s, 3H).

Example 46 N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

199

SUBSTITUTE SHEET (RULE 26)

[00492] Step A: 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 eq) and Fe (259 mg, 4.65 mmol, 5.0 eq) in EtOH (10 mL) was added NEUC1 (25 mg, 0.47 mmol, 0.5 eq) in FEO (5 mL) dropwise at 50 °C. The reaction mixture was heated to 90 °C and stirred for 1 h. Then the mixture was added water (10 mL) and EtOAc (5 mL), filtered, then the filtrate was extracted with EtOAc (15 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SC>4 and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ EtOAc = 3:1) to give (5-amino-7-bromo-3-iodo-2-methyl-2H-indazol-6-yl)(2-chloro-5 - fluorophenyl)methanone (400 mg, 84.7%) as a red oil. LCMS: m/z 507.8, 509.9 ([M+H] ⁺ ). [00493] Step B: To a solution of(5-amino-7-bromo-3-iodo-2-methyl-2H-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (500 mg, 0.98 mmol, 1.0 eq) in MeOH (5 mL) was added. PtO;> (200 mg). The reaction mixture was heated to 40 °C and stirred for 12 h. The mixture

200

SUBSTITUTE SHEET (RULE 26) was filtered, and the filtrate was concentrated to give (5-amino-7-bromo-2-methyl-2H-indazoL6- yl)(2-chloro-5-fluorophenyl)methanone (600 mg. crude) as a brown oil. LCMS: m/z 382.0, 383.9 ([M+H] ⁺ ).

[00494] Step C: A sealed vial was charged with (5-amino-7-bromo-2-methyl-2H-indazol-6- yl)(2-chloro-5-fluorophenyl)methanone (50 mg, 0.13 mmol, 1.0 eq), Zn(CN)2 (46 mg, 0.39 mmol, 3.0 eq), Pd(PPhs)4 (76 mg, 0.066 mmol, 0.5 eq) and DMAc (1 mL). The sealed vial was irradiated in the microwave at 160 °C for 0.5 h. The mixture was added water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine (5 mL x 2), dried over Na2SO4 and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ EtOAc = 1 : 1) to give 5-amino-6-(2-chloro-5-fluorobenzoyl)- 2-methyl-2H-indazole-7-carbonitrile (40 mg, 93.1%) as brown oil. LCMS: m/z 329.1 ([M+H] ⁺ ).

[00495] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-methyl-2H- indazole-7-carbonitrile (50 mg, 0.15 mmol, 1.0 eq) in MeCN (1 mL) / H2O (0.1 mL) was added KOH (5 mg, 0.085 mmol, 0.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 4 h The mixture was added water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine (5 mL x 2), dried over Na2SO4 and concentrated to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-6,7- dihydropyrrolo[3,4-g]indazol-8(2H)-one (50 mg, crude) as yellow oil and directly used for the next step. LCMS: m/z 347.0, 349.1 ([M-C1+H] ⁺ ).

[00496] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl- 6,7-dihydropyrrolo[3,4-g]indazol-8(2H)-one (50 mg, 0.14 mmol, 1.0 eq) in ACN (1 mL) was added 3 -fluoro-5 -(trifluoromethyl) benzoyl chloride (98 mg, 0.43 mmol, 3.0 eq) and Pyridine (57 mg, 0.72 mmol, 5.0 eq). The reaction mixture was stirred at 30 °C for 4 h Then the mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL x 2). The combined organic phases were washed with brine (3 mL), dried over Na2SO4 and concentrated to give N-(6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyr rolo[3,4-g]indazol-5-yl)-3-fluoro- 5-(trifluoromethyl)benzamide (60 mg, crude) as a red oil. LCMS: m/z 535.0 ([M-H]").

[00497] Step F: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (60 mg, 0.11 mmol, 1.0 eq) in TEA (1 mL) was added EtsSiH (65 mg, 0.56 mmol, 5.0 eq). The reaction mixture was heated to 40 °C and stirred for 2 h. Then the reaction mixture was concentrated to

201

SUBSTITUTE SHEET (RULE 26) give a residue. The residue was purified by prep-HPLC (acetonitrile with 0.1% FA in water 35% to 55%) to give N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-2,6,7,8-tetrah ydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (4.0 mg, 5% yield for 3 steps). LCMS: m/z 518.7 ([M-H]-). ¹ H NMR (400 MHz, DMSO-d6): § ppm 10.30 (brs, 1H), 9.13 - 8.75 (m, 1H), 8.57 (s, 1H), 7.93 (d, J= 8.8 Hz, 1H), 7.86 (s, 1H), 7.80 - 7.62 (m, 2H), 7.28 (dd, J= 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.52 - 6.00 (m, 1H), 4.27 (s, 3H).

Example 47 N-[3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-pyrrolo[ 3,4- f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[00498] Step A: To a stirred solution of 3,5-dibromobenzene-l-carbaldehyde (25 g, 94.7 mmol) in MeOH (50 mL) was added 2-amino- 1,1 -di ethoxy ethane (15.2 mL, 104 mmol). The reaction was stirred at room temperature for 2 hr. Sodium cyanoboranuide (11.9 g, 189 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and diluted with EA and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using

202

SUBSTITUTE SHEET (RULE 26) silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0- 30%) to afford compound 2-{[(3,5-dibromophenyl)methyl]amino}-l,l-diethoxyethane (32 g, 83 mmol, 89%) as a yellow oil. LCMS: m/z 381.11 [M+H] ⁺ .

[00499] Step B: To a stirred solvent of chloranesulfonic acid (49.8 mL, 748 mmol) cooled to - 10 °C was added dropwise 2-{[(3,5-dibromophenyl)methyl]amino]-l,l-diethoxyethane (28.5 g, 74.8 mmol). The reaction mixture was stirred at 90 °C for 1 hr. The cooled reaction mixture was diluted with DCM and ice-water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound 5,7- dibromoisoquinoline (3.5 g, 12.2 mmol, 16%) as a brown solid. LCMS: m/z 286.95 [M+H] ⁺ . [00500] Step C: To a solution of 5,7-dibromoisoquinoline (3.34 g, 11.6 mmol) in THF (10 mL) was added dropwise LDA (11.6 mL, 23.3 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 20 min. A solution of 2-chloro-5-fluorobenzene-l-carbaldehyde (2.03 g, 12.8 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at -78 °C for 1 hr. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound (2-chloro-5-fluorophenyl)(5,7-dibromoisoquinolin-6-yl)methan ol (2.4 g, 5.39 mmol, 46%) as a brown solid. LCMS: m/z 445.51 [M+H] ⁺ .

[00501] Step D: To a mixture of (2-chloro-5-fluorophenyl)(5,7-dibromoisoquinolin-6- yl)methanol (2.33 g, 5.23 mmol) in DCM (10 mL) was added l,l,l-triacetoxy-l,3-dihydro-lX5- benzo[d][l,2]iodoxol-3-one (2.22 g, 5.23 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with EtOAc twice. The organic phase was washed with brine, dried with NazSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound (2-chloro-5-fluorophenyl)(5,7-dibromoisoquinolin- 6-yl)methanone (1.6 g, 3.61 mmol, 67%) as a red solid. LCMS: m/z 443.49 [M+H] ⁺ .

[00502] Step E: To a solution of (2-chloro-5-fluorophenyl)(5,7-dibromoisoquinolin-6- yl)methanone (700 mg, 1.58 mmol) in dioxane (5 ml) were added 3-fluoro-5- (trifluoromethyl)benzene-l -carboxamide (327 mg, 1.578 mmol), Pd2(dba)s (145 mg, 0.158 mmol), Xant-PHOS (183 mg, 0.316 mmol) and CS2CO3 (1.54 g, 4.74 mmol). The reaction

203

SUBSTITUTE SHEET (RULE 26) mixture was stirred at 100 °C under N2 for 1 hr. The cooled reaction mixture 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 eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound N-(5-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]isoquinolin-7-yl}-5-fluoro-3-(trifluor omethyl)benzamide (200 mg, 0.351 mmol, 22%) as a yellow oil. LCMS: m/z 569.71 [M+H] ⁺ .

[00503] Step F: To a solution of N-{5-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]isoquinolin-7-yl}-5-fluoro-3-(trifluor omethyl)benzamide (200 mg, 0.351 mmol) in NMP (2 mL) was added CuCN (62.9 mg, 0.702 mmol). The reaction was stirred at 120 °C for 3 hr. The cooled reaction mixture was diluted with EA and water. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluted with methanol in di chloroform (gradient: 0-10%) to afford compound N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5-cyanoisoquinolin- 7-yl}-5-fluoro- 3-(trifluoromethyl)benzamide (150 mg, 0.204 mmol, 58%) as a yellow oil. LCMS: m/z 515.82 [M+H] ⁺ .

[00504] Step G: To a solution of N-{6-[(2-chloro-5-fluorophenyl)carbonyl]-5- cyanoisoquinolin-7-yl}-5-fluoro-3-(trifluoromethyl)benzamide (100 mg, 0.194 mmol) in acetonitrile (5 mL) and H2O (0.5 mL) was added KOH (21.8 mg, 0.388 mmol). The reaction was stirred at room temperature for 2 hr. 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 eluted with methanol in dichloroform (gradient: 0-10%) to afford compound N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo-2,3-dihydro-l H- pyrrolo[4,3-f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl) benzamide (40 mg, 0.075 mmol, 39%) as a white solid. LCMS: m/z 533.84 [M+H] ⁺ .

[00505] Step H: To a solution of N-[3-(2-chloro-5-fluorophenyl)-3-hydroxy-l-oxo-2,3- dihydro-lH-pyrrolo[4,3-f]isoquinolin-4-yl]-5-fluoro-3-(trifl uoromethyl)benzamide (40 mg, 0.075 mmol) in TFA (3 mL) was added EtaSiH (1 mL). The reaction was stirred at 70 °C for 8 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0-100 % acetonitrile in H2O) to afford compound N-[3-(2-chloro-5-fluorophenyl)-l-oxo-2,3- dihydro-lH-pyrrolo[3,4-f]isoquinolin-4-yl]-5-fluoro-3-(trifl uoromethyl)benzamide (23.4 mg, 0.045 mmol, 60%). LCMS: m/z 517.84 [M+H] ⁺ . ^! HNMR (400 MHz, DMSO-d6) 5 10.81 (s,

204

SUBSTITUTE SHEET (RULE 26) 1H), 9.64 (s, 1H), 9.49 (s, 1H), 8.98 (d, J = 6.0 Hz, 1H), 8.75 (d, J = 6.0 Hz, 1H), 8.37 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.34 (dd, J = 8.8, 5.2 Hz, 1H), 7.12 (t, J = 6.9 Hz, 1H), 6.24 (s, 1H).

Example 48 N-(2-acetamido-6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro -6H- thiazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)be nzamide

[00506] Step A: To a solution of methyl 6-amino-3-bromo-2-fluorobenzoate (10 g, 39.9 mmol) in AcOH (100 mL) was Bn (7.03 g, 43.9 mmol) and potassium thiocyanate (9.72 g, 99.9 mmol) at 0 °C - 25 °C. The reaction mixture was stirred at 25 °C for 18h under N2. TEC indicated the reaction was completed. The cooled reaction mixture was concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0-100%) to give methyl 2-amino-6-bromo-5-fluoro-4,5-dihydrocyclohexa[l,2-d][l,3]thi azole-4-carboxylate (2.6 g, 8.46 mmol, 21%) as a white solid.

[00507] Step B: To a solution of methyl 2-amino-6-bromo-5-fluorobenzo[d]thiazole-4- carboxylate (3.04 g, 10.01 mmol) in DMF (20 mL) was acetyl chloride (2.3 g, 30.0 mmol), DCM

205

SUBSTITUTE SHEET (RULE 26) (15 mL) and DIEA (6.5 g, 50.0 mmol) at 0 °C - 25 °C. The reaction mixture was stirred at

35 °C for 18h under N2. TLC indicated the reaction was completed. The cooled reaction mixture was concentrated. The residue was purified by a silica gel column chromatography eluted with PE in EA (gradient: 0-100%) to give methyl 2-acetamido-6-bromo-5-fluorobenzo[d]thiazole-4- carboxylate (2.77 g, 8.01 mmol, 80%) as a white solid.

[00508] Step C: To a solution of methyl 2-acetamido-6-bromo-5-fluorobenzo[d]thiazole-4- carboxylate (1 g, 3.39 mmol) in THF (10 mL) was added a solution of LiOH'lLO (0.43 g, 10.3 mmol) in H2O (3 mL). The mixture was stirred at 50 °C for 3 hr. The reaction mixture was poured into HC1 (20 mL, 0.2 mmol/mL) and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 2-acetamido-6- bromo-5-fluorobenzo[d]thiazole-4-carboxylic acid (0.81 g, 2.88 mmol, 85%) as a white solid. LCMS: m/z 333.14 [M + H] ⁺

[00509] Step D: To a solution of 2-acetamido-6-bromo-5-fluorobenzo[d]thiazole-4-carboxylic acid (3.24 g, 9.79 mmol), 2-chloro-5-fluorobenzene-l-carbaldehyde (1.55 g, 9.79 mmol), PMBNH ₂ (1.34 g, 9.79 mmol) in MeOH (30 mL) was added Z-BuNC (0.81 g, 9.79 mmol). The mixture was stirred at 25 °C for 18hr. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was washed with brine, dried over Na2$O4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give 2-acetamido-6-bromo-N-(2-(tert-butylamino)- l-(2-chloro-5-fluorophenyl)-2-oxoethyl)-5-fluoro-N-(4-methox ybenzyl)benzo[d]thiazole-4- carboxamide (4.38 g, 6.32 mmol, 63%) as a yellow solid. LCMS: m/z 693.12 [M + H] ⁺ [00510] Step E: To a solution of 2-acetamido-6-bromo-N-(2-(tert-butylamino)-l-(2-chloro-5- fluorophenyl)-2-oxoethyl)-5-fluoro-N-(4-methoxybenzyl)benzo[ d]thiazole-4-carboxamide (1.09 g, 1.57 mmol) in DMSO-d6 (15 mL) was potassium tert-butoxide (0.53 g, 4.71 mmol). The mixture was stirred at 25 °C for 13hr. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic layer was washed with brine, dried over Na2$O4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give N-(5-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4- methoxybenzyl)-8-oxo-7,8-dihydro-6H-thiazolo[4,5-e]isoindol- 2-yl)acetamide (0.555 g, 0.942 mmol, 60%) as a yellow oil. LCMS: m/z 590.12 [M + H] ⁺

206

SUBSTITUTE SHEET (RULE 26) [00511] Step F: To a solution of N-(5-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-(4- methoxybenzyl)-8-oxo-7,8-dihydro-6H-thiazolo[4,5-e]isoindol- 2-yl)acetamide (0.33 g, 0.562 mmol) in TFA (10 mL) was added triethylsilane (0.227 mL, 1.41 mmol). The mixture was stirred at 75 °C for 1.5hr. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous water (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over MgSCL, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give N-(5-bromo-6-(2-chloro-5- fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-7,8-dihydro-6H-thiaz olo[4,5-e]isoindol-2- yl)acetamide (0.25 g, 0.444 mmol, 79%) as a yellow solid. LCMS: m/z 573.12 [M + H] ⁺ [00512] Step G: To a mixture of N-(5-bromo-6-(2-chloro-5-fluorophenyl)-7-(4- methoxybenzyl)-8-oxo-7,8-dihydro-6H-thiazolo[4,5-e]isoindol- 2-yl)acetamide (0.22 g, 0.386 mmol) and 3-fluoro-5-(trifluoromethyl)benzene-l-carboxamide (0.10 g, 0.502 mmol) in dioxane (20 mL) was added Xant-PHOS (0.02 g, 0.039 mmol), Pd2(dba)3 (0.02 g, 0.039 mmol) and CS2CO3 (0.38 g, 1.159 mmol). The reaction mixture was stirred at 85 °C under N2 for 16hr. The cooled reaction mixture was concentrated. The residue was poured into saturated aqueous water (20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) give N-(2-acetamido-6-(2-chloro- 5-fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-7,8-dihydro-6H-thi azolo[4,5-e]isoindol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (0.030 g, 0.04 mmol, 13%) as a yellow solid. LCMS: m/z 701.12 [M + H] ⁺

[00513] Step H: To a solution of N-(2-acetamido-6-(2-chloro-5-fluorophenyl)-7-(4- methoxybenzyl)-8-oxo-7,8-dihydro-6H-thiazolo[4,5-e]isoindol- 5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (12 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 reaction 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 prep-HPLC to N-(2-acetamido-6-(2-chloro-5- fluorophenyl)-8-oxo-7,8-dihydro-6H-thiazolo[4,5-e]isoindol-5 -yl)-3-fluoro-5- (trifluoromethyl)benzamide (1.2 mg, 0.003 mmol, 11%). LCMS: m/z 581.12 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 13.06 (brs, 1H), 10.65 (s, 1H), 9.20 (s, 1H), 8.31 (s, 1H), 8.13 (d, J =

207

SUBSTITUTE SHEET (RULE 26) 8.4 Hz, 1H), 7.96 - 7.79 (m, 3H), 7.50 - 7.46 (m, 1H), 7.27 (t, 6.9 Hz, 1H), 6.84 (brs, 1H),

6.23 (brs, 1H), 2.43 (s, 3H).

Example 49 N-(6-(2-chloro-5-fluorophenyl)-3-ethyl-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00514] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitro-2/f-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (2 g, 3.71 mmol) in dioxane (30 mL) and H2O (6 mL) was added K2CO3 (1.03 g, 7.43 mmol), Vinylboronic acid trifluoroborate potassium salt (47.7 mg, 0.36 mmol) and bis[5-(diphenylphosphanyl)cyclopenta-l,3-dienyl]-X2-iron(II) palladium chloride (0.27 g, 0.37 mmol). The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford compound (7- bromo-2-methyl-5-nitro-3-vinyl-277-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1.3 g, 2.82 mmol, 76%) as a yellow solid. LCMS: m/z 438 [M + H] ⁺ .

208

SUBSTITUTE SHEET (RULE 26) [00515] Step B: To a solution of (7-bromo-2-methyl-5-nitro-3-vinyl-27/-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (1.35 g, 3.09 mmol) in EtOH (21 mL) and H2O (7 mL) was added Fe (1.03 g, 18.5 mmol) and NH4CI (0.49 g, 9.2 mmol). The reaction mixture was stirred at 80 °C for 3 h. The cooled reaction mixture was filtered through Buchner funnel and washed with EA. The filtrate was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in di chloroform to afford compound (5- amino-7-bromo-2-methyl-3-vinyl-2H-indazol-6-yl)(2-chloro-5-f luorophenyl)methanone (1 g, 2.23 mmol, 72%) as a yellow solid. LCMS: m/z 408 [M + H] ⁺ .

[00516] Step C: To a solution of (5-amino-7-bromo-2-methyl-3-vinyl-27Z-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (1 g, 2.45 mmol) in DMA (20 mL) was added Zn(CN)2 (0.86 g, 7.34 mmol) and Pd(PPh3)4 (0.7 g, 0.5 mmol). The reaction mixture was stirred at 150 °C for 2h. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford compound 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-methyl-3-vinyl-2H-ind azole-7-carbonitrile (400 mg, 1.02 mmol, 42%) as a yellow solid. LCMS: m/z 355 [M + H] ⁺ .

[00517] Step D: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3- vinylindazole-7-carbonitrile (400 mg, 1.13 mmol) in CH3CN (3 mL) and H2O (0.3 mL) was added KOH (190 mg, 3.4 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound 5-amino-6- (2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3-vinyl-6,7-dih ydropyrrolo[3,4-g]indazol-8(2//)- one (330 mg, 0.8 mmol, 71%) as a yellow solid. LCMS: m/z 373 [M + H] ⁺ .

[00518] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3- vinyl-6,7-dihydropyrrolo[3,4-g]indazol-8(2/7)-one (180 mg, 0.5 mmol) in CH3CN (5 mL) was added Pyridine (0.2 mL, 2.5 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (330 mg, 1.5 mmol), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The organic layer was concentrated under vacuum afford compound JV-(6-(2- chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-3-vinyl-2,6, 7,8-tetrahydropyrrolo[3,4-

209

SUBSTITUTE SHEET (RULE 26) g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (250 mg, 0.36 mmol, 74%) as a yellow solid. LCMS: m/z 563 [M + H] ⁺ .

[00519] Step F: To a solution of A-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-vinyl-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluo ro-5-(trifluoromethyl)benzamide (250 mg, 0.44 mmol) in IF A (5 mL) was added EtaSiH (258 mg, 2.22 mmol), and the mixture was stirred at 70 °C for 1 hour. The cooled reaction mixture was concentrated under vacuum.

The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound /V-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-vinyl- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (200 mg, 0.32 mmol, 71%) as a yellow solid. LCMS: m/z 547 [M + H] ⁺ .

[00520] Step G: To a solution of N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-vinyl-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (20 mg, 0.04 mmol) in MeOH (1 mL) was added Pd/C 10% (0.39 g, O.Olmmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by prep- HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-ethyl-2-methyl-8-oxo-7,8-di hydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (4.8 mg, O.Olmmol, 24%). LCMS: m/z 549 [M + H] ⁺ . ^X H NMR (400 MHz, Methanol-d4) 7.87 (s, 1H), 7.69 - 7.63 (m, 3H), 7.24 (dd, J= 8.8, 5.0 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.45 - 6.35 (m, 2H), 4.23 (s, 3H), 3.18 (q, J = 7.6 Hz, 2H), 1.37 (t, J= 7.6 Hz, 3H).

Example 50 (R* )-N-((R)-6-(2-chloro-5-fluorophenyl)-3-isocyano-2-methyl-8-o xo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluoro-3-hydroxy-3-( trifluoromethyl)indoline-l- carboxamide and Example 51 (R*)-N-((S)-6-(2-chloro-5-fluorophenyl)-3-isocyano-2- methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5 -fluoro-3-hydroxy-3- (trifluoromethyl)indolme-l-carboxamide

210

SUBSTITUTE SHEET (RULE 26)

[00521] Step A: To a solution of 4-amino-5-(5-chloro-2-fluorophenyl)-5-hydroxy-2-methyl- 7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]indazole-3-carbonitrile (400 mg, 1.08 mmol) in TFA (10 mL) was added EtsSiH (0.5 mL). The reaction mixture was stirred at 40 °C for 2 h. The cooled reaction mixture was concentrated. The residue was diluted with EA and saturated NaHCCb solution. The organic phase was washed with brine, dried over Na2$O4 and concentrated to give 4-amino-5-(5-chloro-2-fluorophenyl)-2-methyl-7-oxo-6,7-dihyd ro-5H-pyrrolo[4,3- f]indazole-3 -carbonitrile (250 mg, 0.703 mmol, 65%) as a brown solid. LCMS: m/z 356 [M + H] ⁺ [00522] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazole-3 -carbonitrile (30 mg, 0.084 mmol) in DCM (5 mL) was added Py (0.014 mL, 0.169 mmol) and trichloromethyl [(trichloromethyl)oxy]methanoate (12.5 mg, 0.042 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. A solution of rel-(R)-5-fluoro-3-(trifluoromethyl)indolin-3-ol (22.38 mg, 0.101 mmol) in DCM (1 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction was diluted with

H2O. The aqueous layer was extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluted with methanol in DCM (gradient: 0~9%) and then by prep-HPLC to afford Example 50 (2 mg, 0.0033 mmol, 9%), LCMS: m/z 603 [M + H] ⁺ , NMR (400 MHz, DMSO-d6) 5 9.18 (s, 1H), 8.85 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.44 (s, 1H), 7.35 (dd, J= 8.8, 5.2 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.23 (d, J= 8.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.37 (s, 1H), 6.24 (s, 1H), 4.44 (s, 3H), 3.96 (d, J= 12.0 Hz, 1H), 3.58 (brs, 1H), and Example 51 (2.3 mg, 0.0038 mmol, 8.5%) as a white solid. LCMS: m/z 603 [M + H] ⁺ . ^X HNMR (400 MHz, DMSO- d6) 8 9.18 (s, 1H), 8.85 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.44 (s, 1H), 7.35 (dd, J= 8.8, 5.2 Hz,

211

SUBSTITUTE SHEET (RULE 26) 1H), 7.31 - 7.24 (m, 1H), 7.23 (d, J= 8.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.37 (s, 1H), 6.24 (s, 1H), 4.44 (s, 3H), 4.18 - 4.15 (m, 1H), 3.58 (brs, 1H).

Example 52 7V-(6-(2-chloro-5-fluorophenyl)-3-(difluoromethyl)-2-methyl- 8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00523] Step A: To a solution of7V-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-vinyl- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (80 mg, 0.15 mmol) in dioxane (6 mL) and H2O (2 mL) was added sodium periodate (95 mg, 0.45 mmol) and dipotassium dioxidodioxo-X6-osmium(VI) dihydrate (5.4 mg, 0.015 mmol). The reaction mixture was stirred at 25 °C for 2h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over ISfeSCh and concentrated to afford compound 7V-(6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (40 mg, 0.045 mmol, 46%) as a yellow solid. LCMS: m/z 549 [M + H] ⁺ .

[00524] Step B: To a solution of 7V-(6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (40 mg, 0.073 mmol) in DCM (3 mL) was added DAST (23.5 mg, 0.15 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using prep-HPLC (YMC-Actus Triart Cl 8 150*20mm*5um, 40%-95%, phase A: H2O(0.1%FA), phase B: MeCN) to afford compound 7V-(6-(2-chloro-5-fluorophenyl)-3- (difluoromethyl)-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3, 4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (8.4 mg, 0.014 mmol, 20%). LCMS: m/z 571 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.42 (s, 1H), 9.29 - 8.84 (m, 1H), 7.98 - 7.67 (m, 5H), 7.32 - 7.27 (m, 1H), 7.14 - 7.04 (m, 1H), 6.60 - 5.70 (m, 2H), 4.36 (s, 3H).

212

SUBSTITUTE SHEET (RULE 26) Example 53 N-(3-amino-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide and Example

61 N-(6-(2-chloro-5-fluorophenyl)-2-methyl-3-(methylamino)-8-ox o-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00525] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1 g, 1.8 mmol) in dioxane (10 mL) was added 2-methylpropan-2-yl

213

SUBSTITUTE SHEET (RULE 26) aminomethanoate (0.3 g, 2.7 mmol), Pd2(dba)s (0.17 g, 0.18 mmol), Xant-PHOS (0.2 g, 0.37 mmol) and CS2CO3 (1.8 g, 5.5 mmol). The reaction mixture was stirred at 85 °C for 16 h. The cooled reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SOi and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-40%) to give 2-methylpropan-2- yl ({7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-5-n itroindazol-3- yl}amino)m ethanoate (600 mg, 1.13 mmol, 61%) as a yellow soild. LCMS: m/z 526 [M+H] ⁺ [00526] Step B: To a solution of 2-methylpropan-2-yl ({7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazol-3-yl}amino)me thanoate (600 mg, 1.13 mmol) in EtOH (5 mL) and H2O (5 mL) was added Fe (634. mg, 11.3 mmol) and NH4CI (608 mg, 11 mmol). The reaction mixture was stirred at 80 °C for 2 h. The cooled reaction mixture was filtered, and the filtrate was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2$O4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-40%) to give 2-methylpropan-2- yl ({5-amino-7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-me thylindazol-3- yl]amino)m ethanoate (270 mg, 0.54 mmol, 48%) as a yellow solid. LCMS: m/z 497 [M+H] ⁺ [00527] Step C: To a solution of 2-methylpropan-2-yl ({5-amino-7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methylindazol-3-yl}amino)methanoate (240 mg, 0.48 mmol) in MeCN (10 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (218 mg, 0.96 mmol) and pyridine (0.19 mL, 2.4 mmol). The reaction mixture was stirred at 50 °C for 2 h. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-40%) to give 2-methylpropan-2-yl ({7-bromo-6-[(2- chloro-5-fluorophenyl)carbonyl]-5-({[5-fluoro-3-(trifluorome thyl)phenyl]carbonyl}amino)-2- methylindazol-3-yl}amino)methanoate (250 mg, 0.36 mmol, 75%) as a yellow solid. LCMS: m/z 687 [M+H] ⁺

[00528] Step D: To a solution of 2-methylpropan-2-yl ({7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-5-({[5-fluoro-3-(trifluoromethyl)phen yl]carbonyl}amino)-2- methylindazol-3-yl}amino)methanoate (230 mg, 0.33 mmol) in DCM (5 mL) was added TEA (0.3 mL, 3.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The residue was concentrated in vacuum to give the residue N-{3-amino-7-bromo-6-[(2-chloro-5-

214

SUBSTITUTE SHEET (RULE 26) fluorophenyl)carbonyl]-2-methylindazol-5-yl}-5-fluoro-3-(tri fluoromethyl)benzamide (150 mg, 0.255 mmol, 76%) as a yellow solid. LCMS: m/z 587 [M+H] ⁺

[00529] Step E: To a solution of N-{3-amino-7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methylindazol-5-yl}-5-fluoro-3-(tri fluoromethyl)benzamide (130 mg, 0.22 mmol) in DMA (3 mL) was added Zn(CN)2 (51.9 mg, 0.44 mmol) and Pd(PPh3)4 (25.5 mg, 0.02 mmol). The reaction mixture was stirred at 150 °C for 1 h under microwave. The cooled reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over JSfeSCU and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-80%) to give N-{3-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methylindazol-5-yl}-5-fluor o-3-(trifluoromethyl)benzamide (80 mg, 0.15 mmol, 68%) as a yellow soild. LCMS: m/z 534 [M+H] ⁺

[00530] Step F: To a solution of N-{3-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano- 2-methylindazol-5-yl}-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.15 mmol) in MeCN (2 mL) and ELO (1 mL) was added KOH (84.0 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to give N-[3-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8- oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (50 mg, 0.09 mmol, 60%) as a light yellow soild. LCMS: m/z 552 [M+H] ⁺

[00531] Step G: To a solution of N-[3-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3-

(trifluoromethyl)benzamide (50 mg, 0.09 mmol) in TFA (5 mL) was added triethoxysilane (148 mg, 0.9 mmol). The reaction mixture was stirred at 50 °C for 1 h. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to give N-[3-amino-6-(2-chloro-5- fluorophenyl)-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]in dazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (20 mg, 0.03 mmol, 41%). ¹ H NMR (400 MHz, DMSO-d6) 5 10.10 (s, 1H), 8.71 (brs, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.78 - 7.69 (m, 3H), 7.30 - 7.20 (m, 1H), 7.08 (d, J = 10.4 Hz, 1H), 6.48 (s, 2H), 5.98 (s, 1H), 3.86 (s, 3H). LCMS: m/z 536 [M+H] ⁺

[00532] Step H: To a solution of N-[3-amino-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifl uoromethyl)benzamide (20 mg, 0.03

215

SUBSTITUTE SHEET (RULE 26) mmol) in DCM (5 mL) was added paraformaldehyde (5 mg, mmol) and AcOH (0.002 mL, 0.037 mmol). The reaction mixture was stirred at room temperature for 2 h. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified by prep-HPLC to give N-[6-(2-chloro-5- fluorophenyl)-2-methyl-3-(methylamino)-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (5.2 mg, 0.009 mmol, 25%). ^ NMR (400 MHz, DMSO- d6) 5 10.11 (s, 1H), 8.72 (s, 1H), 7.99 - 7.81 (m, 2H), 7.73 - 7.70 (m, 2H), 7.27 (dd, J = 8.6, 5.2 Hz, 1H), 7.08 (s, 1H), 6.44 (s, 1H), 5.99 (s, 1H), 3.85 (s, 3H), 3.15 (d, J = 5.0 Hz, 3H). LCMS: m/z 550 [M+H] ⁺

Example 54 N-[6-(2-chloro-5-fluorophenyl)-3-fluoro-2-methyl-8-oxo-7,8-d ihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide

[00533] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (2 g, 3.71 mmol) in THF (50 mL) was added dropwise butyllithium (1.34 mL, 3.34 mmol) at -65 °C. The resulting mixture was stirred at -65 °C for 20 min. The

216

SUBSTITUTE SHEET (RULE 26) reaction mixture was quenched by adding sat. aq. NH4CI solution, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel with EA in PE (0— >50%, V/V) to give (7-bromo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5-fluorophen yl)methanone (700 mg, 1.697 mmol, 46%) as a yellow solid. LCMS: m/z 412 [M + H] ⁺ .

[00534] Step B: To a solution of (7-bromo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (0.8 g, 1.94 mmol) in ACN (10 mL) was added 4-(chloromethyl)-l- fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium bis(tetrafluoro-X5-boranuide) (1.37 g, 3.878 mmol) at rt. The reaction mixture was stirred at 80 °C overnight. The cooled reaction solution was diluted with EA. The organic phase was washed with brine, dried over anhydrous Na2$O4 and concentrated. The residue was purified by column chromatography on silica gel with EA in PE (0— >30%, V/V) to give (7-bromo-3-fluoro-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (330 mg, 0.766 mmol, 40%) as a yellow solid. LCMS: m/z 430 [M + H] ⁺ .

[00535] Step C: To a solution of (7-bromo-3-fluoro-2-methyl-5-nitroindazol-6-yl)(2-chloro- 5-fluorophenyl)methanone (330 mg, 0.766 mmol) in ethanol (5 mL) and H2O (0.5 mL) was added NH4CI (204 mg, 3.83 mmol) and Fe (213 mg, 3.83 mmol) at rt. The reaction mixture was degassed with N2 and stirred at 90 °C under N2 atmosphere for 2 h. The cooled reaction mixture was filtered to move Fe. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with PE in EA (gradient: 0-30%) to afford (5-amino-7-bromo-3- fluoro-2-methylindazol-6-yl)(2-chloro-5-fluorophenyl)methano ne (140 mg, 0,349 mmol, 46%) as a red solid. LCMS: m/z 400 [M + H] ⁺ .

[00536] Step D: To a solution of (5-amino-7-bromo-3-fluoro-2-methylindazol-6-yl)(2-chloro- 5-fluorophenyl)methanone (110 mg, 0.275 mmol) in DMA (3 mL) was added Zn(CN)2 (96.7 mg, 0.824 mmol) and Pd(PPh3)4 (31.7 mg, 0.027 mmol). The reaction mixture was degassed with N2 stirred at 150 °Cunder N2 atmosphere for 1 h under microwave. The cooled reaction mixture was diluted with EA and water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (0-80% gradient) to afford compound 5-amino-6- [(2-chloro-5-fluorophenyl)carbonyl]-3-fluoro-2-methylindazol e-7-carbonitrile (70 mg, 0.202 mmol, 73%) as a red solid. LCMS: m/z 347 [M + H] ⁺ .

217

SUBSTITUTE SHEET (RULE 26) [00537] Step E: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-fluoro-2- methylindazole-7-carbonitrile (80 mg, 0.231 mmol) in ACN (5 mL) and H2O (0.5 mL) was added KOH (64.73 mg, 1.154 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. The reaction solution was diluted with EA. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated to afford 5-amino-6-(2-chloro-5-fluorophenyl)-3- fluoro-6-hydroxy-2-methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indaz ol-8-one (80 mg, 0.219 mmol, 95%) as a yellow solid. LCMS: m/z 365 [M + H] ⁺ .

[00538] Step F: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-fluoro-6-hydroxy-2- methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (40 mg, 0.110 mmol) in ACN (3 mL) was added Py (0.044 mL, 0.548 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (29.8 mg, 0.132 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 10 min. The reaction mixture was diluted with EA and water. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated to give a crude product N-[6-(2-chloro-5- fluorophenyl)-3-fluoro-6-hydroxy-2-methyl-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]- 5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.087 mmol, 79%) as a yellow oil. LCMS: m/z 555 [M + H] ⁺ .

[00539] Step G: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-fluoro-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3- (trifluoromethyl)benzamide (120 mg, 0.173 mmol) in triethylsilane (5 mL) was added T2,2,2- trifluoroacetic acid (332.45 mg, 0.865 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 0.5 h. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)-3-fluoro-2-methyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (20.5 mg, 0.038 mmol, 22%) as a white solid. LCMS: m/z 539 [M + H] ⁺ . *H NMR (400 MHz, DMSO-d6) 5 10.33 (s, 1H), 9.08 (s, 1H), 7.95 (d, J= 8.0 Hz, 1H), 7.78 - 7.70 (m, 3H), 7.33 - 7.26 (m, 1H), 7.10 (s, 1H), 6.39 - 6.13 (m, 1H), 4.13 (s, 3H).

Example 55 7V-(6-(2-chloro-5-fluorophenyl)-3-(l-hydroxyethyl)-2-methyl- 8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

218

SUBSTITUTE SHEET (RULE 26)

[00540] To a solution of A-(6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (20 mg, 0.036 mmol) in THF (2 mL) was added magnesium monobromide methanide (0.13 mL, 0.13 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched with NH4CI, diluted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using prep-HPLC (YMC -Actus Triart Cl 8 150*20mm*5um, 40%-95%, phase A: H2O(0.1%FA), phase B: MeCN) to affordA-(6-(2-chloro- 5-fluorophenyl)-3-(l-hydroxyethyl)-2-methyl-8-oxo-2,6,7,8-te trahydropyrrolo[3,4-g]indazol-5- yl)-3-fluoro-5-(trifluoromethyl)benzamide (3.2 mg, 0.006 mmol, 16%). LCMS: m/z 565 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) 6 10.31 (d, J - 11.2 Hz, 1H), 9.06 - 8.83 (m, 1H), 8.00 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.32 - 7.26 (m, 1H), 7.13 - 7.04 (m, 1H), 6.57 - 5.86 (m, 2H), 5.79 (d, J = 3.6 Hz, 1H), 5.46 - 5.37 (m, 1H), 4.23 (s, 3H), 1.58 (d, J = 6.4 Hz, 3H).

Example 56 N-(6-(2-chloro-5-fluorophenyl)-3-((dimethylamino)methyl)-2-m ethyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

219

SUBSTITUTE SHEET (RULE 26) [00541] Step A: To a solution of N-[5-(5-chloro-2-fluorophenyl)-3-formyl-2-methyl-7-oxo- 6,7-dihydro-5H-pyrrolo[4,3-f]indazol-4-yl]-5-fluoro-3-(trifl uoromethyl)benzamide (25 mg, 46 pmol) in MeOH (2 mL) was added Dimethylamine hydrochloride (5.57 mg, 68 pmol). The reaction mixture was stirred at rt for 20min, then NaBFLCN (5.72 mg, 91 pimol) was added. The following reaction mixture was stirred at 45 °C for 2h. The cooled rection mixture was diluted with water (~10 mL) and extracted with EtOAc (~10 mL x 2). The combined organic phases was washed with brine, dried over Na2$O4 and concentrated. The residue was purified by prep-HPLC to give N- [5 -(5 -chi oro-2 -fluorophenyl)-3 - [(dimethylamino)methyl] -2-methyl-7-oxo-6,7-dihy dro- 5H-pyrrolo[4,3-f]indazol-4-yl]-5-fluoro-3-(trifluoromethyl)b enzamide (6 mg, 10 [jmol, 23%).

LCMS: m/z 578 [M+H] ⁺ . NMR (400 MHz, Methanol-d4) 8 8.10 (s, 1H), 7.82 - 7.69 (m, 2H), 7.65 (d, J= 8.8 Hz, 1H), 7.26 (dd, J= 8.8, 5.0 Hz, 1H), 7.04 - 6.89 (m, 1H), 6.40 (s, 1H), 4.99 (s, 2H), 4.41 (s, 3H), 3.03 (s, 6H).

Example 57 N-[(6S)-6-(2-chloro-5-fluorophenyl)-3-fluoro-2-methyl-8-oxo- 7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide and Example 58 N- [(6R)-6-(2-chloro-5-fluorophenyl)-3-fluoro-2-methyl-8-oxo-7, 8-dihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[00542] N-[6-(2-chloro-5-fluorophenyl)-3-fluoro-2-methyl-8-oxo-7,8-d ihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fhioro-3-(trifluoromethyl)benz amide (47 mg, 0.087 mmol) was purified by prep-SFC to give Example 57 (12.5 mg, 0.023 mmol, 27%,) as white solid. LCMS: m/z 539 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 8 10.34 (s, 1H), 9.07 (s, 1H), 7.96 - 7.70 (m, 4H), 7.29 (s, 1H), 7.10 (s, 1H), 6.36 - 6.13 (m, 1H), 4.12 (s, 3H). And Example 58 (11.6 mg, 0.022 mmol, 24.68%) as white solid. LCMS: m/z 539 [M + H] ⁺ . ^J H NMR (400 MHz, DMSO-d6)

220

SUBSTITUTE SHEET (RULE 26) 5 10.34 (s, 1H), 9.06 (s, 1H), 7.94 (d, J= 8.0 Hz, 1H), 7.81 - 7.67 (m, 3H), 7.34 - 7.25 (m, 1H), 7.10 (s, 1H), 6.36 - 6.13 (m, lH), 4.12 (s, 3H).

Example 59 N-(3-chloro-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00543] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (5 g, 9.28 mmol) in THF (50 mL) was added dropwie w-BuLi (3.7 mL, 9.28 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with HC1, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in DCM [Gradient: 0-50%] to afford compound (7-bromo-2-methyl-5- nitroindazol-6-yl)(2-chloro-5-fluorophenyl)methanone (1.5 g, 3.63 mmol, 39%) as a yellow solid. LCMS: m/z 412 [M + H] ⁺

[00544] Step B: To a solution of (7-bromo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1.5 g, 3.63 mmol) in CH3CN (20 mL) was added NCS (0.58 g, 4.36

221

SUBSTITUTE SHEET (RULE 26) mmol). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluting with

EA in PE [Gradient: 0-60%] to afford compound (7-bromo-3-chloro-2-methyl-5-nitroindazol-6- yl)(2-chloro-5-fluorophenyl)methanone (1 g, 2.23 mmol, 62%) as a yellow solid. LCMS: m/z 447 [M + H] ⁺

[00545] Step C: To a solution of (7-bromo-3-chloro-2-methyl-5-nitroindazol-6-yl)(2-chloro- 5-fluorophenyl)methanone (1 g, 2.23 mmol) in EtOH (10 mL) and H2O (4 mL) were added Fe (1.25 g, 22.36 mmol) and NH4CI (2.39 g, 44.7 mmol). The reaction mixture was stirred at 90 °C for 2 h. The cooled reaction mixture was filtered, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford compound (5-amino-7- bromo-3-chloro-2-methylindazol-6-yl)(2-chloro-5-fluorophenyl )methanone (600 mg, 1.44 mmol, 64.3%) as a yellow solid. LCMS: m/z 417 [M + H] ⁺

[00546] Step D: To a solution of (5-amino-7-bromo-3-chloro-2-methylindazol-6-yl)(2-chloro- 5-fluorophenyl)methanone (400 mg, 0.959 mmol) in DMA (6 mL) were added Pd(PPhs)4

(332 mg, 0.288 mmol) and Zn(CN)2 (225 mg, 1.918mmol). The reaction mixture was stirred at 150 °C 1 h at MW. The reaction mixture was diluted with H2O, extracted with EA, washed with brine, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-60%] to afford compound 5-amino-3- chloro-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methylindazol e-7-carbonitrile (120 mg, 0.330 mmol, 34%) as a yellow solid. LCMS: m/z 363 [M + H] ⁺

[00547] Step E: To a solution of (5-amino-7-bromo-3-chloro-2-methylindazol-6-yl)(2-chloro- 5-fluorophenyl)methanone (120 mg, 0.288 mmol) in CH3CN (5 mL) and H2O (1 mL) was added KOH (80.7 mg, 1.43 mmol). The reaction mixture was stirred at RT for 10 min. The reaction mixture was diluted with H2O, extracted with EA, washed with brine, filtered and concentrated to afford compound 5-amino-3-chloro-6-[(2-chloro-5-fluorophenyl)carbonyl]-2- methylindazole-7-carbonitrile (120 mg, 0.330 mmol, 34%) as a yellow solid. LCMS: m/z 381 [M + H] ⁺ [00548] Step F: To a solution of 5-amino-3-chloro-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (70 mg, 0.184 mmol) in CHgCN (2 mL) were added pyridine (72 mg, 0.918 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (124 mg, 0.551 mmol). The reaction mixture was stirred at RT for 10 min. The reaction

222

SUBSTITUTE SHEET (RULE 26) mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-70%] to afford compound N-[3-chloro-6-

(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-di hydro-6H-pyrrolo[4,3-g]indazol-5- yl]-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.053 mmol, 28.5%) as a yellow solid. LCMS: m/z 571 [M + H] ⁺

[00549] Step G: To a solution of N-[3-chloro-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fl uoro-5-

(trifluoromethyl)benzamide (25 mg, 0.044 mmol) in TFA (1 mL) was added EtsSiH (25.44 mg, 0.219 mmol). The reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was diluted with H2O, extracted with EA, washed with brine, filtered and concentrated. The residue was purified by prep-HPLC to afford compound N-[3-chloro-6-(2-chloro-5-fluorophenyl)-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fl uoro-5-

(trifluoromethyl)benzamide (15 mg, 0.027 mmol, 62%) as a white solid. LCMS: m/z 555 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) 8 10.37 (s, 1H), 9.12 (s, 1H), 7.95 (d, .7= 8.4 Hz, 1H), 7.83 - 7.62 (m, 3H), 7.30 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 (s, 1H), 6.28 (d, .7= 8.6 Hz, 1H), 4.24 (s, 3H).

Example 60: A^-(6-(2-chloro-5-fluorophenyl)-3-(hydroxymethyl)-2-methyl-8 -oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00550] Step A: To a solution of A-(6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (20 mg, 0.036 mmol) in MeOH (2 mL) was added NaBHj (1.5 mg, 0.04 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was

223

SUBSTITUTE SHEET (RULE 26) purified using prep-HPLC to afford compound /V-(6-(2-chloro-5-fluorophenyl)-3- (hydroxymethyl)-6-methoxy-2-methyl-8-oxo-2,6,7,8-tetrahydrop yrrolo[3,4-g]indazol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (8 mg, 0.014 mmol, 38%) as a white solid. LCMS: m/z 581 [M + H] ⁺ .

[00551] Step B: To a solution of A-(6-(2-chloro-5-fluorophenyl)-3-(hydroxymethyl)-6- methoxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indaz ol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (8 mg, 0.014 mmol) in TFA (1 mL) was added EtaSiH (16 mg, 0.14 mmol). The reaction mixture was stirred at 70 °C for 1 h. The cooled reraction mixture was concentrated. The residue was purified using prep-HPLC (YMC -Actus Triart Cl 8 150*20mm*5um, 40%-95%, phase A: H2O(0.1%FA), phase B: MeCN ) to afford compound A- (6-(2-chloro-5-fluorophenyl)-3-(hydroxymethyl)-2-methyl-8-ox o-2,6,7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.1 mg, 0.004 mmol, 27%). LCMS: m/z 551 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) 5 10.31 (s, 1H), 9.12 - 8.79 (m, 1H), 7.98 - 7.88 (m, 2H), 7.75 - 7.67 (m, 2H), 7.31 - 7.25 (m, 1H), 7.09 (s, 1H), 6.47 - 5.83 (m, 2H), 5.56 (t, J = 4.0 Hz, 1H), 4.96 (d, J = 4.0 Hz, 2H), 4.23 (s, 3H).

Example 62 N-(2-amino-6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H- thiazolo[4,5- e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[00552] To a solution of N-(2-acetamido-6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro -6H- thiazolo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)be nzamide (10 mg, 0.03 mmol) in EtOH (5 mL) was added con. HC1 (0.1 mL, 1.2 mmol, 12M in H2O). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by prep-HPLC N-(2-amino-6-(2-chloro-5- fluorophenyl)-8-oxo-7,8-dihydro-6H-thiazolo[4,5-e]isoindol-5 -yl)-3-fluoro-5-

224

SUBSTITUTE SHEET (RULE 26) (trifluoromethyl)benzamide (2.6 mg, 0.005 mmol, 17%). LCMS: m/z 539.12 [M + H] ⁺ . 'H NMR. (400 MHz, DMSO-d6) 5 10.26 (s, 1H), 8.80 (s, 1H), 8.01 (s, 2H), 7.93 (d, J= 8.4 Hz, 1H), 7.79 (s, 1H), 7.75 - 7.65 (m, 2H), 7.28 (dd, J= 8.8, 5.2 Hz, 1H), 7.07 (t, J= 6.9 Hz, 1H), 6.50 (s, 1H), 5.96 (s, 1H).

Example 64 (R*)-N-((R)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluoro-3-hydroxy-3-( trifluoromethyl)indoline-l- carboxamide and Example 65 (R*)-N-((S)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluoro-3-hyd roxy-3- (trifluoromethyl)indoline-l-carboxamide

[00553] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-

7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (370 mg, 1.067 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was added triethylsilane (2 mL) at 25 °C. The reaction mixture was stirred at 50 °C for 1 h. The TFA and EtsSiH were removed under vacuum. The following mixture was adjusted pH to 8 by NaHCCh (aqueous), extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated to afford 5-amino-6-(2-chloro-5-fluorophenyl)-2- methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (300 mg, 0.907 mmol, 85%) as a yellow solid. LCMS: m/z 331 [M + H] ⁺ .

[00554] Step B: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2-methyl-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-8-one (270 mg, 0.816 mmol) in THF (5 mL) was added 4-nitrophenyl

225

5UB5TITUTE SHEET (RULE 26) chloromethanoate (197 mg, 0.980 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for 1 h. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SC>4, concentrated in vacuum to affordd-nitrophenyl {[6-(2-chloro-5- fluorophenyl)-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]in dazol-5-yl]amino}methanoate (300 mg, 0.605 mmol, 74%) as a yellow solid. LCMS: m/z 496 [M + H] ⁺ .

[00555] Step C: To a solution of 4-nitrophenyl {[6-(2-chloro-5-fluorophenyl)-2-methyl-8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]amino}methanoate (300 mg, 0.605 mmol) in THF (2 mL) was added rel-(R)-5-fluoro-3-(trifluoromethyl)indolin-3-ol (200 mg, 0.908 mmol) and triethylamine (0.252 mL, 1.815 mmol) in THF (2 mL) at room temperature. The reaction mixture was stirred at 70 °C for 1 h. The cooled reaction solution was diluted with EA. The organic phase was washed with brine, dried over anhydrous NaiSCU and concentrated. The residue was purified by flash chromatography eluted with MeOH in DCM (0~4% gradient) and purified by prep-HPLC to afford rel-(3R)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluoro-3-hyd roxy-3-(trifluoromethyl)indoline-l- carboxamide (152 mg, 0.263 mmol, 43%) as a white solid. LCMS: m/z 578 [M + H] ⁺ .

[00556] Step D: rel-(3R)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-5-fluoro-3-hydroxy-3-( trifluoromethyl)indoline-l- carboxamide (152 mg, 0.263 mmol) was separated by prep-SFC to give Example 64 (50 mg, 0.087 mmol, 33%). LCMS: m/z 578 [M + H] ⁺ . ^NMR (400 MHz, DMSO-d6) 5 8.92 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 7.89 (s, 1H), 7.71 (s, 1H), 7.38 (s, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.28 - 7.12 (m, 3H), 6.32 (s, 1H), 6.14 (s, 1H), 4.26 (s, 3H), 3.97 (d, J = 12.2 Hz, 1H), 3.58 (s, 1H). And Example 65 (48.9 mg, 0.085 mmol, 32%). LCMS: m/z 578 [M + H] ⁺ . ^NMR (400 MHz, DMSO-d6) 6 8.93 (s, 1H), 8.53 (s, 1H), 8.51 (s, 1H), 7.83 - 7.76 (m, 2H), 7.39 (s, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.10 - 7.09 (m, 1H), 6.32 (s, 1H), 6.14 (s, 1H), 4.26 (s, 3H), 4.19 (d, J = 12.2 Hz, 1H), 3.55 (s, 1H).

Example 66 N-[6-(2-chloro-5-fluorophenyl)-3-cyclopropyl-2-methyl-8-oxo- 7,8-dihydro- 6H-pyirolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)b enzamide

226

SUBSTITUTE SHEET (RULE 26)

[00557] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1 g, 1.85 mmol) in dioxane (10 mL) and FEO (3 mL) were added cyclopropylboranediol (0.16 g, 1.85 mmol), K2CO3 (0.77 g, 5.571 mmol) and Pd(dppf)Ch (0.14 g, 0.186 mmol). The reaction mixture was stirred at 80 °C under N2 for 18 hr. LCMS showed the reaction was completed. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 40-50%) to afford compound (7-bromo-3-cyclopropyl-2- methyl-5-nitroindazol-6-yl)(2-chloro-5-fluorophenyl)methanon e (450 mg, 0.994 mmol, 54%)_as a yellow solid. LCMS: m/z 453 [M + H] ⁺ .

[00558] Step B: To a solution of (7-bromo-3-cyclopropyl-2-methyl-5-nitroindazol-6-yl)(2- chloro-5-fluorophenyl)methanone (450 mg, 0.994 mmol) in EtOH (20 mL) and H2O

(5 mL) were added Fe (277 mg, 4.97 mmol), NH4CI (266 mg, 4.97 mmol). The reaction

227

5UB5TITUTE SHEET (RULE 26) mixture was stirred at 90 °C under N2 for 2 hr. LCMS showed the reaction was completed. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 25-30%) to afford compound (5-amino-7-bromo-3-cyclopropyl-2-methylindazol-6-yl)(2-chlor o-5- fluorophenyl)methanone (250 mg, 0.591 mmol, 60%) as a light yellow solid. LCMS: m/z 421/423 [M + H] ⁺ .

[00559] Step C: To a solution of (5-amino-7-bromo-3-cyclopropyl-2-methylindazol-6-yl)(2- chloro-5-fluorophenyl)methanone(140 mg, 0.331 mmol) in DMA (4 mL) were added Zn(CN)2 (58.3 mg, 0.497 mmol), Pd(PPhs)4 (38.1 mg, 0.033 mmol). The reaction was stirred at 150°C under N2 for 3 hr using M.W. LCMS showed the reaction was completed. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 25-35%) to afford compound 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-cyclopropyl- 2-methylindazole-7- carbonitrile (70 mg, 0.190 mmol, 57%) as a red solid. LCMS: m/z 369 [M + H] ⁺ .

[00560] Step D: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-3- cyclopropyl-2-methylindazole-7-carbonitrile (40 mg, 0.108 mmol) in MeCN (9 mL) and H2O (3 mL) were added KOH (18.2 mg, 0.325 mmol). The reaction was stirred at room temperature under N2 for 10 min. LCMS showed the reaction was completed. The reaction mixture was diluted with brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to afford 5-amino-6-(2-chloro-5-fluorophenyl)-3- cyclopropyl-6-hydroxy-2-methyl-7,8-dihydro-6H-pyrrolo[4,3-g] indazol-8-one (25 mg, 0.065 mmol, 60%) as a yellow solid. LCMS: m/z 387 [M + H] ⁺ .

[00561] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-cyclopropyl-6- hydroxy-2-methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (30 mg, 0.078 mmol) in MeCN (3 mL) were added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (52.7 mg, 0.233 mmol) and Py (30.7 mg, 0.388 mmol). The reaction was stirred at room temperature under N2 for 1 hr. LCMS showed the reaction was completed. The reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over NaiSCh and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether

228

SUBSTITUTE SHEET (RULE 26) (gradient: 40-50%) to afford N-[6-(2-chloro-5-fluorophenyl)-3-cyclopropyl-6-hydroxy-2-met hyl- 8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (15 mg, 0.026 mmol, 34%) as a yellow solid. LCMS: m/z 577[M + H] ⁺ .

[00562] Step F: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-cyclopropyl-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3-

(trifluoromethyl)benzamide (15 mg, 0.026 mmol) in TFA (2 mL) were added EtgSiH (9.07 mg, 0.078 mmol). The reaction was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated, diluted with aqueous NaHCOs and extracted with EA. The organic phase was washed with brine, dried over NaiSCU and concentrated. The residue was purified by prep-HPLC to afford compound N-[6-(2-chloro-5-fluorophenyl)-3- cyclopropyl-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]inda zol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (13 mg, 0.023 mmol, 89.1%) . LCMS: m/z 561 [M + H] ⁺ .

¹ HNMR(400 MHz, DMSO-d6) 5 10.27 (s, 1H), 8.92 (s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.74 (dd, J = 19.0, 10.1 Hz, 3H), 7.28 (dd, J= 8.8, 5.2 Hz, 1H), 7.14 - 7.00 (m, 1H), 6.65 (s, 1H), 6.44 - 6.20 (m, 1H), 6.10 (s, 1H), 4.25 (s, 3H), 2.23 - 2.19 (m, 1H), 1.17 (d, J= 8.4 Hz, 2H), 0.96 - 0.93 (m, 2H).

Example 67 7V-(6-(2-chloro-5-fluorophenyl)-2-ethyl-8-oxo-2,6,7,8-tetrah ydropyrrolo [3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

229

SUBSTITUTE SHEET (RULE 26)

[00563] Step A: To a solution of (7-bromo-3-iodo-5-nitro-2/Z-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (2 g, 3.82 mmol) in DCM (30 mL) was added tri ethyl oxonium tetrafluoro-X5-boranuide (4.97 mL, 4.97 mmol). The reaction mixture was stirred at 30 °C 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 afford compound (7-bromo-2-ethyl-3-iodo-5-nitro-2//-indazol-6-yl)(2-chloro-5 -fluorophenyl)methanone (1.08 mg, 1.96 mmol, 50%) as a yellow solid. LCMS: m/z 552 [M + H] ⁺ .

[00564] Step B: To a solution of (7-bromo-2-ethyl-3-iodo-5-nitro-27/-indazol-6-yl)(2-chloro- 5-fluorophenyl)methanone (1.08 g, 1.96 mmol) in THF (10 mL) was added //-BuLi (0.78 mL, 1.96 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 10 minutes. The reaction mixture was quenched with saturated NELCl solution, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford compound (7-bromo-2-ethyl-5-nitro-27/-indazol-6-yl)(2-chloro-5-fluoro phenyl)methanone (340 mg, 0.79 mmol, 40%) as a yellow solid. LCMS: m/z 426 [M + H] ⁺ .

[00565] Step C: To a solution of (7-bromo-2-ethyl-5-nitro-27/-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (340 mg, 0.8 mmol) in EtOH (10 mL) and H2O (3 mL) was added ammonium chloride (128 mg, 2.4 mmol) and iron(0) (267 mg, 4.8 mmol). The reaction mixture was stirred at 80 °C for 3 hours. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified using silica gel column chromatography eluting with 0- 10% methanol in di chloroform to afford compound (5-amino-7-bromo-2-ethyl-2/Z-indazol-6- yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.42 mmol, 52%) as a yellow solid. LCMS: m/z 396 [M + H] ⁺ .

230

SUBSTITUTE SHEET (RULE 26) [00566] Step D: To a solution of (5-amino-7-bromo-2-ethyl-2//-indazol-6-yl)(2-chloro-5- fluorophenyl)methanone (200 mg, 0.5 mmol) in NMP (2 mL) was added CuCN (135 mg, 1.5 mmol). The reaction mixture was stirred at 150 °C under N2 with microwave for 1.5 hour. The cooled reaction mixture was quenched with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in di chloroform to afford compound 5- amino-6-(2-chloro-5-fluorobenzoyl)-2-ethyl-2//-indazole-7-ca rbonitrile (100 mg, 0.18 mmol, 35%) as a yellow solid. LCMS: m/z 343 [M + H] ⁺ .

[00567] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-ethyl-2H-indazole- 7-carbonitrile (100 mg, 0.29 mmol) in CH3CN (5 mL) and H2O (0.5 mL) was added potassium hydroxide (49 mg, 0.88 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford 5-amino-6-(2-chloro-5- fluorophenyl)-2-ethyl-6-hydroxy-6,7-dihydropyrrolo[3,4-g]ind azol-8(27/)-one (50 mg, 0.12 mmol, 39.4%) as a yellow solid. LCMS: m/z 361 [M + H] ⁺ .

[00568] Step F: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-2-ethyl-6-hydroxy-6,7- dihydropyrrolo[3,4-g]indazol-8(27/)-one (50 mg, 0.14 mmol) in CH3CN (3 mL) was added pyridine (0.06 mL, 0.69 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (94 mg, 0.42 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford A-(6-(2-chloro-5-fluorophenyl)-2-ethyl-6-hydroxy-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (50 mg, 0.07 mmol, 52%) as a yellow solid. LCMS: m/z 551 [M + H] ⁺ .

[00569] Step G: To a solution of A-(6-(2-chloro-5-fluorophenyl)-2-ethyl-6-hydroxy-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (50 mg, 0.09 mmol) in TEA (1 mL, 13 mmol) was added Et3SiH (52.8 mg, 0.45 mmol). The reaction mixture was stirred at 75 °C for 1 hour. The cooled mixture was concentrated under vacuum. The residue was purified using prep-HPLC (YMC-Actus Triart C18 150*20mm*5um, 40%-95%, phase A: H2O (0.1%FA), phase B: MeCN) to afford A-(6-(2-chloro-5-fluorophenyl)-2-ethyl-8- oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide (12.4

231

SUBSTITUTE SHEET (RULE 26) mg, 0.023 mmol, 25%) as a white solid. LCMS: m/z 535 [M + H] ⁺ . ^X H NMR (400 MHz, DMSO- d6) 6 10.30 (s, 1H), 9.16 - 8.81 (m, 1H), 8.62 (s, 1H), 7.97 - 7.82 (m, 2H), 7.76 - 7.67 (m, 2H), 7.32 - 7.23 (m, 1H), 7.14 - 7.02 (m, 1H), 6.55 - 5.70 (m, 2H), 4.56 (q, J = 7.2 Hz, 2H), 1.57 (t, J = 7.2 Hz, 3H).

Example 68 N-[3-(2-chloro-5-fluorophenyl)-8-cyano-l-oxo-2,3-dihydro-lH- benzo[e]isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[00570] Step A: To a solution of phosphorus tribromide (13 mL, 138 mmol) in CHCh (280 mL) was added DMF (13 mL, 166 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. 7-bromo-l,2,3,4-tetrahydronaphthalen-l-one (10 g, 44.4 mmol) in CHCh (50 mL) was added at 0 °C. The following mixture was stirred at 70 °C for 2 hours. The cooled mixture was poured into ice water (400 mL) and concentrated to remove CHCh. The resulting

232

SUBSTITUTE SHEET (RULE 26) mixture was extracted with EA (500 mL x 3). The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (20 g column) using 0 - 80% EtOAc/hexane to afford l,7-dibromo-3,4-dihydronaphthalene-2- carbaldehyde (9 g, 28.4 mmol, 64%) as a brown solid. No MS.

[00571] Step B: To a solution of l,7-dibromo-3,4-dihydronaphthalene-2-carbaldehyde (9 g, 28.4 mmol) in toluene (90 mL) was added 4,5-dichloro-3,6-dioxocyclohexa-l,4-diene-l,2- dicarbonitrile (19.4 g, 85.4 mmol). The reaction mixture was stirred at 110 °C for 12 hours. The cooled reaction mixture was filtered. The filtrate was diluted with saturation Na2COs (200 mL), extracted with EA (200 mL x 3). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (10 g column) using 0 - 5% EtOAc/hexane to afford l,7-dibromonaphthalene-2-carbaldehyde (4.1 g, 13.1 mmol, 45%) as a yellow solid.

[00572] Step C: To a solution of l,7-dibromonaphthalene-2-carbaldehyde (3.6 g, 11.4 mmol) in 1,2-di chloroethane (140 mL) was added Tosyl azide (600 mg, 0.29 mmol), bis[iridium(3+)] bis(l,2,3,4,5-pentamethylcyclopenta-2,4-dien-l-ide) tetrachloride (240 mg, 0.28 mmol), silver bis[dioxo(trifhioromethyl)-X6-sulfanyl]azanide (460 mg, 1.2 mmol) and 3,5-bis(trifluoromethyl)aniline (279 mg, 1.2 mmol). The reaction mixture was stirred at 100 °C for 18 hours. To the cooled reaction mixture was added EA (20 mL) and the resulting mixture was stirred at 20 °C for 10 min. The following mixture was poured into water (80 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10 %, MeOH in DCM) to give N-(4,6-dibromo-3-formyl-2-naphthyl)-4- methylbenzenesulfonamide (380 mg, 0.78 mmol, 7%) as a yellow solid. LCMS: m/z 483 [M+H] ⁺ .

[00573] Step D: To a solution of N-(4,6-dibromo-3-formyl-2-naphthyl)-4- methylbenzenesulfonamide (380 mg, 0.78 mmol) in THE (15 mL) was added (2-chloro-5- fluorophenyl)magnesium chloride (650 mg, 3.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C to rt for 1 hour. The reaction mixture was quenched with MeOH and concentrated to give the residue, which was purified by silica gel chromatography (5 g column) using 0 - 30% EtOAc/hexane to afford N-{4,6-dibromo-3-[(2-chloro-5-fluorophenyl)(hydroxy)methyl]- 2-

233

SUBSTITUTE SHEET (RULE 26) naphthyl }-4-m ethylbenzenesulfonamide (280 mg, 0.45 mmol, 58%) as a yellow solid. LCMS: m/z 613[M - H];

[00574] Step E: To a solution of N-{4,6-dibromo-3-[(2-chloro-5- fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesul fonamide (280 mg, 0.45 mmol) in DCM (20 mL) was added Dess-Martin (290 mg, 0.68 mmol). The following mixture was stirred at 20 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give the residue, which was purified by silica gel chromatography (3 g column) using 0 - 30% EtOAc/hexane to afford N-{4,6-dibromo-3-[(2-chloro-5- fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamid e (210 mg, 0.34 mmol, 75%) as a white solid. LCMS: m/z 312 [M + H] ⁺

[00575] Step F: To a stirred solution of N-{4,6-dibromo-3-[(2-chloro-5- fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamid e (200 mg, 0.32 mmol) in NMP (5 mL) was added CuCN (87.86 mg, 0.98 mmol) at rt . After stirred at 180 °C under N2 for 4h, the cooled mixture was poured into brine (50 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried with JSfeSCL, filtered and concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1% TEA) to give N-{3-[(2-chloro-5-fluorophenyl)carbonyl]-4,6-dicyano-2-napht hyl}-4- methylbenzenesulfonamide (90 mg, 0.179 mmol, 55%) as a yellow solid. LCMS: m/z 504 [M+H] ⁺ .

[00576] Step G: To a stirred solution ofN-(3-[(2-chloro-5-fluorophenyl)carbonyl]-4,6- dicyano-2-naphthyl]-4-methylbenzenesulfonamide (90 mg, 0.17 mmol) in MeCN (2 mL)/ FLO (1 mL) was added potassium hydroxide (50 mg, 0.89 mmol) slowly at rt. After stirred at rt for Ih, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2$O4, filtered and concentrated to give crude N-[3-(2-chloro-5-fluorophenyl)-8-cyano-3-hydroxy-l-oxo-2,3-d ihydro-lH- benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (70 mg, 0.11 mmol, 60%) as a yellow solid. LCMS: m/z 522 [M+H] ⁺ .

[00577] Step H: To a stirred solution of N-[3-(2-chloro-5-fluorophenyl)-8-cyano-3-hydroxy- 1 -oxo-2, 3-dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonami de (70 mg, 0.13 mmol) in 2,2,2-trifluoroacetaldehyde (1.5 mL) was added EtsSiH (0.5 mL, 0.13 mmol) slowly at rt. After stirred at 70 °C for Ih, the reaction mixture was concentrated. The residue was purified

234

SUBSTITUTE SHEET (RULE 26) by chromatography (silica gel, 0-70%, EtOAc in PE) to give N-[3-(2-chloro-5-fluorophenyl)-8- cyano-l-oxo-2,3-dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbe nzenesulfonamide (30 mg, 0.06 mmol, 44%) as a brown solid. LCMS: m/z 506 [M+H] ⁺ .

[00578] Step I: To a stirred solution of N-[3-(2-chloro-5-fluorophenyl)-8-cyano-l-oxo-2,3- dihydro-lH-benzo[e]isoindol-4-yl]-4-methylbenzenesulfonamide (30 mg, 0.059 mmol) in H2O (1 mL) was added H2SO4 (2 mL, 37.3 mmol) slowly at rt. After stirred at 35 °C overnight, the mixture was adjusted PH to 7~8 with NaOH (aq, 3N). The following mixture was extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated to give crude 4-amino-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro- lH-benzo[e]isoindole-8-carbonitrile (15 mg, 0.04 mmol, 71%) as a brown solid. LCMS: m/z 352 [M+H] ⁺ .

[00579] Step J: To a stirred solution of 4-amino-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3- dihydro-lH-benzo[e]isoindole-8-carbonitrile (15 mg, 0.04 mmol) in MeCN (2 mL) was added pyridine (16 mg, 0.21mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (19.32 mg, 0.085 mmol) slowly at rt. After stirred at rt for Ih, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (C18, 40 ~ 90 % MeCN in H2O with 0.1 % TEA) to give N-[3-(2-chloro-5-fluorophenyl)-8- cyano-l-oxo-2,3-dihydro-lH-benzo[e]isoindol-4-yl]-3-fluoro-5 -(trifluoromethyl)benzamide (3 mg, 0.006 mmol, 13%). LCMS: m/z 542 [M+H] ⁺ . NMR (400 MHz, DMSO-d6) 5 10.79 (s, IH), 9.57 (s, IH), 9.51 (brs, 2H), 8.34 (d, J= 8.6 Hz, IH), 8.23 (s, IH), 7.98 (d, J= 8.4 Hz, 2H), 7.76 (d, J = 9.0 Hz, IH), 7.69 (s, IH), 7.33 (dd, J = 8.8, 5.2 Hz, IH), 7.13 - 7.09 (m, IH), 6.50 - 7.23 (m, IH).

Example 69 N-[6-(2-chloro-5-fluorophenyl)-3-ethynyl-2-methyl-8-oxo-7,8- dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide

235

SUBSTITUTE SHEET (RULE 26)

[00580] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1 g, 1.857 mmol) in triethylamine (5 mL) was added ethynyl[tri(prop- 2-yl)]silane (0.41 g, 2.228 mmol), Cui (0.07 g, 0.371 mmol) and palladium chloride bis(triphenylphosphane) (0.13 g, 0.186 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 0-10%) to afford compound (7-bromo-2- methyl-5-nitro-3-[[tri(prop-2-yl)silyl]ethynyl}indazol-6-yl) (2-chloro-5-fluorophenyl)methanone (550 mg, 0.928 mmol, 50%) as a yellow solid. LCMS: m/z 592 [M + H] ⁺ .

[00581] Step B: To a solution of (7-bromo-2-methyl-5-nitro-3-{[tri(prop-2- yl)silyl]ethynyl}indazol-6-yl)(2-chloro-5-fluorophenyl)metha none (550 mg, 0.928 mmol) in ethanol (3 mL) and H2O (0.3 mL) was added NH4CI (248 mg, 4.64 mmol) and Fe

236

SUBSTITUTE SHEET (RULE 26) (259 mg, 4.64 mmol) at RT. The reaction mixture was degassed with N2 and stirred at 90 °C for overnight. The cooled reaction mixture was filtered. The filtrate was concentrated to give a crude product which was purified by silica gel column chromatography eluted with PE in EA (gradient: 0-30%) to afford (5-amino-7-bromo-2-methyl-3-{ [tri(prop-2-yl)silyl]ethynyl}indazol- 6-yl)(2-chloro-5-fluorophenyl)methanone (200 mg, 0.355 mmol, 38%) as a red solid. LCMS: m/z 562 [M + H] ⁺ .

[00582] Step C: To a solution of (5-amino-7-bromo-2-methyl-3-{[tri(prop-2- yl)silyl]ethynyl}indazol-6-yl)(2-chloro-5-fluorophenyl)metha none (200 mg, 0.355 mmol) in DMA (3 mL) was added Zn(CNh (62.6 mg, 0.533 mmol) and Pd(PPhs)4 (41.1 mg, 0.036 mmol). The reaction mixture was degassed with N2 and stirred at 150 °C under N2 atmosphere for 1 h under microwave. The cooled reaction mixture was diluted with EA and water. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with DCM to afford compound 5-amino- 6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3-{[tri(prop- 2-yl)silyl]ethynyl}indazole-7- carbonitrile (120 mg, 0.236 mmol, 66%) as a red solid. LCMS: m/z 509 [M + H] ⁺ .

[00583] Step D: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3- {[tri(prop-2-yl)silyl]ethynyl]indazole-7-carbonitrile (120 mg, 0.236 mmol) in ACN (3 mL) and H2O (0.5 mL) was added KOH (66.1 mg, 1.179 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 20 min. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SO4 and concentrated to afford 5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-3-{ [tri (prop-2 -yl)silyl]ethynyl]-7,8-dihydro-6H-pyrrolo[4, 3- g]indazol-8-one (60 mg, 0.114 mmol, 48%) as a green solid. LCMS: m/z 527 [M + H] ⁺ .

[00584] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3- {[tri(prop-2-yl)silyl]ethynyl}-7,8-dihydro-6H-pyrrolo[4,3-g] indazol-8-one (70 mg, 0.133 mmol) in ACN (2 mL) was added Py (0.032 mL, 0.398 mmol) and 3-fluoro-5- (trifluoromethyl)benzoyl chloride (45.1 mg, 0.199 mmol) at RT. The reaction mixture was stirred at RT for 10 min. After 20 min. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to afford N-[6-(2- chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-3-{[tri(prop -2-yl)silyl]ethynyl}-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)b enzamide (80 mg, 0.112 mmol, 84%) as a green solid. LCMS: m/z 717 [M + H] ⁺ .

237

SUBSTITUTE SHEET (RULE 26) [00585] Step F: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-{[tri(prop-2-yl)silyl]ethynyl]-7,8-dihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (80 mg, 0.112 mmol) in 2,2,2-trifluoroacetic acid (2 mL), was added triethylsilane (0.2 mL) at 25 °C. The reaction mixture was stirred at 70 °C for 1 h. The cooled reaction solution was diluted with water, extracted with EA. The organic layer was washed with brine, dried over NaiSCh and concentrated to afford N-[6-(2-chloro-5- fluorophenyl)-2-methyl-8-oxo-3-{[tri(prop-2-yl)silyl]ethynyl }-7,8-dihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (60 mg, 0.086 mmol, 76.71%) as a green oil. LCMS: m/z 701 [M + H] ⁺ .

[00586] Step G: A solution of N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-{[tri(prop-2 - yl)silyl]ethynyl}-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl] -5-fluoro-3- (trifluoromethyl)benzamide (35 mg, 0.050 mmol) in tetrabutyl ammonium fluoride (2 mL, IM in THF) was stirred at 25 °C for 0.5 h. The cooled reaction solution was diluted with water, extracted with EA. The organic layer was washed with brine, dried over NaiSCU and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-3-ethynyl-6-hydroxy-2-methyl- 8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (35 mg, 0.044 mmol, 88%) as a green oil. LCMS: m/z 561 [M + H] ⁺ .

[00587] Step H: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-ethynyl-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3- (trifluoromethyl)benzamide (35 mg, 0.044 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was added triethylsilane (0.2 mL) at room temperature. The reaction mixture was stirred at 70 °C for 1 h. The cooled reaction solution was diluted with water, extracted with EA. The organic layer was washed with brine, dried over NaiSCh and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)-3-ethynyl-2-methyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (12.3 mg, 0.023 mmol, 52%). LCMS: m/z 545 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.38 (s, 1H), 9.11 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.66 (m, 2H), 7.30 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.37 - 6.18 (m, 1H), 5.41 (s, 1H), 4.31 (s, 3H).

Example 70 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2,6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

238

SUBSTITUTE SHEET (RULE 26)

[00588] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (2 g, 3.71 mmol) in dioxane (20 mL) and FEO (4 mL) were added 2-

[(lE)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborol ane (0.66 g, 3.34 mmol), K2CO3

(1.03 g, 7.42 mmol) and Pd(dppf)C12 (0.27 g, 0.371 mmol). The reaction mixture was stirred at

70 °C under N2 for 4 h. The cooled reaction mixture was diluted with H2O, extracted with

EtOAc. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with EtOAc in petroleum ether [Gradie: 0 - 60%] to afford compound {7-bromo-3-[(lE)-2-ethoxyvinyl]-2-methyl-5- nitroindazol-6-yl}(2-chloro-5-fluorophenyl)methanone (1000 mg, 2.07 mmol, 56%) as a yellow

239

SUBSTITUTE SHEET (RULE 26) solid. LCMS: m/z 482 [M + H] ⁺ , 'H NMR (400 MHz, DMSO-d6) 5 9.01 (s, 1H), 7.79 - 7.69 (m, 3H), 7.65 - 7.52 (m, 1H), 6.28 (d, J= 12.8 Hz, 1H), 4.16 (q, J= 7.0 Hz, 2H), 1.35 (t, J= 7.0 Hz, 3H).

[00589] Step B: A solution of (7-bromo-3-[(lE)-2-ethoxyvinyl]-2-methyl-5-nitroindazol-6- yl}(2-chloro-5-fluorophenyl)methanone (200 mg, 0.414 mmol) in TFA (1 mL) and THE (1 mL) was stirred at 60 °C for 5 h. The cooled reaction mixture was diluted with H2O, extracted with EtOAc. The organic layer was washed with brine, dried over ISfeSCL and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0 - 80%] to afford compound 2-{7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazol-3-yl}acetalde hyde (130 mg, 0.286 mmol, 69%) as a yellow solid. LCMS: m/z 454 [M + H] ⁺ [00590] Step C: To a solution of 2-{7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2- methyl-5-nitroindazol-3-yl}acetaldehyde (130 mg, 0.286 mmol) in DCM (3 mL) was added DAST (92.2 mg, 0.572 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O, extracted with EA. The organic layer was washed with aqueous NaHCCh, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-50%] to afford compound [7-bromo-3-(2,2-difluoroethyl)-2-methyl-5-nitroindazol-6-yl] (2-chloro-5- fluorophenyl)methanone (110 mg, 0.231 mmol, 81%). LCMS: m/z 476 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 9.15 (s, 1H), 7.79 (dd, J= 9.0, 3.0 Hz, 1H), 7.71 (dd, J= 9.0, 5.0 Hz, 1H), 7.63 - 7.55 (m, 1H), 6.64 - 6.35 (m, 1H), 4.28 (s, 3H), 4.15 - 4.0 (m, 2H).

[00591] Step D: To a solution of [7-bromo-3-(2,2-difluoroethyl)-2-methyl-5-nitroindazol-6- yl](2-chloro-5-fluorophenyl)methanone (110 mg, 0.231 mmol) in EtOH (3 mL) and H2O (1 mL) were added Fe (64.4 mg, 1.15 mmol) and NH4CI (123.4 mg, 2.30 mmol). The reaction mixture was stirred at 80 °C for 2 h. The cooled reaction mixture was filtered. The filtrate was diluted with H2O, 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 EA in PE [Gradient: 0-90%] to afford compound [5-amino-7-bromo-3-(2,2- difluoroethyl)-2-methylindazol-6-yl](2-chloro-5-fluorophenyl )methanone (90 mg, 0.202 mmol, 87%) as a yellow solid. LCMS: m/z 446 [M + H] ⁺

240

SUBSTITUTE SHEET (RULE 26) [00592] Step E: To a solution of [5-amino-7-bromo-3-(2,2-difluoroethyl)-2-methylindazol-6- yl](2-chloro-5-fluorophenyl)methanone (90 mg, 0.202 mmol) in DMA (3 mL) were added Pd(PPh3)4 (70.03 mg, 0.061 mmol) and Zn(CN)2 (47.4 mg, 0.404 mmol). The reaction mixture was stirred at 150 °C 1 h at MW. The cooled reaction mixture was diluted with

H2O, extracted with EA. The organic layer was washed with aqueous NaHCCf, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-80%] to afford compound 5-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-3-(2,2-difluoroethyl)-2-methylindazol e-7-carbonitrile (50 mg, 0.127 mmol, 63%) as a yellow solid. LCMS: m/z 393 [M + H] ⁺

[00593] Step F: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-(2,2- difluoroethyl)-2-methylindazole-7-carbonitrile (30 mg, 0.076 mmol) in CH3CN (1 mL) and H2O (0.5 mL) was added KOH (21.4 mg, 0.382 mmol). The reaction mixture was stirred at it for 10 min. The reaction mixture was diluted with H2O, extracted with EA The organic layer was washed with aqueous NaHCOi, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 0-10%] to afford compound 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2- methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (25 mg, 0.061 mmol, 80%) as a yellow solid. LCMS: m/z 411 [M + H] ⁺

[00594] Step G: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 6-hydroxy-2-methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-on e (30 mg, 0.073 mmol) in CH3CN (1 mL) were added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (49.6 mg, 0.219 mmol) and pyridine (0.030 mL, 0.365 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O, extracted with EA. The organic layer was washed with aqueous NaHCCL, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-60%] to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydro xy-2-methyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoro methyl)benzamide (15 mg, 0.025 mmol, 34%) as a yellow solid. LCMS: m/z 601 [M + H] ⁺

[00595] Step H: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol- 5-yl]-3-fluoro-5-

(trifluoromethyl)benzamide (15 mg, 0.025 mmol) in TFA (1 mL) was added EtsSiH (14.5 mg,

241

SUBSTITUTE SHEET (RULE 26) 0.125 mmol). The reaction mixture was stirred at 60 °C for 30 min. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The purified by prep-HPLC to afford compound N-[6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-2-methyl-8-oxo-7,8-dihyd ro-6H-pyrrolo[4,3-g]indazol-5-yl]- 3-fluoro-5-(trifluoromethyl)benzamide (2.5 mg, 0.004 mmol, 17%) as a white solid. LCMS: m/z 585[M + H] ⁺ . ’H NMR (400 MHz, DMSO-d6) 6 10.36 (s, 1H), 8.99 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.86 (s, 1H), 7.78 - 7.66 (m, 2H), 7.29 (dd, J= 8.8 5.2 Hz, 1H), 7.10 (s, 1H), 6.58 - 6.10 (m, 2H), 4.24 (s, 3H), 3.95 - 3.85 (m, 2H).

Example 71 N-[6-(2-chloro-5-fluorophenyl)-2-methyl-3-(inethyldioxo-k6-s ulfanyl)-8-oxo- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifl uoromethyl)benzamide

[00596] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (4.5 g, 8.357 mmol) in DMSO-d6 (50 mL) were added sodium methanesulfonate (1.18 g, 10.028 mmol) and Cui (0.16 g, 0.836 mmol). The reaction was stirred at 110 °C for 2 hr. The cooled reaction mixture was diluted with water, extracted with EA. The

242

5UB5TITUTE SHEET (RULE 26) organic phase was washed with brine, dried over NazSCU and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~100%) to afford compound [7-bromo-2-methyl-3-(methyldioxo-X6-sulfanyl)-5- nitroindazol-6-yl](2-chloro-5-fluorophenyl)methanone (1.00 g, 1.325 mmol, 16%) as a yellow solid. LCMS m/z: 490.0 [M+H] ⁺

[00597] Step B: To a solution of [7-bromo-2-methyl-3-(methyldioxo-X6-sulfanyl)-5- nitroindazol-6-yl](2-chloro-5-fluorophenyl)methanone (1.00 g, 2.04 mmol) in H2O (2 mL) and EtOH (10.0 mL) were added Fe (0.57 g, 10.190 mmol), NH4CI (0.55 g, 10.190 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~100%) to afford compound [5-amino-7-bromo-2-methyl-3- (methyldioxo-X6-sulfanyl)indazol-6-yl](2-chloro-5-fluorophen yl)methanone (300 mg, 0.651 mmol, 32%) as yellow oil. LCMS: m/z 461.9 [M+H] ⁺ .

[00598] Step C: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3- (methyldioxo-X6-sulfanyl)indazole-7-carbonitrile (50 mg, 0.123 mmol) in ACN (5 mL) and H2O (0.2 mL) was added KOH (34.5 mg, 0.615 mmol). The reaction mixture was stirred at rt for 1 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2$O4 and concentrated to afford crude compound 5-amino-6-(2- chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3-(methyldioxo-X6- sulfanyl)-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-8-one (65 mg, 0.107 mmol, 87%) as a yellow oil. LCMS: m/z 425.1 [M+H] ⁺ .

[00599] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl- 3-(methyldioxo-X6-sulfanyl)-7,8-dihydro-6H-pyrrolo[4,3-g]ind azol-8-one (60 mg, 0.141 mmol) in ACN (10 mL) were added pyridine (0.057 mL, 0.706 mmol) and 3-fluoro-5- (trifluoromethyl)benzoyl chloride (0.032 mL, 0.212 mmol). The reaction was stirred at 50 °C for 2 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford crude compound N-[6-(2- chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3-(methyldioxo-X6- sulfanyl)-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)b enzamide (50 mg, 0.081 mmol, 57.57%) as a brown oil. LCMS: m/z 613.1 [M-H]"

243

SUBSTITUTE SHEET (RULE 26) [00600] Step E: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3- (methyldioxo-X6-sulfanyl)-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g ]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (3 mL) was added EtgSiH (9.45 mg, 0.081 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0-70% acetonitrile in H2O) to afford compound N-[6-(2-chloro-5-fluorophenyl)-2-methyl-3-(methyldioxo-X6-su lfanyl)-8-oxo-

7.8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(tr ifluoromethyl)benzamide (6 mg, 0.010 mmol, 62%) as a white solid. LCMS: m/z 599.1 [M+H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 5 10.59 (s, 1H), 9.21 (brs, 1H), 8.04 (s, 1H), 7.95 (d, J= 8.8 Hz, 1H), 7.74 (dd, J= 8.8, 1.2 Hz, 1H), 7.67 (s, 1H), 7.31 (dd, J = 8.8, 5.2 Hz, 1H), 7.12 - 7.10 (m, 1H), 6.43 (brs, 1 H) 6.21 (s, 1 H), 4.54 (s, 3H), 3.55 (s, 3H).

Example 72 A-(6-(2-chloro-5-fluorophenyl)-2-methyl-3-((methylsulfonyl)m ethyl)-8-oxo-

2.6.7.8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[00601] Step A: To a solution of A-(6-(2-chloro-5-fluorophenyl)-3-(chloromethyl)-2-methyl- 8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro -5-(trifluoromethyl)benzamide (30 mg, 0.05 mmol) in DMF (1 mL) was added sodium methanesulfmate (27 mg, 0.26 mmol). The reaction mixture was stirred at 25 °C for 3 hour. The reaction mixture was quenched with water, extracted with EA. The organic phase was washed with brine, dried over ISfeSCL and concentrated. The residue was purified using prep-HPLC (YMC -Actus Triart Cl 8 150*20mm*5um, 30%-95%, phase A: H2O (0.1% FA), phase B: MeCN) to afford to afford compound 7V-(6-(2-chloro-5-fluorophenyl)-2-methyl-3-((methylsulfonyl) methyl)-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (3.5 mg, 0.006 mmol, 11 %). LCMS: m/z 613 [M + H] ⁺ . NMR (400 MHz, DMSO-d6) 5 10.43 (s, 1H), 9.12 -

244

SUBSTITUTE SHEET (RULE 26) 8.87 (m, 1H), 7.96 - 7.90 (m, 2H), 7.77 - 7.69 (m, 2H), 7.32 - 7.25 (m, 1H), 7.14 - 7.04 (m, 1H), 6.59 - 5.83 (m, 2H), 5.34 - 5.31 (m, 2H), 4.31 (s, 3H), 3.12 (s, 3H).

Example 73 A-(6-(2-chloro-5-fluorophenyl)-3-(cyanomethyl)-2-methyl-8-ox o-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00602] Step A: To a solution of A-(6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (530 mg, 0.97 mmol) in THF (10 mL) was added NaBHi (40 mg, 1.06 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in di chloroform to afford compound A-(6-(2-chloro-5-fluorophenyl)-3-(hydroxymethyl)-2-methyl-8- oxo-2,6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (400 mg, 0.69 mmol, 71%) as a yellow solid. LCMS: m/z 551 [M + H] ⁺ .

[00603] Step B: To a solution of A-(6-(2-chloro-5-fluorophenyl)-3-(hydroxymethyl)-2- methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3 -fluoro-5- (trifluoromethyl)benzamide (200 mg, 0.36 mmol) in DCM (6 mL) and DMF (2 mL) was added EbN (0.15 mL, 1.09 mmol), DMAP (4.5 mg, 0.036 mmol) and TsCl (207 mg, 1.09 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water,

245

5UB5TITUTE SHEET (RULE 26) extracted with EA. The organic phase was washed with brine, dried over NazSCh and concentrated. The residue was purified using silica gel column chromatography eluting with 0- 10% methanol in di chloroform to afford compound <V-(6-(2-chloro-5-fluorophenyl)-3- (chloromethyl)-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (200 mg, 0.32 mmol, 87%) as a white solid. LCMS: m/z 569 [M + H] ⁺ [00604] Step C: To a solution ofA-(6-(2-chloro-5-fluorophenyl)-3-(chloromethyl)-2-methyl- 8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro -5-(trifluoromethyl)benzamide (140 mg, 0.25 mmol) in DMF (3 mL) was added NaCN (36 mg, 0.74 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water, extracted with EA. The organic phase was washed with brine, dried over NazSCU and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound A-(6-(2-chloro-5-fluorophenyl)-3-(cyanomethyl)-6-hydroxy-2- methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3 -fluoro-5- (trifluoromethyl)benzamide (6 mg, 0.01 mmol, 4%) as a white solid. LCMS: m/z 576 [M + H] ⁺ . [00605] Step D: To a solution of 7V-(6-(2-chloro-5-fluorophenyl)-3-(cyanomethyl)-6-hydroxy- 2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl) -3-fluoro-5- (trifluoromethyl)benzamide (6 mg, 0.01 mmol) in TFA (1 mL) was added EtzSiH (6 mg, 0.052 mmol). The reaction mixture was stirred at 75 °C for 1 hour. The cooled reaction mixture was concentrated under vacuum. The residue was purified using prep-HPLC (YMC-Actus Triart C18 150*20mm*5um, 30%-95%, phase A: H2O (0.1% FA), phase B: MeCN) to afford A-(6-(2- chloro-5-fluorophenyl)-3-(cyanomethyl)-2-methyl-8-oxo-2,6,7, 8-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.1 mg, 0.004 mmol, 36%). LCMS: m/z 560 [M + H] ⁺ . !H NMR (400 MHz, DMSO-d6) 8 10.40 (s, 1H), 9.17 - 8.80 (m, 1H), 8.00 - 7.92 (m, 2H), 7.77 - 7.68 (m, 2H), 7.31 - 7.25 (m, 1H), 7.13 - 7.05 (m, 1H), 6.50 - 6.15 (m, 2 H), 4.80 - 4.72 (m, 2H), 4.26 (s, 3H).

Example 74 N-[6-(2-chloro-5-fluorophenyl)-3-(3-hydroxyprop-l-ynyl)-2-me thyl-8-oxo- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifl uoromethyl)benzamide

246

SUBSTITUTE SHEET (RULE 26)

[00606] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1000 mg, 1.86 mmol) in TEA (15 mL) was added 2,2,3,3-tetramethyl-

4-oxa-3-silahept-6-yne (380 mg, 2.23 mmol), Cui (70 mg, 0.371 mmol) and palladium chloride bis(triphenylphosphane) (130 mg, 0.186 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na^SCU and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 0-10%) to afford compound [7-bromo-2-methyl-

5-nitro-3-(2,2,3,3-tetramethyl-4-oxa-3-silahept-6-yn-7-yl )indazol-6-yl](2-chloro-5- fluorophenyl)methanone (880 mg, 1.51 mmol, 82%) as a brown solid. LCMS: m/z 582.0 [M+H] ⁺ .

[00607] Step B: To a solution of [7-bromo-2-methyl-5-nitro-3-(2,2,3,3-tetramethyl-4-oxa-3- silahept-6-yn-7-yl)indazol-6-yl](2-chloro-5-fluorophenyl)met hanone (880 mg, 1.51 mmol) in H ₂ O (2.00 mL) and EtOH (10 mL) were added Fe (422 mg, 7.57 mmol), NH ₄ C1 (405 mg, 7.57 mmol). The reaction was stirred at 80 °C for 2 hr. The reaction was diluted with water, extracted

247

SUBSTITUTE SHEET (RULE 26) with EA The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~100%) to afford compound 5-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-3-(2,2,3,3-tetramethyl-4-oxa -3-silahept-6-yn-7-yl)indazole-7- carbonitrile (400 mg, 0.805 mmol, 53%) as yellow oil. LCMS: m/z 552 [M+H]“.

[00608] Step C: To a solution of [5-amino-7-bromo-2-methyl-3-(2,2,3,3-tetramethyl-4-oxa-3- silahept-6-yn-7-yl)indazol-6-yl](2-chloro-5-fluorophenyl)met hanone (270 mg, 0.490 mmol) in DMA (6 mL) were added Zn(CN)2 (69.1 mg, 0.588 mmol) and Pd(PPhg)4 (56.6 mg, 0.049 mmol). The reaction mixture was stirred at 150 °C under N2 for 1 hr using M.W. LCMS showed the reaction was completed. The cooled reaction mixture was diluted water, extracted with EA The organic phase was washed with brine, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in di chloroform (gradient: 15-25%) to afford 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2- methyl-3-(2,2,3,3-tetramethyl-4-oxa-3-silahept-6-yn-7-yl)ind azole-7-carbonitrile (90 mg, 0.181 mmol, 37%) as a red solid. LCMS: m/z 498 [M + H] ⁺ .

[00609] Step D: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3- (2,2,3,3-tetramethyl-4-oxa-3-silahept-6-yn-7-yl)indazole-7-c arbonitrile (60 mg, 0.121 mmol) in ACN (4 mL) and H2O (12 mL) were added KOH (20.3 mg, 0.362 mmol). The reaction was stirred at room temperature under N2 for 10 min. LCMS showed the reaction was completed. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The organic layer was separated and concentrated to afford 5-amino-6-(2-chforo-5-fluorophenyl)-6-hydroxy-2-methyl-3-(2, 2,3,3-tetramethyl-4-oxa-3- silahept-6-yn-7-yl)-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-o ne (50 mg, 0.097 mmol, 80%)as a yellow solid. LCMS: m/z 516 [M + H] ⁺ .

[00610] Step E: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3- (2,2,3,3-tetramethyl-4-oxa-3-silahept-6-yn-7-yl)indazole-7-c arbonitrile (50 mg, 0.101 mmol) in ACN (4 mL) were added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (68.4 mg, 0.302 mmol) and Py (39.8 mg, 0.503 mmol). The reaction was stirred at room temperature under N2 for 2 hr. LCMS showed the reaction was completed. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl

248

SUBSTITUTE SHEET (RULE 26) acetate in petroleum ether (gradient:40-50%) to afford N-[6-(2-chloro-5-fluorophenyl)-6- hydroxy-2-methyl-8-oxo-3-(2,2,3,3-tetramethyl-4-oxa-3-silahe pt-6-yn-7-yl)-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fhioro-3-(trifluoromethyl)benz amide (30 mg, 0.043 mmol, 42%) as a yellow solid. LCMS: m/z 706 [M + H] ⁺ .

[00611] Step F: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-(2,2,3,3-tetramethyl-4-oxa-3-silahept-6-yn-7-yl)-7,8-dihyd ro-6H-pyrrolo[4,3-g]indazol-5-yl]- 5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.028 mmol) in TFA (5 mL) were added EtaSiH (6.60 mg, 0.057 mmol). The reaction was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated, diluted aqueous NaHCOa and extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)- 3-(3-hydroxyprop-l-ynyl)-2-methyl-8-oxo-7,8-dihydro-6H-pyrro lo[4,3-g]indazol-5-yl]-5-fluoro- 3-(trifluoromethyl)benzamide (7 mg, 0.012 mmol, 43%). LCMS: m/z 576 [M + H]“. NMR (400 MHz, Methanol-d4) 8 7.87 (s, 1H), 7.67 (dd, J = 17.6, 8.4 Hz, 3H), 7.26 (dd, J = 8.8, 4.8 Hz, 1H), 7.02 - 6.98 (m, 1H), 6.50 - 6.35 (m, 2H), 4.59 (s, 2H), 4.34 (s, 3H).

Example 75 N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(piperidin-4 -yl)-2, 6,7,8- tetrahydropyirolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

249

SUBSTITUTE SHEET (RULE 26)

[00612] Step A: To a mixture of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1000 mg, 1.857 mmol) in dioxane (12 mL) and water (4 mL) was added 2-methylpropan-2-yl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine-1 -carboxylate (631 mg, 2.04 mmol), sodium carbonate (787 mg, 7.428 mmol) and Pd (dppf) Ch (135 mg, 0.186 mmol). The reaction mixture was stirred at 80 °C under N2 atmosphere for 2 hours. The cooled mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by FCC eluting with EA/PE (0-40%) to give a crude, which was triturated with MTBE to give 2-methylpropan-2-yl 4-{7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-5- nitroindazol-3-yl]-l,2,3,6-tetrahydropyridine-l-carboxylate (550 mg, 0.926 mmol, 50%) as a yellow solid. LCMS: m/z 593 [M + H] ⁺ , 595 [M + H]~.

[00613] Step B: To a stirred mixture of 2-methylpropan-2-yl 4-{7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazol-3-yl}-l,2,3,6 -tetrahydropyridine-l-carboxylate (500 mg, 0.842 mmol) in DMA (1.5 mL) was added 557-21-1 (296 mg, 2.52 mmol) and palladium(O) tetrakis(triphenylphosphane) (291 mg, 0.253 mmol). The reaction mixture was stirred at 150 °C under N2 atmosphere for 2 hours. LCMS showed the reaction was complete. The cooled reaction mixture was diluted with water, extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The

250

SUBSTITUTE SHEET (RULE 26) residue was purified by prep-TLC (EA/PE=1:1) to give 2-methylpropan-2-yl 4-{6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methyl-5-nitroindazol-3-yl} -l,2,3,6-tetrahydropyridine-l- carboxylate (40 mg, 0.074 mmol, 9%) as a yellow solid. LCMS: m/z 540 [M + H] ⁺ .

[00614] Step C: To a stirred mixture of 2-methylpropan-2-yl 4-{6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methyl-5-nitroindazol-3-yl} -l,2,3,6-tetrahydropyridine-l- carboxylate (40 mg, 0.074 mmol) in acetonitrile (10 mL) and H2O (1 mL) was added potassium hydroxide (20.78 mg, 0.370 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified by prep- TLC (MeOH/DCM=l : 18) to give 2-methylpropan-2-yl 4-[6-(2-chloro-5-fluorophenyl)-6- hydroxy-2-methyl-5-nitro-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g] indazol-3-yl]-l,2,3,6- tetrahydropyridine-1 -carboxylate (30 mg, 0.054 mmol, 73%) as a yellow solid. LCMS: m/z 558 [M + H] ⁺ .

[00615] Step D: To a stirred mixture of 2-methylpropan-2-yl 4-[6-(2-chloro-5-fluorophenyl)- 6-hydroxy-2-methyl-5-nitro-8-oxo-7,8-dihydro-6H-pyrrolo[4,3- g]indazol-3-yl]-l,2,3,6- tetrahydropyridine-1 -carboxylate (30 mg, 0.054 mmol) in EtOH (10 mL) was added 10% Pd/C(from TCI) (15 mg, 0.141 mmol). The reaction mixture was stirred at room temperature under H2 atmosphere for 2 hours. The reaction mixture was filtered on celite and the filtrate was concentrated. The residue was purified by prep-TLC (MeOH/DCM=l : 12) to give 2- methylpropan-2-yl 4-[5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8- oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-3-yl]hexahydropyridine-l-ca rboxylate (20 mg, 0.038 mmol, 70%) as a yellow solid. LCMS: m/z 530 [M + H] ⁺ .

[00616] Step E: To a mixture of 2-methylpropan-2-yl 4-[5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-3- yl]hexahydropyridine-l -carboxylate (20 mg, 0.038 mmol) and pyridine (0.015 mL, 0.189 mmol) in acetonitrile (5 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (12.8 mg, 0.057 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-TLC (MeOH/DCM=l : 15) to give 2-methylpropan-2-yl 4-[6-(2-chloro-5-fluorophenyl)-5- ({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydr oxy-2-methyl-8-oxo-7,8-dihydro-

251

SUBSTITUTE SHEET (RULE 26) 6H-pyrrolo[4,3-g]indazol-3-yl]hexahydropyridine-l -carboxylate (20 mg, 0.028 mmol, 73%) as a yellow solid. LCMS: m/z 720 [M + H] ⁺ .

[00617] Step F: A reaction mixture of 2-methylpropan-2-yl 4-[6-(2-chloro-5-fluorophenyl)-5- ({[5-fhioro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydr oxy-2-methyl-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-3-yl]hexahydropyridine-l -carboxylate (17 mg, 0.024 mmol) in EtgSiH (1.2 mL) and IF A (12 mL) was stirred at 70 °C for Ihours. The cooled mixture was concentrated. The residue was purified by prep-HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3- (hexahydropyridin-4-yl)-2-methyl-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (3 mg, 0.005 mmol, 21%). LCMS: m/z 604 [M + H] ⁺ , 606 [M + H] ⁺ . !H NMR (400 MHz, Methanol-d4) 5 8.47 (s, 1H), 8.07 (s, 1H), 7.73 (d, J = 9.6 Hz, 2H), 7.66 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 9.2, 5.2 Hz, 1H), 7.03 - 6.95 (m, 1H), 6.45-6.35 (brs, 1H), 4.32 (s, 3H), 3.75 - 3.66 (m, 1H), 3.62 - 3.54 (m, 2H), 3.29 - 3.19 (m, 2H), 2.46 - 2.31 (m, 2H), 2.28 - 2.19 (m, 2H).

Example 76 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethyl)b enzainido)-8- oxo-l,6,7,8-tetrahydroimidazo[4,5-e]isoindole-2-carboxamide

252

SUBSTITUTE SHEET (RULE 26)

[00618] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (10.0 g, 21.9 mmol) in DMSO-d6 (60 mL) were added DIEA (11.4 mL, 65.8 mmol) and (2,4-dimethoxyphenyl)methanamine (3.29 mL, 21.9 mmol). The reaction mixture was stirred at 130 °C for 30 min. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over NaiSCE and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~30%) to afford compound (2-chloro-5-fluorophenyl)(2,6-dibromo-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-nitrophenyl)methanone (9.0 g, 14.9 mmol, 68%) as a yellow solid. LCMS m/z: 601.2 [M+H] ⁺

[00619] Step B: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-nitrophenyl)methanone (9.0 g, 14.9 mmol) in FLO (10 mL) and EtOH (50 mL) were added Fe (4.17 g, 74.671 mmol), NH ₄ C1 (3.99 g, 74.6 mmol). The reaction mixture was stirred at 80 °C for 2 hr. The cooled reaction mixture was filtered, concentrated, diluted with water and extracted with EA. The organic layer was washed brine, dried over Na^SCU and concentrated. The residue was purified using silica gel column

253

SUBSTITUTE SHEET (RULE 26) chromatography eluting with ethyl acetate in petroleum ether (1%~100%) to afford compound (3-amino-2,6-dibromo-4-([(2,4-dimethoxyphenyl)methyl]amino}p henyl)(2-chloro-5- fluorophenyl)methanone (5.5 g, 9.60 mmol, 64%) as yellow oil. LCMS: m/z 571.0 [M+H] ⁺ . [00620] Step C: To a solution of (3-amino-2,6-dibromo-4-{[(2,4- dimethoxyphenyl)methyl]amino}phenyl)(2-chloro-5-fluorophenyl )methanone (5.50 g, 9.604 mmol) in toluene (50 mL) were added ethyl 2,2,2-triethoxyacetate (4.23 g, 19.2 mmol) and 4- methylbenzenesulfonic acid (0.17 g, 0.960 mmol). The reaction mixture was stirred at 100 °C for 1.5 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~30%) to afford compound ethyl 4,6-dibromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-[(2,4- dimethoxyphenyl)methyl]benzo[d]imidazole-2-carboxylate (3 g, 4.582 mmol, 48%) as white solid. LCMS: m/z 654.9 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 7.73 (dd, J= 8.8, 4.8 Hz, 1H), 7.67 (s, 1H), 7.61 (td, J= 8.4, 3.2 Hz, 1H), 7.53 - 7.48 (m, 1H), 6.93 (d, J= 8.4 Hz, 1H), 6.65 (d, J= 2.0 Hz, 1H), 6.43 (dd, J= 8.4, 2.0 Hz, 1H), 5.31 (s, 2H), 4.52 (q, J= 7.2 Hz, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 1.44 (t, J= 7.2 Hz, 3H).

[00621] Step D: To a solution of ethyl 5,7-dibromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-l- [(2,4-dimethoxyphenyl)methyl]benzo[d]imidazole-2-carboxylate (1.50 g, 2.29 mmol) in dioxane (15 mL) were added Pd2(dba)s (0.21 g, 0.229 mmol), Xant-PHOS (0.27 g, 0.458 mmol), and CS2CO3 (1.49 g, 4.582 mmol). The reaction mixture was stirred at 110 °C under N2 for 3 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1%~100%) to afford crude 1.5 g. The residue was purified by prep-HPLC (Cl 8, 0~90 % acetonitrile in H2O) to afford compound ethyl 4-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-[(2,4- dimethoxyphenyl)methyl]-6-({[3-fluoro-5- (trifluoromethyl)phenyl]carbonyl}amino)benzo[d]imidazole-2-c arboxylate (360 mg, 0.461 mmol, 20%) as a light yellow solid. ^X H NMR (400 MHz, DMSO-d6) 5 10.69 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.78 (s, 2H), 7.54 (dd, J- 8.8, 4.8 Hz, 1H), 7.40-7.35 (m, 2H), 7.31 (s, 1H), 6.85 (d, J= 8.4 Hz, 1H), 6.61 (d, J= 2.4 Hz, 1H), 6.40 (dd, J= 8.4, 2.4 Hz, 1H), 5.25 (s, 2H), 4.55 (q, J= 7.2 Hz, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 1.46 (t, J= 7.2 Hz, 3H).

254

SUBSTITUTE SHEET (RULE 26) [00622] Step E: To a solution of ethyl 4-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l- [(2,4-dimethoxyphenyl)methyl]-6-([[3-fluoro-5-

(trifluoromethyl)phenyl]carbonyl}amino)benzo[d]imidazole- 2-carboxylate (300 mg, 0.384 mmol) in DMA (5 mL) was added Zn(CN)a (67.6 mg, 0.576 mmol) and Pd(PPhs)4 (44.4 mg, 0.038 mmol). The reaction mixture was degassed with N2 and stirred under at 150 °C N2 atmosphere for Ihr under microwave. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with DCM to afford compound ethyl 5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-l-[(2,4- dimethoxyphenyl)methyl]-6-({[3-fluoro-5- (trifluoromethyl)phenyl]carbonyl}amino)benzo[d]imidazole-2-c arboxylate (100 mg, 0.138 mmol, 36%) as a red solid. LCMS: m/z 727.0 [M+H] ⁺

[00623] Step F: To a solution of ethyl 5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-l- [(2,4-dimethoxyphenyl)methyl]-6-({[3-fluoro-5- trifluoromethyl)phenyl]carbonyl}amino)benzo[d]imidazole-2-ca rboxylate (10 mg, 0.014 mmol) in ACN (5 mL) and H2O (0.50 mL) was added KOH (3.86 mg, 0,069 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SC>4 and concentrated to afford crude compound ethyl 6-(2-chloro-5-fluorophenyl)-3-[(2,4-dimethoxyphenyl)methyl]- 5- ({[3-fluoro-5-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydr oxy-8-oxo-7,8-dihydro-6H- imidazo[5,4-e]isoindole-2-carboxylate (10 mg, 0.013 mmol, 97%) as a yellow oil. LCMS: m/z 746.0 [M+H] ⁺ .

[00624] Step G: A solution of ethyl 6-(2-chloro-5-fluorophenyl)-3-[(2,4- dimethoxyphenyl)methyl]-5-({[5-fluoro-3-(trifluoromethyl)phe nyl]carbonyl}amino)-6-hydroxy- 8-oxo-7,8-dihydro-6H-imidazo[4,5-e]isoindole-2-carboxylate (10 mg, 0.013 mmol) in NHVMeOH (7 M) (5 mL) was stirred at 70 °C under N2 atmosphere for 18 h. The cooled reaction mixture was concentrated in vacuo to afford crude 6-(2-chloro-5-fluorophenyl)- 3-[(2,4-dimethoxyphenyl)methyl]-5-(([5-fluoro-3-(trifluorome thyl)phenyl]carbonyl}amino)-6- hydroxy-8-oxo-7,8-dihydro-6H-imidazo[4,5-e]isoindole-2-carbo xamide (5 mg, 0.007 mmol, 52%) as a yellow oil. LCMS: m/z 716.2 [M+H] ⁺ .

255

SUBSTITUTE SHEET (RULE 26) [00625] Step H: To a solution of ethyl 6-(2-chloro-5-fluorophenyl)-3-[(2,4- dimethoxyphenyl)methyl]-5-({[5-fluoro-3-(trifluoromethyl)phe nyl]carbonyl}amino)-6-hydroxy- 8-oxo-7,8-dihydro-6H-imidazo[4,5-e]isoindole-2-carboxylate (5 mg, 0.007 mmol) in TFA (5 mL) was added EtsSiH (8.12 mg, 0.07 mmol). The reaction was stirred at 70 °C for 1 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0-70 % acetonitrile in H2O) to afford 6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5- (trifluoromethyl)benzamido)-8-oxo-l,6,7,8-tetrahydroimidazo[ 4,5-e]isoindole-2-carboxamide (1.0 mg, 0.002 mmol, 26%). LCMS: m/z 550.1 [M+H] ⁺ . Tf NMR (400 MHz, DMSO-d6) 5 12.41 (s, 1H), 10.34 (s, 1H), 8.81 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.80 - 7.66 (m, 2H), 7.64 (s, 1H), 7.33 - 7.18 (m, 3H), 7.12 - 7.04 (m, 1H), 6.68-6.60 (brs, 1H), 5.98 - 5.90 (brs, 1H).

Example 77 (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl-8-oxo-

2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide and Example 78 (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl-8-oxo-

2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[00626] A solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-

7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(tr ifluoromethyl)benzamide (150 mg, 0.257 mmol) in prep-SFC to afford: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2- methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3 -fluoro-5-

(trifluoromethyl)benzamide (57.6 mg, 0.098 mmol, 26%). LCMS: m/z 556 [M + H] ⁺ , 'H NMR (400 MHz, DMSO-d6) 8 10.36 (s, 1H), 8.97 (s, 1H), 7.93 (d, J- 8.4 Hz, 1H), 7.86 (s, 1H), 7.78 - 7.65 (m, 2H), 7.29 (dd, J= 9.2, 5.2 Hz, 1H), 7.10 (brs, 1H), 6.61 - 6.03 (m, 2H), 4.24 (s, 3H), 3.95 - 3.85 (m, 2H). and (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl-8- oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide(57.6

256

SUBSTITUTE SHEET (RULE 26) mg, 0.098 mmol, 26%). LCMS: m/z 556 [M + H] ⁺ , ^X HNMR (400 MHz, DMSO-d6) 5 10.36 (s, 1H), 8.97 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.86 (s, 1H), 7.78 - 7.65 (m, 2H), 7.29 (dd, J= 9.2, 5.2 Hz, 1H), 7.10 (s, 1H), 6.61 - 6.03 (m, 2H), 4.24 (s, 3H), 3.95 - 3.85 (m, 2H).

Example 79 N-[6-(2-chloro-5-fluorophenyl)-3-(3H-imidazol-4-yl)-2-methyl -8-oxo-7,8- dihydro-6H-pyirolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide

[00627] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (500 mg, 0.929 mmol) in dioxane (10 mL) were added 5-(tributyl-X4- stannanyl)-3-(triphenylmethyl)imidazole (667 mg, 1.11 mmol), Pd(PPh3)4 (107 mg, 0.093 mmol). The reaction mixture was stirred at 120 °C for 18 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SOr and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~100%) to afford compound {7-bromo-2-methyl-5-nitro-3- [l-(triphenylmethyl)imidazol-4-yl]indazol-6-yl}(2-chloro-5-f luorophenyl)m ethanone (600 mg, 0.832 mmol, 90%) as yellow oil. ^X HNMR (400 MHz, DMSO-d6) 5 9.12 (s, 1H), 7.89 (s, 1H),

257

SUBSTITUTE SHEET (RULE 26) 7.84 (d, J = 0.8 Hz, 1H), 7.76 (dd, J = 9.2, 3.2 Hz, 1H), 7.70 (dd, J = 8.8, 5.2 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.49 - 7.42 (m, 9H), 7.28 - 7.25 (m, 6H), 4.31 (s, 3H)

[00628] Step B: To a solution of {7-bromo-2-methyl-5-nitro-3-[l-(triphenylmethyl)imidazol- 4-yl]indazol-6-yl}(2-chloro-5-fluorophenyl)methanone (200 mg, 0.277 mmol) in EtOH (10.00 mL) and H ₂ O (2.00 mL) were added Fe (77.45 mg, 1.387 mmol), NH ₄ C1 (74.19 mg, 1.387 mmol). The reaction mixture was stirred at 80 °C for 24 hr. The cooled reaction mixture was filtered, concentrated, diluted with water and extracted with EA. The organic layer was washed brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~100%) to afford compound [5-amino-7-bromo-2-methyl-3-[l-(triphenylmethyl)imidazol-4-y l]indazol-6-yl}(2-chloro-5- fluorophenyl)methanone (100 mg, 0.145 mmol, 52%) as yellow oil. LCMS: m/z 692.0 [M+H] ⁺ . [00629] Step C: To a solution of [5-amino-7-bromo-2-methyl-3-[l-

(triphenylmethyl)imidazol-4-yl]indazol-6-yl}(2-chloro-5-f luorophenyl)methanone (100 mg, 0.145 mmol) in DMA (5 mL) was added Zn(CN) ₂ (25.49 mg, 0.217 mmol) and Pd(PPhs)4 (16.72 mg, 0.014 mmol). The reaction mixture was degassed with N ₂ and stirred under N ₂ atmosphere at 150 °C for 1 h under microwave. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified using silica gel column chromatography eluted with DCM to afford compound 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3-[l- (triphenylmethyl)imidazol-4-yl]indazole-7-carbonitrile (60 mg, 0.094 mmol, 65%) as a red solid. LCMS: m/z MS m/z (ESI): 637.0 [M+H] ⁺

[00630] Step D: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-3- [l-(triphenylmethyl)imidazol-4-yl]indazole-7-carbonitrile (50 mg, 0.078 mmol) in ACN (5.00 mL) and H ₂ O (1 mL) was added KOH (22.02 mg, 0.392 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na ₂ SO ₄ and concentrated to afford crude compound 5-amino-6-(2- chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3-[l-(triphenylmet hyl)imidazol-4-yl]-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-8-one (50 mg, 0.076 mmol, 97%) as a yellow oil. LCMS: m/z 655.3 [M+H] ⁺ .

[00631] Step E: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3- [l-(triphenylmethyl)imidazol-4-yl]-7,8-dihydro-6H-pyrrolo[4, 3-g]indazol-8-one (50 mg, 0.076

258

SUBSTITUTE SHEET (RULE 26) mmol) in ACN (5 mL) were added pyridine (0.031 mL, 0.382 mmol) and 3-fluoro-5- (trifluoromethyl)benzoyl chloride (25.9 mg, 0.114 mmol). The reaction was stirred at rt for 1 hr. The cooled reaction mixture was concentrated. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over NazSCU and concentrated to afford crude compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-3-[l - (triphenylmethyl)imidazol-4-yl]-7,8-dihydro-6H-pyrrolo[4,3-g ]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (50 mg, 0.059 mmol, 77%) as a yellow solid. LCMS: m/z 846.1 [M+H] ⁺ .

[00632] Step F: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-[l-(triphenylmethyl)imidazol-4-yl]-7,8-dihydro-6H-pyrrolo[ 4,3-g]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (50 mg, 0.059 mmol) in TEA (5 mL) was added EtgSiH (137 mg, 1.18 mmol). The reaction was stirred at 70 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in H2O) to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-(3H-imidazol-4-yl)-2-methyl -8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (8 mg, 0.014 mmol, 23%) as a white solid. LCMS: m/z 587.1 [M+H] ⁺ . NMR (400 MHz, DMSO-d6) 5 10.34 (s, 1H), 9.02 (s, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 8.02 - 7.91 (m, 2H), 7.78 - 7.66 (m, 2H), 7.30 (dd, J= 8.8, 5.2 Hz, 1H), 7.09 (t, J= 8.4 Hz, 1H), 6.30-6.20 (m, 1H), 4.39 (s, 3H).

Example 80 N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-7,8-dihydro-6H -thiazolo [4,5- e]isoindol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

259

SUBSTITUTE SHEET (RULE 26)

[00633] Step A: To a solution of methyl 6-amino-3-bromo-2-fluorobenzoate (10.0 g, 40.3 mmol) in DMF (100 mL) was added NIS (13.6 g, 60.5 mmol) and HOAc (0.717 mL, 4.03 mmol). The reaction mixture was stirred at 50 °C overnight. The reaction was completed and detected by TLC. The cooled reaction mixture was dissolved in EA (100 mL), washed with sodium thiosulphate aqueous solution (100 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-20% EA in PE) to afford methyl 6-amino-3-bromo-2-fluoro-5-iodobenzoate (7.30 g, 19.5 mmol, 48%) as a white solid. LCMS: m/z 374.95/376.95 [M + H] ⁺ .

[00634] Step B: To a solution of methyl 6-amino-3-bromo-2-fluoro-5-iodobenzoate (7.30 g, 19.5 mmol) was added AC2O (60 mL). The reaction mixture was stirred at 140 °C overnight. The reaction mixture was completed and detected by LCMS. The cooled reaction mixture was quenched with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with 0- 60% EA in PE) to afford methyl 3-bromo-6-(diacetylamino)-2-fluoro-5-iodobenzoate (7.30 g, 15.9 mmol, 82%) as a yellow solid. LCMS: m/z 458.2/460.02 [M + H] ⁺ .

[00635] Step C: To a solution of methyl 3-bromo-6-(diacetylamino)-2-fluoro-5-iodobenzoate (7.30 g, 15.9 mmol) in MeOH (70 mL) was added ISfeCCL (5.07 g, 47.8 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was completed and detected by LCMS. The reaction mixture was quenched with H2O, extracted with EA. The organic phase was washed with brine, dried over ISfeSCL and concentrated. The residue was purified by silica gel chromatography (eluting with 0-80% EA in PE) to afford methyl 6- (acetylamino)-3-bromo-2-fluoro-5-iodobenzoate (4.20 g, 10.1 mmol, 63%) as a white solid. LCMS: m/z 416.98/418.98 [M + H] ⁺ . NMR (400 MHz, DMSO-d6) 5 9.90 (s, 1H), 8.41 (d, J = 7.6 Hz, 1H), 3.80 (s, 3H), 2.00 (s, 3H).

260

SUBSTITUTE SHEET (RULE 26) [00636] Step D: To a solution of methyl 6-(acetylamino)-3-bromo-2-fluoro-5-iodobenzoate (2.40 g, 5.77 mmol) in DMF (40 mL) was added NazS OITO (242 mg, 3.10 mmol) and Cui (0.110 g, 0.577 mmol). The reaction mixture was stirred at 80 °C under N2 overnight. After LCMS showed completion, the reaction mixture was quenched with water (10 mL), adjust pH = 7 with IN HC1, extracted with EA (60 mL). The combined organic layers were washed with brine (30 mL), dried over NaiSCU and concentrated. The residue was purified by prep-HPLC (C18, 5 ~ 30 % ACN in H2O with 0.1 % FA) to afford 6-bromo-5-fluoro-2-methylbenzo[2,l- d][l,3]thiazole-4-carboxylic acid (650 mg, 2.24 mmol, 39%) as a yellow solid. LCMS: m/z 290.11/292.11 [M + H] ⁺ .

[00637] Step E: To a solution of 6-bromo-5-fluoro-2-methylbenzo[2,l-d][l,3]thiazole-4- carboxylic acid (660 mg, 2.28 mmol) in MeOH (40 mL) was added 2-chloro-5-fluorobenzene-l- carbaldehyde (360 mg, 2.28 mmol), 4-methoxyaniline (0.264 mL, 2.28 mmol) and tert-butyl isocyanide (8.60 mg, 0.103 mmol). The reaction mixture was stirred at 50 °C for 3d. The reaction mixture was concentrated and purified by silica gel chromatography (eluting with 0-60% EA in PE) to afford 6-bromo-N-[l-(2-chloro-5-fluorophenyl)-2-[(2-methylprop-2-yl )amino]-2- oxoethyl]-5-fluoro-N-[(4-methoxyphenyl)methyl]-2-methylbenzo [2,l-d][l,3]thiazole-4- carboxamide (680 mg, 1.05 mmol, 46%) as a yellow solid. LCMS: m/z 650.96/652.96 [M + H] ⁺ . [00638] Step F: To a solution of 6-bromo-N-[l-(2-chloro-5-fluorophenyl)-2-[(2-methylprop- 2-yl)amino]-2-oxoethyl]-5-fluoro-N-[(4-methoxyphenyl)methyl] -2-methylbenzo[2,l- d][l,3]thiazole-4-carboxamide (250 mg, 0.384 mmol) in DMA (5 mL) was added 1,1- bis(dimethylamino)-N-(2-methylprop-2-yl)methanimine (197 mg, 1.15 mmol). The reaction mixture was stirred at 140 °C for Ih using microwave. The reaction mixture was dissolved in EA (20 mL), washed with H2O (20 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-100% EA in PE) to afford 5- bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-7-[(4-methoxyphe nyl)methyl]-2-methyl-7,8- dihydro-6H-[l,3]thiazolo[4,5-e]isoindol-8-one (35.0 mg, 0.0640 mmol, 17%) as a yellow solid. LCMS: m/z 530.99/532.99 [M + H] ⁺ .

[00639] Step G: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-7-[(4- methoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-[l,3]thiazolo[ 4,5-e]isoindol-8-one (45.0 mg, 0.0850 mmol) in dioxane (2 mL) was added 5-fluoro-3-(trifluoromethyl)benzene-l-carboxamide (26.3 mg, 0.127 mmol), CS2CO3 (55.1 mg, 0.169 mmol), Pd2(dba)s (15.5 mg, 0.0170 mmol) and

261

SUBSTITUTE SHEET (RULE 26) Xantphos (9.79 mg, 0.0170 mmol). The reaction mixture was stirred at 100 °C under N2 for 1 hr. The reaction was completed and detected by LCMS. The cooled reaction mixture was quenched with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with 20-100% EA in PE) to afford N-[6-(2-chloro-5-fluorophenyl)-7-[(4-methoxyphenyl)methyl]-2 -methyl-8-oxo- 7,8-dihydro-6H-[l,3]thiazolo[4,5-e]isoindol-5-yl]-3-fluoro-5 -(trifluoromethyl)benzamide (25.0 mg, 0.0380 mmol, 45%) as a yellow solid. LCMS: m/z 658.04 [M + H] ⁺ .

[00640] Step H: A solution ofN-[6-(2-chloro-5-fluorophenyl)-7-[(4-methoxyphenyl)methyl] - 2-methyl-8-oxo-7,8-dihydro-6H-[l,3]thiazolo[4,5-e]isoindol-5 -yl]-3-fluoro-5- (trifluoromethyl)benzamide (20.0 mg, 0.0300 mmol) in TFA (2 mL) was added TfOH (0.00300 mL, 0.0300 mmol) and EtgSiH (3.53 mg, 0.0300 mmol). The reaction was stirred at 90 °C for 30 min. LCMS showed the reaction was completed. The reaction mixture was concentrated and purified by prep-HPLC (C18, 30 - 95 % ACN in H2O with 0.1 % FA) to afford N-[6-(2-chloro- 5-fluorophenyl)-2-methyl-8-oxo-7,8-dihydro-6H-[l,3]thiazolo[ 4,5-e]isoindol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (4.10 mg, 0.00800 mmol, 25%). LCMS: m/z 538.89 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-d6) 6 10.51 (s, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.95 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 8.8 Hz, 1H), 7.67 (s, 1H), 7.29 (dd, J= 8.8, 5.2 Hz, 1H), 7.09 (brs, 1H), 6.50 - 6.20 (m, 2H), 2.90 (d, J= 12.0 Hz, 3H).

Example 81 N-[6-(2-chloro-5-fluorophenyl)-3- [(difluor omethyl)oxy]-2-methyl-8-oxo-7, 8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide

262

SUBSTITUTE SHEET (RULE 26)

[00641] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (2 g, 3.71 mmol) and (E)-phenylmethanal oxime (0.49 g, 4.08 mmol) in DMF (50 mL) was added CS2CO3 (2.42 g, 7.43 mmol) and RockPhos Pd G3 (7.79 mg, 0.009 mmol). The mixture was stirred at 100 °C under N2 for 2 hours. The cooled mixture was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with MeOH in DCM (gradient: 0-15%) to give (7-bromo-3-hydroxy-2- methyl-5-nitroindazol-6-yl)(2-chloro-5-fluorophenyl)methanon e (1.5 g, 3.50 mmol, 94%) as a red solid. LCMS: m/z 430.3 [M + H] ⁺ . ^! H NMR (400 MHz, DMSO-d6) 8 8.37 (s, 1H), 7.64 (dd, J = 8.8, 5.2 Hz, 1H), 7.58 (dd, J = 9.2, 2.8 Hz, 1H), 7.54 - 7.47 (m, 1H), 3.50 (s, 3H).

[00642] Step B: To a solution of (7-bromo-3-hydroxy-2-methyl-5-nitroindazol-6-yl)(2- chloro-5-fluorophenyl)methanone (800 mg, 1.87 mmol) in CH3CN (50 mL) and water (10 mL) was added diethyl (bromodifluoromethyl)phosphonate (997 mg, 3.73 mmol) and KOH (209 mg, 3.73 mmol). The mixture was stirred at 20 °C for 1 hour. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-30%) to give [7-bromo-3-[(difluoromethyl)oxy]-2-methyl-5- nitroindazol-6-yl}(2-chloro-5-fluorophenyl)methanone (570 mg, 1.19 mmol, 64%) as a yellow solid. LCMS: m/z 480.2 [M + H] ⁺

[00643] Step C: To a solution of {7-bromo-3-[(difluoromethyl)oxy]-2-methyl-5-nitroindazol- 6-yl}(2-chloro-5-fluorophenyl)methanone (570 mg, 1.19 mmol) in EtOH (20 mL) and water (5 mL) was added Fe (399 mg, 7.15 mmol) and NH4CI (255 mg, 4.76 mmol). The mixture was stirred at 75 °C for 1 hour. The cooled mixture was filtered, and the filtrate was concentrated. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum to give the residue. The

263

SUBSTITUTE SHEET (RULE 26) residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-30%) to give {5-amino-7-bromo-3-[(difluoromethyl)oxy]-2-methylindazol-6-y l}(2-chloro-5- fluorophenyl)methanone (170 mg, 0.379 mmol, 32%) as a red solid. LCMS: m/z 450.3 [M + H] ⁺ [00644] Step D: To a solution of {5-amino-7-bromo-3-[(difluoromethyl)oxy]-2- methylindazol-6-yl}(2-chloro-5-fluorophenyl)methanone (160 mg, 0.357 mmol) in NMP (4 mL) was added CuCN (47.9 mg, 0.535 mmol). The reaction mixture was stirred at 150 °C under N2 for 1 hour in microwave. The cooled reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-40%) to give 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-3-[(difluorome thyl)oxy]-2- methylindazole-7-carbonitrile (100 mg, 0.253 mmol, 71%) as a red solid. LCMS: m/z 395.3 [M + H] ⁺ [00645] Step E: To a solution of 5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-3- [(difluoromethyl)oxy]-2-methylindazole-7-carbonitrile (90 mg, 0.228 mmol) in CH3CN (9 mL) and water (4.5 mL) was added KOH (38.4 mg, 0.684 mmol). The mixture was stirred at 20 °C for 1 hour. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum to give 5-amino-6-(2- chloro-5-fluorophenyl)-3-[(difluoromethyl)oxy]-6-hydroxy-2-m ethyl-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-8-one (90 mg, 0.218 mmol, 96%) as a brown solid. LCMS: m/z 413.4 [M + H] ⁺ .

[00646] Step F: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3- [(difluoromethyl)oxy]-6-hydroxy-2-methyl-7,8-dihydro-6H-pyrr olo[4,3-g]indazol-8-one (90 mg, 0.218 mmol) in CH3CN (10 mL) was added pyridine (51.7 mg, 0.654 mmol) and 3-fluoro-5- (trifluoromethyl)benzoyl chloride (59.3 mg, 0.262 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under vacuum to give a crude, which was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-80%) to give N-[6-(2-chloro-5-fluorophenyl)-3- [(difluoromethyl)oxy]-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6 H-pyrrolo[4,3-g]indazol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (118 mg, 0.196 mmol, 90%) as a brown solid. LCMS: m/z 603.4 [M + H] ⁺

264

SUBSTITUTE SHEET (RULE 26) [00647] Step G: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-[(difluoromethyl)oxy]-6- hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol- 5-yl]-5-fluoro-3-

(trifluoromethyl)benzamide (90 mg, 0.149 mmol) in TFA (9 mL) was added EhSiH (2 mL) and the mixture was stirred at 50 °C for 30 min. The mixture was concentrated. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na^SCU and concentrated. The residue was purified by prep-HPLC to give N-[6-(2-chloro-5- fluorophenyl)-3-[(difluoromethyl)oxy]-2-methyl-8-oxo-7,8-dih ydro-6H-pyrrolo[4,3-g]indazol-5- yl]-5-fluoro-3-(trifluoromethyl)benzamide (18.4 mg, 0.031 mmol, 21%). LCMS: m/z 587.2 [M + H] ⁺ . NMR (400 MHz, DMSO-d6) 5 10.37 (s, 1H), 9.06 (brs, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.70 - 7.33 (m, 3H), 7.30 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 (s, 1H), 6.30 - 6.10 (m, 2H), 4.12 (s, 3H).

Example 82 A-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-trifl uoroethyl)- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

[00648] Step A: To a solution of A-(6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (40 mg, 0.073 mmol) in THF (3 mL) was added trimethyl(trifluoromethyl)silane (104 mg, 0.73 mmol) and tetrabutylammonium fluoride (0.007 mL, 0.007 mmol). The reaction mixture was stirred at

60 °C for 1 hour. The cooled reaction mixture was diluted with H2O, extracted with EA. The

265

SUBSTITUTE SHEET (RULE 26) organic phase was washed with brine, dried over NazSCU and concentrated to afford compound A-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-trifl uoro-l-((trimethylsilyl)oxy)ethyl)- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (40 mg, 0.03 mmol, crude) as a yellow solid. LCMS: m/z 691 [M + H] ⁺ .

[00649] Step B: To a solution of A-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoro-l-((trimethylsilyl)oxy)ethyl)-2,6,7,8-tetrahydropy rrolo[3,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (40 mg, 0.06 mmol) in TFA (2 mL) was added EbSiH (34 mg, 0.29 mmol. The reaction mixture was stirred at 75 °C for 1 hour. The cooled reaction mixture was concentrated under vacuum. The residue was purified using prep-TLC eluting with 10% methanol in dichloroform to afford compound A-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo- 3-(2,2,2-trifluoro-l-hydroxyethyl)-2,6,7,8-tetrahydropyrrolo [3,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (10 mg, 0.016 mmol, 23%) as a yellow solid. LCMS: m/z 619 [M + H] ⁺ [00650] Step C: To a solution of/V-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoro-l-hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]in dazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (10 mg, 0.016 mmol) in DCM (2 mL) was added 4- (dimethylamino)pyridine (0.2 mg, 0.0016 mmol), triethylamine (0.002 mL, 0.072 mmol) and 4- methylbenzenesulfonyl chloride (10 mg, 0.072 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with FLO, extracted with EA. The organic phase was washed with brine, dried over IS^SCk and concentrated to afford compound A-(3-(l-chloro- 2,2,2-trifluoroethyl)-6-(2-chloro-5-fluorophenyl)-2-methyl-8 -oxo-2,6,7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fhioro-5-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, crude). LCMS: m/z 637 [M + H] ⁺ .

[00651] Step D: To a solution of A-(3-(l-chloro-2,2,2-trifluoroethyl)-6-(2-chloro-5- fluorophenyl)-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g ]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (10 mg, 0.016 mmol) in MeOH (2 mL) was added Pd/C 10% (3 mg, 0.003 mmol). The reaction mixture was stirred at 50 °C under H2 using a H2 balloon for 1 hour. The reaction mixture was filtered. The filtrate was concentrated under vacuo. The organic layer was concentrated under vacuum. The residue was purified using prep-HPLC (YMC -Actus Triart C18 150*20mm*5um, 30%-95%, phase A: H2O(0.1%FA), phase B: MeCN) to afford compound A-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2, 2, 2-trifluoroethyl)-2, 6,7,8-

266

SUBSTITUTE SHEET (RULE 26) tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (2.1 mg, 0.003 mmol, 22%). LCMS: m/z 603 [M + H] ⁺ . 'H NMR (400 MHz, Methanol-d4) 5 7.91 (s, 1H), 7.71 - 7.68 (m, 2H), 7.67 - 7.63 (m, 1H), 7.27 - 7.23 (m, 1H), 7.03 - 6.97 (m, 1H), 6.61 - 6.15 (m, 2H), 4.32 (s, 3H), 4.30 - 4.24 (m, 2H).

Example 83 N- [6-(2-chloro-5-fluorophenyl)-3-(lH-pyrazol-4-yl)-2-methyl-8- oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide

[00652] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (5 g, 9.28 mmol) in THF (50 mL) was added butyllithium (2.5 M in hexanes, 3.3 mL, 8.357 mmol) at -65 °C. The resulting mixture was stirred at -65 °C for 20 min. Then the reaction mixture was quenched by adding sat. aq. NH4CI solution, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel with EA in PE (0— >50%, V/V) to give (7-bromo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fhiorophenyl)methanone (1.5 g, 3.63 mmol, 39%) as a yellow solid. LCMS: m/z 414 [M + H]“.

267

SUBSTITUTE SHEET (RULE 26) [00653] Step B: To a solution of (7-bromo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (800 mg, 1.939 mmol) in DMA (10 mL) was added Zn(CN)2 (342 mg, 2.90 mmol) and Pd(PPh3)4 (224 mg, 0.194 mmol). The reaction mixture was was stirred at 150 °C under N2 atmosphere for 1 h using microwave. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous NazSCU, filtered and concentrated. The residue was purified using silica gel column chromatography eluted with DCM in PE (gradient: 0-80%) to afford compound 6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazole-7-carbonitri le (380 mg, 1.059 mmol, 55%) as a red solid. LCMS: m/z 359 [M + H] ⁺ .

[00654] Step C: To a solution of 6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-5- nitroindazole-7-carbonitrile (560 mg, 1.561 mmol) in acetic acid (10 mL) was added NBS (555 mg, 3.12 mmol). The resulting reaction mixture was stirred at 120 °C overnight. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by column chromatography eluted with ethyl acetate in petroleum ether (0~6% gradient) to give 3- bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-5-nitro indazole-7-carbonitrile (230 mg, 0.526 mmol, 34%) as a yellow solid. LCMS: m/z 439 [M + H] ⁺ .

[00655] Step D: To a solution of 3-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-5- nitroindazole-7-carbonitrile (350 mg, 0.800 mmol) in ACN (5 mL) and H2O (1 mL) was added KOH (224 mg, 3.999 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2$O4, filtered and concentrated to afford 3-bromo-6- (2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-5-nitro-7,8-dih ydro-6H-pyrrolo[4,3-g]indazol-8- one (280 mg, 0.615 mmol, 77%) as a yellow solid. LCMS: m/z 457 [M + H] ⁺ .

[00656] Step E: To a solution of 3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl- 5-nitro-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (280 mg, 0.615 mmol) in ethanol (4 mL) and H2O (1 mL) was added NH4CI (164 mg, 3.073 mmol) and Fe (171 mg, 3.073 mmol) at RT. The reaction mixture was stirred at 90 °C for 4 hr. The reaction mixture was filtered to move Fe.

The filtrate was concentrated under vacuum to afford 5-amino-3-bromo-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-7,8-dihydro-6H-pyrrolo[4,3- g]indazol-8-one (330 mg, 0.543 mmol, 88%) as a red solid. LCMS: m/z 427 [M + H] ⁺ .

268

SUBSTITUTE SHEET (RULE 26) [00657] Step F: To a solution of 5-amino-3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-one (300 mg, 0.493 mmol) in ACN (6 mL), was added Py (0.120 mL, 1.48 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (134 mg, 0.592 mmol) at RT. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous NazSCL, fdtered and concentrated. The residue was purified by column chromatography on silica gel with MeOH in DCM (0— >5%, V/V) to give N-[3-bromo-6-(2- chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]- 5-fluoro-3-(trifluoromethyl)benzamide (200 mg, 0.325 mmol, 66%) as a yellow solid. LCMS: m/z 617 [M + H] ⁺ . ^! H NMR (400 MHz, DMSO-d6) 5 9.57 (s, 1H), 9.09 (s, 1H), 8.02 - 7.93 (m, 2H), 7.79 - 7.70 (m, 4H), 7.40 (s, 1H), 7.30 (dd, J = 8.6, 5.4 Hz, 1H), 7.07 - 7.00 (m, 1H), 4.25 (s, 3H).

[00658] Step G: To a solution of N-[3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3- (trifluoromethyl)benzamide (50 mg, 0.081 mmol) in dioxane (2 mL) and H2O (0.2 mL) was added l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)pyrazole (34 mg, 0.122 mmol), K2CO3 (28.0 mg, 0.203 mmol) and bis[5- (diphenylphosphanyl)cyclopenta-l,3-dienyl]-X2-iron(II) palladium chloride (6 mg, 0.008 mmol) at 25 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 4 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-3-[l -(3,4,5,6-tetrahydro- 2H-pyran-2-yl)pyrazol-4-yl]-7,8-dihydro-6H-pyrrolo[4,3-g]ind azol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.044 mmol, 54%) as a yellow solid. LCMS: m/z 687 [M + H] ⁺ .

[00659] Step H: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-[l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-4-yl]-7,8-dih ydro-6H-pyrrolo[4,3-g]indazol-5- yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.044 mmol) in 2,2,2-trifluoroacetic acid (3 mL) was added tri ethyl silane (0.3 mL). The reaction was stirred at 70 °C for 4 h. The cooled reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford

269

SUBSTITUTE SHEET (RULE 26) compound N-[6-(2-chloro-5-fluorophenyl)-3-(lH-pyrazol-4-yl)-2-methyl- 8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (19 mg, 0.032 mmol, 74.1%) as a white solid. LCMS: m/z 587 [M + H] ⁺ . ^NMR (400 MHz, DMSO-d6) 5 13.49 (s, 1H), 10.29 (s, 1H), 8.99 (s, 1H), 8.42 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.75 - 7.29 (m, 2H), 7.34 - 7.24 (m, 1H), 7.09 (brs, 1H), 6.30 - 6.15 (m, 2H), 4.28 (s, 3H).

Example 84 N-[6-(2-chloro-5-fluorophenyl)-3-(2H-pyrazol-3-yl)-2-methyl- 8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide

[00660] Step A: To a solution of N-[3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3- (trifluoromethyl)benzamide (50 mg, 0.081 mmol) in dioxane (2 mL) and H2O (0.2 mL) was added l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)pyrazole (34 mg, 0.122 mmol), K2CO3 (28 mg, 0.203 mmol) and bis[5- (diphenylphosphanyl)cyclopenta-l,3-dienyl]-X2-iron(II) palladium chloride (6 mg, 0.008 mmol) at 25 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 4 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford compound N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-3-[2 -(3, 4,5,6- tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (30 mg, 0.044 mmol, 54%) as a yellow solid. LCMS: m/z 687 [M + H] ⁺ . [00661] Step B: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-[2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]-7,8-dih ydro-6H-pyrrolo[4,3-g]indazol-5- yl]-5-fluoro-3-(trifluoromethyl)benzamide (30 mg, 0.044 mmol) in 2,2,2-trifluoroacetic acid (3

270

SUBSTITUTE SHEET (RULE 26) mL) was added triethylsilane (0.3 mL). The reaction mixture was stirred at 70 °C for 1 h. The cooled reaction mixture was concentrated in vacuo and purified by prep-HPLC to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-(2H-pyrazol-3-yl)-2-methyl- 8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (15.1 mg, 0.026 mmol, 59%) . LCMS: m/z 587 [M + H] ⁺ . ^NMR (400 MHz, DMSO-d6) 5 13.49 (s, 1H), 10.35 (s, 1H), 9.01 (brs, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.30 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.95 (s, 1H), 6.35 - 6.20 (m, 2H), 4.44 (s, 3H).

Example 85 N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(tetrahydro- lH-pyrrol-3- yl)-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(t rifluoromethyl)benzamide

[00662] Step A: To a solution of N-[3-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3- (trifluoromethyl)benzamide (30 mg, 0.0487 mmol) in dioxane (2 mL) and H2O (0.2 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro- lH-pyrrole-l- carboxylate (22 mg, 0.0731 mmol), ISfeCCh (13 mg, 0.122 mmol) and bis[5- (diphenylphosphanyl)cyclopenta-l,3-dienyl]-X2-iron(II) palladium chloride (4 mg, 0.00487 mmol) at 25 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 3 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SOi and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford compound tert-butyl 4-(6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethy l)benzamido)- 6-hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]ind azol-3-yl)-2,3-dihydro-lH- pyrrole-1 -carboxylate (30 mg, 0.0427 mmol, 88%) as a yellow solid. LCMS: m/z 704 [M + H] ⁺ . [00663] Step B: To a solution of 2-methylpropan-2-yl 4-[6-(2-chloro-5-fluorophenyl)-5-({[5- fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-2 -methyl-8-oxo-7,8-dihydro-6H-

271

SUBSTITUTE SHEET (RULE 26) pyrrolo[4,3-g]indazol-3-yl]-2,3-dihydro-lH-pyrrole-l-carboxy late (30 mg, 0.043 mmol) in 2,2,2- trifluoroacetic acid (3 mL) was added triethylsilane (0.3 mL). The reaction was stirred at 70 °C for 1 h. The cooled reaction was concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(tetrahydro- lH-pyrrol-3-yl)-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fhioro-3-(trifluoromethyl)benz amide (11 mg, 0.019 mmol, 44%) as a white solid. LCMS: m/z 590 [M + H] ⁺ . NMR (400 MHz, DMSO-d6) 6 10.36 (d, J= 15.6 Hz, 1H), 9.05 (s, 3H), 8.09 - 7.91 (m, 2H), 7.75 (d, J= 7.2 Hz, 2H), 7.35 - 7.21 (m, 1H), 7.09 (s, 1H), 6.41-6.10 (m, 1H), 4.27 (s, 3H), 4.11 (s, 1H), 3.79 (s, 1H), 3.57 (s, 2H), 3.29 (d, J= 5.6 Hz, 2H), 2.39 - 2.20 (m, 1H).

Example 86 N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

272

SUBSTITUTE SHEET (RULE 26)

[00664] Step A: To a solution of 2,6-dibromo-4-fluorobenzene-l-carbaldehyde (4 g, 14.2 mmol) in DCE (50 L) was added ethylene glycol (4.75 mL, 85.1 mmol), triethoxymethane (2.10 g, 14.2 mmol) and 4-methylbenzenesulfonic acid (0.24 g, 1.42 mmol). The reaction mixture was stirred at 80 °C overnight. TLC showed the reaction was completed. The cooled mixture was adjust pH to 8 by NaHCCh (a.q), extracted with DCM (50 mL*2). The combined organic layer was washed with brine, dried over NaiSCU, filtered and the filtrate was concentrated. The residue was purified by silica gel column (Pet.ether: EtOAc=10: 1, 5: 1) to give 2-(2,6-dibromo- 4-fluorophenyl)-l,3-dioxolane (3.9 g, 10.7 mmol, 76%) as yellow solid.

[00665] Step B: To a solution of 2-(2,6-dibromo-4-fluorophenyl)-l,3-dioxolane (3.9 g, 11.9 mmol) in THF (50 mL) was added EDA (7.78 mL, 15.5 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 15 min, then hexahydropyridine- 1-carbaldehyde (1.76 g, 15.5 mmol) was added. The following mixture was stirred at -78 °C for 30 min. TLC showed the reaction was completed. The mixture was quenched with NH4CI (a.q.), extracted with EtOAc (50 mL*2). The combined organic layer was washed with brine, dried over NaiSCU, filtered and the filtrate was concentrated. The residue was purified by silical gel column (Pet.ether: EtOAc=10: 1, 5: 1, 3: 1) to give 2,4-dibromo-3-(l,3-dioxolan-2-yl)-6-fluorobenzene-l-carbalde hyde (3.6 g,

273

SUBSTITUTE SHEET (RULE 26) 9.15 mmol, 76%) as yellow solid. NMR (400 MHz, DMSO-d6) 6 10.19 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 6.36 (s, 1H), 4.25 (dd, J = 8.2, 5.2 Hz, 2H), 4.05 (dd, J = 8.2, 5.2 Hz, 2H).

[00666] Step C: To a solution of 2,4-dibromo-3-(l,3-dioxolan-2-yl)-6-fluorobenzene-l- carbaldehyde (3.6 g, 10.1 mmol) in dioxane (60 mL) was added aminoammonium hydroxide (6.36 mL, 101.7 mmol). The reaction mixture was stirred at 100 °C overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated. The residue was purified by silical gel column (PE: EtOAc=5: 1 to 1 : 1) to give 4,6-dibromo-5-(l,3-dioxolan-2-yl)-lH- indazole (2.7 g, 6.98 mmol, 69%) as yellow solid. LCMS: m/z 349.1 [M+H] ⁺

[00667] Step D: 4,6-dibromo-5-(l,3-dioxolan-2-yl)-2-methyl-2H-indazole

[00668] To a solution of 4,6-dibromo-5-(l,3-dioxolan-2-yl)-lH-indazole (2.7 g, 7.76 mmol) in DCM (40 mL) was added trimethyloxonium tetrafl uoro-L5-boranui de (1.38 g, 9.31 mmol). The reaction mixture was stirred at rt for 2h. TEC showed the reaction was completed. The mixture was poured in water (20 mL), extracted with DCM (20 mL*2). The combined organic layers were dried over Na2SOi, filtered and the filtrate was concentrated. The residue was purified by silical gel column (Pet.ether: EtOAc=5: 1 to 1 : 1) to give 4,6-dibromo-5- (l,3-dioxolan-2-yl)-2-methylindazole (1.6 g, 3,98 mmol, 51%) as yellow solid. LCMS: m/z 363.1 [M+H] ⁺ . T1 NMR (400 MHz, DMSO-d6) 6 8.56 (s, 1H), 7.99 (s, 1H), 6.34 (s, 1H), 4.32 - 4.18 (m, 5H), 4.07 - 3.96 (m, 2H).

[00669] Step E: To a solution of 4,6-dibromo-5-(l,3-dioxolan-2-yl)-2-methylindazole (1.6 g, 4.42 mmol) in THE (30 mL) was added 2M HC1 (10 mL, 20.0 mmol). The mixture was stirred at rt for 4 h, then diluted with LA and washed with brine. The organic phase was washed with brine, dried over anhydrous ISfeSCL and concentrated under reduced pressure. The residue was purified by flash chromatography eluting silica gel with PE: LA =3 : 1 to give 4,6-dibromo-2- methylindazole-5-carbaldehyde (1.2 g, 3.77 mmol, 85%) as a brown solid. LCMS: m/z 319 [M+H+2] ⁺ .

[00670] Step F: To a solution of 4,6-dibromo-2-methylindazole-5-carbaldehyde (1.2 g, 3.77 mmol) in THE (25 mL) was added 2-chloro-5-fluorophenyl)magnesium chloride (15.1 mL, 0.5 M) at 0 °C. The reaction mixture was stirred at rt for Ih, then diluted with aqueous solution of NH4CI, extracted with LA. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel

274

SUBSTITUTE SHEET (RULE 26) (eluted with EAZPE = 0-30%) to afford (2-chloro-4-fluorophenyl)(4,6-dibromo-2-methylindazol- 5-yl)methanol (1.6 g, 3.57 mmol, 94%) as a white solid. LCMS: m/z 449 [M+H+2] ⁺

[00671] Step G: To a solution of (2-chloro-4-fluorophenyl)(4,6-dibromo-2-methylindazol-5- yl)methanol (1.6 g, 3.57 mmol) in DCM (40 mL) was added DMP (3.03 g, 7.14 mmol). The reaction mixture was stirred at rt for 1 hour. The reaction mixture was treated with H2O (10 mL) and extracted with DCM (2x10 mL). The organic phase was washed with brine, dried over anhydrous NazSCU and concentrated. The crude product was pre-purified by column chromatography to give (2-chloro-4-fluorophenyl)(4,6-dibromo-2-methylindazol-5- yl)methanone (1.2 g, 2.69 mmol, 75%) as a brown solid. LCMS: m/z 447 [M+H+2] ⁺ .

[00672] Step H: A sealed vial was charged with (2-chloro-4-fluorophenyl)(4,6-dibromo-2- methylindazol-5-yl)methanone (580 mg, 1.30 mmol), CuCN (140 mg, 1.56 mmol) and NMP (10 mL). The mixture was stirred at 100 °C for 16 h. The cooled reaction mixture was diluted with water (~10 mL) and extracted with EtOAc (~10 mL x 2). The organic phase was washed with brine, dried over anhydrous NaiSCU and concentrated. The residue was purified by column (eluted with (EA: PE=30%) to give 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-2- methylindazole-4-carbonitrile (100 mg, 0.255 mmol, 20%) as a brown solid. LCMS: m/z 394 [M+H+2] ⁺ .

[00673] Step I: To a solution of 6-bromo-5-[(2-chloro-4-fluorophenyl)carbonyl]-2- methylindazole-4-carbonitrile (30 mg, 76 pmol) in ACN (1 mL) and H2O (0.1 mL) was added KOH (21.4 mg, 0.382 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2$O4 and concentrated to give 5-bromo-6-(2- chloro-4-fluorophenyl)-6-hydroxy-2-methyl-7,8-dihydro-6H-pyr rolo[4,3-e]indazol-8-one (30 mg, 73 pmol, 96%) as a brown solid. LCMS: m/z 412 [M+H+2] ⁺ .

[00674] Step J: To a solution of 5-bromo-6-(2-chloro-4-fluorophenyl)-6-hydroxy-2-methyl- 7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (30 mg, 73 pmol) in TEA (1 mL) was added EtiSiH (0.1 mL). The reaction mixture was stirred at 60 °C for 30 min. The cooled reaction mixture was concentrated. The residue was purified by column chromatography (SiCL, MeOH: DCM=l : 10) to give 5-bromo-6-(2-chloro-4-fhiorophenyl)-2-methyl-7,8-dihydro-6H- pyrrolo[4,3- e]indazol-8-one (25 mg, 63 pmmol, 87%) as a brown solid. LCMS: m/z 396 [M+H+2] ⁺ .

275

SUBSTITUTE SHEET (RULE 26) [00675] Step K: A mixture of 5-bromo-6-(2-chloro-4-fluorophenyl)-2-methyl-7,8-dihydro- 6H-pyrrolo[4,3-e]indazol-8-one (15 mg, 38 pmol), 5-fluoro-3-(trifluoromethyl)benzene-l- carboxamide (9.45 mg, 46 pmol), Pd2(dba)s (3.48 mg, 4 pmol), Xantphos (4.39 mg, 8 pmol), CS2CO3 (37.1 mg, 0.114 mmol) and dioxane (1 mL) was stirred at 100 °C under N2 for 16 h. The cooled reaction mixture was concentrated. The residue was purified by column chromatography (SiCL, MeOH: DCM=1 : 10) to give N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy- 2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl) -3-fluoro-5- (trifluoromethyl)benzamide (15 mg, 27.9 pmol, 74%) as a brown solid. LCMS: m/z 537 [M+H] ⁺ .

[00676] Step L: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-

2.6.7.8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (15 mg, 27.9 pmol) in TFA (1 mL) was added EtaSiH (0.1 mL). The reaction mixture was stirred at 60 °C for 30 min. The cooled reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give N-[6-(2-chloro-4-fluorophenyl)-2-methyl-8-oxo-7,8-dihydro-6H - pyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (5.2 mg, 10 pmol, 36%) as a white solid. LCMS: m/z 521 [M+H] ⁺ . ^NMR (400 MHz, Methanol-d4) 5 8.66 (s, 1H), 7.78 (s, 1H), 7.70 - 7.64 (m, 3H), 7.26 (dd, J- 8.8, 5.2 Hz, 1H), 7.00 (t, J- 8.4 Hz, 1H), 6.38 (brs, 2H), 4.33 (s, 3H).

Example 87 (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl-8-oxo-

2.6.7.8-tetrahydropyrrolo [3,4-g]indazol-5-yl)benzo [d] isothiazole-3-carboxamide and Example 88 (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl-8-oxo-

2.6.7.8-tetrahydropyrrolo [3,4-g]indazol-5-yl)benzo [d] isothiazole-3-carboxamide and

276

SUBSTITUTE SHEET (RULE 26)

[00677] Step A: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-

6-hydroxy-2-methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8 -one (300 mg, 0.730 mmol) in CH3CN (3 mL) were added benzo[d][l,2]thiazole-3 -carbonyl chloride (144 mg, 0.730 mmol) and pyridine (0.295 mL, 3.65 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-60%] to afford compound N-[6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2-met hyl-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]benzo[d][l,2]thiazole-3-carboxami de (226 mg, 0.395 mmol, 54%) as a yellow solid. LCMS: m/z 572 [M + H] ⁺

[00678] Step B: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol- 5-yl]benzo[d][l,2]thiazole-3- carboxamide (226 mg, 0.395 mmol) in TFA (1 mL) was added EtsSiH (45.9 mg, 0.395 mmol). The reaction mixture was stirred at 60 °C for 30 min. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Combi Flash (CH3CN: H2O with 0.1% HCOOH= 4:6) to afford compound N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2- methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)be nzo[d]isothiazole-3-carboxamide (145 mg, 0.261 mmol, 66%) as a white solid. LCMS: m/z 556 [M + H] ⁺

[00679] Step C: N-(6-(2-chloro-5-fhiorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)benzo[d]isothia zole-3-carboxamide (145 mg, 0.261 mmol) was purified by prep-SFC to afford (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)benzo[d]isothiazole- 3-carboxamide (28.7 mg, 0.052 mmol, 39%). LCMS: m/z 556 [M + H] ⁺ . ^NMR (400 MHz,

277

SUBSTITUTE SHEET (RULE 26) DMSO-d6) 6 10.20 (s, 1H), 8.95 (s, 1H), 8.59 (d, J= 7.6 Hz, 1H), 8.31 (d, J= 8.4 Hz, 1H), 8.06 (s, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 6.59 - 6.24 (m, 2H), 4.24 (s, 3H), 3.98-3.85 (m, 2H). and (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)benzo[d]isothiazole- 3-carboxamide (23.7 mg, 0.043 mmol, 33%) as a white solid. LCMS: m/z 556 [M + H] ⁺ . ^J H NMR (400 MHz, DMSO-d6) 6 10.20 (s, 1H), 8.96 (s, 1H), 8.59 (d, J= 7.6 Hz, 1H), 8.32 (d, J= 8.4 Hz, 1H), 8.06 (s, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.15 (s, 1H), 6.97 (s, 1H), 6.59 - 6.24 (m, 2H), 4.25 (s, 3H), 3.98 - 3.85 (m, 2H).

General route to synthesize the aryl amide:

[00680] The following examples were synthesized with the general method showing in the scheme above: Example 90, Example 91, Example 98, Example 109, Example 115, Example 116, Example 117, Example 118, Example 119, Example 121, Example 124, Example 128, Example 129, Example 130, Example 131, Example 132.

Example 90 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo [4,3-g] indazol-5-yl] -5-fluorobenzo [d] [1 ,2]thiazole-3-carboxamide

[00681] (7 mg, 0.012 mmol, 12%). LCMS (ESI): m/z 574.1 [M+H] ⁺ . NMR (400 MHz, DMSO-d6) 5 10.26 (brs, 1H), 8.97 (brs, 1H), 8.39 (dd, J = 9.2, 4.8 Hz, 1H), 8.25 (d, J= 8.4 Hz, 1H), 8.03 (s, 1H), 7.65 - 7.61 (m, 1H), 7.15 (s, 1H), 6.95 (s, 1H), 6.50 - 6.20 (m, 3H), 4.25 (s, 3H), 3.98 - 3.80 (m, 2H).

278

SUBSTITUTE SHEET (RULE 26) Example 91 4,5-dichloro-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)-2-methyl-8- oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)isothiazole -3-carboxamide

[00682] (4.4 mg, 0.008 mmol, 15%). LCMS: m/z 575 [M + H] ⁺ , ^J H NMR (400 MHz, DMSO- d6) 5 10.20 (s, 1H), 8.95 (s, 1H), 7.94 (s, 1H), 7.34 (s, 1H), 7.14 - 7.09 (m, 1H), 6.57 - 6.13 (m, 2H), 4.23 (s, 3H), 3.95 - 3.75 (m, 2H).

Example 98 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6-fluorobenzo[b]thiop hene-3-carboxamide

[00683] (4.4 mg, 0.008 mmol, 15%). LCMS: m/z 573 [M + H] ⁺ , Ti NMR (400 MHz, DMSO- d6) 5 10.07 (s, 1H), 8.95 (s, 1H), 8.29 (brs, 1H), 8.03 (s, 1H), 7.97 (dd, J= 9.2, 2.4 Hz, 1H), 7.87 (s, 1H), 7.36 - 7.24 (m, 2H), 7.08 (t, J= 6.8 Hz, 1H), 6.60 - 6.16 (m, 2H), 4.25 (s, 3H), 4.00 - 3.76 (m, 2H).

Example 109 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)hexahydro-2,5-methanope ntalene-3a(lH)- carboxamide

279

SUBSTITUTE SHEET (RULE 26)

[00684] (19.3 mg, 0.036 mmol, 66%). LCMS: m/z 543 [M + H] ⁺ , ^X H NMR (400 MHz,

DMSO-d6) 5 8.99 (s, 1H), 8.90 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.23 - 7.19 (m, 1H), 6.60 - 6.35 (m, 2H), 6.13 (brs, 1H), 4.22 (s, 3H), 4.05 - 3.75 (m, 2H), 2.26 (s, 1H), 2.16 (s, 2H), 1.70- 1.65 (m, 3H), 1.60-1.52 (m, 3H), 1.49-1.42 (m, 4H).

Example 115 5-chloro-N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl )-2-methyl-8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluorobenzamide

[00685] (6 mg, 0.011 mmol, 21%). LCMS: m/z 551.32 [M+H] ⁺ . ^X HNMR (400 MHz, DMSO- d6) 5 10.21 (s, 1H), 8.99 (s, 1H), 7.86 (s, 1H), 7.68 - 7.66 (m, 1H), 7.43 (s, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 5.2 Hz, 1H), 7.18 - 7.06 (m, 1H), 6.40 - 6.22 (m, 3H), 4.25 (s, 3H), 3.95 - 3.92 (m, 2H).

Example 116 4-chloro-N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl )-2-methyl-8- oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6-fluoropyrid ine-2-carboxamide

280

SUBSTITUTE SHEET (RULE 26)

[00686] (4.9 mg, 0.009 mmol, 17%). LCMS: m/z 552 [M + H] ⁺ , ^NMR (400 MHz, DMSO- d6) 5 10.04 (s, 1H), 8.96 (s, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.34 - 7.22 (m, 1H), 7.06 (brs, 1H), 6.62 - 6.18 (m, 3H), 4.23 (s, 3H), 3.97 - 3.78 (m, 2H).

Example 117 3,5-dichloro-N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)-2-methyl-8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]benzamide

[00687] (5.6 mg, 0.01 mmol, 19%). LCMS: m/z 567.77 [M+H] ⁺ . 'H NMR (400 MHz, DMSO- d6) 5 10.24 (s, 1H), 9.00 (s, 1H), 7.84 - 7.83 (m, 2H), 7.53 (s, 2H), 7.35 (dd, J = 8.8, 5.2 Hz, 1H), 7.16 - 7.13 (tm, 1H), 6.60 - 6.10 (m, 3H), 4.25 (s, 3H), 3.99 - 3.88 (m, 2H).

Example 118 2,6-dichloro-N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)-2-methyl-8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]pyridine-4-carboxami de

281

SUBSTITUTE SHEET (RULE 26) [00688] (12.4 mg, 0.022 mmol, 42%) as a white solid. LCMS: m/z 568 [M + H]", NMR (400 MHz, DMSO-d6) 5 10.47 (s, 1H), 9.02 (s, 1H), 7.87 (s, 1H), 7.58 (s, 2H), 7.37 (dd, J= 8.8, 5.2 Hz, 1H), 7.16 (t, J= 7.2 Hz, 1H), 6.55 - 6.10 (m, 3H), 6.08 (s, 1H), 4.24 (s, 3H), 3.90 (t, J= 18.0 Hz, 2H).

Example 119 4,6-dichloro-N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)-2-methyl-8- oxo-7, 8-dihydro-6H-pyrr olo [4,3-g] indazol-5-yl] pyridine-2-carboxamide

[00689] (12.3 mg, 0.022 mmol, 42%). LCMS: m/z 568 [M + H] ⁺ , ^J H NMR (400 MHz, DMS0-d6) 5 10.00 (s, 1H), 8.98 (s, 1H), 8.07 - 8.06 (m, 2H), 7.91 (s, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 6.55 - 6.10 (m, 3H), 4.24 (s, 3H), 3.94 - 3.82 (m, 2H).

Example 121 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-7-fluorobenzo[b]thiop hene-3-carboxamide

[00690] (2.3 mg, 0.004 mmol, 8%). LCMS: m/z 573 [M + H] ⁺ . ^! H NMR (400 MHz, DMSO- d6) 5 10.13 (s, 1H), 8.96 (s, 1H), 8.34 (d, J= 8.4 Hz, 1H), 8.13 - 8.12 (m, 2H), 7.88 (s, 1H), 7.50

- 7.47 (m, 1H), 7.35 - 7.25 (m, 2H), 7.08 (brs, 1H), 6.55 - 6.10 (m, 3H), 6.17 (s, 1H), 4.25 (s, 3H), 3.95-3.85 (m, 2H).

282

SUBSTITUTE SHEET (RULE 26) Example 124 6-chloro-N- [6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methyl- 8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-2-fluoropyridine-4- carboxamide

[00691] 6-chloro-N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl )-2-methyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-2-fluoropyridine-4-ca rboxamide (5.3 mg, 0.010 mmol, 18%). LCMS: m/z 552 [M + H] ⁺ . NMR (400 MHz, DMS0-d6) 6 10.13 (s, 1H), 8.96 (s, 1H), 8.34 (d, J= 8.4 Hz, 1H), 8.13 (s, 2H), 7.88 (s, 1H), 7.48 (dd, J= 13.6, 8.0 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.08 (s, 1H), 6.50 - 6.21 (m, 2H), 6.17 (s, 1H), 4.25 (s, 3H), 3.95-3.70 (m, 2H).

Example 128 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-5,7-difluorobenzo[d]is othiazole-3-carboxamide

[00692] N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]-5,7-difluorobenzo[d][l,2]thia zole-3-carboxamide (26.9 mg, 0.045 mmol, 34%) as a white solid. LCMS: m/z 591.94 [M + H] ⁺ . 'H NMR (400 MHz, DMSO- d6) 5 10.40 (s, 1H), 8.96 (s, 1H), 8.16 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.80 (td, J = 9.6, 2.0 Hz, 1H), 7.21 - 7.08 (m, 1H), 7.01 - 6.89 (m, 1H), 6.60 - 6.20 (m, 2H), 4.24 (s, 3H), 3.99 - 3.80 (m, 2H).

283

SUBSTITUTE SHEET (RULE 26) Example 129 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5,7-difluorobenzo[b]t hiophene-3-carboxamide

[00693] N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]-5,7-difluorobenzo[b]thiophene -3-carboxamide (12 mg, 0.020 mmol, 41%). LCMS: m/z 591 [M + H] ⁺ , ^NMR (400 MHz, DMS0-d6) 6 10.18 (s, 1H), 8.96 (s, 1H), 8.31 (s, 1H), 7.92 - 7.87 (m, 2H), 7.53 - 7.41 (m, 1H), 7.30 - 7.21 (m, 1H), 7.08 - 7.06 (m, 1H), 6.62-6.28 (m, 2H), 6.15 (brs, 1H), 4.25 (s, 3H), 3.99 - 3.78 (m, 2H).

Example 130 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6-fluoronaphthalene-l -carboxamide

[00694] (17 mg, 0.030 mmol, 18%). LCMS: m/z 567 [M+H] ⁺ . Tl NMR (400 MHz, DMSO- d6) 5 10.20 (s, 1H), 8.98 (s, 1H), 8.11 - 8.04 (m, 1H), 8.04 - 7.99 (m, 2H), 7.79 (dd, J= 10.0, 2.8 Hz, 1H), 7.49 - 7.39 (m, 3H), 7.31 - 7.23 (m, 1H), 7.04 - 6.96 (m, 1H), 6.74 - 6.09 (m, 3H), 4.25 (s, 3H), 4.01 - 3.79 (m, 2H).

Example 131 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoronaphthalene-l -carboxamide

284

SUBSTITUTE SHEET (RULE 26)

[00695] (1.9 mg, 0.003 mmol, 7%). LCMS: m/z 567 [M+H] ⁺ . ^J H NMR (400 MHz, Methanol- d4) 5 8.10 - 8.00 (m, 2H), 7.89 (dd, J= 8.4 Hz, 1H), 7.67 (dd, J= 9.2, 2.4 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.50 - 7.45 (m, 1H), 7.45 - 7.40 (m, 1H), 7.19 - 7.10 (m, 1H), 6.85 (s, 1H), 6.65 - 6.06 (m, 3H), 4.31 (s, 3H), 3.95 - 3.77 (m, 2H).

Example 132 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5,7-difluorobenzo[b]t hiophene-3-carboxamide

[00696] (0.9 mg, 0.002 mmol, 4.1%) as a white solid. LCMS: m/z 591 [M + H]", 'H NMR

(400 MHz, Methanol-d4) 5 7.93 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.49 - 7.40 (m, 1H), 7.31 - 7.25 (m, 1H), 7.23 - 7.16 (m, 1H), 7.03 - 6.95 (m, 1H), 6.45 - 6.10 (m, 2H), 4.30 (s, 3H), 3.91 3.80 (m, 2H).

Example 89 N-[6-(2-chloro-5-fluorophenyl)-3-(3-hydroxyazetidin-3-yl)-2- methyl-8-oxo- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifl uoromethyl)benzamide

285

SUBSTITUTE SHEET (RULE 26)

[00697] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (0.8 g, 1.48 mmol) in THF (20 mL) cooled to -78 °C was added dropwise /z-BuLi (0.565 mL, 1.41 mmol, 2.5 M in hexane). The reaction was stirred at -65 °C for 45 min. Then a solution of 2-methylpropan-2-yl 3 -oxoazetidine- 1 -carboxylate (0.28 g, 1.634 mmol) in THF (1 mL) was added dropwise at -78 °C. The reaction was stirred at - 65°C for 1 hr. The reaction mixture was quenched with water, extracted with EA. The organic layer was washed brine, dried over Na2SO ₄ and concentrated. The residue was purified by chromatography eluted with PE/EA (100: 1 to 1 : 1) to afford 2-methylpropan-2-yl 3-{7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazol-3-yl}-3-hydro xyazetidine-l-carboxylate (555 mg, 0.951 mmol, 64%) as a yellow solid. LCMS: m/z 585.1 [M+2+H] ⁺ .

[00698] Step B: To a solution of 2-methylpropan-2-yl 3-{7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazol-3-yl}-3-hydro xyazetidine-l-carboxylate (550 mg, 0.942 mmol) in EtOH/H ₂ O(4: 1) (10 mL) were added Fe (263 mg, 4.71 mmol), NH ₄ C1 (251 mg, 4.71 mmol). The reaction mixture was stirred at 85 °C for 1.5hr. The cooled reaction mixture

286

SUBSTITUTE SHEET (RULE 26) was filtered, concentrated, diluted with water and extracted with EA. The organic layer was washed brine, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1%~100%) to afford compound 2-methylpropan-2-yl 3-{5-amino-7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2- methylindazol-3-yl}-3-hydroxyazetidine-l-carboxylate (200 mg, 0.361 mmol, 38%) as yellow oil. LCMS: m/z 555.2 [M+H] ⁺ .

[00699] Step C: To a solution of 2-methylpropan-2-yl 3-{5-amino-7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methylindazol-3-yl}-3-hydroxyazetid ine-l-carboxylate (250 mg, 0.451 mmol) in N,N-dimethylacetamide (5 mL) was added Zn(CN)2 (63.6 mg, 0.542 mmol) and Pd(PPhs)4 (52.2 mg, 0.045 mmol). The reaction mixture was degassed with N2 and stirred at 150 “Cvunder N2 atmosphere for 1 h under microwave. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over TsfeSCE and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (l%~100%) to afford compound 2-methylpropan-2-yl 3-{5-amino-6- [(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-methylindazol- 3-yl}-3-hydroxyazetidine-l- carboxylate (150 mg, 0.300 mmol, 66%) as a red solid. LCMS: m/z MS m/z (ESI): 500.2 [M+H] ⁺ .

[00700] Step D: To a solution of 2-methylpropan-2-yl 3-{5-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methylindazol-3-yl}-3-hydro xyazetidine-l-carboxylate (150 mg, 0.300 mmol) in ACN (5 mL) and H2O (1.00 mL) was added KOH (84.2 mg, 1.50 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted with water, extracted with EA The organic layer was washed brine, dried over Na2SC>4 and concentrated to afford crude compound 2-methylpropan-2-yl 3-[5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-3-yl]-3-hy droxyazetidine-l-carboxylate (150 mg, 0.290 mmol, 96%) as a yellow oil. LCMS: m/z 518.2 [M+H] ⁺ .

[00701] Step E: To a solution of 2-methylpropan-2-yl 3-[5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-3-yl]-3- hydroxyazetidine-1 -carboxylate (100 mg, 0.193 mmol) in ACN (5 mL) were added pyridine (0.078 mL, 0.965 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (65.61 mg, 0.290 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SO4 and concentrated to

287

SUBSTITUTE SHEET (RULE 26) afford crude compound 2-methylpropan-2-yl 3-[6-(2-chloro-5-fhiorophenyl)-5-({[5-fhioro-3- (trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-2-methyl-8 -oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-3-yl]-3-hydroxyazetidine-l-carboxylate (100 mg, 0.141 mmol, 73%) as a yellow solid. LCMS: m/z 708.3 [M+H] ⁺ .

[00702] Step F: To a solution of 2-methylpropan-2-yl 3-[6-(2-chloro-5-fluorophenyl)-5-({[5- fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-2 -methyl-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-3-yl]-3-hydroxyazetidine-l-carboxylate (20 mg, 0.028 mmol) in TFA (3 mL) was added EtsSiH (32.8 mg, 0.282 mmol). The reaction was stirred at 70 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in H2O) to afford N-[6-(2-chloro-5-fluorophenyl)-3-(3-hydroxyazetidin-3- yl)-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl ]-5-fluoro-3- (trifluoromethyl)benzamide (8 mg, 0.014 mmol, 48%) as a white solid. LCMS: m/z 592.1 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.36 (s, 1H), 9.64 (brs, 1H), 9.07 (brs, 1H), 8.89 (brs, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.76 - 7.73 (m, 3H), 7.30 (dd, J = 8.8, 5.2 Hz, 1H), 7.24 (s, 1H), 7.15 - 7.05 (m, 1H), 6.40 - 6.02 (m, 2H), 4.97 - 4.70 (m, 2H), 4.41 - 4.27 (m, 2H), 4.17 (s, 3H).

Example 92 N-[6-(2-chloro-5-fluorophenyl)-3-(fluoromethyl)-2-methyl-8-o xo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)b enzamide

[00703] Step A: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(hydroxymethyl)-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3-

(trifluoromethyl)benzamide (40 mg, 0.073 mmol) in DCM (3 mL) was added DAST (23.4 mg, 0.145 mmol). The reaction mixture was stirred at 0 °C for 30 min. The mixture was concentrated to give a crude, which was purified by prep-HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-

288

5UB5TITUTE SHEET (RULE 26) (fluoromethyl)-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]i ndazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (8.9 mg, 0.016 mmol, 22%). LCMS: m/z 553.4 [M + H] ⁺ 'H NMR (400 MHz, DMSO-d6) 5 10.38 (s, 1H), 9.03 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.35 - 6.15 (m, 1H), 6.08 (d, J = 2.8 Hz, 1H), 5.96 (d, J = 2.8 Hz, 1H), 4.32 (s, 3H).

Example 93 N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluoroethyl)-2-methyl-8- oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide and Example 104 N-(6-(2-chloro-5-fluorophenyl)-3-(2-hydroxyethyl)-2-methyl-8 -oxo-2, 6,7,8- tetrahydropyirolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

289

SUBSTITUTE SHEET (RULE 26)

[00704] Step A: To a solution of (E)-(7-bromo-3-(2-ethoxyvinyl)-2-methyl-5-nitro-2H- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (1.5 g, 3.1 mmol) in EtOH (20 mL) and FLO (5 mL) was added NH4CI (0.5 g, 9.3 mmol). Then Fe (1.04 g, 18.6 mmol) was added, and the mixture was stirred at 75 °C for 3h. The cooled reaction mixture was filtered, concentrated, diluted with water and extracted with EA. The organic layer was washed brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound (E)-(5-amino-7-bromo-3-(2- ethoxyvinyl)-2-methyl-2H-indazol-6-yl)(2-chloro-5-fluorophen yl)methanone (600 mg, 0.93 mmol, 30%) as a yellow solid. LCMS: m/z 452 [M+H] ⁺ .

[00705] Step B: To a solution of (E)-(5-amino-7-bromo-3-(2-ethoxyvinyl)-2-methyl-2H- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (600 mg, 1.33 mmol) in DMA (10 mL) was added Zn(CN)2 (467 mg, 3.98 mmol) and Pd(PPhg)4 (154 mg, 0.13 mmol). The reaction mixture was stirred at 150 °C with microwave for 1 hour. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over NaiSCh and concentrated. The residue was purified using silica gel column chromatography eluting with 0- 50% ethyl acetate in petroleum ether to afford (E)-5-amino-6-(2-chloro-5-fluorobenzoyl)-3-(2- ethoxyvinyl)-2-methyl-2H-indazole-7-carbonitrile (300 mg, 0.68 mmol, 51%) as a yellow solid. LCMS: m/z 399 [M+H] ⁺ .

[00706] Step C: To a solution of (E)-5-amino-6-(2-chloro-5-fluorobenzoyl)-3-(2- ethoxyvinyl)-2-methyl-2H-indazole-7-carbonitrile (300 mg, 0.75 mmol) in CH3CN (10 mL) and H2O (1 mL) was added potassium hydroxide (127 mg, 2.26 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2$O4 and concentrated. The residue was purified

290

5UB5TITUTE SHEET (RULE 26) using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound (E)-5-amino-6-(2-chloro-5-fluorophenyl)-3-(2-ethoxyvinyl)-6- hydroxy-2-methyl-6,7- dihydropyrrolo[3,4-g]indazol-8(2H)-one (300 mg, 0.65 mmol, 86%) as a yellow solid. LCMS: m/z 417 [M+H] ⁺ .

[00707] Step D: To a solution of (E)-5-amino-6-(2-chloro-5-fluorophenyl)-3-(2-ethoxyvinyl)- 6-hydroxy-2-methyl-6,7-dihydropyrrolo[3,4-g]indazol-8(2H)-on e (300 mg, 0.72 mmol) in CEhCN (10 mL) was added pyridine (0.18 mL, 2.16 mmol) and 5-fluoro-3- (trifluoromethyl)benzoyl chloride (245 mg, 1.08 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in di chloroform to afford compound (E)- N-(6-(2-chloro-5-fluorophenyl)-3-(2-ethoxyvinyl)-6-hydroxy-2 -methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (350 mg, 0.519 mmol, 72%) as a yellow solid. LCMS: m/z 607 [M+H] ⁺ .

[00708] Step E: To a solution of (E)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-ethoxyvinyl)-6- hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indaz ol-5-yl)-3-(l,l-difluoroethyl)-5- fluorobenzamide (30 mg, 0.05 mmol) in TFA (2 mL) was added EtsSiH (28 mg, 0.25 mmol).

The mixture was stirred at 75 °C for 1 hour. The cooled mixture was concentrated under vacuum to afford compound 2-(6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5-(trifluoromethy l)benzamido)- 2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-3-yl) ethyl 2,2,2-trifluoroacetate (30 mg, 0.036 mmol, crude) as a yellow solid. LCMS: m/z 661 [M+H] ⁺ .

[00709] Step F: To a solution of 2-(6-(2-chloro-5-fluorophenyl)-5-(3-fluoro-5- (trifluoromethyl)benzamido)-2-methyl-8-oxo-2,6,7,8-tetrahydr opyrrolo[3,4-g]indazol-3-yl)ethyl 2,2,2-trifluoroacetate (30 mg, 0.045 mmol) in MeOH (5 mL) was added potassium carbonate (12 mg, 0.090mmol). The reaction mixture was stirred at 25 °C for 5 minutes. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound to afford compound N-(6-(2- chloro-5-fluorophenyl)-3-(2-hydroxyethyl)-2-methyl-8-oxo-2,6 ,7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.034 mmol, 50%) as a yellow solid. LCMS: m/z 565 [M+H] ⁺ .

291

SUBSTITUTE SHEET (RULE 26) [00710] Step G: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-(2-hydroxyethyl)-2- methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3 -fluoro-5-

(trifluoromethyl)benzamide (10 mg, 0.017 mmol) in DCM (3 mL) was added DAST (10.84 mg, 0.034 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water, extracted with DCM. The organic layer was washed brine, dried over Na2SC>4 and concentrated. The residue was purified using prep-HPLC to afford compound N-(6-(2- chloro-5-fluorophenyl)-3-(2-fluoroethyl)-2-methyl-8-oxo-2,6, 7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (2.1 mg, 0.004 mmol, 20%). LCMS: m/z 567 [M+H] ⁺ . NMR (400 MHz, DMSO-d6) 5 10.33 (s, 1H), 8.96 (brs, 1H), 7.95 - 7.91 (m, 1H), 7.86 (s, 1H), 7.76 - 7.70 (m, 2H), 7.31 - 7.25 (m, 1H), 7.13 - 7.06 (m, 1H), 6.52 - 5.81 (m, 2H), 4.81 (t, J = 5.6 Hz, 1H), 4.70 (t, J = 6.0 Hz, 1H), 4.21 (s, 3H), 3.65 - 3.52 (m, 2H).

Example 94 N-[6-(2-chloro-5-fluorophenyl)-2-methyl-3-[(methyldioxo-X6- sulfanyl)amino]-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5 -yl]-5-fluoro-3- (trifluoromethyl)benzamide

[00711] Step A: To a solution of N-[3-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3-

(trifluoromethyl)benzamide (100 mg, 0.181 mmol) in pyridine (3 mL) was added MsCl

292

5UB5TITUTE SHEET (RULE 26) (24.9 mg, 0.217 mmol). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with water, extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over Na2SO4 and concentrated to give N-[3-[bis(methyldioxo-X6- sulfanyl)amino]-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-meth yl-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl}-5-fluoro-3-(trifluoromethyl)benz amide (100 mg, 0.141 mmol, 78%) as a brown solid. LCMS: m/z 708 [M + H] ⁺

[00712] Step B: To a solution of N-{3-[bis(methyldioxo-X6-sulfanyl)amino]-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-5-yl}-5-fluoro- 3-(trifluoromethyl)benzamide (100 mg, 0.141 mmol) in MeOH (5 mL) and water (3 mL) was added NaOH (28.2 mg, 0.706 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over NaaSCL and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-100%) to give N-[6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-3-[(methyldioxo-X6-sulfanyl )amino]-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (30 mg, 0.048 mmol, 34%) as a brown solid. LCMS: m/z 630.3 [M + H] ⁺

[00713] Step C: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3- [(methyldioxo-X6-sulfanyl)amino]-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-5-yl]-5-fluoro- 3-(trifluoromethyl)benzamide (30 mg, 0.048 mmol) in TEA (4 mL) was added EtaSiH (1 mL). The reaction mixture was stirred at 50 °C for 1 hour. The mixture was concentrated to give a crude, which was purified by prep-HPLC to give N-[6-(2-chloro-5-fluorophenyl)-2-methyl-3- [(methyldioxo-X6-sulfanyl)amino]-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-5-yl]-5-fluoro- 3-(trifluoromethyl)benzamide (16.5 mg, 0.027 mmol, 56%). LCMS: m/z 614.4 [M + H] ⁺ 'H NMR (400 MHz, DMSO-d6) 6 10.45 (s, 1H), 10.36 (s, 1H), 9.02 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 (s, 1H), 6.40 - 6.10 (m, 1H), 4.14 (s, 3H), 3.15 (s, 3H).

Example 95 N-[3-(azetidin-3-yl)-6-(2-chloro-5-fluorophenyl)-2-methyl-8- oxo-7,8-dihydro- 6H-pyirolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)b enzamide

293

SUBSTITUTE SHEET (RULE 26)

[00714] Step A: Zn (313 mg, 4.79 mmol) powder was added to dry DMF (10 mL) under N2.

The reaction mixture was stirred at 45 °C, 1,2-dibromoethane (0.097 mL, 1.12 mmol) and chlorotrimethylsilane (0.142 mL, 1.12 mmol) was added. The following mixture was stirred at 45 °C under N2 for 0.5 hr. A solution of 2-methylpropan-2-yl 3 -iodoazetidine- 1 -carboxylate (1005 mg, 3.551 mmol) in DMF (8 mL) was added, and the following mixture was stirred at 45 °C for 2 hr. The reaction mixture was ready for use. (7-bromo-3-iodo-2-methyl-5- nitroindazol-6-yl)(2-chloro-5-fluorophenyl)methanone (861 mg, 1.60 mmol), Cui (91.4 mg, 0.480 mmol) and Pd(dppf)C12 (117 mg, 0.160 mmol) were added to DMF (5 mL). The above- Zinc solution was added dropwise to it. The reaction solution was stirred at 60 °C under N2 for 1 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over ISfeSCL and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate in petroleum ether: 1% ~ 80%) to afford 2-methylpropan- 2-yl 3-{7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-5- nitroindazol-3-yl}azetidine-

294

SUBSTITUTE SHEET (RULE 26) 1 -carboxylate (280 mg, 0.493 mmol, 31%) as a yellow solid. LCMS: m/z MS m/z (ESI): 566.9 [M-H+2]".

[00715] Step B: To a solution of 2-methylpropan-2-yl 3-{7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazol-3-yl}azetidin e-l-carboxylate (280 mg, 0.493 mmol) in EtOH/FbO (5: 1) (10 mL) were added Fe (137.68 mg, 2.46 mmol) and N1LC1 (131 mg, 2.46 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction mixture was filtered, concentrated, diluted with water and extracted with EA. The organic layer was washed brine, dried over NaiSCU and concentrated to afford crude compound 2-methylpropan-2-yl 3-{5-amino- 7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2-methylindazo l-3-yl}azetidine-l-carboxylate (150 mg, 0.279 mmol, 56%) as a red solid. LCMS: m/z 539.1 [M+H] ⁺ .

[00716] Step C: To a solution of 2-methylpropan-2-yl 3-{5-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methylindazol-3-yl}azetidin e-l-carboxylate (150 mg, 0.310 mmol) in DMA (5 mL) was added Zn(CN)2 (43.6 mg, 0.372 mmol) and Pd(PPh3)4 (35.8 mg, 0.031 mmol). The reaction mixture was degassed with N2 and stirred under N2 atmosphere at 150 °C for 1 h under microwave. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SOi and concentrated. The residue was purified using silica gel column chromatography eluted with DCM to afford compound 2- methylpropan-2-yl 3-{5-amino-6-[(2-chloro-5-fluorophenyl)carbonyl]-7-cyano-2-m ethylindazol- 3-yl}azetidine-l-carboxylate (90 mg, 0.157 mmol, 50%) as a red oil. LCMS: m/z MS m/z (ESI): 484.2 [M+H] ⁺

[00717] Step D: To a solution of 2-methylpropan-2-yl 3-{5-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methylindazol-3-yl}azetidin e-l-carboxylate (90 mg, 0.186 mmol) in ACN (5 mL) and H2O (0.50 mL) was added KOH (52.1 mg, 0.930 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na2SO4 and concentrated to afford crude compound 2-methylpropan-2-yl 3-[5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-3-yl]azetidine-l-carboxyl ate (90 mg, 0.179 mmol, 96%) as a yellow solid. LCMS: m/z 502.2 [M+H] ⁺ .

[00718] Step E: To a solution of 2-methylpropan-2-yl 3-[5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-3-yl]azetidine- 1 -carboxylate (90 mg, 0.179 mmol) in ACN (5 mL) were added pyridine (0.073 mL, 0.897

295

SUBSTITUTE SHEET (RULE 26) mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (0.033 mL, 0.215 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed brine, dried over Na^SCU and concentrated to afford crude compound 2-methylpropan-2-yl 3-[6-(2-chloro-5-fluorophenyl)-5-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-2-methyl-8 -oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-3-yl]azetidine-l-carboxylate (90 mg, 0.130 mmol, 72%) as a yellow solid. LCMS: m/z 692.1 [M+H] ⁺ .

[00719] Step F: To a solution of 2-methylpropan-2-yl 3-[6-(2-chloro-5-fluorophenyl)-5-({[5- fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-2 -methyl-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-3-yl]azetidine-l-carboxylate (80 mg, 0.116 mmol) in TFA (10 mL) was added EtgSiH (134 mg, 1.156 mmol). The reaction was stirred at 70 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in ELO) to afford compound N-[3-(azetidin-3-yl)-6-(2-chloro-5-fluorophenyl)-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3- (trifluoromethyl)benzamide (46 mg, 0.080 mmol, 69%). LCMS: m/z 576.2 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.41 (s, 1H), 9.25 (s, 1H), 9.10-8.75 (m, 2H), 8.14 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.77 (s, 2H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 (s, 1H), 6.40 - 6.20 (m, 2H), 4.80 (p, J = 9.2 Hz, 1H), 4.53 - 4.37 (m, 4H), 4.19 (s, 3H).

Example 96 N-(6-(2-chloro-5-fluorophenyl)-3-(cyclopropyl(hydroxy)methyl )-2-methyl-8- oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide and Example 97 N-(6-(2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2-methy l-8-oxo- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

[00720] Step A: N-[6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo-7,8-d ihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (60 mg, 0.11 mmol) was

296

SUBSTITUTE SHEET (RULE 26) dissolved in THF (1 mL) and the reaction solution was cooled in an ice bath. After purging three times with nitrogen, cyclopropylmagnesium bromide (15% in Tetrahydrofuran, ca. Imol/L) (0.11 mL, 0.11 mmol) was added dropwise. The reaction was warmed up to room temperature gradually, carried out for 1 h. The reaction mixture was quenched with 20 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate (50 mL*3). The organic phase was washed with brine, dried over NaiSCU and concentrated. The residue was purified by prep-HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-[cyclopropyl(hydroxy)methyl ]-2-methyl- 8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (28 mg, 0.047 mmol, 43%). The compound delivery 8 mg. LCMS: m/z 591 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.30 (d, J= 15.6 Hz, 1H), 8.92 (s, 1H), 8.01 (s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.79 - 7.66 (m, 2H), 7.28 (dd, J= 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.40 - 6-10 (m, 2H), 5.80 (d, J- 4.4 Hz, 1H), 4.75-4.60 (m, 1H), 4.26 (s, 3H), 1.54 - 1.32 (m, 1H), 0.70 - 0.29 (m, 4H). [00721] Step B: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-3- [cyclopropyl(hydroxy)methyl]-2-methyl-8-oxo-7,8-dihydro-6H-p yrrolo[4,3-g]indazol-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.034 mmol) in TFA (1 mL) at room temperature was added triethylsilane (0.2 mL). The reaction mixture was stirred at 50 °C for 1 hour. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to give N-[6- (2-chloro-5-fluorophenyl)-3-(cyclopropylmethyl)-2-methyl-8-o xo-7,8-dihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (5 mg, 0.01 mmol, 26%). LCMS: m/z 575 [M + H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 5 10.28 (s, 1H), 8.93 (s, 1H), 8.01 - 7.82 (m, 2H), 7.75 - 7.72 (m, 2H), 7.28 (dd, J= 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.40 - 6.10 (m, 2H), 4.21 (s, 3H), 3.08 (d, J= 6.8 Hz, 2H), 1.21 - 1.07 (m, 1H), 0.51 (dd, J= 5.2, 2.8 Hz, 2H), 0.33 (t, J = 4.4 Hz, 2H).

Example 99 N-[6-(2-chloro-5-fluorophenyl)-2-(dimethylamino)-8-oxo-l, 6,7,8- tetrahydroimidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide

297

SUBSTITUTE SHEET (RULE 26)

[00722] Step A: To a solution of 2,4-dibromo-6-nitroaniline (25 g, 84.5 mmol) and Fe (23.6 g, 422 mmol) in EtOH (250 mL) was added NEUC1 (22.6 g, 422 mmol) in FLO (50 mL). The reaction mixture was heated to 90 °C and stirred for 2 h. Then the mixture was filtered, the filtrate was concentrated, and purified by column to give 3,5-dibromobenzene-l,2-diamine (18.3 g, 68.8mmol, 81%) as a brown solid. LCMS: m/z 267 [M+2+H] ⁺ .

[00723] Step B: To a solution of 3,5-dibromobenzene-l,2-diamine (4 g, 15 mmol) in DMF

(80 mL) was added GDI (3.17 g, 19.5 mmol) at 0°C. The reaction solution stirred for 18 hour at rt. The resulting solution was extracted with EA. The combined organic layers were washed with brine and concentrated. The reaction mixture was washed with 80 mL of DCM and the filter

298

SUBSTITUTE SHEET (RULE 26) cake was filtered, dried in vacuum to give 4,6-dibromo-2,3-dihydro-lH-benzo[d]imidazol-2-one (2.5 g, 8.56 mmol, 57%) as a white solid. LCMS: m/z 291/293 [M + H] ⁺ .

[00724] Step C: To a solution of 4, 6-dibromo-2, 3 -dihydro- lH-benzo[d]imidazol -2-one (6.5 g,

22.2 mmol) in POCE (100 mL). The reaction was stirred at 100°C under Nifor 18 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated, diluted aqueous NaHCOs and extracted with EA The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford 5,7-dibromo-2-chloro-lH-benzo[d]imidazole (6 g, 19.3 mmol, 87%) as a white solid.

[00725] LCMS: m/z 309/311 [M + H] ⁺ .

[00726] Step D: To a solution of 5,7-dibromo-2-chloro-lH-benzo[d]imidazole (3.5 g, 11.2 mmol) in DMF (60 mL) were added l-(chloromethyl)-4-methoxybenzene (2.65 g, 16.9 mmol), NaH (1.9 g, 79.1 mmol). The reaction was stirred at 40°C under N2 for 18 hr. LCMS showed the reaction was completed. The reaction mixture was quenched EtOH, extracted with EA and H2O. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 10-20%) to afford 5,7-dibromo-2-chloro-l-[(4- methoxyphenyl)methyl]benzo[d]imidazole (4 g, 9.29 mmol, 82%)as a yellow solid. LCMS: m/z 429/431 [M + H] ⁺ .

[00727] Step E: To a solution of 5,7-dibromo-2-chloro-l-[(4- methoxyphenyl)methyl]benzo[d]imidazole (5 g, 11.6 mmol) in DMF (50 mL) were added dimethylamine (1.54 mL, 23.2 mmol), K2CO3 (1.49 g, 23.2 mmol). The reaction was stirred at 90°C under N2 for 3 hr. LCMS showed the reaction was completed. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether(gradient:20-30%) to afford 5,7- dibromo-2-(dimethylamino)-l-[(4-methoxyphenyl)methyl]benzo[d ]imidazole (3.5 g, 7.97 mmol, 69%)as a yellow solid.

[00728] LCMS : m/z 440/441 [M + H] ⁺ .

[00729] Step F: To a solution of 5,7-dibromo-2-(dimethylamino)-l-[(4- methoxyphenyl)methyl]benzo[d]imidazole (3.5 g, 7.97 mmol) in THE (40 mL) was added LDA (1.71 g, 15.9 mmol) at -78 °C. The mixture was stirred at -78 °C for 30 min, then 2-chloro-5-

299

SUBSTITUTE SHEET (RULE 26) fluorobenzene- 1-carbaldehy de (2.53 g, 15.9 mmol). The reaction mixture was stirred at -78 °C for another 2 h. LCMS showed the reaction was completed. The reaction was diluted with aqueous solution of NH4CI and EA. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 5-10%) to afford compound (2-chloro-5-fluorophenyl)[4,6-dibromo-2- (dimethylamino)-3-[(4-methoxyphenyl)methyl]benzo[d]imidazol- 5-yl]methanol (1.6 g, 2.67 mmol, 34%) as a white solid. LCMS: m/z 596/598 [M + H] ⁺ .

[00730] Step G: To a solution of (2-chloro-5-fluorophenyl)[4,6-dibromo-2-(dimethylamino)- 3-[(4-methoxyphenyl)methyl]benzo[d]imidazol-5-yl]methanol (1.6 g, 2.68 mmol) in CH2CI2 (20 mL) were added Dess-Martin periodinane (2.27 g, 5.35 mmol). The mixture was stirred at rt for 1 hr. LCMS showed the reaction was completed. The reaction was diluted with DCM and H2O. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether(gradient:30- 40%) to afford (2-chloro-5-fluorophenyl)[4,6-dibromo-2-(dimethylamino)-3-[( 4- methoxyphenyl)methyl]benzo[d]imidazol-5-yl]methanone (1.3 g, 2.18 mmol, 82%) as a white solid. LCMS: m/z 594/596 [M + H] ⁺ .

[00731] Step H: To a solution of (2-chloro-5-fluorophenyl)[4,6-dibromo-2-(dimethylamino)- l-[(4-methoxyphenyl)methyl]benzo[d]imidazol-5-yl]methanone (300 mg, 0.504 mmol) in NMP (4 mL) were added CuCN (45.1 mg, 0.504 mmol).The reaction was stirred at 130°C under N2 for 50 min using M.W. LCMS showed the reaction was completed. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford compound 6- bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-(dimethylamino )-l-[(4- methoxyphenyl)methyl]benzo[d]imidazole-4-carbonitrile (50 mg, 0.092 mmol, 18%) as a yellow solid. LCMS: m/z 541/543 [M + H] ⁺ .

[00732] Step I: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-2- (dimethylamino)-l-[(4-methoxyphenyl)methyl]benzo[d]imidazole -4-carbonitrile (40 mg, 0.074 mmol) in ACN (4 mL) and H2O (1 mL) were added KOH (12.4 mg, 0.221 mmol). The reaction was stirred at room temperature under N2 for 1 hr. LCMS showed the reaction was completed. The reaction mixture was diluted brine, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The organic layer was separated and concentrated to

300

SUBSTITUTE SHEET (RULE 26) afford 5-bromo-6-(2-chloro-5-fluorophenyl)-2-(dimethylamino)-6-hydr oxy-3-[(4- methoxyphenyl)methyl]-7,8-dihydro-6H-imidazo[5,4-e]isoindol- 8-one (30 mg, 0.054 mmol, 73%) as a yellow solid. LCMS: m/z 559/561 [M + H]“.

[00733] Step J: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-2-(dimethylamino)-6- hydroxy-3-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H-imidazo[5 ,4-e]isoindol-8-one (50 mg, 0.089 mmol) in TFA (5 mL) were added EhSiH (20.8 mg, 0.179 mmol). The reaction was stirred at room temperature for 1 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated, diluted aqueous NaHCCF and extracted with EA. The organic phase was washed with brine, dried over NaiSCU and concentrated. The residue was purified by pre- TLC methanol in dichloroform gradient: (0-10%) to afford 5-bromo-6-(2-chloro-5-fluorophenyl)- 2-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H -imidazo[5,4-e]isoindol-8-one (45 mg, 0.083 mmol, 93%) as a yellow solid. LCMS: m/z 543/545 [M + H] ⁺ .

[00734] Step K: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-2-(dimethylamino)-3- [(4-methoxyphenyl)methyl]-7,8-dihydro-6H-imidazo[5,4-e]isoin dol-8-one (40 mg, 0.074 mmol) in dioxane (3 mL) were added XANT PHOS (8.56 mg, 0.015 mmol), CS2CO3 (72.3 mg, 0.222 mmol), and CS2CO3 (72.3 mg, 0.222 mmol), Pd2(dba)3 (6.78 mg, 0.007 mmol)3-fluoro-5- (trifluoromethyl)benzene-l -carboxamide (23 mg, 0.111 mmol) .The reaction was stirred at 110°C for 5 hr. LCMS showed the reaction was completed. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by pre-TLC methanol in dichloroform gradient:(0-10%) to afford compound N-[6-(2-chloro-5-fluorophenyl)-2-(dimethylamino)-3-[(4- methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-imidazo[4,5-e]iso indol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.015 mmol, 20%) as a yellow solid. LCMS: m/z 670 [M + H] ⁺ .

[00735] Step L: To a solution of N-[6-(2-chloro-5-fluorophenyl)-2-(dimethylamino)-3-[(4- methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-imidazo[4,5-e]iso indol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.015 mmol) in TFA (3 mL) were added Et3SiH (1.74 mg, 0.015 mmol) and TfOH (0.001 mL, 0.015 mmol). The reaction was stirred at 90 °C for 1 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated, diluted aqueous NaHCCL and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-

301

SUBSTITUTE SHEET (RULE 26) chloro-5-fluorophenyl)-2-(dimethylamino)-8-oxo-l,6,7,8-tetra hydroimidazo[4,5-e]isoindol-5- yl]-5-fluoro-3-(trifluoromethyl)benzamide (1.8 mg, 0.003 mmol, 22%). LCMS: m/z 550 [M +

H] ⁺ . ¹ HNMR (400 MHz, Methanol-d4) 5 7.71 - 7.61 (m, 3H), 7.53 (s, 1H), 7.27 (dd, J = 8.8, 5.2

Hz, 1H), 7.00 (s, 1H), 6.29 (brs, 1H), 3.37 (s, 6H).

Example 100 N-(6-(2-chloro-5-fluorophenyl)-3-(3,3-difluoropropyl)-2-meth yl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00736] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitro-2H-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (2.40 g, 4.46 mmol) in TEA (35 mL) was added 2, 2,3,3-

302

SUBSTITUTE SHEET (RULE 26) tetramethyl-4-oxa-3-silahept-6-yne (0.910 g, 5.35 mmol), Pd(PPhs)2C12 (0.310 g, 0.446 mmol) and Cui (0.170 g, 0.891 mmol). The reaction mixture was stirred at room temperature under N2 for 2 hrs. The reaction was completed and detected by LCMS. The cooled reaction mixture was dissolved in EA (60 mL), washed with H2O (40 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 20-60% EA in PE) to afford (7-bromo-3-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)- 2-methyl-5-nitro- 2H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (2.10 g, 3.61 mmol, 81%) as a yellow solid. LCMS: m/z 580.91/582.91 [M + H] ⁺ .

[00737] Step B: A solution of (7-bromo-3-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)- 2- methyl-5-nitro-2H-indazol-6-yl)(2-chloro-5-fluorophenyl)meth anone (2.10 g, 3.61 mmol) in HCl/dioxane (20 mL) was stirred at room temperature for 20 min. The reaction mixture was completed and detected by LCMS. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to afford (7-bromo-3-(3- hydroxyprop-l-yn-l-yl)-2-methyl-5-nitro-2H-indazol-6-yl)(2-c hloro-5-fluorophenyl)methanone (1.60 g, 3.43 mmol, 95%) as a yellow solid. LCMS: m/z 466.65/468.65 [M + H] ⁺ .

[00738] Step C: To a solution of (7-bromo-3-(3-hydroxyprop-l-yn-l-yl)-2-methyl-5-nitro- 2H-indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (1.90 g, 4.07 mmol) in EtOH (50 mL) was added Rh (10%, 0.420 g, 0.407 mmol). The reaction mixture was stirred at room temperature under H2 for 1 hr. The reaction was completed and detected by LCMS. The cooled reaction mixture was filtrated and purified by silica gel chromatography (eluting with 0-100% EA in PE) to afford (5-amino-7-bromo-3-(3-hydroxypropyl)-2-methyl-2H-indazol-6-y l)(2-chloro-5- fluorophenyl)methanone (1.30 g, 2.95 mmol, 72%) as a yellow solid. LCMS: m/z 440.70/442.70 [M + H] ⁺ .

[00739] Step D: To a solution of (5-amino-7-bromo-3-(3-hydroxypropyl)-2-methyl-2H- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (500 mg, 1.13 mmol) in ACN (8 mL) was added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (257 mg, 1.13 mmol) and Py (0.275 mL, 3.40 mmol). The reaction mixture was stirred at room temperature for 0.5 hr. The reaction was completed and detected by LCMS. The reaction mixture was quenched with H2O (20 mL), extracted with EA (20 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with 0-12% MeOH in DCM) to afford N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-3-(3-hydroxypropyl)- 2-methyl-2H-

303

SUBSTITUTE SHEET (RULE 26) indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (500 mg, 0.793 mmol, 70%) as a yellow solid. LCMS: m/z 630.79/632.79 [M + H] ⁺ .

[00740] Step E: To a solution of N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-3-(3- hydroxypropyl)-2-methyl-2H-indazol-5-yl)-3-fluoro-5-(trifluo romethyl)benzamide (600 mg, 0.951 mmol) in DCM (6 mL) was added Dess-Martin (1.00 g, 2.37 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The reaction was completed and detected by TLC The reaction mixture was quenched with H2O, extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford N-(7-bromo-6-(2-chloro-5- fluorobenzoyl)-2-methyl-3-(3-oxopropyl)-2H-indazol-5-yl)-3-f luoro-5- (trifluoromethyl)benzamide (598 mg, 0.951 mmol, 100%) as a yellow solid. LCMS: m/z 628.78/630.78 [M + H] ⁺ .

[00741] Step F: To a solution of N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-2-methyl-3-(3- oxopropyl)-2H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benz amide (600 mg, 0.954 mmol) in DCM (10 mL) was added DAST (153 mg, 0.954 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hr. The reaction was completed and detected by TLC The reaction mixture was quenched with H2O, extracted with DCM. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (eluting with 0-12% MeOH in DCM) to afford N-(7-bromo-6-(2-chloro-5- fluorobenzoyl)-3-(3,3-difluoropropyl)-2-methyl-2H-indazol-5- yl)-3-fluoro-5- (trifluoromethyl)benzamide (600 mg, 0.922 mmol, 97%) as a brown solid. LCMS: m/z 650.78/652.78 [M + H] ⁺ .

[00742] Step G: To a solution of N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-3-(3,3- difluoropropyl)-2-methyl-2H-indazol-5-yl)-3-fluoro-5-(triflu oromethyl)benzamide (600 mg, 0.922 mmol) in NMP (6 mL) was added CuCN (165 mg, 1.84 mmol). The reaction mixture was stirred at 120 °C under N2 for 2 hr. The reaction was completed and detected by LCMS. The reaction mixture was quenched with FLO, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with 30-60% EA in PE) to afford N-(6-(2-chloro-5-fluorobenzoyl)-7- cyano-3-(3,3-difluoropropyl)-2-methyl-2H-indazol-5-yl)-3-flu oro-5-(trifluoromethyl)benzamide (360 mg, 0.603 mmol, 65%) as a yellow solid. LCMS: m/z 597.06 [M + H] ⁺ .

304

SUBSTITUTE SHEET (RULE 26) [00743] Step H: To a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-3-(3,3- difluoropropyl)-2-methyl-2H-indazol-5-yl)-3-fluoro-5-(triflu oromethyl)benzamide (360 mg, 0.603 mmol) in ACN (3 mL) and H2O (3 mL) was added KOH (101 mg, 1.81 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was completed and detected by LCMS. The reaction mixture was dissolved in EA (10 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate and concentrated to afford N-(6-(2-chloro-5- fluorophenyl)-3-(3,3-difluoropropyl)-6-hydroxy-2-methyl-8-ox o-2,6,7,8-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (260 mg, 0.423 mmol, 70%) as a yellow solid. LCMS: m/z 615.90 [M + H] ⁺ .

[00744] Step I: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-(3,3-difluoropropyl)-6- hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indaz ol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (260 mg, 0.423 mmol) in TFA (3 mL) was added EtaSiH (0.6 mL). The reaction mixture was stirred at 70 °C for 1 hr. The reaction mixture was completed and detected by LCMS. The reaction mixture was concentrated and purified by prep-HPLC (Cl 8, 30 ~ 95 % ACN in H2O with 0.1 % FA) to afford N-(6-(2-chloro-5-fluorophenyl)-3-(3,3- difhioropropyl)-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4 -g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (90.0 mg, 0.150 mmol, 35%). LCMS: m/z 599.91 [M + H] ⁺ .

NMR (400 MHz, DMSO-d6) 6 10.30 (s, 1H), 8.96 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.75 - 7.72 (m, 2H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (s, 1H), 6.40-6.10 (m, 2H), 4.21 (s, 3H), 3.28 (s, 2H), 2.26 (s, 2H).

Example 101 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-oxo-3 , 6,7,8- tetrahydropyirolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

305

SUBSTITUTE SHEET (RULE 26)

[00745] Step A: To a solution of 4-bromo-6-fluoro-lH-indazole (1.03 g, 4.79 mmol) in N,N- dimethylmethanamide (10 mL) cooling in an ice bath was added NaH (0.25 g, 6.23 mmol, 60% in mineral). The mixture was stirred for 10 min. SEM-C1 (0.96 g, 5.75 mmol) was added dropwise. The reaction was stirred at 0 °C for 30 min. The reaction was diluted with water and extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by FCC eluting with EA/PE(0-5%) to afford 4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6-fluoroindazo le (1 g, 2.90 mmol, 60%) as a white solid. LCMS: m/z 345 [M + H] ⁺ , 347 [M + H] ⁺ .

[00746] Step B: To a -67 °C solution of 4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6- fluoroindazole (1 g, 2.90 mmol) in THF (15 mL) was added dropwise EDA (2.17 mL, 4.34 mmol) under N2. The mixture was stirred at this temperature for 30 min. A solution of 2-chloro- 5-fluorobenzene-l-carbaldehyde (0.69 g, 4.34 mmol) in THF (1 mL) was added dropwise at - 67 °C. The reaction was stirred at this temperature for 1 hour. The reaction was quenched with water and extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by FCC eluting with EA/PE(0-9%- 15%) to afford [4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6-fluoroindaz ol-5-yl](2-chloro- 5-fluorophenyl)methanol (540 mg, 1.07 mmol, 37%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 5 8.17 (s, 1H), 7.71 (d, J = 10.2 Hz, 1H), 7.60 (d, J= 11.2 Hz, 1H), 7.37 (dd, J= 8.8, 5.2 Hz, 1H), 7.18 (td, J- 8.4, 3.2 Hz, 1H), 6.57 (d, J- 4.8 Hz, 1H), 6.26 (d, 4.8 Hz, 1H), 5.70 (s, 2H), 3.50 (t, J= 8.0 Hz, 2H), 0.77 (td, J= 7.6 Hz, 1.4, 2H), -0.13 (s, 9H).

306

SUBSTITUTE SHEET (RULE 26) [00747] Step C: To a solution of [4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6- fluoroindazol-5-yl](2-chloro-5-fluorophenyl)methanol (540 mg, 1.07 mmol) in DCM (10 mL) was added Dess-Martin periodinane (545 mg, 1.29 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with a aqueous solution of NaiSiO? and extracted with DCM. The organic layer was washed with brine, dried over ISfeSCL and concentrated. The residue was purified by FCC eluting with EA/PE(0-10%) to afford [4-bromo-l-(5,5-dimethyl-2- oxa-5-silahex-l-yl)-6-fluoroindazol-5-yl](2-chloro-5-fluorop henyl)methanone (370 mg, 0.737 mmol, 69%) as a white solid. LCMS: m/z 501 [M + H] ⁺ ,503 [M + H] ⁺ .

[00748] Step D: To a solution of [4-bromo-l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)-6- fluoroindazol-5-yl](2-chloro-5-fluorophenyl)methanone (330 mg, 0.658 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give a residue. The residue was dissolved in MeCN (2 mL), followed by the addition of 0.4 mL aqueous ammonia. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, diluted with water and extracted with LA The organic layer was washed with brine, dried over ISfeSCL and concentrated to give (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5-fluorophenyl)m ethanone (240 mg, 0.646 mmol, 98%) as a white solid. LCMS: m/z 371 [M + H] ⁺ ,373 [M + H] ⁺ .

[00749] Step E: To a solution of (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5- fluorophenyl)methanone (1.4 g, 3.77 mmol) in DMF (20 mL) was added CS2CO3 (2.46 g, 7.54 mmol).The mixture was stirred at room temperature for 30min.l,l-difluoro-2-iodoethane (2.53 g, 13.2 mmol) was added and the mixture was stirred at 70 °C for 1-2 hours. The cooled mixture was diluted with water and extracted with LA twice. The combined organic layer was washed with brine, dired over NaiSCh and concentrated. The residue was purified by FCC eluting with EA/PE(0-5%) to give [4-bromo-l-(2,2-difluoroethyl)-6-fluoroindazol-5-yl](2-chlor o-5- fluorophenyl)methanone (850 mg, 1.951 mmol, 52%) as a white solid. LCMS: m/z 435 [M + H] ⁺ ,437 [M + H] ⁺ .

[00750] Step F: The mixture of [4-bromo-l-(2,2-difluoroethyl)-6-fluoroindazol-5-yl](2- chloro-5-fluorophenyl)methanone (400 mg, 0.918 mmol)and CuCN (411 mg, 4.59 mmol) in NMP (10 mL) was stirred at 120 °C under N2 for 2 hours. The cooled mixture was diluted with water and extracted with LA. The organic layer was washed brine twice, dried over Na2SO4 and concentrated. The residue was purified by FCC eluting with EA/PE(50%) to give 5-

307

SUBSTITUTE SHEET (RULE 26) [(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)-6- fluoroindazole-4-carbonitrile (200 mg, 0.524 mmol, 57%) as a white solid. LCMS: m/z 382 [M + H] ⁺ .

[00751] Step G: The mixture of 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 6-fluoroindazole-4-carbonitrile (330 mg, 0.865 mmol) and DIEA (335 mg, 2.60 mmol) in DMSO-d6 (10 mL) was stirred at 120 °C. (4-methoxyphenyl)methanamine (237 mg, 1.73 mmol) was added and the mixture was stirred at 120 °C for 4 hours. The cooled reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over JSfeSCU and concentrated. The residue was purified by prep-HPLC to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 6-{[(4- methoxyphenyl)methyl]amino}indazole-4-carbonitrile (66 mg, 0.132 mmol, 15%) as a white solid. LCMS: m/z 499 [M + H] ⁺ .

[00752] Step H: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)- 6-{[(4-methoxyphenyl)methyl]amino}indazole-4-carbonitrile (62 mg, 0.124 mmol) in MeCN (6 mL) and H2O (4 mL) was added potassium hydroxide (69.7 mg, 1.24 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 6-(2- chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-5-{[( 4-methoxyphenyl)methyl]amino}- 7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (48 mg, 0.093 mmol, 75%) as a white solid. LCMS: m/z 517 [M + H] ⁺ .

[00753] Step I: To the mixture of 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-5-([(4-methoxyphenyl)methyl]amino}-7,8-dihydro-6H-py rrolo[4,3-e]indazol-8-one (26 mg, 0.050 mmol) in TFA (4 mL) and triethylsilane (0.4 mL) was added TfOH (3 drops).The mixture was stirred at 80 °C for 30min. The cooled reaction mixture was concentrated. The residue was diluted with aqueous sodium bicarbonate and extracted with EA twice. The organic layer was washed with brine, dried over Na2SC>4 and concentrated to give a crude of 5-amino-6- (2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8-dihydro- 6H-pyrrolo[4,3-e]indazol-8-one (19.2 mg, 0.050 mmol) as a light pink solid. The crude was used directly in the next step. [00754] Step J: To a mixture of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (19 mg, 0.050 mmol) and pyridine (0.020 mL, 0.250 mmol) in acetonitrile (3 mL) was added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (17.0 mg, 0.075 mmol) at room temperature. The mixture was stirred at room temperature for 20 min.

308

SUBSTITUTE SHEET (RULE 26) The mixture was diluted with water and extracted with EA twice. The organic layer was washed with brine three times, dried over TsfeSCE and concentrated. The crude was purified by prep- HPLC to give N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-oxo-7 ,8-dihydro-6H- pyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (4 mg, 0.007 mmol, 14%). LCMS: m/z 571 [M + H] ⁺ . ^ NMR (400 MHz, DMSO-d6) 5 10.64 (s, 1H), 9.27 (s, 1H), 8.50 (s, 1H), 7.97 - 7.95 (m, 2H), 7.76 (d, <7= 8.8 Hz, 1H), 7.71 (s, 1H), 7.31 (dd, <7= 8.8, 5.2 Hz, 1H), 7.10 (t, J= 6.8 Hz, 1H), 6.52 - 6.13 (m, 2H), 5.10 - 5.00 (m, 2H).

Example 102 N-[6-(2-chloro-5-fluorophenyl)-2-methyl-3-(l-methylazetidin- 3-yl)-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide

[00755] Step A: To a solution of N-[3-(azeti din-3 -yl)-6-(2-chl oro-5-fluorophenyl)-2-m ethyl- 8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (20 mg, 0.035 mmol) in THF (3 mL) was added Paraformaldehyde (10 mg, 0.035 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol). The reaction was stirred at rt for 18 hrs. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na^SCU and concentrated to afford crude compound N-[6-(2-chloro-5-fluorophenyl)- 6-hydroxy-2-methyl-3-(l-methylazetidin-3-yl)-8-oxo-7,8-dihyd ro-6H-pyrrolo[4,3-g]indazol-5- yl]-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.033 mmol, 94%) as a yellow solid. LCMS: m/z 629.2 [M+23+H] ⁺ .

[00756] Step B: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3-(l- methylazetidin-3-yl)-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]inda zol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (20 mg, 0.033 mmol) in TEA (5 mL) was added EtaSiH (19.19 mg, 0.165 mmol). The reaction was stirred at 80 °C for 18 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in H2O) to afford compound N-[6-(2-chloro-5-fluorophenyl)-2-methyl-3-(l-methylazetidin- 3-yl)-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (2.5 mg, 0.004

309

SUBSTITUTE SHEET (RULE 26) mmol, 13%). LCMS: m/z 590.5 [M+H] ⁺ . ^NMR (400 MHz, Methanol-d4) 5 8.08 (s, 1H), 7.73 - 7.68 (m, 2H), 7.66 (d, J= 8.8 Hz, 1H), 7.26 (dd, J= 8.8, 5.2 Hz, 1H), 7.00 (td, J= 8.4, 2.4 Hz, 1H), 6.45 - 6.25 (m, 2H), 4.62 - 4.56 (m, 1H), 4.33 (t, J= 8.4 Hz, 2H), 4.23 - 4.20 (m, 1H), 4.18 (s, 3H), 2.77 (s, 3H).

Example 103 /V-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-trif luoro-l- hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)- 3-fluoro-5- (trifluoromethyl)benzamide

[00757] Step A: To a solution of A-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoro-l-((trimethylsilyl)oxy)ethyl)-2,6,7,8-tetrahydropy rrolo[3,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (30 mg, 0.044 mmol) in TFA (2 mL) was added Eta Si H (25 mg, 0.2 mmol). The reaction mixture was stirred at 75 °C for 1 hour. The mixture was concentrated. The residue was purified using prep-HPLC to afford compound A-(6-(2-chloro-5-fluorophenyl)-2- methyl-8-oxo-3-(2,2,2-trifluoro-l-hydroxyethyl)-2,6,7,8-tetr ahydropyrrolo[3,4-g]indazol-5-yl)- 3-fluoro-5-(trifluoromethyl)benzamide (6.1 mg, 0.01 mmol, 22%). LCMS: m/z 619 [M + H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 8 10.39 (d, J= 12.8 Hz, 1H), 9.03 (s, 1H), 8.04 - 7.89 (m, 2H), 7.74 (d, J= 8.8 Hz, 1H), 7.69 (s, 1H), 7.53 (dd, J= 15.2, 5.2 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.10 (s, 1H), 6.59 - 5.66 (m, 3H), 4.32 (s, 3H).

Example 105 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6-fluoro-l,l-dioxo-lk ⁶- benzo [b]thiophene-3-carboxamide

310

SUBSTITUTE SHEET (RULE 26)

[00758] Step A: A solution ofN-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy -2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6 -fluorobenzothiophene-3- carboxamide (30 mg, 0.051 mmol) in TFA (1 mL) and H2O2 (1 mL) was stirred at RT for 1 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrro lo[4,3-g]indazol-5-yl]-6-fluoro- l,l-dioxo-lX ⁶ -benzothiophene-3-carboxamide (30 mg, 0.048 mmol, 95%) as a white solid. LCMS: m/z 621 [M + H] ⁺ .

[00759] Step B: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol- 5-yl]-6-fluoro-l,l-dioxo-lX ⁶ - benzothiophene-3-carboxamide (30 mg, 0.048 mmol) in TFA (2 mL) was added EtaSiH (28.1 mg, 0.242 mmol). The reaction mixture was stirred at 60 °C for 30 min. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4, 3 -g]indazol-5-yl]-6-fluoro- 1,1 -di oxo- lX ⁶ -benzothiophene-3 -carboxamide (3.2 mg, 0.005 mmol, 11%) as a white solid. LCMS: m/z 605 [M + H] ⁺ , 'H NMR (400 MHz, DMSO-d6) 5 10.46 (s, 1H), 9.02 (s, 1H), 8.05 (dd, J= 7.2, 2.4 Hz, 1H), 7.91 (s, 1H), 7.74 (dd, J = 8.4, 4.8 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.37 (dd, J= 8.8, 5.2 Hz, 1H), 7.25 - 7.10 (m, 2H), 6.55 - 6,35 (m, 2H), 6.10 (brs, 1H), 4.26 (s, 3H), 3.90 (t, J= 18.5 Hz, 2H).

Example 106 N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(3,3,3-trifl uoropropyl)- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

311

5UB5TITUTE SHEET (RULE 26)

[00760] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitro-2H-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (537 mg, 1.01 mmol) in dioxane (30 mL) and H2O (4 mL) were added trifluoro(3,3,3-trifluoropropyl)-14-borane, potassium salt (306 mg, 1.52 mmol), CS2CO3 (978 mg, 3.01 mmol) and Pd(dppf)C12 (100 mg, 0.16 mmol). The reaction mixture was stirred at 80 °C under N2 for 2 h. The cooled reaction mixture was diluted with

H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-60%] to afford (7-bromo-2-methyl-5-nitro-3-(3,3,3-trifluoropropyl)-2H- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (290 mg, 0.57 mmol, 57%) as a yellow solid.

LCMS: m/z 508 [M + H] ⁺ .

[00761] Step B: To a solution of (7-bromo-2-methyl-5-nitro-3-(3,3,3-trifluoropropyl)-2H- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (507 mg, 1.01 mmol) in EtOH

(20 mL) and H2O (5 mL) were added Fe (330 mg, 5.01 mmol) and NH4CI (335 mg, 5.03

312

SUBSTITUTE SHEET (RULE 26) mmol). The reaction mixture was stirred at 80 °C for 2 h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-90%] to afford compound (5-amino-7-bromo-2-methyl-3-

(3,3,3-trifluoropropyl)-2H-indazol-6-yl)(2-chloro-5-fluor ophenyl)methanone (300 mg, 0.63 mmol, 63%) as a yellow solid. LCMS: m/z 478 [M + H] ⁺ .

[00762] Step C: To a solution of (5-amino-7-bromo-2-methyl-3-(3,3,3-trifluoropropyl)-2H- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (490 mg, 1.01 mmol) in DMA (5 mL) were added Pd(PPh3)4 (110 g, 0.11 mmol) and Zn(CN)2 (176 mg, 1.50 mmol). The reaction mixture was stirred at 150 °C for 2 h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-

80%] to afford compound 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-methyl-3-(3,3,3- trifluoropropyl)-2H-indazole-7-carbonitrile (350 mg, 0.82 mmol, 82%) as a red solid. LCMS: m/z 425 [M+H] ⁺ .

[00763] Step D: To a solution of 5-amino-6-(2-chloro-5-fluorobenzoyl)-2-methyl-3-(3,3,3- trifluoropropyl)-2H-indazole-7-carbonitrile (425 mg, 1.01 mmol) in CH3CN (6 mL) was added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (496 mg, 2.19 mmol) and pyridine (0.30 mL, 3.65 mmol). The reaction mixture was stirred at RT for 1 h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford compound N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-2- methyl-3-(3,3,3-trifluoropropyl)-2H-indazol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide (500 mg, 0.81 mmol, 81%) as a yellow solid. LCMS: m/z 615[M + H] ⁺ .

[00764] Step E: To a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-2-methyl-3-(3,3,3- trifluoropropyl)-2H-indazol-5-yl)-3-fluoro-5-(trifluoromethy l)benzamide (615 mg, 1.01 mmol) in CH3CN (7 mL) and H2O (3 mL) was added KOH (1.01 g, 17.9 mmol) . The reaction mixture was stirred at RT 10 min. The reaction mixture was diluted with H2O, extracted with EA, washed with brine, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient : 0-10%] to afford compound

N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo-3 -(3,3,3-trifluoropropyl)-2,6,7,8-

313

SUBSTITUTE SHEET (RULE 26) tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (580 mg, 0.92 mmol, 92%) as a yellow solid. LCMS: m/z 633 [M + H] ⁺ .

[00765] Step F: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-(3,3,3-trifluoropropyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]in dazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (170 mg, 0.27 mmol) in TFA (3 mL) was added EtaSiH (218 mg, 1.88 mmol). The reaction mixture was stirred at 80 °C for 30 min. The cooled reaction mixture was concentrated, diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC to afford compound N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(3,3,3-trifl uoropropyl)-2,6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (64.5 mg, 0.10 mmol, 39%). LCMS: m/z 617[M + H] ⁺ . ^X HNMR (400 MHz, DMSO-d6) 5 (400 MHz, DMSO- d6) 5 10.31 (s, 1H), 8.97 (s, 1H), 8.02 - 7.80 (m, 2H), 7.76 - 7.72 (m, 2H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.10 (s, 1H), 6.40 - 6.10 (m, 2H), 4.23 (s, 3H), 3.53 - 3.35 (m, 3H), 2.84 - 2.66 (m, 2H).

Example 107 N-[6-(2-chloro-5-fluorophenyl)-3-{[(difluoromethyl)oxy]methy l}-2-methyl-8- oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(t rifluoromethyl)benzamide

[00766] Step A: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(hydroxymethyl)-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3- (trifluoromethyl)benzamide (10 mg, 0.018 mmol) in DCM (1 mL) and water (1 mL) was added F2HK (1.41 mg, 0.018 mmol). Then (bromodifluoromethyl)trimethylsilane (11 mg, 0.054 mmol) was added and the mixture was stirred at 20 °C for 2 hours. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC>4 and concentrated in vacuum to give N-[6-(2-chloro-5-fluorophenyl)-3- {[(difluoromethyl)oxy]methyl}-6-hydroxy-2-methyl-8-oxo-7,8-d ihydro-6H-pyrrolo[4,3-

314

SUBSTITUTE SHEET (RULE 26) g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (10 mg, 0.008 mmol, 45%) as a white solid. LCMS: m/z 617.4 [M + H] ⁺

[00767] Step B: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-3- {[(difluoromethyl)oxy]methyl}-6-hydroxy-2-methyl-8-oxo-7,8-d ihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-5-fhioro-3-(trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (1 mL) was added EtgSiH (0.25 mL). The reaction mixture was stirred at 50 °C for 30 min. The cooled mixture was concentrated to give a crude, which was purified by prep-HPLC to give N-[6-(2- chloro-5-fluorophenyl)-3-{[(difluoromethyl)oxy]methyl}-2-met hyl-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benz amide (0.5 mg, 8.32 umol, 5%). LCMS: m/z 601.3 [M + H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 6 10.38 (s, 1H), 9.04 (s, 1H), 7.95 - 7.93 (m, 2H), 7.76 - 7.69 (m, 2H), 7.29 (dd, J= 92, 5.2 Hz, 1H), 7.15-6.85 (m, 3H), 6.40 - 6.10 (m, 1H), 5.56 - 5.47 (m, 2H), 4.27 (s, 3H).

Example 108 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl-6-d)-3-fluoro-5-(triflu oromethyl)benzamide

[00768] Step A: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fl uoro-3-

(trifluoromethyl)benzamide (20 mg, 0.034 mmol) in Methanol-d4 (0.5 mL) was added

40% NaOD (5.58 mg, 0.136 mmol) in D2O (4.09 mg, 0.204 mmol). The reaction mixture was stirred at rt for 2 h. To the cooled mixture was added IN HC1 and the pH was adjusted to about 7. The reaction mixture was directly purified by prep-HPLC to give N-[6-(2-chloro-5- fluorophenyl)-6-deuterio-3-(2,2-difluoroethyl)-2-methyl-8-ox o-7,8-dihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (2.8 mg, 0.005 mmol, 14%). LCMS: m/z 586.1 [M + H] ⁺ . !HNMR (400 MHz, Methanol-d4) 6 7.88 (dd, J= 8.4, 4.8 Hz, 1H), 7.75 - 7.55

315

5UB5TITUTE SHEET (RULE 26) (m, 3H), 7.26 - 7.23 (m, 1H), 7.05 - 6.90 (m, 1H), 6.40 - 6.10 (m, 2H), 4.25 (s, 3H), 3.85 - 3.65 (m, 2H).

Example 110 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6-fluoro-l-oxo-lX< sup>4</sup>- benzo[b]thiophene-3-carboxamide

[00769] Step A: A solution ofN-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy -2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6 -fluorobenzothiophene-3- carboxamide (30 mg, 0.051 mmol) in TFA (1 mL) was added hydrogen peroxide (1.73 mg, 0.051 mmol). The mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over NaiSCU and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydro xy-2- methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-6-fl uoro-l,l-dioxo-lX ⁶ - benzothiophene-3-carboxamide (30 mg, 0.048 mmol, 95%) as a white solid. LCMS: m/z 605 [M + H] ⁺ .

[00770] Step B: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol- 5-yl]-6-fluoro-l-oxo-lX ⁴ - benzothiophene-3-carboxamide (30 mg, 0.050 mmol) in TFA (1 mL) was added EtgSiH (29.1 mg, 0.250 mmol). The reaction mixture was stirred at 60 °C for 30 min. The cooled reaction mixture was concentrated, diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-6-fluoro-l-oxo-lX ⁴ -benzothiophene-3-carboxamide (2.0 mg, 0.003 mmol, 7%). LCMS: m/z 589 [M + H] ⁺ , 'H NMR (400 MHz, Methanol-d4) 8 8.03 - 7.87 (m,

316

SUBSTITUTE SHEET (RULE 26) 2H), 7.83 (dd, J= 7.2, 2.4 Hz, 1H), 7.43 - 7.30 (m, 2H), 7.20 - 7.17 (m, 1H), 7.05 - 7.04 (m, 1H), 6.45-6.15 (m, 2H), 4.30 (s, 3H), 3.84 (t, J= 16.8 Hz, 2H).

Example 111 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-6-fluoro-2,3-dihydrobe nzo[d]isothiazole-3- carboxamide 1,1-dioxide

[00771] Step A. To a solution of 2-methylpropan-2-amine (1.6 mL, 15.4 mmol) in DCM (40 mL) was added TEA (3.5 mL, 25.6 mmol) in nitrogen atmosphere. After 3- fluorobenzenesulfonyl chloride (2 g, 10.2 mmol) was added at 0 °C. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted by DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-20%) to give 3-fluoro-N-(2- methylprop-2-yl)benzenesulfonamide (2.3 g, 9.94 mmol, 97%) as a colorless oil. LCMS: m/z 232 [M+H] ⁺

317

SUBSTITUTE SHEET (RULE 26) [00772] Step B. To a solution of 3-fluoro-N-(2-methylprop-2-yl)benzenesulfonamide (2.3 g, 9.94 mmol) in THF (5 mL) was added //-BuLi (9.9 mL, 24.8 mmol) in nitrogen atmosphere at - 68 °C. The reaction mixture was stirred at -20 °C for 1 hr. After ethyl 2-ethoxy-2-oxoacetate (4.0 mL, 29.8 mmol) was added at -68 °C. Then the reaction mixture was stirre at -68 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EA. The combined organic layers were washed with brine, dried over anhydrous NaiSCL, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-30%) to give ethyl 6-fluoro-3-hydroxy-2- (2-methylprop-2-yl)-l,l-dioxo-2,3-dihydro-lX6-benzo[d][l,2]t hiazole-3-carboxylate (3 g, 9.05 mmol, 91%) as a yellow oil. LCMS: m/z 330 [M-H]"

[00773] Step C. A solution of ethyl 6-fluoro-3-hydroxy-2-(2-methylprop-2-yl)-l,l-dioxo-2,3- dihydro-lX6-benzo[d][l,2]thiazole-3-carboxylate (3 g, 9.054mmol) in formic acid (30 mL) was stirred at room temperature for 24 hours. The reaction mixed concentrated under reduced pressure to afford the crude product. The residue was diluted with DCM and washed with saturated sodium bicarbonate solution. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-30%) to give ethyl 6-fluoro-3 -hydroxy- 1,1 -di oxo-2, 3 -dihydro- lX6-benzo[d][l,2]thiazole-3 -carboxylate (1.4 g, 5.090 mmol, 56%) as a yellow oil. LCMS: m/z 274 [M-H]"

[00774] Step D. A solution of ethyl 6-fluoro-3 -hydroxy- 1,1 -di oxo-2, 3 -dihydro- 1X6- benzo[d][l,2]thiazole-3 -carboxylate (500 mg, 1.81 mmol) in formic acid (10 mL) was stirred at room temperature for 60 hours. The reaction mixed concentrated under reduced pressure to afford the crude product. The residue was diluted with DCM and washed with saturated sodium bicarbonate solution. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-35%) to give ethyl 6-fluoro-l,l-dioxo-lX6-benzo[d][l,2]thiazole-3-carboxylate (250 mg, 0.972 mmol, 53%) as a yellow oily. LCMS: m/z 258 [M+H] ⁺

[00775] Step E. To a solution of ethyl 6-fluoro-l,l-dioxo-lX6-benzo[d][l,2]thiazole-3- carboxylate (50 mg, 0.194 mmol) in THF (2 mL) and H2O (1 mL) was added LiOH (24.4 mg, 0.583 mmol). The reaction mixture was stirred at room temperature for 1 hour. 0.5 M HC1 was

318

SUBSTITUTE SHEET (RULE 26) added dropwise 0 °C to adjust the pH to 6, extract EA. The combined organic layers were dried over anhydrous Na2$O4, filtered and concentrated under reduced pressure to afford crude product 6-fluoro-l,l-dioxo-lX6-benzo[d][l,2]thiazole-3-carboxylic acid (50 mg, 0.218 mmol, 100%) as a yellow solid. LCMS: m/z 230 [M+H] ⁺

[00776] Step F: A solution of 6-fluoro- 1,1 -di oxo- lX6-benzo[d][l,2]thiazole-3 -carboxylic acid (20 mg, 0.101 mmol) in SOCh (2 mL) was stirred at 80 °C for 2 h. The reaction mixture was cooled and concentrated to afford 6-fluorobenzo[d]isothiazole-3-carbonyl chloride 1,1-dioxide (20 mg, crude) as a white solid.

[00777] Step G: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 6-hydroxy-2-methyl-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-8-on e (30 mg, 0.073 mmol) in CH3CN (2 mL) were added pyridine (28.5 mg, 0.073 mmol) and 6- fluorobenzo[d]isothiazole-3-carbonyl chloride 1,1-dioxide (17.3 mg, 0.080 mmol). The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford N- (6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy -2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-6-fluorobenzo[d]isothi azole-3-carboxamide 1,1-dioxide (30 mg, 0.051 mmol, 70%) as a white solid. LCMS: m/z 622 [M + H] ⁺

[00778] Step H: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-methyl-8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indaz ol-5-yl)-6- fluorobenzo[d]isothiazole-3-carboxamide 1,1-dioxide (30 mg, 0.050 mmol) in TFA (1 mL) was added EtgSiH (29.1 mg, 0.250 mmol). The reaction mixture was stirred at 60 °C for 30 min. The cooled reaction mixture was concentrated, diluted with H2O, extracted with EA The organic phase was washed with brine, dried over NaiSCL and concentrated. The residue was purified by prep-HPLC to afford compound N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l- 8-oxo-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-6-fluoro -2,3-dihydrobenzo[d]isothiazole-3- carboxamide 1,1-dioxide (3.4 mg, 0.006 mmol, 12%). LCMS: m/z 608 [M + H] ⁺ , 'H NMR (400 MHz, Methanol-d4) 5 7.98 (d, J= 12.4 Hz, 1H), 7.67 (dd, J= 6.8, 3.6 Hz, 1H), 7.57 (d, J= 7.6 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.04 (t, J= 8.4 Hz, 1H), 6.45 - 6.15 (m, 2H), 5.16 (s, 1H), 4.26 (s, 3H), 3.79 (t, J- 16.4 Hz, 2H).

Example 112 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-6-fluorobenzo[d]thiazo le-3(2H)-carboxamide 1-oxide

319

SUBSTITUTE SHEET (RULE 26)

[00779] Step A: To a solution of 6-fluorobenzo[d][l,3]thiazole (1.24 g, 8.10 mmol) and 4- nitrophenyl chloromethanoate (1.96 g, 9.72 mmol) in ACN (15 mL) was added trimethylamine borane (650 mg, 8.91 mmol) at -10 °C. The mixture was stirred at 0 °C for 15min, then quenched with H2O, extracted with EA. The organic phase was washed with brine, dried over NaiSCU and concentrated. The residue was purified by silica gel column chromatography (EA:PE = 1:5) to give 4-nitrophenyl 6-fluoro-2, 3 -dihydrobenzo[d][l, 3 ]thiazole-3 -carboxylate (2.5 g, 7.81 mmol, 96%) as a yellow solid. LCMS: m/z no MS.

[00780] Step B: To a stirred solution of 4-nitrophenyl 6-fluoro-2,3- dihydrobenzo[d][l, 3 ]thiazole-3 -carboxylate (1 g, 3.12 mmol), 4-amino-5-(5-chloro-2- fluorophenyl)-3-(2,2-difluoroethyl)-5-hydroxy-2-methyl-6,7-d ihydro-5H-pyrrolo[4,3-f]indazol- 7-one (1.28 g, 3.12 mmol) in tetrahydrofuran (15 mL) was added LiHMDS (25 mL, IM in THE) at 0 °C. The mixture was stirred at rt for Ih, then quenched with aqueous NH4CI, extracted with EA The organic phase was washed with brine, dried over NaiSCh and concentrated. The residue was purified by column chromatography on silica gel (eluted with EA/PE = 0-30%) to afford N-[5-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-5-hydro xy-2-methyl-7-oxo-6,7- dihydro-5H-pyrrolo[4,3-f]indazol-4-yl]-6-fluoro-2,3-dihydrob enzo[d][l,3]thiazole-3- carboxamide (80 mg, 0.135 mmol, 4%) as a brown solid. LCMS: m/z 592 [M+H] ⁺ .

320

SUBSTITUTE SHEET (RULE 26) [00781] Step C: To a solution ofN-[5-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-5- hydroxy-2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]indazol- 4-yl]-6-fluoro-2,3- dihydrobenzo[d][l, 3 ]thiazole-3 -carboxamide (100 mg, 0.169 mmol) in TFA (2 mL) was added EtsSiH (0.2 mL). The reaction mixture was stirred at 60 °C for 30min. Then the cooled reaction mixture was concentrated to give a residue. The residue was purified by prep- HPLC to give N-[5-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-7-oxo-6,7- dihydro-5H-pyrrolo[4,3-f]indazol-4-yl]-6-fluoro-2,3-dihydrob enzo[d][l,3]thiazole-3- carboxamide (3.2 mg, 6 pmol, 3%). LCMS: m/z 576 [M+H] ⁺ . ’H NMR. (400 MHz, Methanol- d4) 5 8.61 (s, 1H), 7.76 (s, 1H), 7.40 - 7.38 (m, 2H), 7.06 - 7.02 (m, 1H), 6.97 (dd, J= 8.4, 2.4 Hz, 1H), 6.73 - 6.70 (m, 1H), 6.50 - 6.10 (m, 2H), 5.14 (d, J= 7.6 Hz, 1H), 4.89 (s, 1H), 4.27 (s, 3H), 3.80 (t, J= 17.6 Hz, 2H).

Example 113 N-(3-(2-chloro-5-fluorophenyl)-6,6-dioxido-l-oxo-2,3,7,8-tet rahydro-lH- thieno[3,2-e]isoindol-4-yl)-3-fluoro-5-(trifluoromethyl)benz amide

321

SUBSTITUTE SHEET (RULE 26) [00782] Step A: To a solution of benzo[b]thiophen-5-amine (1.5 g, 10.1 mmol) in ACN (30 mL) and was added NBS (5.3 g, 30.3 mmol). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-60%] to afford 4,6- dibromobenzo[b]thiophen-5-amine (500 mg, 1.65 mmol, 16%) as a yellow solid. LCMS: m/z 306 [M + H] ⁺ .

[00783] Step B: To a solution of 4,6-dibromobenzo[b]thiophen-5-amine (306 mg, 1.01 mmol) in ACN (20 mL) were added Cui (380 mg, 2.01 mmol) and isoamyl nitrite (351 mg, 3.03 mmol). The reaction mixture was stirred at 75 °C for 5 h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over NaiSCh and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-90%] to afford compound 4,6-dibromo-5- iodobenzo[b]thiophene (180 mg, 0.43 mmol, 43%) as a yellow solid. LCMS: m/z 416 [M + H] ⁺ .

[00784] Step C: To a solution of 4,6-dibromo-5-iodobenzo[b]thiophene (416 mg, 1.01 mmol) in THF (10 mL) was added i-PrMgBr (0.8 ml, 1.3 mmol/ml). The reaction mixture was stirred at -78 °C for 1 h, piperidine- 1-carbaldehy de (339 mg, 3.01 mmol) was added at -78 °C for 1 h. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with ammonium chloride (20 ml), extracted with EA. The organic phase was washed with brine, dried over Na2SOi and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-80%] to afford compound 4,6-dibromobenzo[b]thiophene- 5-carbaldehyde (280 mg, 0.88 mmol, 88%) as a white solid. LCMS: m/z 319[M+H] ⁺ .

[00785] Step D: To a solution of 4,6-dibromobenzo[b]thiophene-5-carbaldehyde (319 mg, 1.01 mmol) in THF (5 mL) was added (2-chloro-5-fluorophenyl)magnesium bromide (10.00 ml, 0.50 mmol/ml). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with ammonium chloride (20 ml), extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-80%] to afford compound (2-chloro-5- fluorophenyl)(4,6-dibromobenzo[b]thiophen-5-yl)methanol (300 mg, 0.67 mmol, 77%) as a white solid. LCMS: m/z 449 [M+H] ⁺ .

322

SUBSTITUTE SHEET (RULE 26) [00786] Step E: To a solution of (2-chloro-5-fluorophenyl)(4,6-dibromobenzo[b]thiophen-5- yl)methanol (449 mg, 1.01 mmol) in DCM (5 mL) was added Dess-Martin Oxidizer (848 mg, 2.01 mmol). The reaction mixture was stirred at 25 oC for 5 h. The reaction mixture was diluted with NaHCO3(aq) (20 ml), extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-80%] to afford compound (2-chloro-5- fluorophenyl)(4,6-dibromobenzo[b]thiophen-5-yl)methanone (390 mg, 0.87 mmol, 87%) as a white solid. LCMS: m/z 447 [M+H] ⁺ .

[00787] Step F: To a solution of (2-chloro-5-fluorophenyl)(4,6-dibromobenzo[b]thiophen-5- yl)methanone (448 mg, 1.01 mmol) in NMP (5 mL) was added CuCN (90 mg, 1.01 mmol). The reaction mixture was stirred at 130 °C for 2 h. The reaction mixture was diluted with H2O (20 ml), extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-80%] to afford compound 6-bromo-5-(2-chloro-5- fluorobenzoyl)benzo[b]thiophene-4-carbonitrile (50 mg, 0.13 mmol, 13%) as a white oil. LCMS: m/z 393 [M+H] ⁺ .

[00788] Step G: To a solution of 6-bromo-5-(2-chloro-5-fluorobenzoyl)benzo[b]thiophene-4- carbonitrile (393 mg, 1.01 mmol) in CH3CN (7 mL) and H2O (3 mL) was added KOH (1.01 g, 17.9 mmol). The reaction mixture was stirred at rt for 10 min. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient : 0-10%] to afford compound 4-bromo-3-(2-chloro-5-fluorophenyl)-

3-hydroxy-2,3-dihydro-lH-thieno[3,2-e]isoindol-l-one (395 mg, 0.92 mmol, 92%) as a yellow solid. LCMS: m/z 412 [M + H] ⁺ .

[00789] Step H: To a solution of 4-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2,3- dihydro-lH-thieno[3,2-e]isoindol-l-one (412 mg, 1.01 mmol) in TFA (5 mL) was added H2O2 (1 ml). The reaction mixture was stirred at 50°C for 12 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over ISfeSCU and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 0-10%] to afford compound 4-bromo-3-(2-chloro-5-fluorophenyl)-

323

SUBSTITUTE SHEET (RULE 26) 3-hydroxy-2,3-dihydro-lH-thieno[3,2-e]isoindol-l-one 6,6-dioxide (300 mg, 0.68 mmol, 68%) as a yellow solid. LCMS: m/z 444 [M + H] ⁺ .

[00790] Step I: To a solution of 4-bromo-3-(2-chloro-5-fhiorophenyl)-3-hydroxy-2,3- dihydro-lH-thieno[3,2-e]isoindol-l-one 6,6-dioxide (444 mg, 1.01 mmol) in THF (5 mL) was added NaBFL (76.5 mg, 2.02 mmol). The reaction mixture was stirred at 25°C for 3 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient : 0-10%] to afford compound 4-bromo-

3-(2-chloro-5-fluorophenyl)-3-hydroxy-2,3,7,8-tetrahydro- lH-thieno[3,2-e]isoindol-l-one 6,6- dioxide (300 mg, 0.67 mmol, 67%) as a yellow solid. LCMS: m/z 446 [M + H] ⁺ .

[00791] Step J: To a solution of 4-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2, 3,7,8- tetrahydro-lH-thieno[3,2-e]isoindol-l-one 6,6-dioxide (223 mg, 0.51 mmol) in TFA

(5 mL) was added TES (ImL). The reaction mixture was stirred at 75°C for 0.5 h. The cooled reaction mixture was concentrated, diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over TsfeSCL and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient : 0-10%] to afford compound

4-bromo-3-(2-chloro-5-fluorophenyl)-2,3,7,8-tetrahydro-lH -thieno[3,2-e]isoindol-l-one 6,6- dioxide (172 mg, 0.41 mmol, 80%) as a yellow solid. LCMS: m/z 430 [M + H] ⁺ .

[00792] Step K: To a solution of (7-bromo-3-iodo-2-methyl-5-nitro-2H-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (90.0 mg, 0.21 mmol) in dioxane (8 mL) were added 3-fluoro-

5-(trifluoromethyl)benzamide (63.5 mg, 0.31 mmol), Cs2CO3 (205 mg, 0.63 mmol), Xantphos (11.2 mg, 0.02 mmol) and Pd2(dba)s (10.8 mg, 0.04 mmol). The reaction mixture was stirred at 80 °C under N2 for 5 h. The cooled reaction mixture was diluted with H2O, extracted with EA The organic phase was washed with brine, dried over ISfeSCL and concentrated. The purified by prep-HPLC to afford compound N-(3-(2-chloro-5-fluorophenyl)-6,6-dioxido-l-oxo- 2,3,7,8-tetrahydro-lH-thieno[3,2-e]isoindol-4-yl)-3-fluoro-5 -(trifluoromethyl)benzamide (1.00 mg, 0.002 mmol, 1%). LCMS: m/z 555[M - H]", NMR (400 MHz, DMSO-d6) 6 10.02 (s, 1H), 9.79 (s, 1H), 8.12 (s, 1H), 8.02 - 7.96 (m, 3H), 7.55 - 7.40 (m, 2H), 7.35 - 7.22 (m, 1H), 3.80 - 3.58 (m, 4H).

Example 114 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-6-fluorobenzo[d]thiazo le-3(2H)-carboxamide

324

SUBSTITUTE SHEET (RULE 26)

[00793] Step A: To a solution of N-[5-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-5- hydroxy -2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]indazol-4-yl]-6 -fluoro-2, 3- dihydrobenzo[d][l, 3 ]thiazole-3 -carboxamide (20 mg, 34 pmol) in DCM (2 mL) was added TFA (0.25 mL) and H2O2 (0.25 mL). The mixture was stirred at rt for 15min, then quenched with aqueous Na2S2Ch, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated to give N-[5-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-5- hydroxy-2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]indazol- 4-yl]-6-fluoro-l-oxo-2,3- dihydro-lX ⁴ -benzo[d][l,3]thiazole-3-carboxamide (20 mg, 33 pmol, 97%) a brown solid (crude). LCMS: m/z 608 [M+H] ⁺ .

[00794] Step B: To a solution ofN-[5-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-5- hydroxy-2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-f]indazol- 4-yl]-6-fluoro-l-oxo-2,3- dihydro-lX ⁴ -benzo[d][l,3]thiazole-3-carboxamide (20 mg, 33 pmol) in TFA (2 mL) was added EtgSiH (0.2 mL). The reaction mixture was stirred at 60 °C for 30min. Then the cooled reaction mixture was concentrated. The residue was purified by pre-HPLC to give N-[5-(5- chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-2-methyl-7-oxo- 6,7-dihydro-5H-pyrrolo[4,3- f]indazol-4-yl]-6-fluoro-l-oxo-2,3-dihydro-lX4-benzo[d][l,3] thiazole-3-carboxamide (2.5 mg, 4 pmol, 13%). LCMS: m/z 592 [M+H] ⁺ . 'H NMR (400 MHz, Methanol-d4) 5 7.80 (s, 1H), 7.75 (dd, J= 7.2, 2.8 Hz, 1H), 7.66 (brs, 1H), 7.38 - 7.28 (m, 2H), 7.04 - 7.01 (m, 1H), 6.55 - 6.45 (m, 1H), 6.30 - 6.15 (m, 2H), 4.75 (d, J= 3.4 Hz, 2H), 4.28 (s, 3H), 3.82 (t, J= 17.6 Hz, 2H).

Example 120 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-oxo-7 ,8-dihydro-6H- imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)ben zamide

325

SUBSTITUTE SHEET (RULE 26)

326

SUBSTITUTE SHEET (RULE 26) [00795] Step A: To a solution of 2,6-dibromo-4-fluorobenzene-l-carbaldehyde (20 g, 70.9 mmol) in H2SO4 (100 mL) was added dropwise HNO3 (3.27 mL, 78.0 mmol) at 0 °C. The reaction was stirred at 0 °C for 4 hr. The reaction mixture was poured into ice water, extracted with EA. The organic layer was washed with brine, dried over NaiSCU and concentrated to afford compound 2,6-dibromo-4-fluoro-3-nitrobenzene-l-carbaldehyde (23 g, 70.4 mmol, 99%) as a black solid. LCMS: m/z 326.90 [M+H] ⁺ .

[00796] Step B: To a solution of 2,6-dibromo-4-fluoro-3-nitrobenzene-l-carbaldehyde (12.5 g, 38.2 mmol) in THF (5 mL) was added bromo(2-chloro-5-fluorophenyl)magnesium (35.8 g, 153 mmol). The reaction was stirred at 0 °C for Ih. The reaction was diluted with saturated NH4CI solution and extracted with brine. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-20%) to afford compound (2-chloro-5- fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl)methanol (15 g, 32.8 mmol, 86%) as a yellow oil. LCMS: m/z 457.45 [M+H] ⁺ .

[00797] Step C: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanol (15 g, 32.8 mmol) in DCM (100 mL) was added 1, 1,1 -triacetoxy- 1,3- dihydro-lX5-benzo[d][l,2]iodoxol-3-one (13.9 g, 32.8 mmol). The reaction was stirred at rt overnight. The reaction was diluted with water, extracted with DCM. The organic layer was washed with brine, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-20%) to afford compound (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3-nitrophenyl )methanone (11 g, 24.2 mmol, 74%) as a white solid. LCMS: m/z 455.43 [M+H] ⁺ .

[00798] Step D: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-fluoro-3- nitrophenyl)methanone (10 g, 22.0 mmol) in DMSO-d6 (100 mL) were added (2,4- dimethoxyphenyl)methanamine (3.67 g, 22.0 mmol) and DIEA (8.51 g, 65.9 mmol). The reaction was stirred at rt-130 °C for 30 min. The reaction was diluted with water, extracted EA. The organic layer was washed with brine, dried over ISfeSCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-20%) to afford compound (2-chloro-5-fluorophenyl)(2,6-dibromo-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-nitrophenyl)methanone (9 g, 14.9 mmol, 68%) as a yellow solid. LCMS: m/z 602.64 [M + H] ⁺ .

327

SUBSTITUTE SHEET (RULE 26) [00799] Step E: To a solution of (2-chloro-5-fluorophenyl)(2,6-dibromo-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-nitrophenyl)methanone (9.1 g, 15.1 mmol) in EtOH (30 mL) and FLO (10 mL) were added Fe (4.22 g, 75.5 mmol) and NH4CI (4.04 g, 75.5 mmol). The reaction was stirred at 60 °C for 4 hr. The cooled reaction mixture was filtered, diluted with water and then extracted with EA. The organic layer was washed with brine, dried over NazSCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound (3-amino-2,6- dibromo-4-{[(2,4-dimethoxyphenyl)methyl]amino}phenyl)(2-chlo ro-5-fluorophenyl)methanone (5.4 g, 9.43 mmol, 62%) as a yellow oil. LCMS: m/z 572.65 [M + H] ⁺ .

[00800] Step F: To a solution of (3-amino-2,6-dibromo-4-{[(2,4- dimethoxyphenyl)methyl]amino}phenyl)(2-chloro-5-fluorophenyl )methanone (3.3 g, 5.76 mmol) in tol (20 mL) were added tri ethoxy methane (4.27 g, 28.8 mmol) and 4- methylbenzenesulfonic acid (0.10 g, 0.576 mmol). The reaction was stirred at 100 °C for 1 hr. The cooled reaction was diluted water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-50%) to afford compound (2-chloro-5-fluorophenyl){4,6-dibromo-l-[(2,4- dimethoxyphenyl)methyl]benzo[d]imidazol-5-yl}methanone (3.3 g, 5.66 mmol, 98%) as a yellow oil. LCMS: m/z 582.65 [M+ H] ⁺ .

[00801] Step G: To a solution of (2-chloro-5-fluorophenyl){4,6-dibromo-l-[(2,4- dimethoxyphenyl)methyl]benzo[d]imidazol-5-yl]methanone (1.5 g, 2.57 mmol) in TFA (5 mL). The reaction was stirred at 60 °C overnight. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient:0-30%) to afford compound (2-chloro-5-fluorophenyl)(4,6- dibromo-lH-benzo[d]imidazol-5-yl)methanone (1.1 g, 2.54 mmol, 99%) as a yellow solid. LCMS: m/z 432.47 [M + H] ⁺ .

[00802] Step H: To a solution of (2-chloro-5-fluorophenyl){4,6-dibromo-l-[(2,4- dimethoxyphenyl)methyl]benzo[d]imidazol-5-yl}methanone (100 mg, 0.172 mmol) in 1- methyltetrahydropyrrol-2-one (2 mL) was added CuCN (0.27 g, 3.01 mmol). The reaction was stirred at 110 °C for 6 hr with sealed tube. The cooled reaction was diluted with water, extracted

328

SUBSTITUTE SHEET (RULE 26) with EA The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-80%) to afford compound 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-lH-benzo[d]imidazole-4-carbonitrile (200 mg, 0.528 mmol, 18%) as a white solid. LCMS: m/z 378.59 [M + H] ⁺ .

[00803] Step I: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-lH- benzo[d]imidazole-4-carbonitrile (150 mg, 0.396 mmol) in DMA (10 mL) were added K2CO3 (164.27 mg, 1.189 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (169 mg, 0.792 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over ISfeSCL and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in DCM (0%~10%) to afford compound 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2-difluoroethyl)benzo[d]imidazol e-4-carbonitrile (100 mg, 0.226 mmol, 57%) as a yellow solid. LCMS m/z (ESI): 443.9[M+H+2] ⁺ .

[00804] Step J: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)benzo[d]imidazole-4-carbonitrile (130 mg, 0.294 mmol) in ACN (5 mL) and LLO (1.001 mL) was added KOH (82.48 mg, 1.470 mmol). The reaction was stirred at rt for 2 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (l%~60%) to afford compound 5- bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6-hy droxy-7,8-dihydro-6H- imidazo[4,5-e]isoindol-8-one (110 mg, 0.239 mmol, 81%) as a white solid. LCMS m/z (ESI): 462.0 [M+H] ⁺ .

[00805] Step K: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 6-hydroxy-7,8-dihydro-6H-imidazo[4,5-e]isoindol-8-one (100 mg, 0.217 mmol) in TFA (2 mL) was added EtsSiH (252 mg, 2.17 mmol). The reaction was stirred at 70 °C for 2 hr. The cooled reaction mixture was concentrated, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford crude compound 5-bromo- 6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-7,8-dihydr o-6H-imidazo[4,5-e]isoindol-8-one (80 mg, 0.180 mmol, 83%) as a white solid. LCMS: m/z 446.0 [M+H] ⁺ .

329

SUBSTITUTE SHEET (RULE 26) [00806] Step L: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 7,8-dihydro-6H-imidazo[4,5-e]isoindol-8-one (50 mg, 0.112 mmol) in dioxane (5 mL) were added 5-fluoro-3-(trifluoromethyl)benzene-l-carboxamide (23.3 mg, 0.112 mmol), Pd2(dba)3 (10.30 mg, 0.011 mmol), Xant-PHOS (13.0 mg, 0.022 mmol) and CS2CO3 (73.28 mg, 0.225 mmol). The reaction was stirred at 120 °C under N2 for 1.5hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (PE/EA = 1/100-100/1) to give 50 mg crude. The residue was purified by prep-HPLC (Cl 8, 0-70 % acetonitrile in H2O) to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-oxo-7 ,8-dihydro-6H- imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)ben zamide (1 mg, 0.002 mmol, 2%). LCMS: m/z 571.2[M+H] ⁺ . ¹ HNMR(400 MHz, Methanol-d4) 6 8.43 (s, 1H), 7.86 (s, 1H), 7.72- 7.65 (m, 3H), 7.25 tdd, ./- 8.8, 5.2 Hz, 1H), 6.98 (td, J = 8.6, 3.0 Hz, 1H), 6.68 - 6.00 (m, 3H), 4.85 - 4.83 (m, 2H).

Example 122 N-[3-(azetidin-3-ylmethyl)-6-(2-chloro-5-fluorophenyl)-2-met hyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide

330

SUBSTITUTE SHEET (RULE 26)

[00807] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitroindazol-6-yl)(2-chloro-5- fluorophenyl)methanone (1.8 g, 3.343 mmol) in dioxane (20 mL) and Water (2 mL) was added 2246802-17-3 (0.99 g, 3.343 mmol), Na ₂ CO ₃ (0.89 g, 8.357 mmol) and Pd(dppf)Cl ₂ (0.24 g, 0.334 mmol) at 25 °C. The reaction mixture was degassed with N ₂ and it was stirred under N ₂ atmosphere at 100 °C for 3 hr. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na ₂ SC>4, concentrated in vacuum. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 0-55%) to afford compound 2-methylpropan-2-yl 3-({7-bromo-6-[(2-chloro-5-fluorophenyl)carbonyl]-2- methyl-5-nitroindazol-3-yl}methylidene)azetidine-l-carboxyla te (1 g, 1.725 mmol, 52%) as a yellow solid. LCMS: m/z 579 [M + H] ⁺ .

[00808] Step B: To a solution of 2-methylpropan-2-yl 3-({7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methyl-5-nitroindazol-3-yl}methylid ene)azetidine-l-carboxylate (800 mg, 1.380 mmol) in acetic acid (10 mL) was added Fe (385 mg, 6.90 mmol) at 25 °C. The reaction mixture was degassed with N ₂ and it was stirred under N ₂ atmosphere at 70 °C for 2 hr. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na ₂ SO4, concentrated in vacuum. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford compound 2- methylpropan-2-yl 3 -( { 5 -amino-7-bromo-6-[(2-chl oro-5 -fluorophenyl)carbonyl] -2- methylindazol-3-yl}methylidene)azetidine-l-carboxylate (450 mg, 0.818 mmol, 59%) as a red solid.. LCMS: m/z 549 [M + H] ⁺ .

[00809] Step C: To a solution of 2-methylpropan-2-yl 3-({5-amino-7-bromo-6-[(2-chloro-5- fluorophenyl)carbonyl]-2-methylindazol-3 -yl }methylidene)azetidine- 1 -carboxylate (380 mg, 0.691 mmol) in DMA (4 mL) was added 557-21-1 (122 mg, 1.037 mmol) and Pd(PPh ₃ )4 (80 mg, 0.069 mmol). The reaction mixture was degassed with N ₂ and it was stirred under N ₂

331

SUBSTITUTE SHEET (RULE 26) atmosphere at 150 °C for 1 h under microwave. The reaction was diluted with EA and water. The organic layer was separated, washed with further saturated NaCl solution, and concentrated in vacuo to afford compound 2-methylpropan-2-yl 3-({5-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methylindazol-3-yl}methylid ene)azetidine-l-carboxylate (200 mg, 0.403 mmol, 58%) as a red solid. LCMS: m/z 496 [M + H] ⁺ .

[00810] Step D: To a solution of 2-methylpropan-2-yl 3-({5-amino-6-[(2-chloro-5- fluorophenyl)carbonyl]-7-cyano-2-methylindazol-3-yl}methylid ene)azetidine-l-carboxylate (200 mg, 0.403 mmol) in ACN (10 mL) and H2O (3 mL) was added KOH (113 mg, 2.016 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over NaiSCU and concentrated to afford 2-methylpropan-2-yl 3-{[5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-3- yl]methylidene} azetidine- 1 -carboxylate (200 mg, 0.389 mmol, 97%) as a yellow solid. LCMS: m/z 514 [M + H] ⁺ .

[00811] Step E: To a solution of 2-methylpropan-2-yl 3-{[5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-pyrrol o[4,3-g]indazol-3- yl]methylidene) azetidine- 1 -carboxylate (200 mg, 0.389 mmol) in ACN (6 mL), was added Py (0.063 mL, 0.778 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (105.79 mg, 0.467 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 2-methylpropan-2-yl 3-{[6-(2-chloro-5- fluorophenyl)-5-({[5-fluoro-3-(trifluoromethyl)phenyl]carbon yl}amino)-6-hydroxy-2-methyl-8- oxo-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-3-yl]methylidene}az etidine-l-carboxylate (220 mg, 0.312 mmol, 80%) as a brown solid. LCMS: m/z 704 [M + H] ⁺ .

[00812] Step F: To a solution of 2-methylpropan-2-yl 3-{[6-(2-chloro-5-fluorophenyl)-5- ({[5-fhioro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydr oxy-2-methyl-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-3-yl]methylidene] azetidine- 1 -carboxylate (30 mg, 0.043 mmol) in MeOH (3 mL) was added Palladium 10% on Carbon (5 mg, 0.047 mmol, wetted with ca. 55% Water)) at RT. The reaction mixture was degassed with FL and stirred under TE atmosphere at 25 °C for overnight. The reaction mixture was filtered to move Pd/C, the reaction solution was concentrated in vacuum to afford 2-methylpropan-2-yl 3-{[6-(2-chloro-5-fluorophenyl)-5-({[5-

332

SUBSTITUTE SHEET (RULE 26) fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydroxy-2 -methyl-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-3-yl]methyl}azetidine-l-carboxylate (20 mg, 0.028 mmol, 66%) as a yellow solid. LCMS: m/z 706 [M + H] ⁺ .

[00813] Step G: To a solution of 2-methylpropan-2-yl 3-{[6-(2-chloro-5-fluorophenyl)-5- ({[5-fluoro-3-(trifluoromethyl)phenyl]carbonyl}amino)-6-hydr oxy-2-methyl-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-3-yl]methyl] azetidine- 1 -carboxylate (20 mg, 0.028 mmol) in 2,2,2- trifluoroacetic acid (2 mL) and triethylsilane (0.2 mL). The reaction was stirred at 70 °C for 1.5 h. The cooled reaction was concentrated in vacuo and purified by prep-HPLC directly to afford compound N-[3-(azetidin-3-ylmethyl)-6-(2-chloro-5-fluorophenyl)-2-met hyl-8-oxo-7,8-dihydro- 6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)b enzamide (8.4 mg, 0.014 mmol, 50%). LCMS: m/z 590 [M + H] ⁺ . NMR (400 MHz, DMSO-d6) 6 10.33 (s, 1H), 8.96 (s, 1H), 8.66 (brs, 2H), 7.97 - 7.95 (m, 2H), 7.75 - 7.74 (m, 2H), 7.29 (dd, J- 8.8, 5.2 Hz, 1H), 7.10 (brs, 1H), 6.40 - 6.10 (m, 1H), 4.21 (s, 3H), 4. 00 - 3.98 (m, 2H), 3.75 - 3.70 (m, 2H), 3.51 (d, J = 7.6 Hz, 2H), 3.26 - 3.15 (m, 1H)

Example 123 (E)-N-(6-(2-chloro-5-fluorophenyl)-3-(2-fluorovinyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl-6-d)-3-fluoro-5-(triflu oromethyl)benzamide

[00814] Step A: N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (50 mg, 0.085 mmol) was dissolved in dry THF (2 mL). The solution was cooled to -78 °C, and a solution of LiHMDS (0.427 mL, 0.427 mmol, IM in THF) was added at -78 °C for 0.5 h. The reaction was quenched by D2O, extracted with EA (10 mL). The aqueous layer was extracted with EA (10 mL). The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified by prep-HPLC to give N-[6-(2-chloro-5-fluorophenyl)-6-deuterio-3-[(lE)-2- fluorovinyl]-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-g]ind azol-5-yl]-5-fluoro-3-

333

SUBSTITUTE SHEET (RULE 26) (trifluoromethyl)benzamide (7.8 mg, 0.014 mmol, 16%). LCMS: m/z 566 [M + H] ⁺ . 'H NMR (400 MHz, Methanol-d4) 6 8.19 (s, 1H), 7.91 - 7.88 (m, 1H), 7.83 - 7.73 (m, 1H), 7.71 - 7.57 (m, 3H), 7.29 - 7.23 m, 1H), 7.05 - 6.81 (m, 2H), 6.44 (brs, 1H), 4.24 (d, J= 4 Hz, 3H).

Example 125 (R)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-t rifluoroethyl)- 2,6,7,8-tetrahydropyrrolo [3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide and & Example 126 (S)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-t rifluoroethyl)- 2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

[00815] 7V-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-trif luoroethyl)-2,6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (200 mg, 0.3 mmol, 95 %) was purified using prep-SFC to afford (R)-N-(6-(2-chloro-5-fluorophenyl)-2- methyl-8-oxo-3-(2,2,2-trifluoroethyl)-2,6,7,8-tetrahydropyrr olo[3,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (72.5 mg, 0.12 mmol, 72%). LCMS: m/z 603 [M + H] ⁺ . ^L H NMR (400 MHz, DMSO-d6) 5 10.39 (s, 1H), 9.03 (brs, 1H), 7.99 - 7.83 (m, 2H), 7.74 (d, J= 8.8 Hz, 1H), 7.71 (s, 1H), 7.34 - 7.22 (m, 1H), 7.15 - 7.03 (m, 1H), 6.42 (brs, 1H), 6.11 (brs, 1H), 4.6O - 4.38 (m, 2H), 4.27 (s, 3H). And (S)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoroethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl )-3-fluoro-5- (trifluoromethyl)benzamide(72.1 mg, 0.12 mmol, 72%). LCMS: m/z 603 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.39 (s, 1H), 9.03 (brs, 1H), 7.99 - 7.83 (m, 2H), 7.74 (d, J= 8.8 Hz, 1H), 7.71 (s, 1H), 7.34 - 7.22 (m, 1H), 7.15 - 7.03 (m, 1H), 6.42 (brs, 1H), 6.11 (brs, 1H), 4.6O - 4.38 (m, 2H), 4.27 (s, 3H).

Example 127 N-[6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroethyl )-7,8-dihydro-6H- imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)ben zamide

334

SUBSTITUTE SHEET (RULE 26)

[00816] Step A: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-lH- benzo[d]imidazole-4-carbonitrile (50 mg, 0.132 mmol) in DMA (2 mL) were added K2CO3 (54.8 mg, 0.396 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.038 mL, 0.264 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2$O4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in DCM (0%~10%) to afford compound 6-bromo-5-[(2-chloro-5- fluorophenyl)carbonyl]-l-(2,2,2-trifluoroethyl)benzo[d]imida zole-4-carbonitrile (50 mg, 0.109 mmol, 82%) as a white solid. LCMS : 462.0 [M+H+2] ⁺

[00817] Step B: To a solution of 6-bromo-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2,2- trifluoroethyl)benzo[d]imidazole-4-carbonitrile (50 mg, 0.109 mmol) in ACN (3 mL) and H2O (0.60 mL) was added KOH (30.5 mg, 0.543 mmol). The reaction was stirred at rt for 2 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (l%~60%) to afford compound 5- bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2,2,2-trifluo roethyl)-7,8-dihydro-6H- imidazo[4,5-e]isoindol-8-one (32 mg, 0.067 mmol, 62%) as a white solid. LCMS: m/z 480.0 [M+H] ⁺

[00818] Step C: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-8-one (30 mg, 0.063 mmol) in TFA (3

335

SUBSTITUTE SHEET (RULE 26) mL) was added EtsSiH (72.9 mg, 0.627 mmol). The reaction solution was stirred at 70 °C for 1 hr. The reaction was detected as complete by LCMS. The cooled reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient:0-100%) to afford compound 5-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-8-one (15 mg, 0.032 mmol, 52%) as a white solid. LCMS: m/z 464.0 [M+H] ⁺ .

[00819] Step D: To a solution of 5-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-imidazo[4,5-e]isoindol-8-one (15 mg, 0.032 mmol) in dioxane (5 mL) were added 5-fluoro-3-(trifluoromethyl)benzene-l-carboxamide (6.72 mg, 0.032 mmol), CS2CO3 (21.1 mg, 0.065 mmol), Xant Phos (3.75 mg, 0.006 mmol) and Pd2(dba)s (2.97 mg, 0.003 mmol). The reaction was stirred at 120 °C under N2 for 3 hr. The cooled reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in H2O) to afford compound N-[6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroethyl )-7,8- dihydro-6H-imidazo[4,5-e]isoindol-5-yl]-5-fluoro-3-(trifluor omethyl)benzamide (2.1 mg, 0.004 mmol, 11 %). LCMS: m/z 589.1 [M+H] ⁺ . ¹ HNMR(400 MHz, DMSO-d6) 5 10.49 (s, 1H), 9.07 (s, 1H), 8.53 (s, 1H), 7.98 - 7.88 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.14 - 7.03 (m, 1H), 6.42 (brs, 1H), 6.08 (brs, 1H), 5.53 - 5.40 (m, 2H).

Example 133 N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroethyl )-3,6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

336

SUBSTITUTE SHEET (RULE 26)

[00820] Step A: To the mixture of (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5- fluorophenyl)methanone (500 mg, 1.35 mmol) and potassium carbonate (558 mg, 4.04 mmol) in N,N-dimethylacetamide (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (565 mg, 2.43 mmol). The mixture was stirred at 80 °C under N2 overnight. The cooled mixture was diluted with water and extracted with EA twice. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by prep-TLC(EA/PE=l :4) to give the less polar point [4-bromo-6-fluoro-l -(2,2,2- trifluoroethyl)indazol-5-yl](2-chloro-5-fluorophenyl)methano ne (180 mg, 0.397 mmol, 30%) as a yellow solid. LCMS: m/z 453 [M + H] ⁺ .

[00821] Step B: The mixture of [4-bromo-6-fluoro-l-(2,2,2-trifluoroethyl)indazol-5-yl](2- chloro-5-fluorophenyl)methanone (180 mg, 0.397 mmol) and CuCN (178 mg, 1.98 mmol) in NMP (5 mL) was stirred at 120 °C under N2 for 2 hours. The cooled mixture was diluted with water and EA, filtered on celite. The filtrate was extracted with EA twice. The organic layer was washed with brine twice, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC(EA/PE=l : l) to give 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro- l-(2,2,2-trifluoroethyl)indazole-4-carbonitrile (80 mg, 0.200 mmol, 50%) as a white solid.

LCMS: m/z 400 [M + H] ⁺ .

[00822] Step C: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-l-(2,2,2- trifluoroethyl)indazole-4-carbonitrile (65 mg, 0.163 mmol) and DIPEA (63.0 mg, 0.488 mmol) in DMSO-d6 (1 mL) under N2 was added a solution of (2,4- dimethoxyphenyl)methanamine (82 mg, 0.489 mmol) in DMSO-d6 (O.lmL). The mixture was stirred at 120 °C overnight (40 hours). The cooled mixture was diluted with water and EA. The organic layer was washed with brine twice, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC(EA/PE=l : 1) to give a crude of 5-[(2-chloro-5-fluorophenyl)carbonyl]-

337

SUBSTITUTE SHEET (RULE 26) 6-{[(2,4-dimethoxyphenyl)methyl]amino}-l-(2,2,2-trifluoroeth yl)indazole-4-carbonitrile (65mg,0.119 mmol, 73%) as a white solid. LCMS: m/z 547 [M+H] ⁺ .

[00823] Step D: i) To the mixture of 5-[(2-chloro-5-fhiorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-l-(2,2,2-trifluoroethyl)indazo le-4-carbonitrile (65 mg, 0.119 mmol) in MeCN (2 mL) and H2O (0.5 mL) was added KOH (133 mg, 2.38 mmol). The mixture was stirred at room temperature for 1 hour. ii) The mixture was heated to 100 °C. 4mL of con.HCl was added and the mixture was stirred for 30 min. The cooled mixture was adjusted PH to 8 and extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (EA/PE=2: 3) to give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-3- (2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol- 8-one (15 mg, 0.036 mmol, 30%) as a yellow solid. LCMS: m/z 415 [M+H] ⁺ .

[00824] Step E: To a mixture of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-8-one (15 mg, 0.036 mmol) and pyridine (0.015 mL, 0.181 mmol) in acetonitrile (2 mL) was added 5-fluoro-3-(trifluoromethyl)benzoyl chloride (12.3 mg, 0.054 mmol). The mixture was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was used directly in the next step. LCMS: m/z 605 [M+H] ⁺ .

[00825] Step F: To a mixture of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]-3 -fluoro-5-

(trifluoromethyl)benzamide (20 mg, 0.033 mmol) in 2,2,2-trifluoroacetaldehyde (2 mL) was added EtsSiH (0.2 mL).The mixture was stirred at 50 °C for lOmin.The reaction was poured into a cold KOH solution and extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude was purified by prep-HPLC to give N-[6-(2- chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroethyl)-7,8-di hydro-6H-pyrrolo[4,3-e]indazol-5- yl]-3-fluoro-5-(trifluoromethyl)benzamide (1.3 mg, 0.002 mmol, 7%). LCMS: m/z 589[M+H] ⁺ . !H NMR (400 MHz, Methanol-d4) 5 8.61 (s, 1H), 7.90 (s, 1H), 7.74 - 7.61 (m, 3H), 7.27 (dd, J- 8.8, 5.2 Hz, 1H), 7.06 - 6.94 (m, 1H), 6.40 (s, 1H), 5.40 - 5.24 (m, 2H).

Example 134 (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-o xo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide and Example

338

SUBSTITUTE SHEET (RULE 26) 135 (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-o xo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00826] The crude of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-oxo-7 ,8- dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (150 mg, 0.263 mmol) was purified by prep-SFC to give (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4-e]indazol -5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (56 mg, 0.098 mmol, 19%). LCMS: m/z 571 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.63 (s, 1H), 9.27 (brs, 1H), 8.49 (s, 1H), 7.99 - 7.89 (m, 2H), 7.76 (d, J= 9.2 Hz, 1H), 7.70 (s, 1H), 7.30 (dd, J= 8.8, 5.2 Hz, 1H), 7.14 - 7.04 (m, 1H), 6.65 - 6.31 (m, 2H), 6.12 (brs, 1H), 5.17 - 4.94 (m, 2H).

[00827] And (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-o xo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (56 mg, 0.098 mmol, 19%). LCMS: m/z 571 [M + H] ⁺ . ^NMR (400 MHz, DMSO-d6) 5 10.63 (s, 1H), 9.26 (brs, 1H), 8.49 (s, 1H), 7.99 - 7.89 (m, 2H), 7.76 (d, J= 9.2 Hz, 1H), 7.70 (s, 1H), 7.30 (dd, J= 8.8, 5.2 Hz, 1H), 7.14 - 7.04 (m, 1H), 6.66 - 6.31 (m, 2H), 6.14 (brs, 1H), 5.17 - 4.94 (m, 2H).

Example 136 N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluorocyclobutyl)-2- methyl-8-oxo- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifl uoromethyl)benzamide

339

SUBSTITUTE SHEET (RULE 26)

[00828] Step A: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifl uoromethyl)benzamide (500 mg, 0.911 mmol) in THF (5 mL) was added bromo(cyclopropyl)magnesium (1.82 mL, 1.82 mmol). The reaction was stirred at 0 °C under N2 for 1 hr. The reaction was diluted with water, extracted with EA The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with methanol in dichloroform (gradient: 0-10%) to afford compound N-[6-(2-chloro-5-fluorophenyl)-3- [cyclopropyl(hydroxy)methyl]-2-methyl-8-oxo-7,8-dihydro-6H-p yrrolo[4,3-g]indazol-5-yl]-3- fluoro-5-(trifluoromethyl)benzamide (350 mg, 0.457 mmol, 65%) as a yellow oil. LCMS: m/z 590.94 [M + H] ⁺ .

[00829] Step B: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-3- [cyclopropyl(hydroxy)methyl]-2-methyl-8-oxo-7,8-dihydro-6H-p yrrolo[4,3-g]indazol-5-yl]-3- fluoro-5-(trifluoromethyl)benzamide (350 mg, 0.592 mmol) in toluene (3 mL) was added 4- methylbenzenesulfonic acid (306 mg, 1.78 mmol). The reaction was stirred at 120 °C for 1 hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with methanol in di chloroform (gradient: 0-10%) to afford compound [6- (2-chloro-5-fluorophenyl)-5-({[3-fluoro-5-(trifluoromethyl)p henyl]carbonyl}amino)-2-methyl-8- oxo-7, 8-dihydro-6H-pyrrolo[4,3-g]indazol-3-yl](cyclopropyl)methyl 4-methylbenzenesulfonate (250 mg, 0.336 mmol, 57%) as a yellow solid. LCMS: m/z 745.12 [M + H] ⁺ .

[00830] Step C: To a solution of [6-(2-chloro-5-fluorophenyl)-5-(([3-fluoro-5- (trifluoromethyl)phenyl]carbonyl}amino)-2-methyl-8-oxo-7,8-d ihydro-6H-pyrrolo[4,3- g]indazol-3-yl](cyclopropyl)methyl 4-methylbenzenesulfonate (150 mg, 0.201 mmol) in THF (3 mL) was added KOH (22.6 mg, 0.402 mmol). The reaction was stirred at 80 °C for 1 hr. The

340

SUBSTITUTE SHEET (RULE 26) cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-(cyclopropylidenemethyl)-2- methyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoro methyl)benzamide (60 mg, 0.105 mmol, 52%) as a yellow oil. LCMS: m/z 572.92 [M + H] ⁺ .

[00831] Step D: To a solution of 4-(chloromethyl)-l-fluoro-l,4-diazabicyclo[2.2.2]octane- 1,4-diium bis(tetrafluoro-X5-boranuide) (55.7 mg, 0.157 mmol) in toluene (1 mL) were added Py (0.051 mL, 0.628 mmol) and fluorane pyridine (664 mg, 6.70 mmol) at 40 °C for 15 min. N-[6- (2-chloro-5-fluorophenyl)-3-(cyclopropylidenemethyl)-2-methy l-8-oxo-7,8-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benz amide (60 mg, 0.105 mmol) was added. The reaction was stirred at 40 °C for 2 hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by prep-HPLC (Cl 8, 0~80 % acetonitrile in H2O) to afford compound N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluorocyclobutyl)-2- methyl-8-oxo- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifl uoromethyl)benzamide (1.4 mg, 0.002 mmol, 2%). LCMS: m/z 610.92 [M + H] ⁺ . ^NMR (400 MHz, Methanol-d4) 5 7.75 - 7.61 (m, 2H), 7.50 - 7.44 (m, 1H), 7.39 - 7.29 (m, 2H), 7.29 - 7.17 (m, 1H), 7.05 - 6.88 (m, 1H), 6.74 - 6.57 (m, 1H), 5.37 - 5.31 (m, 1H), 4.58 (s, 3H), 2.23 - 2.15 (m, 1H), 2.07 - 1.99 (m, 1H), 1.65 - 1.54 (m, 2H).

Example 137 N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(l,2,2,2-tet rafluoroethyl)- 7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifl uoromethyl)benzamide

341

SUBSTITUTE SHEET (RULE 26) [00832] Step A: To a solution of N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoro-l-hydroxyethyl)-7,8-dihydro-6H-pyrrolo[4,3-g]indaz ol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (70 mg, 0.113 mmol) in DCM (2 mL) was added DAST (2 mL) at 0 °C. The reaction mixture was stirred at rt for 2 hr. The reaction was diluted with water, extracted with EA The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Cl 8, 0-80 % acetonitrile in H2O) to afford N-[6-(2-chloro- 5-fluorophenyl)-2-methyl-8-oxo-3-(l,2,2,2-tetrafluoroethyl)- 7,8-dihydro-6H-pyrrolo[4,3- g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1.7 mg, 0.003 mmol, 2%) as a white solid. LCMS: m/z 620.86 [M + H] ⁺ . ^X HNMR (400 MHz, DMSO-d6) 5 10.44 (d, J = 8.8 Hz, 1H), 9.13 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.32 - 7.22 (m, 2H), 7.15 - 7.02 (m, 1H), 6.60 - 5.99 (m, 1H), 4.37 (s, 3H).

Example 138 l-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-(2-(dimethylamino)ph enyl)ure

[00833] Step A: A solution of 4-amino-5-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-5- hydroxy-2-methyl-6,7-dihydro-5H-pyrrolo[4,3-f]indazol-7-one (200 mg, 0.487 mmol) and 4- nitrophenyl chloromethanoate (103 mg, 0.511 mmol) in THF (5 mL) was stirred at 70 °C for 2 h. The cooled reaction mixture was used directly in the next step without further purification. LCMS: m/z 576 [M+H] ⁺

342

SUBSTITUTE SHEET (RULE 26) [00834] Step B: To the above mixture was added benzene- 1,2-diamine (105 mg, 0.974 mmol) and Py (77.0 mg, 0.974 mmol) in THF (2 mL) at it The mixture was stirred at 40 °C for 16h. The mixture was quenched by saturated NaHCOa solution and extracted with ethyl acetate. The organic layers were combined and concentrated to give l-[(2-aminophenyl)amino]-N-[5-(5- chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-5-hydroxy-2-met hyl-7-oxo-6,7-dihydro-5H- pyrrolo[4,3-f]indazol-4-yl]methanamide (50 mg, 92 pmol, 19%) as a brown solid. LCMS: m/z 545 [M+H] ⁺

[00835] Step C: To a solution of l-[(2-aminophenyl)amino]-N-[5-(5-chloro-2-fluorophenyl)- 3-(2,2-difluoroethyl)-5-hydroxy-2-methyl-7-oxo-6,7-dihydro-5 H-pyrrolo[4,3-f]indazol-4- yl]methanamide (50 mg, 92 nmol ) in TFA (2 mL) was added EtaSiH (0.2 mL). The reaction mixture was stirred at 60 °C for 30min. Then the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give l-[(2-aminophenyl)amino]-N-[5-(5- chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-2-methyl-7-oxo- 6,7-dihydro-5H-pyrrolo[4,3- f]indazol-4-yl]methanamide (40 mg, 76 pmol, 82%) as a red solid. LCMS: m/z 529[M+H] ⁺ [00836] Step D: To a solution of l-[(2-aminophenyl)amino]-N-[5-(5-chloro-2-fluorophenyl)- 3-(2,2-difluoroethyl)-2-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[ 4,3-f]indazol-4-yl]methanamide (25 mg, 47 pmol) in MeOH (2 mL) was added Formaldehyde solution (1.42 mg, 47 pmol;

37wt% in H2O). The mixture was stirred at rt for 15min, then NaCNBFL was added. The mixture was stirred at rt for another 2h, then diluted with EA and FLO. The organic layers were concentrated to give a residue. The residue was purified by pre-HPLC to give N-[5-(5- chloro-2-fluorophenyl)-3-(2,2-difluoroethyl)-2-methyl-7-oxo- 6,7-dihydro-5H-pyrrolo[4,3- f]indazol-4-yl]-l-[[2-(dimethylamino)phenyl]amino}methanamid e (6.6 mg, 12 pmol, 25%) as a red solid. LCMS: m/z 557 [M+H]". NMR (400 MHz, CDCh) 5 7.91 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.44 (t, J= 6.8 Hz, 1H), 7.30 (m, 2H), 6.91 - 6.81 (m, 1H), 6.68 (s, 1H), 6.57 (m, 1H), 6.35 (s, 1H), 6.25 - 5.90 (m, 1H), 4.30 (s, 3H), 3.64 (t, J= 4.0 Hz, 2H), 3.03 (s, 6H).

Example 139 N-(6-(2-chloro-5-fluorophenyl)-3-(3,3-difluorocyclopentyl)-2 -methyl-8-oxo- 2,6,7,8-tetrahydropyirolo[3,4-g]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

343

SUBSTITUTE SHEET (RULE 26)

[00837] Step A: To a solution of (7-bromo-3-iodo-2-methyl-5-nitro-2H-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (537 mg, 1.01 mmol) in EtOH (20 mL) and FLO

(5 mL) were added Fe (330 mg, 5.01 mmol) and NH4CI (335 mg, 5.03 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, concentrated, diluted with H2O, and extracted with EA. The organic phase was washed with brine, dried over ISfeSCL

344

SUBSTITUTE SHEET (RULE 26) and concentrated. The residue was purified using silica gel column chromatography eluting with

EA in PE (Gradient: 0-90%) to afford compound (5-amino-7-bromo-3-iodo-2-methyl-2H- indazol-6-yl)(2-chloro-5-fluorophenyl)methanone (315 mg, 0.63 mmol, 63%) as a yellow solid. LCMS: m/z 508 [M + H] ⁺ .

[00838] Step B: To a solution of (5-amino-7-bromo-3-iodo-2-methyl-2H-indazol-6-yl)(2- chloro-5-fluorophenyl)methanone (510 mg, 1.01 mmol) in CH3CN (6 mL) were added 5- fluoro-3-(trifluoromethyl)benzoyl chloride (496 mg, 2.19 mmol) and pyridine (0.30 mL, 3.65 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over NaiSCU and concentrated to afford compound N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-3-iodo-2-methyl- 2H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (560 mg, 0.81 mmol, 82%) as a yellow solid. LCMS: m/z 698 [M + H] ⁺ .

[00839] Step C: To a solution of N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-3-iodo-2-methyl- 2H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (700 mg, 1.01 mmol) in dioxane (30 mL) and H2O (4 mL) were added 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-2-e n- 1-one (315 mg, 1.52 mmol), JSteCCh (318 mg, 3.01 mmol) and Pd(dppf)C12 (100 mg, 0.16 mmol). The reaction mixture was stirred at 50 °C under N2 for 12 h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient : 0-60%] to afford N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-

2-methyl-3-(3-oxocyclopent-l-en-l-yl)-2H-indazol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (195 mg, 0.32 mmol, 32 %) as a yellow solid. LCMS: m/z 652 [M + H] ⁺ .

[00840] Step D: To a solution of N-(7-bromo-6-(2-chloro-5-fluorobenzoyl)-2-methyl-3-(3- oxocyclopent-l-en-l-yl)-2H-indazol-5-yl)-3-fluoro-5-(trifluo romethyl)benzamide(655 mg, 1.01 mmol) in NMP (5 mL) was added CuCN (270 mg, 1.50 mmol). The reaction mixture was stirred at 150 °C for 5 h. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE (Gradient: 0-80%) to afford N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-2-methyl-3-(3-oxocyc lopent-l-en-l-yl)-2H- indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (300 mg, 0.52 mmol, 52%) as a red solid.

LCMS: m/z 599 [M+H] ⁺ .

345

SUBSTITUTE SHEET (RULE 26) [00841] Step E: To a solution of N-(6-(2-chloro-5-fluorobenzoyl)-7-cyano-2-methyl-3-(3- oxocyclopent-l-en-l-yl)-2H-indazol-5-yl)-3-fluoro-5-(trifluo romethyl)benzamide (600 mg, 1.01 mmol) in CH3CN (7 mL) and H2O (3 mL) was added KOH (1.01 g, 17.9 mmol). The reaction mixture was stirred at RT 10 min. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in

DCM [Gradient : 0-10%] to afford compound N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2- methyl-8-oxo-3-(3-oxocyclopent-l-en-l-yl)-2,6,7,8-tetrahydro pyrrolo[3,4-g]indazol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (600 mg, 0.92 mmol, 92%) as a yellow solid. LCMS: m/z 617 [M + H] ⁺ .

[00842] Step F: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-(3-oxocyclopent-l-en-l-yl)-2,6,7,8-tetrahydropyrrolo[3,4-g ]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (180 mg, 0.27 mmol) in TFA (3 mL) was added EtaSiH (218 mg, 1.88 mmol). The reaction mixture was stirred at 80 °C for 30 min. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The purified by silica gel column chromatography eluting with MeOH in DCM (Gradient: 0-10%) to afford compound N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8- oxo-3-(3-oxocyclopent-l-en-l-yl)-2,6,7,8-tetrahydropyrrolo[3 ,4-g]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (150 mg, 0.25 mmol, 93%) as a white solid. LCMS: m/z 601 [M + H] ⁺ .

[00843] Step G: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(3- oxocyclopent-l-en-l-yl)-2,6,7,8-tetrahydropyrrolo[3,4-g]inda zol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (300 mg, 0.50 mmol) in MeOH (10 mL) was added 10% of Pd/C (60 mg). The reaction mixture was stirred at 25 °C for 30 min under H2. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography eluting with MeOH in DCM [Gradient : 0-10%] to afford compound N-(6-(2-chloro-5- fluorophenyl)-2-methyl-8-oxo-3-(3-oxocyclopentyl)-2,6,7,8-te trahydropyrrolo[3,4-g]indazol-5- yl)-3-fluoro-5-(trifluoromethyl)benzamide (151 mg, 0.25 mmol, 50%) as a white solid. LCMS: m/z 603 [M + H] ⁺ .

[00844] Step H: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(3- oxocyclopentyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl )-3-fluoro-5-

346

SUBSTITUTE SHEET (RULE 26) (trifluoromethyl)benzamide (60 mg, 0.10 mmol) in DCM (3 mL) was added DAST (48.5 mg, 0.31 mmol). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with EEO, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The purified by prep-HPLC to afford compound N-(6-(2-chloro-5-fluorophenyl)-3- (3,3-difluorocyclopentyl)-2-methyl-8-oxo-2,6,7,8-tetrahydrop yrrolo[3,4-g]indazol-5-yl)-3- fluoro-5-(trifluoromethyl)benzamide (0.91 mg, 0.002 mmol, 2%) as a white solid. LCMS: m/z 625 [M + H] ⁺ . 'H NMR (400 MHz, CDCh) 8 7.51 - 7.42 (m, 4H), 7.01 (d, J= 6.0 Hz, 1H), 6.67 (brs, 1H), 6.28 (brs, 1H), 4.10 (m, 3H), 2.82 - 2.17 (m, 1H), 2.01 (s, 1H).

Example 140 N-(6-(2-chloro-5-fluorophenyl)-3-((2,2-difluorocyclobutyl)me thyl)-2-methyl- 8-oxo-2,6,7,8-tetrahydropyirolo[3,4-g]indazol-5-yl)-3-fluoro -5-(trifluoromethyl)benzamide

[00845] Step A: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-formyl-2-methyl-8-oxo-

7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(tr ifluoromethyl)benzamide (500 mg, 0.911 mmol) in EtOH (15 mL) was added calcium hydroxide (135 mg, 1.82 mmol), cyclobutanone (639 mg, 9.11 mmol). The reaction mixture was stirred at 80 °C for 18 h. The cooled mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over JSfeSCU and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% methanol in dichloroform to afford compound N-(6-(2- chloro-5-fluorophenyl)-3-(hydroxy(2-oxocyclobutyl)methyl)-2- methyl-8-oxo-2, 6,7,8-

347

SUBSTITUTE SHEET (RULE 26) tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (200 mg, 0.315 mmol, 35%) as a yellow solid.

[00846] Step B: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-[hydroxy(2- oxocyclobutyl)methyl]-2-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[ 4,3-g]indazol-5-yl]-3-fluoro-5- (trifluoromethyl)benzamide (150 mg, 0.242 mmol) in DCM (3 mL) was added TEA (0.101 mL, Q.1T1 mmol) and 4-methylbenzenesulfonyl chloride (231 mg, 1.21 mmol) at rt. The reaction mixture was stirred at room temperature for 18 hrs. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography (DCM: MeOH = 10:1) to give N- [6-(2-chloro-5-fluorophenyl)-3-{[(lZ)-2-oxocyclobutylidene]m ethyl}-2-methyl-8-oxo-7,8- dihydro-6H-pyrrolo[4,3-g]indazol-5-yl]-3-fluoro-5-(trifluoro methyl)benzamide (50 mg, 0.083 mmol, 34 %) as a yellow solid. LCMS: m/z 601 [M + H] ⁺ .

[00847] Step C: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-{[(lZ)-2- oxocyclobutylidene]methyl}-2-methyl-8-oxo-7,8-dihydro-6H-pyr rolo[4,3-g]indazol-5-yl]-3- fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.083 mmol) in THF (2 mL) was added Pd/C 10% (1.77 mg, 0.017 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 18 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-[(2- oxocyclobutyl)methyl]-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5 -yl]-3-fluoro-5- (trifluoromethyl)benzamide (30 mg, 0.05 mmol, 60%) as a yellow oil. LCMS: m/z 603 [M + H] ⁺ . [00848] Step D: To a solution of N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-[(2- oxocyclobutyl)methyl]-7,8-dihydro-6H-pyrrolo[4,3-g]indazol-5 -yl]-3-fluoro-5- (trifluoromethyl)benzamide (20 mg, 0.033 mmol) in DCM (2 mL) was added DAST (16 mg, 0.099 mmol). The reaction mixture was stirred at 0 °C for 3 h. The cooled mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford N-[6-(2-chloro-5-fluorophenyl)- 3-[(2,2-difluorocyclobutyl)methyl]-2-methyl-8-oxo-7,8-dihydr o-6H-pyrrolo[4,3-g]indazol-5-yl]- 3-fluoro-5-(trifluoromethyl)benzamide (1 mg, 0.002 mmol, 5%) as a white solid. LCMS: m/z 625 [M + H] ⁺ . ^X H NMR (400 MHz, CD ₃ OD) 5 7.90 (s, 1H), 7.72 - 7.62 (m, 3H), 7.29 - 7.21 (m, 1H), 7.05 - 6.94 (m, 1H), 6.70 - 6.11 (m, 1H), 4.26 (s, 3H), 3.53 - 3.40 (m, 2H), 3.38 - 3.35 (m, 1H), 2.61 - 2.34 (m, 2H), 1.66 - 1.54 (m, 2H).

348

SUBSTITUTE SHEET (RULE 26) Example 141 N-((S)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2-trifluoro-l- hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)- 3-fluoro-5- (trifluoromethyl)benzamide

Example 142 N-((S)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2-trifluoro-l- hydroxyethyl)-2,6,7,8-tetrahydropyirolo[3,4-g]indazol-5-yl)- 3-fluoro-5- (trifluoromethyl)benzamide

Example 143 N-((R)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2-trifluoro-l- hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)- 3-fluoro-5- (trifluoromethyl)benzamide

Example 144 N-((R)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2-trifluoro-l- hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)- 3-fluoro-5- (trifluoromethyl)benzamide

[00849] Step A: N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-trifl uoro-l- hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)- 3-fluoro-5-

(trifluoromethyl)benzamide (95 mg, 0.153 mmol) was separated by prep-SFC to afforded [00850] Pl Example 141 : N-((S)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2- trifluoro-l-hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]in dazol-5-yl)-3-fluoro-5-

(trifluoromethyl)benzamide (15.0 mg, 0.024 mmol, 16 %) as a white solid. 'H NMR (400 MHz,

349

5UB5TITUTE SHEET (RULE 26) DMSO) 5 10.41 (s, 1H), 9.03 (s, 1H), 8.04 - 7.88 (m, 2H), 7.80 - 7.63 (m, 2H), 7.55 (d, J= 3.0 Hz, 1H), 7.28 (dd, J= 8.4 Hz, 1H), 7.09 (s, 1H), 6.23 (m, 2H), 4.32 (s, 3H).

[00851] P2 Example 142: N-((S)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2- trifluoro-l-hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]in dazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (13.7 mg, 0.022 mmol, 14%) as a white solid. 'H NMR (400 MHz, DMSO) 5 10.38 (s, 1H), 9.03 (s, 1H), 8.03 - 7.86 (m, 2H), 7.81 - 7.64 (m, 2H), 7.52 (d, J= 3.0 Hz, 1H), 7.29 (dd, J= 8.4, 1H), 7.10 (s, 1H), 6.17 (m, 2H), 4.32 (s, 3H).

[00852] P3 Example 143: N-((R)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2- trifluoro-l-hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]in dazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (5.1 mg, 0.008 mmol, 6%) as a white solid. ^X H NMR (400 MHz, DMSO) 5 10.38 (s, 1H), 9.01 (s, 1H), 8.01 - 7.87 (m, 2H), 7.81 - 7.65 (m, 2H), 7.52 (d, J= 4.8 Hz, 1H), 7.29 (dd, J- 8.4, 5.6 Hz, 1H), 7.10 (s, 1H), 6.17 (m, 2H), 4.32 (s, 3H).

[00853] P4 Example 144: N-((R)-6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-((R*)-2, 2,2- trifluoro-l-hydroxyethyl)-2,6,7,8-tetrahydropyrrolo[3,4-g]in dazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (6.4 mg, 0.01 mmol, 7%) as a white solid. 'H NMR (400 MHz, DMSO) 5 10.41 (s, 1H), 9.05 (s, 1H), 8.06 - 7.85 (m, 2H), 7.79 - 7.64 (m, 2H), 7.55 (d, J= 4.4 Hz, 1H), 7.28 (dd, J- 8.8, 5.6 Hz, 1H), 7.09 (s, 1H), 6.23 (m, 2H), 4.32 (s, 3H).

Example 145 (S)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-3,6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

Example 146 (R)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-3,6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00854] Step A: N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroethyl )-3,6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (18 mg, 0.030 mmol) was separated by prep-SFC to afforded

350

5UB5TITUTE SHEET (RULE 26) [00855] Pl Example 145: (S)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-

3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (5.8 mg, 0.010 mmol, 33 %) as a white solid. 'H NMR (400 MHz, DMSO) 5 10.65 (s, 1H), 9.28 (s, 1H), 8.54 (s, 1H), 8.15 - 7.88 (m, 2H), 7.83 - 7.65 (m, 2H), 7.30 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 (t, J-- 6.8 Hz, 1H), 6.71 - 5.94 (m, 2H), 5.71 - 5.45 (m, 2H).

[00856] P2 Example 146: (R)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-

3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (5.9 mg, 0.010 mmol, 33%) as a white solid. 'H NMR (400 MHz, DMSO) 5 10.65 (s, 1H), 9.28 (s, 1H), 8.54 (s, 1H), 8.15 - 7.88 (m, 2H), 7.83 - 7.65 (m, 2H), 7.30 (dd, J= 8.8, 5.2 Hz, 1H), 7.10 (t, J-- 6.8 Hz, 1H), 6.71 - 5.94 (m, 2H), 5.71 - 5.45 (m, 2H).

Example 147 (S)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-3,6,7,8- tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoro methyl)benzamide

Example 148 (R)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-3,6,7,8- tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoro methyl)benzamide

[00857] Step A: The compound N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3 -(2,2,2- trifluoroethyl)-3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-y l)-3-fluoro-5-

(trifluoromethyl)benzamide (90 mg, 0.153 mmol) was separated by prep-SFC to afforded: [00858] Pl Example 147: (S)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-

3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide (23.5 mg, 0.040 mmol, 24%) as a yellow solid. ¹ H NMR(400 MHz, DMSO-d6) 5 10.49 (s, 1H), 9.07 (s, 1H), 8.53 (s, 1H), 7.99 - 7.89 (m, 2H), 7.80 - 7.68 (m, 2H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.14 - 7.03 (m, 1H), 6.44 (brs, 0.5H), 6.07 (brs, 1H), 5.56 - 5.36 (m, 2H). LCMS: m/z 589.2 [M+H] ⁺

351

SUBSTITUTE SHEET (RULE 26) [00859] P2 Example 148: (R)-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-

3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide (22.4 mg,

0.038 mmol, 22%) as a yellow solid. ¹ HNMR(400 MHz, DMSO-d6) 5 10.49 (s, 1H), 9.07 (s,

1H), 8.53 (s, 1H), 7.99 - 7.86 (m, 2H), 7.80 - 7.69 (m, 2H), 7.28 (dd,J 8.8, 5.2 Hz, 1H), 7.14

7.03 (m, 1H), 6.44 (brs, 0.5H), 6.07 (brs, 1H), 5.55 - 5.36 (m, 2H). LCMS: m/z 589.1[M+H] ⁺

Example 149 (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-o xo-3, 6,7,8- tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trilluoro methyl)benzamide

Example 150 (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-o xo-3, 6,7,8- tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoro methyl)benzamide

352

SUBSTITUTE SHEET (RULE 26)

[00860] Step A: To a solution of (2-chloro-5-fluorophenyl)(2,4-dibromo-3-methoxy-6- nitrophenyl)methanone (9.2 g, 19.7 mmol) and 2-methylpropan-2-yl aminomethanoate (2.31 g, 19.7 mmol) in dioxane (100 mL) was added CS2CO3 (19.2 g, 59.0 mmol), Xant Phos (2.28 g, 3.94 mmol) and Pd2(dba)s (0.90 g, 0.98 mmol). The mixture was stirred at 90 °C under N2 for 2 hours. The cooled mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (30 g column) using 0 - 10% EtOAc/hexane to afford 2-methylpropan-2-yl ( { 3 -bromo-4- [(2-chl oro-5 -fluorophenyl) carbonyl]-2-methoxy-5 -nitrophenyl } amino)methanoate (7.7 g, 15.3 mmol, 78 %) as a brown solid. LCMS: m/z 505 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d6) 5 9.45 (s, 1H), 8.94 (s, 1H), 7.76 - 7.69 (m, 2H), 7.62 - 7.56 (m, 1H), 3.85 (s, 3H), 1.53 (s, 9H).

[00861] Step B: To a solution of 2-methylpropan-2-yl ({3-bromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-methoxy-5-nitrophenyl}amino)methano ate (7.7 g, 15.3 mmol) in Pyridine (60 mL) was added (2,4-dimethoxyphenyl)methanamine (7.67 g, 45.9 mmol). The reaction mixture was stirred at 20 °C for 48 hours. The mixture was concentrated under vauum to remove pyridine. The residue was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2$O4 and concentrated in vacuum to give 2- methylpropan-2-yl ({3-bromo-4-[(2-chloro-5-fluorophenyl)carbonyl]-2-{[(2,4- dimethoxyphenyl)methyl]amino}-5-nitrophenyl}amino)methanoate (11 g, 13.8 mmol, 90%) as a brown oil. LCMS: m/z 638 [M + H] ⁺ .

[00862] Step C: A solution of 2-methylpropan-2-yl ({3-bromo-4-[(2-chloro-5- fluorophenyl)carbonyl]-2-{[(2,4-dimethoxyphenyl)methyl]amino }-5- nitrophenyl]amino)methanoate (11 g, 17.2 mmol) in TFA (60 mL) was stirred at 50 °C for 1 hour. The mixture was concentrated under vacuum to remove TFA. The residue was poured into water and adjusted pH to 8 with NaOH, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum to give the residue. The residue was

353

SUBSTITUTE SHEET (RULE 26) purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-30%) to give (2-chloro-5-fluorophenyl)(3,4-diamino-2-bromo-6-nitrophenyl) methanone (3.8 g, 9.78 mmol, 57%) as an orange solid. LCMS: m/z 390.1 [M + H] ⁺ . NMR (400 MHz, DMSO-d6) 5 7.66 (dd, J = 8.8, 5.2 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.45 (s, 1H), 6.37 (s, 2H), 5.77 (s, 2H).

[00863] Step D: To a solution of (2-chloro-5-fluorophenyl)(3,4-diamino-2-bromo-6- nitrophenyl)methanone (1 g, 2.57 mmol) in toluene (20 mL) was added triethoxymethane (1.14 g, 7.72 mmol) and 4-methylbenzenesulfonic acid (40 mg, 0.257 mmol). The mixture was stirred at 100 °C for 2 hours. The cooled mixture was concentrated and the residue was purified by silica gel chromatography (10 g column) using 0 - 20% EtOAc/hexane to afford (4-bromo-6- nitro-lH-benzo[d]imidazol-5-yl)(2-chloro-5-fluorophenyl)meth anone (1 g, 2.51 mmol, 97%) as a brown oil. LCMS: m/z 400.1 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d6) 6 13.70 (s, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 7.70 (dd, J = 10.0, 7.2 Hz, 2H), 7.59 (dd, J = 10.8, 5.6 Hz, 1H).

[00864] Step E: To a solution of (4-bromo-6-nitro-lH-benzo[d]imidazol-5-yl)(2-chloro-5- fluorophenyl)methanone (915 mg, 2.31 mmol) in DMA (15 mL) was added K2CO3 (952 mg, 6.93 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.2 g, 5.72 mmol). The mixture was stirred at 80 °C for 2 hours. The cooled mixture was added into water and extracted with

EA. The organic phase was dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0 - 60% EtOAc/hexane to afford [4-bromo-l-(2,2- difluoroethyl)-6-nitrobenzo[d]imidazol-5-yl](2-chloro-5-fluo rophenyl)methanone (1 g, 2.16 mmol, 94%) as brown oil. LCMS: m/z 462.2 [M + H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 5 8.99 (s, 1H), 8.83 (s, 1H), 7.76 - 7.70 (m, 2H), 7.63 - 7.57 (m, 1H), 6.57 (t, J = 54.4 Hz, 1H), 5.11 (td, J = 16.0, 2.8 Hz, 2H).

[00865] Step F: To a solution of [4-bromo-l-(2,2-difluoroethyl)-6-nitrobenzo[d]imidazol-5- yl](2-chloro-5-fluorophenyl)methanone (900 mg, 1.95 mmol) in EtOH (20 mL) and H2O

(7 mL) was added Fe (652 mg, 11.7 mmol) and NH4CI (520 mg, 9.72 mmol). The mixture was stirred at 80 °C for 1 hour. The mixture was filtrated and concentrated in vacuo to remove

EtOH. The mixture was poured into saturation NaHCO^, extracted with EtOAc. The organic layer was washed with brine, dried over Na2$O4 and concentrated in vacuum to give [6-amino-4- bromo-l-(2,2-difluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5 -fluorophenyl)methanone (750 mg, 1.73 mmol, 89%) as an orange oil. LCMS: m/z 434.1 [M + H] ⁺ .

354

SUBSTITUTE SHEET (RULE 26) [00866] Step G: To a solution of [6-amino-4-bromo-l-(2,2-difluoroethyl)benzo[d]imidazol-5- yl](2-chloro-5-fluorophenyl)methanone (600 mg, 1.39 mmol) in NMP (8 mL) was added CuCN (186 mg, 2.08 mmol) and the mixture was stirred at 150 °C for 1 hour in microwave. The cooled mixture was diluted with water, extracted with EA. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0 - 80% EtOAc/hexane to afford 6-amino-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)benzo[d]imidazole-4-carbonitrile (400 mg, 1.06 mmol, 76%) as an orange solid. LCMS: m/z 379.2 [M + H] ⁺ .

[00867] Step H: To a solution of 6-amino-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)benzo[d]imidazole-4-carbonitrile (360 mg, 0.95 mmol) in CH3CN

(20 mL) and H2O (5 mL) was added KOH (160 mg, 2.85 mmol). The mixture was stirred at 20 °C for 1 hour. The following mixture was concentrated and the residue was purified by silica gel chromatography (3 g column) using 0 - 10% MeOH/DCM to afford 5-amino-6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-7,8-dihydro-6H -imidazo[5,4-e]isoindol-8-one (150 mg, 0.38 mmol, 39%) as a brown solid. LCMS: m/z 397.2 [M + H] ⁺ .

[00868] Step I: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 6-hydroxy-7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-one (150 mg, 0.38 mmol) in CH3CN (2 mL) was added pyridine (90 mg, 1.13 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (103 mg, 0.45 mmol). The mixture was stirred at 20 °C for 30 min. The following mixture was concentrated and the residue was purified by silica gel chromatography (3 g column) using 0 - 10% MeOH/DCM to afford N-[6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-8-oxo-7,8-dihydro-6H-imidazo[5,4-e] isoindol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (120 mg, 0.20 mmol, 54%) as a brown solid. LCMS: m/z 587.3 [M + H] ⁺ .

[00869] Step J: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-8-oxo-7,8-dihydro-6H-iniidazo[5,4-e]isoindol-5-yl]-5 -fluoro-3- (trifluoromethyl)benzamide (100 mg, 0.17 mmol) in TFA (4 mL) was added Et3SiH (1 mL) and the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated and the residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 10%) to afford a crude, which was separated by prep-SFC in step K to give:

355

SUBSTITUTE SHEET (RULE 26) [00870] Pl Example 149 (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-o xo- 3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(t rifluoromethyl)benzamide (8.7 mg, 0.015 mmol, 9%) as a white solid. LCMS: m/z 571.4 [M + H] ⁺ . TiNMR (400 MHz, DMSO-d6) 5 10.46 (s, 1H), 9.00 (s, 1H), 8.43 (s, 1H), 7.90 (s, 2H), 7.79 - 7.72 (m, 2H), 7.29 (dd, J = 8.8,

5.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.70 - 5.73 (m, 3H), 4.90 (t, J = 16.2 Hz, 2H).

[00871] P2 Example 150 (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-8-o xo-

3.6.7.8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide (12.0 mg, 0.021 mmol, 12%) as a white solid. LCMS: m/z 571.4 [M + H] ⁺ . 'H NMR (400 MHz, DMSO- d6) 5 10.46 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.78 - 7.71 (m, 2H), 7.29 (dd, J = 8.8, 5.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.68 - 5.81 (m, 3H), 4.91 (t, J =

17.2 Hz, 2H).

Example 151 (S)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)-8-oxo-

3.6.7.8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide Example 152 (R)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)-8-oxo- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

356

SUBSTITUTE SHEET (RULE 26)

[00872] Step A: To a solution of (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5- fluorophenyl)methanone (2 g, 5.38 mmol) in DMF (0.5 mL) were added NCS (0.86 g, 6.46 mmol) and KOH (0.3 g, 5.38 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound (4-bromo-3-chloro-6-fluoro-lH-indazol-5-yl)(2-chloro-5-fluor ophenyl)methanone (850 mg, 2.09 mmol, 39 %) as a yellow solid. LCMS: m/z 406.01 [M + H] ⁺ .

[00873] Step B: To a solution of (4-bromo-3-chloro-6-fluoro-lH-indazol-5-yl)(2-chloro-5- fluorophenyl)methanone (850 mg, 2.09 mmol) in NMP (2 mL) was added CuCN (188 mg, 2.09 mmol). The reaction was stirred at 120 °C under N2 with sealed tube for 2 hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound 3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-lH-i ndazole-4-carbonitrile (600 mg, 1.70 mmol, 81%) as a yellow solid. LCMS: m/z 352.12 [M + H] ⁺ .

[00874] Step C: To a solution of 3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro- lH-indazole-4-carbonitrile (600 mg, 1.704 mmol) in DMSO (5 ml) was added (2,4- dimethoxyphenyl)methanamine (285 mg, 1.70 mmol) and DIEA (661 mg, 5.11 mmol). The reaction was stirred at 140 °C for 2 d. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over NaiSCh and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound 3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-6- [(2,4-dimethoxyphenyl)amino]-lH-indazole-4-carbonitrile (180 mg, 0.371 mmol, 22%) as a red solid. LCMS: m/z 485.30 [M + H] ⁺ .

357

SUBSTITUTE SHEET (RULE 26) [00875] Step D: To a solution of 3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-[(2,4- dimethoxyphenyl)amino]-lH-indazole-4-carbonitrile (100 mg, 0.206 mmol) in DMA (1 mL) were added 2,2-difluoroethyl trifluoromethanesulfonate (88.2 mg, 0.412 mmol) and CS2CO3 (201 mg, 0.618 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over NaiSCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound 3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-l-(2,2-difluo roethyl)-6-[(2,4- dimethoxyphenyl)amino]indazole-4-carbonitrile (100 mg, 0.182 mmol, 88 %) as a red solid. LCMS: m/z 549.33 [M + H] ⁺ .

[00876] Step E: A solution of l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-5 - {[(2,4-dimethoxyphenyl)methyl]amino}-6-hydroxy-7,8-dihydro-6 H-pyrrolo[4,3-e]indazol-8-one (85 mg, 0.146 mmol) in EtiSiH (0.5 mL) and TEA (3 mL) was stirred at 50 °C for 1 hr. The cooled reaction was concentrated, 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 eluted with ethyl acetate in petroleum ether (gradient: 0- 30%) to afford compound 5-amino-l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoro ethyl)- 7,8-dihydro-6H-pyrrolo[3,4-e]indazol-8-one (40 mg, 0.096 mmol, 66%) as a yellow solid. LCMS: m/z 415.20 [M + H] ⁺ .

[00877] Step F: To a solution of 5-amino-l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-7,8-dihydro-6H-pyrrolo[3,4-e]indazol-8-one (50 mg, 0.120 mmol) in acetonitrile (2 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (54.6 mg, 0.241 mmol) and Py (0.029 mL, 0.361 mmol). The reaction was stirred at rt for 4 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over IsfeSCL and concentrated. The residue was purified by prep-HPLC (Cl 8, 0~80 % acetonitrile in H2O) to afford compound N-[l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl )-8-oxo-7,8- dihydro-6H-pyrrolo[3,4-e]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (6 mg, 0.010 mmol, 8%) as a white solid. LCMS: m/z 605.29 [M + H] ⁺ .

[00878] Step G: N-[l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl )-8-oxo-7,8- dihydro-6H-pyrrolo[3,4-e]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (6 mg, 0.010 mmol ) was separated by prep-SFC to give:

358

SUBSTITUTE SHEET (RULE 26) [00879] Pl Example 151 : (S)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)- 8-oxo-3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro -5-(trifluoromethyl)benzamide (2.6 mg) as a white solid. LCMS: m/z 605.29 [M + H] ⁺ . ^! H NMR (400 MHz, DMSO-d6) 5 10.63 (s, 1H), 9.27 (s, 1H), 8.02 - 7.94 (m, 2H), 7.79 - 7.66 (m, 2H), 7.35 - 7.26 (m, 1H), 7.10 (brs, 1H), 6.69 - 6.31 (m, 2H), 6.16 (s, 1H), 5.11 - 4.95 (m, 2H).

[00880] P2 Example 152: (R)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroe thyl)- 8-oxo-3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro -5-(trifluoromethyl)benzamide (2.3 mg) as a white solid. LCMS: m/z 605.29 [M + H] ⁺ . ^! H NMR (400 MHz, DMSO-d6) 5 10.63 (s, 1H), 9.27 (s, 1H), 8.02 - 7.94 (m, 2H), 7.79 - 7.66 (m, 2H), 7.35 - 7.26 (m, 1H), 7.10 (brs, 1H), 6.69 - 6.31 (m, 2H), 6.16 (s, 1H), 5.11 - 4.95 (m, 2H).

Example 153 N-[6-(2-chloro-5-fluorophenyl)-8-oxo-3-(l,l,l-trifluoroprop- 2-yl)-7,8- dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]-3-fluoro-5-(trifluoro methyl)benzamide

359

SUBSTITUTE SHEET (RULE 26) [00881] Step A: To a solution of (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5- fluorophenyl)methanone (1 g, 2.69 mmol) in NMP (10 mL) was added CuCN (0.48 g, 5.38 mmol) and the mixture was stirred at 150 °C under N2 for 1 hour in microwave. The cooled mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC>4 and concentrated in vacuum and the residue was purified by silica gel chromatography (5 g column) using 0 - 30% EtOAc/hexane to afford 5-[(2-chloro-5- fluorophenyl)carbonyl]-6-fluoro-lH-indazole-4-carbonitrile (415 mg, 1.31 mmol, 48%) as a brown solid. LCMS: m/z 318.3 [M + H] ⁺ .

[00882] Step B: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-fluoro-lH- indazole-4-carbonitrile (415 mg, 1.31 mmol) and (2,4-dimethoxyphenyl)methanamine (218 mg, 1.31 mmol) in DMSO (8 mL) was added DIEA (169 mg, 1.31 mmol). The mixture was stirred at 130 °C for 5 hours. The cooled mixture was added into ice water and extracted with EA. The organic phase was dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (3 g column) using 0 - 50% EtOAc/hexane to afford a crude, which was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% gradient in 10 min; detector with UV 254 nm to give 5-[(2-chloro-5- fluorophenyl)carbonyl]-6-{[(2,4-dimethoxyphenyl)methyl]amino }-lH-indazole-4-carbonitrile (40 mg, 0.086 mmol, 6 %) as a red solid. LCMS: m/z 465.1 [M + H] ⁺ .

[00883] Step C: A solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-lH-indazole-4-carbonitrile (40 mg, 0.086 mmol) in TFA (1 mL) was stirred at 20 °C for 30 min. The mixture was concentrated under vacuum to give 6- amino-5-[(2-chloro-5-fluorophenyl)carbonyl]-lH-indazole-4-ca rbonitrile (27 mg, 0.086 mmol, 99%) as a brown solid. LCMS: m/z 315.0 [M + H] ⁺ .

[00884] Step D: To a solution of 6-amino-5-[(2-chloro-5-fluorophenyl)carbonyl]-lH- indazole-4-carbonitrile (27 mg, 0.086 mmol) in CH3CN (2 mL) was added pyridine (20.4 mg, 0.257 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (19.4 mg, 0.086 mmol). The mixture was stirred at 20 °C for 30 min. The mixture was concentrated under vacuum to give a crude, which was purified by prep-TLC (PE/EA=1: 1) to give N-{5-[(2-chloro-5- fluorophenyl)carbonyl]-4-cyano-lH-indazol-6-yl}-3-fluoro-5-( trifluoromethyl)benzamide (20 mg, 0.040 mmol, 46 %) as a brown solid. LCMS: m/z 505.1 [M + H] ⁺ . ^J H NMR (400 MHz, DMSO-d6) 5 14.02 (s, 1H), 10.89 (s, 1H), 8.50 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H),

360

SUBSTITUTE SHEET (RULE 26) 7.77 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.45 (dd, J = 8.8, 4.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 7.27 (td, J = 8.4, 3.2 Hz, 1H).

[00885] Step E: To a solution of N-{5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-lH- indazol-6-yl}-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.040 mmol) in DMA (2 mL) was added CS2CO3 (38.7 mg, 0.119 mmol) and l,l,l-trifhioropropan-2-yl 1, 1,2, 2, 3, 3, 4,4,4- nonafluorobutane-1 -sulfonate (15.7 mg, 0.040 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over JSfeSCU and concentrated in vacuum to give a crude, which was purified by prep-TLC (PE/EA=7:) to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-3-(l,l,l- trifluoroprop-2-yl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-5-y l]-3-fluoro-5-

(trifluoromethyl)benzamide (8 mg, 0.013 mmol, 33 %) as a brown solid. LCMS: m/z 601.2 [M + H] ⁺ . ^! H NMR (400 MHz, DMSO-d6) 8 11.04 (s, 1H), 8.69 (s, 1H), 8.27 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 11.6 Hz, 2H), 7.46 (dd, J = 8.8, 4.8 Hz, 1H), 7.35 (dd, J = 8.8, 3.2 Hz, 1H), 7.28 (td, J = 8.4, 3.2 Hz, 1H), 6.08 (dd, J = 14.0, 7.2 Hz, 1H), 1.84 (d, J = 6.8 Hz, 3H).

[00886] Step F: To a solution ofN-{5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-l-(l,l,l- trifluoroprop-2-yl)indazol-6-yl]-3-fluoro-5-(trifluoromethyl )benzamide (10 mg, 0.017 mmol) in CH3CN (1 mL) and H2O (0.5 mL) was added KOH (2.80 mg, 0.050 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was added water and extracted with EA.

The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-3-(l,l,l-trif luoroprop-2-yl)-7,8-dihydro- 6H-pyrrolo[4,3-e]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)b enzamide (10 mg, 0.016 mmol, 97%) as a brown solid. LCMS: m/z 619 [M + H] ⁺ .

[00887] Step G: To a solution of N-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-3-(l,l,l- trifluoroprop-2-yl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazol-5-y l]-3-fluoro-5-

(trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TEA (1 mL) was added Et3SiH (0.25 mL) and the mixture was stirred at 60 °C for 30 min. The mixture was concentrated under vacuum to give a cmde, which was purified by prep-HPLC to give N-[6-(2-chloro-5- fluorophenyl)-8-oxo-3-(l,l,l-trifluoroprop-2-yl)-7,8-dihydro -6H-pyrrolo[4,3-e]indazol-5-yl]-3- fluoro-5-(trifluoromethyl)benzamide (2 mg, 0.003 mmol, 20 %) as a white solid. LCMS: m/z 603.2 [M + H] ⁺ . ^X H NMR (400 MHz, DMSO-d6) 8 10.72 - 10.55 (m, 1H), 9.29 (s, 1H), 8.57 (s,

361

SUBSTITUTE SHEET (RULE 26) 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.80 - 7.67 (m, 2H), 7.28 (s, 1H), 7.09 (s, 1H), 6.75 - 5.60 (m,

3H), 1.87 - 1.79 (m, 3H).

Example 154 (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl-8-oxo-

3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide

Example 155 (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl-8-oxo-

3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5 -(trifluoromethyl)benzamide

[00888] Step A: To a solution of (2-chloro-5-fluorophenyl)(3,4-diamino-2-bromo-6- nitrophenyl)methanone (1.0 g, 2.57 mmol) in toluene (10 mL) were added 4- methylbenzenesulfonic acid (44.3 mg, 0.257 mmol) and 1,1,1 -tri ethoxy ethane (2.09 mg, 12.8 mmol). The reaction was stirred at 100 °C for 1 hr. The cooled reaction was diluted water,

362

SUBSTITUTE SHEET (RULE 26) extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-50%) to afford compound (4-bromo-2-methyl-6-nitro-lH- benzo[d]imidazol-5-yl)(2-chloro-5-fluorophenyl)methanone (500 mg, 1.21 mmol, 47%) as a yellow oil. LCMS: m/z 411.0 [M- H]".

[00889] Step B: To a solution of (4-bromo-2-methyl-6-nitro-lH-benzo[d]imidazol-5-yl)(5- chloro-2-fluorophenyl)methanone (500 mg, 1.212 mmol) in DMA (10 mL) were added K2CO3 (502 mg, 3.636 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (306 mg, 1.320 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction was diluted water, extracted with EA. The organic layer was washed with brine, dried over ISfeSCL and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in DCM (0%~50%) to afford compound [4-bromo-l-(2,2-difluoroethyl)-2-methyl-6- nitrobenzo[d]imidazol-5-yl](5-chloro-2-fluorophenyl)methanon e (200 mg, 0.420 mmol, 35%) as a yellow solid. LCMS m/z: 478.1[M+H+2] ⁺

[00890] Step C: To a solution of [4-bromo-l-(2,2-difluoroethyl)-2-methyl-6- nitrobenzo[d]imidazol-5-yl](5-chloro-2-fluorophenyl)methanon e (200 mg, 0.420 mmol) in EtOH/H2O (5: 1) (10 mL) were added Fe (117.16 mg, 2.09 mmol) and NH ₄ C1 (112 mg, 2.09 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction mixture was concentrated, diluted water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford crude compound [6-amino-4-bromo-l-(2,2-difluoroethyl)-2- methylbenzo[d]imidazol-5-yl](5-chloro-2-fluorophenyl)methano ne (150 mg, 0.336 mmol, 80%) as a yellow oil. LCMS: m/z 446.1 [M+H] ⁺

[00891] Step D: To a solution of [6-amino-4-bromo-l-(2,2-difluoroethyl)-2- methylbenzo[d]imidazol-5-yl](5-chloro-2-fluorophenyl)methano ne (150 mg, 0.336 mmol) in NMP (3 mL) was added CuCN (60 mg, 0.672 mmol). The reaction mixture was stirred under N2 atmosphere at 150 °C for 1 h under microwave. The cooled reaction was diluted water, extracted with EA The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (l%~10%) to afford compound 6-amino-5-[(5-chloro-2-fluorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-methylbenzo[d]imidazole-4-carbonitrile (80 mg, 0.204 mmol, 61%) as a yellow oil. LCMS: m/z 393.1 [M+H] ⁺

363

SUBSTITUTE SHEET (RULE 26) [00892] Step E: To a solution of 6-amino-5-[(2-chloro-5-fhiorophenyl)carbonyl]-l-(2,2- difluoroethyl)-2-methylbenzo[d]imidazole-4-carbonitrile (200 mg, 0.509 mmol) in ACN (5 mL) and H2O (1.00 mL) was added KOH (142.86 mg, 2.546 mmol). The reaction was stirred at rt for 2 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (l%~60%) to afford compound 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-methyl-7,8- dihydro-6H-imidazo[5,4-e]isoindol-8-one (100 mg, 0.243 mmol, 48%) as a white solid. LCMS: m/z 411.1[M+H] ⁺ .

[00893] Step F: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- 6-hydroxy-2-methyl-7,8-dihydro-6H-imidazo[5,4-e]isoindol-8-o ne (80 mg, 0.195 mmol) in ACN (5 mL) was added Pyridine (0.032 mL, 0.390 mmol) and 5-fluoro-3-(trifluoromethyl)benzoyl chloride (88.24 mg, 0.390 mmol). The reaction was stirred at rt for 3 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (1 %~60%) to afford compound N-[6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-6-hydroxy-2-methyl-8-oxo -7,8-dihydro-6H-imidazo[5,4- e]isoindol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (80 mg, 0.133 mmol, 68%) as a white solid. LCMS: m/z 601.1 [M+H] ⁺ .

[00894] Step G: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-2-methyl-8-oxo-7,8-dihydro-6H-imidazo[5,4-e]isoindol -5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (80 mg, 0.133 mmol) in TEA (5 mL) was added Et3SiH (154.81 mg, 1.331 mmol). The reaction was stirred at 70 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in H2O) to afford compound N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo-3, 6,7,8- tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(trifluoro methyl)benzamide (37 mg, 0.063 mmol, 48%) as a white solid. LCMS: m/z 585.1 [M+H] ⁺ .

[00895] Step H: The N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-methy l-8-oxo- 3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(t rifluoromethyl)benzamide (37 mg, 0.063 mmol) was separated by prep-SFC to afforded:

364

SUBSTITUTE SHEET (RULE 26) [00896] Pl Example 154: (R)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl- 8-oxo-3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluor o-5-(trifluoromethyl)benzamide (11.8 mg, 0.020 mmol, 32%) as a white solid. ^! H NMR (400 MHz, DMSO-d6) 5 10.42 (s, 1H), 8.97 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.79 - 7.68 (m, 3H), 7.31 - 7.25 (m, 1H), 7.13 - 7.03 (m, 1H), 6.65 - 6.31 (m, 1.5H), 6.03 (brs, 1H), 4.96 - 4.74 (m, 2H), 2.66 (s, 3H). LCMS: m/z 585.1 [M+H] ⁺

[00897] P2 Example 155: (S)-N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-2-m ethyl- 8-oxo-3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluor o-5-(trifluoromethyl)benzamide (14.3 mg, 0.024 mmol, 39%) as a white solid. ¹ HNMR(400 MHz, DMSO-d6) 5 10.42 (s, 1H), 8.96 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79 - 7.66 (m, 3H), 7.33 - 7.23 (m, 1H), 7.14 - 7.03 (m, 1H), 6.70 - 6.29 (m, 1.5H), 6.07 (brs, 1H), 4.94 - 4.73 (m, 2H), 2.66 (s, 3H). LCMS: m/z 585.1 [M+H] ⁺

Example 156 (S)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-t rifluoroethyl)- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide Example 157 (R)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-t rifluoroethyl)- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide

365

SUBSTITUTE SHEET (RULE 26)

[00898] Step A: To a solution of 3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-6-[(2,4- dimethoxyphenyl)amino]-lH-indazole-4-carbonitrile (90 mg, 0.185 mmol) in TFA (3 mL) was added EtaSiH (0.5 mL).The reaction was stirred at 50 °C for 1 hr. The cooled reaction was diluted with EA and saturated NaHCOa solution. The organic layer was washed with brine, dried over NaaSO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound 6-amino-3- chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-lH-indazole-4-c arbonitrile (35 mg, 0.100 mmol, 54%) as a yellow solid. LCMS: m/z 349.15 [M + H] ⁺ .

[00899] Step B: To a solution of 6-amino-3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]- lH-indazole-4-carbonitrile (35 mg, 0.100 mmol) in acetonitrile (2 mL) were added 3-fluoro-5- (trifluoromethyl)benzoyl chloride (27.1 mg, 0.120 mmol) and Py (0.024 mL, 0.301 mmol). The reaction was stirred at rt for 4 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over ISfeSCL and concentrated to afford compound N-{3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-4-cyano-l- {[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}indazol-6-yl}-5-fluoro-3-(t rifluoromethyl)benzamide (30 mg, 0.041 mmol, 41%) as a yellow oil. LCMS: m/z 729.34 [M + H] ⁺ .

366

SUBSTITUTE SHEET (RULE 26) [00900] Step C: To a solution of N-{3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-4- cy ano- 1 - { [5 -fluoro-3 -(trifluoromethyl)phenyl] carbonyl } indazol-6-yl } -5 -fluoro-3 - (trifluoromethyl)benzamide (30 mg, 0.041 mmol) in H2O (1 mL) and THF (1 mL) was added NaiCCh (4.36 mg, 0.041 mmol). The reaction was stirred at rt for 2 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over NazSCU and concentrated to afford compound N-{3-chloro-5-[(2-chloro-5- fluorophenyl)carbonyl]-4-cyano-lH-indazol-6-yl}-5-fluoro-3-( trifluoromethyl)benzamide (20 mg, 0.037 mmol, 90%) as a yellow oil. LCMS: m/z 539.24 [M + H] ⁺ .

[00901] Step D: To a solution of N-(3-chloro-5-[(2-chloro-5-fluorophenyl)carbonyl]-4- cyano-lH-indazol-6-yl}-5-fluoro-3-(trifluoromethyl)benzamide (20 mg, 0.037 mmol) in EEO (1 mL) and acetonitrile (3 mL) was added KOH (2.08 mg, 0.037 mmol). The reaction was stirred at rt for 2 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound N-[l-chloro-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-3, 6,7,8- tetrahydropyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3-(trifluorom ethyl)benzamide (15 mg, 0.027 mmol, 73%) as a white solid. LCMS: m/z 557.26 [M + H] ⁺ .

[00902] Step E: To a solution ofN-[l-chloro-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-

3.6.7.8-tetrahydropyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (20 mg, 0.036 mmol) in DMA (2 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (16.7 mg, 0.072 mmol) and CS2CO3 (35.1 mg, 0.108 mmol). The reaction was stirred at 80 °C for 2 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford compound N-[l-chloro-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-3-(2 ,2,2-trifluoroethyl)-

7.8-dihydro-6H-pyrrolo[4,3-e]indazol-5-yl]-5-fluoro-3-(tr ifluoromethyl)benzamide (10 mg, 0.016 mmol, 44%) as a white solid. LCMS: m/z 639.28 [M + H] ⁺ .

[00903] Step F: To a solution ofN-[l-chloro-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo- 3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrrolo[4,3-e]indazo l-5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TEA (2 mL) was added EtgSiH (0.5 mL). The reaction was stirred at 50 °C for 2 hr. The cooled reaction was concentrated in vacuo. The

367

SUBSTITUTE SHEET (RULE 26) residue was purified by prep-HPLC (Cl 8, 0-80 % acetonitrile in H2O) to afford compound N-[l- chloro-6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifluoroe thyl)-7,8-dihydro-6H-pyrrolo[3,4- e]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (6 mg, 0.010 mmol, 62%) as a white solid. LCMS: m/z 623.28 [M + H] ⁺ .

[00904] Step G: N-[l-chloro-6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2-trifl uoroethyl)-7,8- dihydro-6H-pyrrolo[3,4-e]indazol-5-yl]-5-fluoro-3-(trifluoro methyl)benzamide (6 mg, 0.010 mmol) was separated by prep-SFC to give

[00905] Pl: Example 156: (S)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2- trifluoroethyl)-3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl )-3-fluoro-5-

(trifluoromethyl)benzamide (2 mg) as a white solid. LCMS: m/z 623.28 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.66 (s, 1H), 9.30 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.30 (M, 1H), 7.11 (M, 1H), 6.63 (M, 1H), 6.15 (s, 1H), 5.57 (M, 2H). [00906] P2: Example 157: (R)-N-(l-chloro-6-(2-chloro-5-fluorophenyl)-8-oxo-3-(2,2,2- trifluoroethyl)-3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl )-3-fluoro-5-

(trifluoromethyl)benzamide (2 mg) as a white solid. LCMS: m/z 623.28 [M + H] ⁺ . 'H NMR (400 MHz, DMSO-d6) 5 10.66 (s, 1H), 9.30 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.70 (s, 1H), 7.30 (M, 1H), 7.11 (M, 1H), 6.63 (M, 1H), 6.15 (s, 1H), 5.57 (M, 2H).

Example 158 (R)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-t rifluoroethyl)- 3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(t rifluoromethyl)benzamide Example 159 (S)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-t rifluoroethyl)- 3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-yl)-3-fluoro-5-(t rifluoromethyl)benzamide

368

SUBSTITUTE SHEET (RULE 26)

[00907] Step A: To a solution of (2-chloro-5-fluorophenyl)(3,4-diamino-2-bromo-6- nitrophenyl)methanone (1.0 g, 2.57 mmol) in toluene (10 mL) were added 4- methylbenzenesulfonic acid (44.3 mg, 0.257 mmol) and 1,1,1 -tri ethoxy ethane (2.09 mg, 12.8 mmol). The reaction was stirred at 100 °C for 1 hr. The cooled reaction was diluted water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-50%) to afford compound (4-bromo-2-methyl-6-nitro-lH- benzo[d]imidazol-5-yl)(2-chloro-5-fluorophenyl)methanone (500 mg, 1.21 mmol, 47%) as a yellow oil. LCMS: m/z 411.0 [M- H]".

[00908] Step B: To a solution of (4-bromo-2-methyl-6-nitro-lH-benzo[d]imidazol-5-yl)(2- chloro-5-fluorophenyl)methanone (300 mg, QHT1 mmol) in DMA (5 mL) were added K2CO3 (301 mg, 2.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (337 mg, 1.45 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction was diluted water, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in DCM (0%~50%) to afford [4-bromo-2-methyl-6-nitro-l-(2,2,2-trifluoroethyl)benzo[d]im idazol-5- yl](2-chloro-5-fluorophenyl)methanone (250 mg, 0.505 mmol, 70%) as a yellow solid. LCMS m/z: 496.0 [M+H] ⁺ .

369

SUBSTITUTE SHEET (RULE 26) [00909] Step C: To a solution of [4-bromo-2-methyl-6-nitro-l -(2,2,2- trifluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluoropheny l)methanone (250 mg, 0.505 mmol) in EtOH (5 mL) and H2O (1.00 mL) were added Fe (141 mg, 2.52 mmol) and NH4CI (135 mg, 2.53 mmol). The reaction was stirred at 80 °C for 2 hr. The cooled reaction mixture was filtered and concentrated. The residue was diluted with EA and water. The organic layer was separated, washed with brine, dried over NaiSCL and concentrated to afford crude compound [6- amino-4-bromo-2-methyl-l-(2,2,2-trifluoroethyl)benzo[d]imida zol-5-yl](2-chloro-5- fluorophenyl)methanone (111 mg, 0.239 mmol, 47%) as a yellow oil. LCMS: m/z 466.0 [M+H] ⁺ .

[00910] Step D: To a solution of [6-amino-4-bromo-2-methyl-l -(2,2,2- trifluoroethyl)benzo[d]imidazol-5-yl](2-chloro-5-fluoropheny l)methanone (111 mg, 0.239 mmol) in NMP (2 mL) was added CuCN (42.79 mg, 0.478 mmol). The reaction mixture was degassed with N2 and stirred under N2 atmosphere at 150 °C for 1 h. The cooled reaction was diluted with EA and water. The organic layer was separated, washed with further saturated NaCl solution, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (l%~10%) to afford compound 6-amino-5-[(2- chloro-5-fluorophenyl)carbonyl]-2-methyl-l-(2,2,2-trifluoroe thyl)benzo[d]imidazole-4- carbonitrile (60 mg, 0.146 mmol, 61%) as a yellow oil. LCMS: m/z 411.1 [M+H] ⁺

[00911] Step E: To a solution of 6-amino-5-[(2-chloro-5-fluorophenyl)carbonyl]-2-methyl-l- (2,2,2-trifluoroethyl)benzo[d]imidazole-4-carbonitrile (60 mg, 0.146 mmol) in ACN (5 mL) and H2O (1 mL) was added KOH (40.9 mg, 0.730 mmol). The reaction was stirred at rt for 2 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford crude compound 5-amino-6-(2-chloro-5- fluorophenyl)-6-hydroxy-2-methyl-3-(2,2,2-trifluoroethyl)-7, 8-dihydro-6H-imidazo[5,4- e]isoindol-8-one (50 mg, 0.117 mmol, 80%) as a yellow solid. LCMS m/z: 429.1 [M+H] ⁺ .

[00912] Step F: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-3- (2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol -8-one (100 mg, 0.107 mmol) in ACN (5 mL) and pyridine (0.026 mL, 0.322 mmol) was added 3-fluoro-5- (trifluoromethyl)benzoyl chloride (60.7 mg, 0.268 mmol). The reaction was stirred at rt for 3 hr. The reaction mixture was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford N-[6-(2-chloro-5-fluorophenyl)-6-

370

SUBSTITUTE SHEET (RULE 26) hydroxy -2-methyl-8-oxo-3-(2, 2, 2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl ]-3- fluoro-5-(trifluoromethyl)benzamide (100 mg, 0.081 mmol, 75%) as a yellow solid. LCMS m/z: 619.0 [M+H] ⁺ .

[00913] Step G: To a solution ofN-[6-(2-chloro-5-fluorophenyl)-6-hydroxy-2-methyl-8-oxo- 3-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoind ol-5-yl]-3-fluoro-5-

(trifluoromethyl)benzamide (50 mg, 0.081 mmol) in TFA (5 mL) was added EtgSiH (93.9 mg, 0.808 mmol). The reaction was stirred at 70 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluted with ACN in H2O (5%~95%) to afford compound N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoroethyl)-7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]- 3-fluoro-5-

(trifluoromethyl)benzamide (35 mg, 0.046 mmol, 57%) as a yellow solid. LCMS m/z: 603.1 [M+H] ⁺ .

[00914] Step H: The N-[6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2-trifl uoroethyl)- 7,8-dihydro-6H-imidazo[5,4-e]isoindol-5-yl]-3-fluoro-5-(trif luoromethyl)benzamide (35 mg, 0.058 mmol) was separated by prep-SFC to afforded

[00915] Pl Example 158: (R)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoroethyl)-3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-y l)-3-fluoro-5-

(trifluoromethyl)benzamide (5.3 mg, 0.009 mmol, 15%) as a yellow solid. 'H NMR (400 MHz, CD3OD) 8 7.77 (s, 1H), 7.72 - 7.62 (m, 3H), 7.25 (dd, J = 8.8, 5.2 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.47 (brs, 1H), 6.31 (brs, 1H), 5.25 - 5.16 (m, 2H), 2.75 (s, 3H). LCMS m/z: 603.1 [M+H] ⁺ [00916] P2 Example 159: (S)-N-(6-(2-chloro-5-fluorophenyl)-2-methyl-8-oxo-3-(2,2,2- trifluoroethyl)-3,6,7,8-tetrahydroimidazo[4,5-e]isoindol-5-y l)-3-fluoro-5-

(trifluoromethyl)benzamide (8.0 mg, 0.013 mmol, 23%) as a yellow solid. 'H NMR (400 MHz, CD3OD) 8 7.77 (s, 1H), 7.72 - 7.62 (m, 3H), 7.25 (dd, J = 8.8, 5.2 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.47 (brs, 1H), 6.31 (brs, 1H), 5.25 - 5.16 (m, 2H), 2.75 (s, 3H). LCMS m/z: 603.1 [M+H] ⁺

Example 160 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-methy l-8-oxo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

371

SUBSTITUTE SHEET (RULE 26)

[00917] Step A: To a solution ofN-(l-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4 -e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (20 mg, 0.030 mmol) in dioxane (3 mL) and H2O (1 mL) were added K2CO3 (8.30 mg, 0.060 mmol) and Pd(dppf)Cb (2.20 mg, 0.003 mmol). The reaction was stirred at 100 °C under N2 for 2 hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SOi and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford the compound N-(6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-l-methyl-8-oxo-3,6,7,8-tetrahydropy rrolo[3,4-e]indazol-5-yl)-3-fluoro- 5-(trifluoromethyl)benzamide (10 mg, 0.017 mmol, 56 %) as a yellow solid. LCMS: m/z 600.88 [M + H] ⁺ .

[00918] Step B: To a solution of N-[6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-l-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-e]indazol- 5-yl]-5-fluoro-3- (trifluoromethyl)benzamide (10 mg, 0.017 mmol) in TEA (3 mL) was added EtaSiH (0.5 mL). The reaction was stirred at 50 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0~80 % acetonitrile in H2O) to afford the compound N-(6-(2-chloro-5-fluorophenyl)-3-(2, 2-difluoroethyl)-l-methyl-8-oxo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (1.3 mg, 0.002 mmol, 13 %) as a white solid. LCMS: m/z 584.88 [M + H] ⁺ . NMR (400 MHz, CD3OD) 5 7.78 (s, 1H), 7.73 - 7.59 (m, 4H), 7.29 - 7.21 (m, 1H), 7.03 - 6.93 (m, 1H), 6.53 - 6.09 (m, 2H), 4.76 - 4.72 (m, 2H), 2.95 (s, 3H).

Example 161 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-(meth yl-d3)-8-oxo- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzainide

372

SUBSTITUTE SHEET (RULE 26)

[00919] Step A: To a solution ofN-(l-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4 -e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (20 mg, 0.03 mmol) in dioxane (ImL) and H2O (0.1 mL) were added 4,4,5,5-tetramethyl-2-(methyl-d3)-l,3,2-dioxaborolane (8.7 mg, 0.06 mmol), K2CO3 (8.3 mg, 0.06 mmol) and bis[5-(diphenylphosphanyl)cyclopenta-l,3-dienyl]-X2-iron(II) palladium chloride (2.2 mg, 0.003 mmol). The reaction mixture was stirred at 100 °C under N2 for 2 h. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-40% ethyl acetate in petroleum ether to afford compound N-(6- (2-chloro-5-fluorophenyl)-3-(2, 2-difluoroethyl)-6-hydroxy-l-(methyl-d3)-8-oxo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (10 mg, 0.02 mmol, 55%) as a yellow solid. LCMS: m/z 604 [M + H] ⁺ .

[00920] Step B: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-6- hydroxy-l-(methyl-d3)-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4-e] indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (10 mg, 0.02 mmol) in TFA (1 mL) was added EtaSiH (9.6 mg, 0.08 mmol). The reaction mixture was stirred at 70 °C for 1 hour. The cooled mixture was concentrated. The residue was purified using prep-HPLC to afford N-(6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-(methyl-d3)-8-oxo-3,6, 7,8-tetrahydropyrrolo[3,4- e]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1 mg, 0.002 mmol, 10%) as a white solid. LCMS: m/z 588 [M + H] ⁺ . *H NMR (400 MHz, CD3OD) 6 7.78 (s, 1H), 7.74 - 7.58 (m, 3H), 7.26 (dd, J = 8.8, 5.2 Hz, 1H), 6.99 (td, J = 8.4, 3.0 Hz, 1H), 6.63 - 6.01 (m, 3H), 4.81 - 4.76 (m, 2H).

Example 162 N-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l-fluor o-8-oxo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

373

SUBSTITUTE SHEET (RULE 26)

[00921] Step A: To a solution of 3-bromo-2,4-dimethylaniline (15 g, 74.9 mmol) in DCM

(170 mL) were added acetyl chloride (7.90 mL, 112 mmol) and TEA (31.3 mL, 224 mmol). The

374

SUBSTITUTE SHEET (RULE 26) reaction was stirred at 0 °C for 1 hr. LCMS showed the reaction was completed. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in dichloroform (gradient: 40-50%) to afford N-(3-bromo-2,4- dimethylphenyl)acetamide (15 g, 61.9 mmol, 83%) as a yellow solid. LCMS: m/z 242/244 [M- H] ⁺ [00922] Step B: To a solution of N-(3-bromo-2,4-dimethylphenyl)acetamide (18 g, 74.3 mmol) in con.ELSCL (180 mL) were added dropwise con.HNOs (4.36 mL, 104 mmol) at 0 °C . The reaction was stirred at 0 °C under N2 for 2 hrs. LCMS showed the reaction was completed. Pour the solution into ice water, and the solid was obtained by suction filtration to give N-(3- bromo-2,4-dimethyl-5-nitrophenyl)acetamide (18 g, 62.6 mmol, 84%) as a light yellow solid. LCMS: m/z 287/289 [M-H] ⁺ .

[00923] Step C: To a solution of N-(3-bromo-2,4-dimethyl-5-nitrophenyl)acetamide (24 g, 83.5 mmol) in MeOH (200 mL) were added con.HCl (50 mL, 167 mmol). The reaction was stirred at 70 °C for 2 hrs. LCMS showed the reaction was completed. The cool reaction mixture was concentrated, diluted aqueous NaHCCf and extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 15-25%) to afford 3-bromo-2,4-dimethyl-5-nitroaniline (15 g, 61.2 mmol, 73%) as a yellow solid. LCMS: m/z 246/248 [M-H] ⁺ .

[00924] Step D: To a solution of 3 -brom o-2,4-dimethyl-5 -nitroaniline (12 g, 48.9 mmol) in HOAc (100 mL) and H2O (10 mL) was added batchwise sodium nitrite (6.76 g, 97.9 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 hr. LCMS showed the reaction was completed. The reaction mixture was diluted water, extracted with EA The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in di chloroform (gradient: 10-20%) to afford 4-bromo-5-methyl-6-nitro-lH-indazole (4 g, 15.6 mmol, 32%) as a yellow solid. LCMS: m/z 257/259 [M-H] ⁺ .

[00925] Step E: Selectfluor (6.64 g, 18.7 mmol) was added to a solution of 4-bromo-5- methyl-6-nitro-lH-indazole (2.40 g, 9.37 mmol) in ACN (25 mL) and the reaction was heated to 80° C overnight. After cooling, the reaction mixture was poured onto water. The reaction

375

SUBSTITUTE SHEET (RULE 26) mixture was extracted with EA (35 mL). The organic phase was washed with H2O (30 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-10% EA in PE) to afford 4-bromo-3-fluoro-5-methyl-6-nitro- IH-indazole (0.56 g, 2.04 mmol, 21%) as a yellow solid. LCMS: m/z 272.05/274.05[M - H] ⁺ . [00926] Step F: To a solution of 4-bromo-3-fluoro-5-methyl-6-nitro-lH-indazole (0.560 g, 2.04 mmol) in DMA (10 mL) was added CS2CO3 (2.00 g, 6.13 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.35 mL, 10.2 mmol). The reaction mixture was stirred at 80 °C for 1 hr. The reaction mixture was completed and detected by TEC. The cooled reaction mixture was quenched with H2O (15 mL), extracted with EA (25 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-10% EA in PE) to afford 4-bromo-l-(2,2-difluoroethyl)-3- fluoro-5-methyl-6-nitroindazole (580 mg, 1.71 mmol, 83%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 8.56 (d, 1H), 6.58 - 6.28 (m, 1H), 5.01 - 4.89 (m, 2H), 2.48 (s, 3H).

Step G: To a solution of 4-bromo-l-(2,2-difluoroethyl)-3-fluoro-5-methyl-6-nitroindaz ole (700 mg, 2.07 mmol) in CCU (15 mL) was added NBS (442 mg, 2.48 mmol) and BPO (50.1 mg, 0.207 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was completed and detected by TLC. The reaction mixture was dissolved in EA (25 mL), washed with H2O (15 mL) and brine, dried over sodium sulfate and concentrated to afford 4-bromo-5 -(bromomethyl)- 1- (2,2-difluoroethyl)-3-fluoro-6-nitroindazole (700 mg, 1.67 mmol, 81%) as a yellow solid. No MS.

[00927] Step H: NMO (589 mg, 5.03 mmol) was added to a solution of 4-bromo-5- (bromomethyl)-l-(2,2-difluoroethyl)-3-fluoro-6-nitroindazole (700 mg, 1.67 mmol) in ACN (10 mL) and the reaction was heated to 60 °C for 1 hr. After cooling, the reaction mixture was poured onto water, extracted with EA (20 mL). The organic phase was washed with H2O (10 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-10% EA in PE) to afford 4-bromo-l-(2,2-difluoroethyl)-3- fluoro-6-nitro-lH-indazole-5-carbaldehyde (250 mg, 0.0910 mmol, 19%) as a yellow solid. LCMS: m/z 352.07 [M + H] ⁺ .

[00928] Step I: To a solution of 4-bromo-l-(2,2-difluoroethyl)-3-fluoro-6-nitroindazole-5- carbaldehyde (580 mg, 1.64 mmol) in THE (10 mL) was added (2-chloro-5- fluorophenyl)magnesium bromide (1.00 mL, 0.0570 mmol) at 0 °C. The reaction mixture was

376

SUBSTITUTE SHEET (RULE 26) stirred at 0 °C under N2 for 1 hr. The reaction was completed and detected by TLC. The reaction mixture was dissolved in EA (20 mL), washed with H2O (15 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-10% EA in PE) to afford (4-bromo-l-(2,2-difluoroethyl)-3-fluoro-6-nitro-lH-indazol-5 -yl)(2- chloro-5-fluorophenyl)methanol (700 mg, 1.45 mmol, 88%) as a yellow solid. LCMS: m/z 482.61 [M+H] ⁺ . !HNMR (400 MHz, DMSO-d6) 5 8.48 (s, 1H), 7.52 (dd, J = 8.8, 5.2 Hz, 1H), 7.24 (td, J = 8.4, 3.2 Hz, 1H), 7.08 (dd, J = 9.8, 3.2 Hz, 1H), 6.84 (d, J = 5.6 Hz, 1H), 6.60 (s, 1H), 6.44 (t, J = 3.2 Hz, 1H), 6.40 (d, J = 5.6 Hz, 1H), 6.32 (s, 1H), 4.96 (m, 2H).

[00929] Step J: To a solution of (4-bromo-l-(2,2-difluoroethyl)-3-fluoro-6-nitro-lH-indazol- 5-yl)(2-chloro-5-fluorophenyl)methanol (700 mg, 1.45 mmol) in DCM (10 mL) was added Dess- Martin (1.23 g, 2.90 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hr. The reaction was completed and detected by TLC. The reaction mixture was quenched with H2O (20 mL), extracted with DCM (20 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-10% EA in PE) to afford (4-bromo-l-(2,2-difluoroethyl)-3-fluoro-6-nitro-lH- indazol-5-yl)(2-chloro-5-fluorophenyl)methanone (650 mg, 1.35 mmol, 93%) as a yellow solid. LCMS: m/z 480.6 [M + H] ⁺ .

[00930] Step K: To a solution of (4-bromo-l-(2,2-difluoroethyl)-3-fluoro-6-nitro-lH-indazol- 5-yl)(2-chloro-5-fluorophenyl)methanone (680 mg, 1.41 mmol) in EtOH (6.00 mL) and H2O (2 mL) was added NH4CI (227 mg, 4.24 mmol) and Fe (790 mg, 14. Immol). The reaction mixture was stirred at 80 °C under N2 for Ihr. The reaction was completed and detected by TLC. The cooled reaction mixture was filtered, concentrated and extracted with EA (15 mL). The organic phase was washed with H2O (15 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-20% EA in PE) to afford (6- amino-4-bromo- 1 -(2,2-difluoroethyl)-3 -fluoro- 1 H-indazol-5 -y 1) (2 -chi oro-5 - fluorophenyl)methanone (330 mg, 0.732 mmol, 51%) as a yellow solid. LCMS: m/z 450.62 [M + H] ⁺ .

[00931] Step L: To a solution of (6-amino-4-bromo-l-(2,2-difluoroethyl)-3-fluoro-lH- indazol-5-yl)(2-chloro-5-fluorophenyl)methanone (330 mg, 0.732 mmol) in DMA (5 mL) was added Zn(CN)2 (171 mg, 1.46 mmol) and Pd(PPhs)4 (169 mg, 0.146 mmol). The reaction mixture was stirred at 150 °C under N2 for 3 hr. The reaction was completed and detected by

377

SUBSTITUTE SHEET (RULE 26) LCMS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with and brine, dried over sodium sulfate and concentrated to afford 6-amino- 5-(2-chloro-5-fluorobenzoyl)-l-(2,2-difluoroethyl)-3-fluoro- lH-indazole-4-carbonitrile (200 mg, 0.504 mmol, 68%) as a yellow solid. LCMS: m/z 396.73 [M + H] ⁺ .

[00932] Step M: To a solution of 6-amino-5-(2-chloro-5-fluorobenzoyl)-l-(2,2- difluoroethyl)-3-fluoro-lH-indazole-4-carbonitrile (200 mg, 0.504 mmol) in ACN (4.00 mL) and H2O (0.8 mL) was added KOH (84.8 mg, 1.51 mmol). The reaction mixture was stirred at room temperature for 0.5 hr. The reaction mixture was completed and detected by LCMS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with and brine, dried over sodium sulfate and concentrated to afford 5-amino-6-(2-chloro-5-fluorophenyl)-3- (2,2-difluoroethyl)-l-fluoro-6-hydroxy-6,7-dihydropyrrolo[3, 4-e]indazol-8(3H)-one (180 mg, 0.434 mmol, 86%) as a brown solid. LCMS: m/z 414.74 [M + H] ⁺ .

[00933] Step N: To a solution of 5-amino-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)- l-fluoro-6-hydroxy-6,7-dihydropyrrolo[3,4-e]indazol-8(3H)-on e (180 mg, 0.434 mmol) in ACN (3 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (294 mg, 1.30 mmol) and Py (0.105 mL, 1.30 mmol). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was completed and detected by LCMS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue purified by silica gel chromatography (eluting with 0-100% EA in PE) to afford N-(6-(2-chloro-5-fhiorophenyl)-3-(2,2-difluoroethyl)-l-fluor o-6-hydroxy-8-oxo- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (120 mg, 0.198 mmol, 45%) as a pink solid. LCMS: m/z 604.84 [M+H] ⁺ .

[00934] Step O: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl)-l- fluoro-6-hydroxy-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4-e]indaz ol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (60.0 mg, 0.0990 mmol) in TFA (2 mL) was added EtsSiH (0.400 mL). The reaction mixture was stirred at 70 °C for 1 hr. The reaction mixture was completed and detected by LCMS. The cooled reaction mixture was concentrated. The residue purified by prep- HPLC (C18, 30 - 95 % ACN in H2O with 0.1 % TFA) to afford N-(6-(2-chloro-5- fluorophenyl)-3-(2,2-difluoroethyl)-l-fluoro-8-oxo-3,6,7,8-t etrahydropyrrolo[3,4-e]indazol-5- yl)-3-fluoro-5-(trifluoromethyl)benzamide (40.5 mg, 0.0690 mmol, 69%) as a white solid.

LCMS: m/z 588.84 [M+H] ⁺ . ^! HNMR (400 MHz, DMSO-d6) 5 10.64 (s, 1H), 9.32 (s, 1H), 8.01

378

SUBSTITUTE SHEET (RULE 26) - 7.91 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.12 (t, J = 6.8 Hz, 1H), 6.62 - 6.29 (m, 2H), 6.16 (brs, 1H), 5.01 - 4.84 (m, 2H).

Example 163 N-(6-(2-chloro-5-fluorophenyl)-l-cyano-3-(2,2-difluoroethyl) -8-oxo-3, 6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide

[00935] Step A: To a solution of (4-bromo-6-fluoro-lH-indazol-5-yl)(2-chloro-5- fluorophenyl)methanone (4 g, 10.8 mmol) in NMP (10 mL) was added CuCN (1.93 g, 21.5 mmol). The reaction mixture was stirred at 120 °C under N2 for 2 hours. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford compound 5-(2-chloro-5-

379

SUBSTITUTE SHEET (RULE 26) fluorobenzoyl)-6-fluoro-lH-indazole-4-carbonitrile (1.7 g, 5.35 mmol, 50%) as a yellow solid. LCMS: m/z 318 [M + H] ⁺ .

[00936] Step B: To a solution of 5-(2-chloro-5-fluorobenzoyl)-6-fluoro-lH-indazole-4- carbonitrile (1.7 g, 5.35 mmol) in DMF (20 mL) was added NBS (1.9 g, 10.7 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with FLO, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0- 30% ethyl acetate in petroleum ether to afford compound 3-bromo-5-(2-chloro-5-fluorobenzoyl)- 6-fhioro-lH-indazole-4-carbonitrile (1.9 g, 4.8 mmol, 90%) as a yellow solid. LCMS: m/z 396 [M + H] ⁺ .

[00937] Step C: To a solution of 3-bromo-5-(2-chloro-5-fluorobenzoyl)-6-fluoro-lH- indazole-4-carbonitrile (500 mg, 1.2 mmol) in DMSO (10 mL) was added DIEA (490 mg, 3.6 mmol) and (2,4-dimethoxyphenyl)methanamine (400 mg, 2.4 mmol). The reaction mixture was stirred at 120 °C overnight. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford compound 3-bromo-5-(2-chloro-5-fluorobenzoyl)-6-((3,4- dimethylbenzyl)amino)-lH-indazole-4-carbonitrile (170 mg, 0.31 mmol, 25%) as a yellow solid. LCMS: m/z 511 [M + H] ⁺ .

[00938] Step D: A solution of 3-bromo-5-(2-chloro-5-fluorobenzoyl)-6-((3,4- dimethylbenzyl)amino)-lH-indazole-4-carbonitrile (170 mg, 0.31 mmol) in TFA (5 mL) was stirred at 50 °C for 1 hour. The mixture was concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford compound 6-amino-3-bromo-5-(2-chloro-5-fluorobenzoyl)-lH-indazole-4- carbonitrile (90 mg, 0.23 mmol, 73%) as a yellow solid. LCMS: m/z 393 [M + H] ⁺ .

[00939] Step E: To a solution of 6-amino-3-bromo-5-(2-chloro-5-fluorobenzoyl)-lH- indazole-4-carbonitrile (90 mg, 0.23 mmol) in CH3CN (3 mL) was added pyridine (0.2 mL, 2.9 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (156 mg, 0.69 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O, extracted with EA The organic layer was washed with brine, dried over ISfeSCL and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in

380

SUBSTITUTE SHEET (RULE 26) petroleum ether to afford compound N-(3-bromo-5-(2-chloro-5-fluorobenzoyl)-4-cyano-l-(3- fluoro-5-(trifluoromethyl)benzoyl)-lH-indazol-6-yl)-3-fluoro -5-(trifluoromethyl)benzamide (70 mg, 0.09 mmol, 40%) as a yellow solid. LCMS: m/z 773 [M + H] ⁺ .

[00940] Step F: To a solution of N-(3-bromo-5-(2-chloro-5-fluorobenzoyl)-4-cyano-l-(3- fluoro-5-(trifluoromethyl)benzoyl)-lH-indazol-6-yl)-3-fluoro -5-(trifluoromethyl)benzamide (70 mg, 0.09 mmol) in CH3CN (3 mL) and H2O (0.5 mL) was added KOH (15 mg, 0.27 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0- 30% ethyl acetate in petroleum ether to afford compound N-(l-bromo-6-(2-chloro-5- fluorophenyl)-6-hydroxy-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4- e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (50 mg, 0.08 mmol, 92%) as a yellow solid. LCMS: m/z 601 [M + H] ⁺ [00941] Step G: To a solution ofN-(l-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (50 mg, 0.08 mmol) in DMA (3 mL) was added CS2CO3 (82 mg, 0.25 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (54 mg, 0.25 mmol). The reaction mixture was stirred at 80 °C under N2 for 1 hour. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford compound N-(l-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2-difluoroethyl) -6-hydroxy-8-oxo- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (18 mg, 0.027 mmol, 33%) as a yellow solid. LCMS: m/z 665 [M + H] ⁺ .

[00942] Step H: To a solution ofN-(l-bromo-6-(2-chloro-5-fluorophenyl)-3-(2,2- difluoroethyl)-6-hydroxy-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4 -e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (15 mg, 0.023 mmol) in NMP (2 mL) was added CuCN (6 mg, 0.068 mmol). The reaction mixture was stirred at 150 °C for 4 hours. The cooled mixture was diluted with H2O, extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated to afford N-(6-(2-chloro-5-fluorophenyl)-l-cyano-3-(2,2-difluoroethyl) -6-hydroxy- 8-oxo-3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro -5-(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 73%) as a yellow solid. LCMS: m/z 612 [M + H] ⁺

381

SUBSTITUTE SHEET (RULE 26) [00943] Step I: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-l-cyano-3-(2,2- difluoroethyl)-6-hydroxy-8-oxo-3,6,7,8-tetrahydropyrrolo[3,4 -e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (1 mL) was added EtgSiH (9.5 mg, 0.08 mmol). The reaction mixture was stirred at 70 °C for 1 hour. The cooled mixture was concentrated under vacuum. The residue was purified using prep-HPLC to afford compound N- (6-(2-chloro-5-fluorophenyl)-l-cyano-3-(2,2-difluoroethyl)-8 -oxo-3,6,7,8-tetrahydropyrrolo[3,4- e]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1.1 mg, 0.002 mmol, 12%) as a yellow solid. LCMS: m/z 596 [M + H] ⁺ . 'H NMR (400 MHz, CD ₃ OD) 5 8.05 (s, 1H), 7.74 - 7.61 (m, 3H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.01 (td, J = 8.4, 2.8 Hz, 1H), 6.63 - 6.18 (m, 3H), 5.14 - 5.05 (m, 2H).

Example 164 N-(6-(2-chloro-5-fluorophenyl)-l-methyl-8-oxo-3-(2,2,2-trifl uoroethyl)-

3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide

[00944] Step A: To a solution of N-(l-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo- 3,6,7,8-tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(tr ifluoromethyl)benzamide (40 mg, 0.066 mmol) in DMA (2 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (30.9

382

SUBSTITUTE SHEET (RULE 26) mg, 0.133 mmol) and CS2CO3 (65.0 mg, 0.199 mmol). The reaction was stirred at 80 °C for 2 hr. The reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2 SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford N-(l- bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo-3-(2,2,2-t rifluoroethyl)-3,6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (40 mg, 0.059 mmol, 88%) as a yellow solid. LCMS: m/z 683.74 [M + H] ⁺ .

[00945] Step B: To a solution of N-(l-bromo-6-(2-chloro-5-fluorophenyl)-6-hydroxy-8-oxo- 3-(2,2,2-trifluoroethyl)-3,6,7,8-tetrahydropyrrolo[3,4-e]ind azol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (20 mg, 0.029 mmol) in dioxane (3 mL) and H2O (1 mL) were added K2CO3 (8.08 mg, 0.059 mmol) and Pd(dppf)Ch (2.14 mg, 0.003 mmol). The reaction was stirred at 100 °C under N2 for 2 hr. The cooled reaction was diluted with water, extracted with EA. The organic layer was washed with brine, dried over Na2SOi and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford N-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-8-oxo-3- (2,2,2-trifluoroethyl)-3,6,7,8-tetrahydropyrrolo[3,4-e]indaz ol-5-yl)-3-fluoro-5-

(trifluoromethyl)benzamide (10 mg, 0.016 mmol, 55%) as a yellow solid. LCMS: m/z 618.87 [M + H] ⁺ .

[00946] Step C: To a solution ofN-(6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-8-oxo- 3-(2,2,2-trifluoroethyl)-3,6,7,8-tetrahydropyrrolo[3,4-e]ind azol-5-yl)-3-fluoro-5- (trifluoromethyl)benzamide (10 mg, 0.016 mmol) in TFA (3 mL) was added EtgSiH (0.5 mL). The reaction was stirred at 50 °C for 2 hr. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC (Cl 8, 0-80 % acetonitrile in H2O ) to afford compound N- (6-(2-chloro-5-fluorophenyl)-l-methyl-8-oxo-3-(2,2,2-trifluo roethyl)-3,6,7,8- tetrahydropyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluorom ethyl)benzamide (2.2 mg, 0.004 mmol, 22%) as a white solid. LCMS: m/z 602.87 [M + H] ⁺ . ^NMR (400 MHz, CD3OD) 5 7.81

(s, 1H), 7.74 - 7.56 (m, 3H), 7.32 - 7.18 (m, 1H), 7.06 - 6.93 (m, 1H), 6.38 (hrs, 2H), 5.26 - 5.13 (m, 2H), 2.95 (s, 3H).

Table 2. Biochemical Potency for Exemplary Compounds

383

SUBSTITUTE SHEET (RULE 26)

384

SUBSTITUTE SHEET (RULE 26)

385

SUBSTITUTE SHEET (RULE 26)

386

SUBSTITUTE SHEET (RULE 26)

387

SUBSTITUTE SHEET (RULE 26)

388

SUBSTITUTE SHEET (RULE 26)

389

SUBSTITUTE SHEET (RULE 26)

PI3Ka enzymatic ADP-Glo assay

[00947] All the compounds were initially prepared as 10 mM stock solution in 100% DMSO. The stock solution was then serially diluted 3-fold in 100% DMSO to 10 concentrations. 50 nL of each compound dilution was subsequently added to 384-well plate in duplicate. To each well, 2.5 pL of enzyme solution containing PI3Ka protein (PI3Ka WT, H1047R, E542K, E545K) with final concentrations 0.15 pg/ml for WT, 0.05 pg/ml for PI3Ka H1047R, 0.07 pg/ml for PI3Ka E542K, and 0.07 pg/ml for PI3Ka E545K, respectively in 1 x Kinase buffer (50 mM HEPES pH 7.5, 3 mM MgCb, 2 mM DTT and 0.03% CHAPS, WOmM NaCl, ImM EGTA). For negative control, 2.5 uL of assay buffer was added instead. The mixture was incubated at room temperature for 10 min. 2.5 pL of substrate solution containing PIP2 peptide (final concentrations 50 pg/ml) and ATP (final concentration 25 pM for WT and H1047R, 68 pM and 100 pM for E542K and E545K, respectively) in 1 x Kinase buffer was added into each well to initiate each reaction. All the reactions were incubated at room temperature for 60 min. Then 5 pL of ADP-Glo reagent 1 was subsequently added to stop the reactions. After equilibrating for 120 min at room temperature, 10 pL ADP-Glo reagent 2 was added to each well, followed by shaking for 1 min and equilibrating for 30 min at room temperature. All the samples were then subjected to analysis using Envision to read luminescence RLU values. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.

[00948] Results of the ADP-Glo Biochemical PI3Ka enzymatic assays using PI3Ka H1047R, E545K, E542K and WT enzymes are presented in Table 2. Compounds having an IC50 less than or equal to 200 nM are represented as “A”; Compounds having an IC50 greater than 200 nM but less than or equal to 1 uM are represented as “B”; Compounds having an IC50 greater than 1 uM but less than 10 uM are represented as “C”; Compounds having an IC50 greater than or equal to 10 uM are represented as “D”

Table 3 Cellular Potency of Exemplary Compounds

390

SUBSTITUTE SHEET (RULE 26)

391

SUBSTITUTE SHEET (RULE 26)

392

SUBSTITUTE SHEET (RULE 26)

393

SUBSTITUTE SHEET (RULE 26)

394

SUBSTITUTE SHEET (RULE 26)

395

SUBSTITUTE SHEET (RULE 26)

396

SUBSTITUTE SHEET (RULE 26)

HIRE PHOSPHO-AKT (SER473) Assay

[00949] HCC1954 cells (American Type Culture Collection) are maintained by culturing in the medium recommended by the provider. To each well of a flat-bottom 384-well plate, 10,000 cells were added in a volume of 35 pL of culture medium. Cells were allowed to recover overnight. On the following day, the plated cells were treated with 9 concentrations of compounds in 3-fold serial dilution or with DMSO. Compounds were prepared as 10 mM DMSO stock solution, and 100 pL of the diluted compounds were added to the cells, with a final concentration of 0.1% DMSO. Cells were treated for 2 h and the culture medium was removed by aspiration. To each well, 20 pL of lysis buffer were added (Perkin Elmer phospho- AKT Ser473 kit) and the plates were incubated for 30 minutes at room temperature. AKT phosphorylation at Ser473 was detected using a pair of donor and acceptor antibodies specific for the total and phosphorylated protein provided in the assay kit. A pre-mixed antibody solution was added to each well of cell lysate and the plates were incubated at room temperature for 16h. Fluorescence emission by the two antibodies was measured at 665 and 620 nm in a plate reader. Data analysis:

[00950] Calculate the ratio of the acceptor and donor emission signals for each individual well.

Cell Proliferation Assay

[00951] Cancer cells were grown in culture media according to vendors’ instructions. Cells were plated in clear bottom tissue culture treated 96-well plates at a density of 1250-5000 cells/well in a volume of 100 pL and allowed to recover overnight. The edge wells were filled with cell culture media only. The plated cells were treated with a 3-fold 9-point serial dilution doses of test compounds, or DMSO control. Compounds were prepared as 10 mM DMSO stock solution and added to the cells with a HP D300 digital dispenser. The top final concentration varied from 10 to 1 pM depending on the potency of the compounds, with the final concentration

397

SUBSTITUTE SHEET (RULE 26) of DMSO to be 0.1%. Following 7 days of drug treatment, 100 pF of CellTiter-Glo (CIG) (Promega, G7570) reagent was added to the cells using a Multidrop Combi instrument and the plates were placed on an orbital shaker for 15 minutes. The luminescence signal was read on an Envision plate reader with a measurement time of 0.1 s.

[00952] Cell proliferation percent inhibition values were calculated using the following equation:

Inhibition% — [l-(T168compound-T168blank)/(T168DMSO- T168blank)] ^x 100%.

T168 _C ompounci: the signals from compound-treated wells;

T168biank: the signals from blank wells;

T 168DMSO: the signals from 0.1%DMSO-treated wells.

[00953] XLfit software (Fit model: Dose response one site/ 205 [fit = (A+((B-A)/(I+((C/X) ^A D))))] ) was used for curve fitting and ICso calculation.

[00954] Results of the HTRF pAKT assay on HCC1954 cell line and CIG cell proliferation assay on NCI-H1048 cell line are presented in Table 3. Compounds having an ICso less than or equal to 500 nM are represented as “A”; Compounds having an ICso greater than 500 nM but less than or equal to 1 uM are represented as “B”; Compounds having an ICso greater than 1 uM but less than 10 uM are represented as “C”; Compounds having an ICso greater than or equal to 10 uM are represented as “D”

[00955] Although the present invention has been described in detail with preferred embodiments, those of ordinary skill in the art should understand that modifications, variations, and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.

[00956] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

398

SUBSTITUTE SHEET (RULE 26) [00957] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[00958] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

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

Incorporation by Reference

[00959] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

Equivalents

[00960] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature

399

SUBSTITUTE SHEET (RULE 26) included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

400

SUBSTITUTE SHEET (RULE 26)