Tricyclic aryl derivatives, and compositions and methods thereof

Abstract

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

Description

TRICYCLIC ARYL DERIVATIVES, AND COMPOSITIONS AND METHODSTHEREOFPriority 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—1SUBSTITUTE 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 / or2SUBSTITUTE 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, whereinRing A is a 5- or 6-membered aromatic ring, substituted with 0-6 Ras;R1is ZB-RB;R2is Zc-Rc;V is C or N;W is C or N;X is N, CH or CRX;Rxis Zx-Rx; each of ZB, Zcand Zxis 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 RBand Rcindependently 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 Rb, Rcor Rx, respectivelyRxis deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, - S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(0)NRR’, -C(O)N(R)OR, -OC(O)R, -3SUBSTITUTE 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)2NRR’, or -N(R)S(O)2R; each of Ra, Rb, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)N(R)OR, -OC(O)R, - OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, -N(R)C(NR)NRR’, - N(R)S(O)2NRR’ or -N(R)S(O)2R; or an optionally substituted group selected from Ci-6 alkyl or 4- to 6-membered carbocyclic ring, provided that at least one Rais 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.4SUBSTITUTE 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.5SUBSTITUTE 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 is6SUBSTITUTE 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 exemplary7compounds 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 functional7SUBSTITUTE 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, -CH2CN, -O-Ci-Ce alkyl, Ci-C6alkyl, -OCi-C6alkenyl, -OCi-C6alkynyl, -Ci-C6alkenyl, -Ci-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi- C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -NHC(O)CI-C6alkyl, -C(O)NHCI-C6alkyl, - S(O)2-C1-C6alkyl, -S(O)NHCI-C6alkyl, and S(O)N(CI-C6alkyl)2.

[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,8SUBSTITUTE 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 of9SUBSTITUTE 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 pH10SUBSTITUTE 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.11SUBSTITUTE 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 greater12SUBSTITUTE 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.13SUBSTITUTE 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(Rx)3 , -ORX, -SRX, -OC(O)-RX, -N(RX)2, - C(O)RX, -C(O)ORX, -OC(O)N(RX)2, -C(O)N(RX)2, -N(RX)C(O)ORX, -N(RX)C(O)RX, - N(RX)C(O)N(RX)2, -N(RX)C(NRX)N(RX)2, -N(RX)S(O)IN(RX)2(where t is 1 or 2), -P(=O)(RX)(RX), or -O-P(=O)(ORX)2wherein each Rxis independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl,14SUBSTITUTE 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-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi- Cealkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -S(O)2-Ci-C6alkyl, -S(O)NHCi-C6alkyl, and S(O)N(Ci-Ce alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthal enyl, and 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,15SUBSTITUTE 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 groups16SUBSTITUTE 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(Ra)3 , -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tN(Ra)2(where t is 1 or 2), - P(=O)(Ra)(Ra), or -O-P(=O)(ORa)2where each Rais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[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 of17SUBSTITUTE 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 and18SUBSTITUTE 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, whereinRing A is a 5- or 6-membered aromatic ring, substituted with 0-6 Ras;R1is ZB-RB;R2is Zc-Rc;V is C or N;W is C or N;X is N, CH or CRX;Rxis Zx-Rx; each of ZB, Zcand Zxis 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 RBand Rcindependently 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 Rb, Rcor Rx, respectivelyRxis deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, - S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(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)2NRR’, or -N(R)S(O)2R;19SUBSTITUTE SHEET (RULE 26)each of Ra, Rb, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, -S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)N(R)OR, -OC(O)R, - OC(O)NRR’, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NRR’, -N(R)C(NR)NRR’, - N(R)S(O)2NRR’ or -N(R)S(O)2R; or an optionally substituted group selected from C1-6 alkyl or 4- to 6-membered carbocyclic ring, provided that at least one Rais 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 Ras, having the structural formula (Ia):wherein each of Y1, Y2and Y3is independently CH, N, NH, 0, S or C(O), provided that at least one of Y1, Y2and Y3is not N orNH and at least one of Y1, Y2and Y3is C or CH.

[0063] In certain embodiments of (I), Ring A is a 6-membered aromatic ring, substituted with 1-4 Ras, having the structural formula (lb):20SUBSTITUTE SHEET (RULE 26)wherein each of Y1, Y2, Y3and Y4is independently CH, N, NH, O, S or C(O), provided that at least two of Y1, Y2, Y3and Y4is not N or NH and at least two of Y1, Y2, Y3and Y4is C or CH.

[0064] In certain embodiments of (I)-(Ib), RBis 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 Rb’s; and Rcis 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 Rc’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), ZBis NH-C(O) and Zcis a single bond, having the structural formula (Id):

[0066] In certain embodiments of (I)-(Ic), ZBis C(O)-NH and Zcis a single bond, having the structural formula (Ie):21SUBSTITUTE 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)-(Ie), 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 Y1and Y2is NH, optionally substituted with Ra.

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

[0073] In certain embodiments, Y1and Y2is NH.

[0074] In certain embodiments of (I)-(Ie), Ring A is selected from:wherein22SUBSTITUTE SHEET (RULE 26)Rais H, optionally substituted Ci-6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; andRais 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, NRSO2R’3, 4- to 6-membered carbocyclic or heterocyclic, provided that for at least one of Raand Rais not H.

[0075] In certain embodiments, Rais selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C2H5, CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH3, CH(OH)CF3, CH2OH, CH2CN, CH2NH2, CH2N(CH3)2, CH2OCHF2, CH2OCF3, NHCH3, isopropyl, cyclopropyl, CCH, CHCH2, CH2-azetidine, CN, OCHF2, SO2CH3, NHSO2CH3, CH2- cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0076] In certain embodiments, Rais CH2CH2F, CH2CHF2, CH2CF3, CH2-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:whereinRais H, Cl, F, CN, CH3or CD3; andRais H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3and CH2CN, provided that for each structure at least one of Raand Rais not H.

[0079] In certain embodiments, Rais CH2CHF2or CH2CF3.

[0080] In certain embodiments, Rais H.

[0081] In certain embodiments, Rais Cl, F, CN, CH3or CD3.

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

[0083] In certain embodiments of (I)-(Ie), Ring A is selected from:23SUBSTITUTE SHEET (RULE 26)

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

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

[0086] In certain embodiments, each of Y1and Y2is CH.

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

[0088] In certain embodiments of (I)-(Ie), Rais not H.

[0089] In certain embodiments of (I)-(Ie), Ring A is selected from:24SUBSTITUTE 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:25SUBSTITUTE SHEET (RULE 26)

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

[0094] In certain embodiments of (I)-(Ie), X is CRX.

[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.26SUBSTITUTE 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.

[0100] Non-limiting examples of Ring B include:

[0101] In certain embodiments of (I)-(Ie), Ring B is selected from:27SUBSTITUTE SHEET (RULE 26)

[0102] In certain embodiments of (I)-(Ie), Ring B is selected from:

[0103] In certain embodiments of (I)-(Ie), Ring B is selected from:

[0104] In certain embodiments, Ring B is:

[0105] In certain embodiments of (I)-(Ie), Ring B is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

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

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

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

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

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

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

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

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

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

[0115] In certain embodiments of (I)-(Ie), each of Ring B and Ring C is independently a substituted or unsubstituted phenyl.

[0116] Non-limiting examples of Ring C include:28SUBSTITUTE SHEET (RULE 26)

[0117] In certain embodiments, Ring C is:

[0118] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (If):wherein at least one Rais selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN.

[0119] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ig):29SUBSTITUTE SHEET (RULE 26)

[0120] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ig’):wherein Ring A is selected from:

[0121] In certain embodiments, Ring A is selected from:30SUBSTITUTE SHEET (RULE 26)whereinRais H, optionally substituted Ci-6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; andRais 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 Raand Rais not H.

[0122] In certain embodiments, Ring A is:

[0123] In certain embodiments, Rais selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C2H5, CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH3, CH(OH)CF3, CH2OH, CH2CN, CH2NH2, CH2N(CH3)2, CH2OCHF2, CH2OCF3, NHCH3, isopropyl, cyclopropyl, CCH, CHCH2, CH2-azetidine, CN, OCHF2, SO2CH3, NHSO2CH3, CH2- cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0124] In certain embodiments, Rais CH2CH2F, CH2CHF2, CH2CF3, QT-cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0125] In certain embodiments, Ring A is selected from:whereinRais H, Cl, F, CN, CH3or CD3; andRais H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN, provided that for each structure at least one of Raand Rais not H.31SUBSTITUTE SHEET (RULE 26)

[0126] In certain embodiments, Ring A is

[0127] In certain embodiments, Ring A is:

[0128] In certain embodiments, Rais selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN. In certain embodiments, Rais CH2CHF2 or CH2CF3.

[0129] In certain embodiments, Rais H. In certain embodiments, Rais Cl, F, CN, CHs andCDs.

[0130] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ih):

[0131] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (1):32SUBSTITUTE SHEET (RULE 26)

[0132] In certain embodiments, a compound of the invention exhibits the following chirality in R1:

[0133] In certain embodiments, a compound of the invention exhibits the following chirality in R1:

[0134] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ij):33SUBSTITUTE SHEET (RULE 26)

[0135] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ik):

[0136] In certain embodiments, X is CH.

[0137] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula Ik’:wherein Ring A is selected from:34SUBSTITUTE SHEET (RULE 26)

[0138] In certain embodiments, Ring A is selected from:whereinRais H, optionally substituted Ci-6 alkyl, or an optionally substituted 4- to 6-membered carbocyclic ring; andRais 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 Raand Rais not H.

[0139] In certain embodiments, Ring A is:

[0140] In certain embodiments, Rais selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C2H5, CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH3, CH(OH)CF3, CH2OH, CH2CN, CH2NH2, CH2N(CH3)2, CH2OCHF2, CH2OCF3, NHCHs, isopropyl, cyclopropyl, CCH, CHCH2, CH2-azetidine, CN, OCHF2, SO2CH3, NHSO2CH3, CH2- cyclopropyl, difluoro-propyl and trifluoro-propyl.

[0141] In certain embodiments, Rais CH2CH2F, CH2CHF2, CH2CF3, QT-cyclopropyl, difluoro-propyl and trifluoro-propyl.35SUBSTITUTE SHEET (RULE 26)

[0142] In certain embodiments, Ring A is selected from:whereinRais H, Cl, F, CN, CH3or CD3; andRa’ is H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN, provided that for each structure at least one of Raand Rais not H.

[0143] In certain embodiments, Ring A is

[0144] In certain embodiments, Ring A is:

[0145] In certain embodiments, Rais selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN In certain embodiments, Rais CH2CHF2 or CH2CF3.

[0146] In certain embodiments, Rais H. In certain embodiments, Rais Cl, F, CN, CH3 andCD3.

[0147] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Ii):36SUBSTITUTE SHEET (RULE 26)(II)

[0148] In certain embodiments of (I)-(Ie), a compound of the invention has the structural formula (Im):

[0149] In certain embodiments of (I)-(Ie), a compound of the invention exhibits the following chirality at the carbon to which R2is bond:

[0150] In certain embodiments of (I)-(Ie), a compound of the invention exhibits the following chirality at the carbon to which R2is bond:

[0151] Non-limiting examples of compounds of the invention include:37SUBSTITUTE SHEET (RULE 26)38SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy; and each Rais independently H or an optionally substituted Ci-e alkyl, provided that at least one of Raand Rais not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

[0152] Non-limiting examples of compounds of the invention include:39SUBSTITUTE SHEET (RULE 26)40SUBSTITUTE SHEET (RULE 26)wherein41SUBSTITUTE SHEET (RULE 26)each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy; and each Rais independently H or an optionally substituted Ci-e alkyl, provided that at least one of Raand Rais not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

[0153] In certain embodiments, at least one of Raand Ra, if present, is CH2CH3, CD2CD3, CH2CHF2, CH2CF3 or CH2CN.

[0154] In certain embodiments, at least one of Raand Ra, if present, is CH2CHF2 or CH2CF3.

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

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

[0157] Non-limiting examples of compounds of the invention also include:42SUBSTITUTE SHEET (RULE 26)43SUBSTITUTE SHEET (RULE 26)44SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, provided that at least one Rais not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

[0158] Non-limiting examples of compounds of the invention also include:45SUBSTITUTE SHEET (RULE 26)46SUBSTITUTE SHEET (RULE 26)47SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, provided that at least one Rais not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

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

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

[0161] In certain embodiments, a compound of the invention exhibits the following chirality at the carbon to which R2is bond:

[0162] In certain embodiments, a compound of the invention exhibits the following chirality at the carbon to which R2is bond:

[0163] Non-limiting examples of compounds of the invention also include:48SUBSTITUTE SHEET (RULE 26)49SUBSTITUTE SHEET (RULE 26)50SUBSTITUTE SHEET (RULE 26)51SUBSTITUTE SHEET (RULE 26)

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

[0165] 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.

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

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

[0168] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

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

[0170] Pharmaceutically acceptable carriers, adjuvants and vehicles that 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.

[0171] 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).52SUBSTITUTE SHEET (RULE 26)

[0172] 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.

[0173] 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.

[0174] 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 inert53SUBSTITUTE SHEET (RULE 26)diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

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

[0176] In yet another aspect, the invention generally relates to a method for inhibiting PI3Ka activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0177] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by PI3Ka, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

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

[0179] 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.

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

[0181] 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, large54SUBSTITUTE 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.

[0182] 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.

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

[0184] In certain embodiments, the subject has a mutated class IA PI3K pl 10a.

[0185] In certain embodiments, the subject has at least one of the following PI3Ka mutations: H1047R, E542K, and E545K.

[0186] In certain embodiments, the subject does not have a PI3Ka mutant protein.

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

[0188] 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.

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

[0190] 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.

[0191] 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 of55SUBSTITUTE 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.

[0192] 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.

[0193] 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.

[0194] 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.56SUBSTITUTE SHEET (RULE 26)

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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,57SUBSTITUTE 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.

[0199] 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.

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

[0201] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For 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.

[0202] 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 further58SUBSTITUTE SHEET (RULE 26)administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

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

[0208] 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.

[0209] 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),59SUBSTITUTE 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,60SUBSTITUTE 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.

[0210] 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 and61SUBSTITUTE SHEET (RULE 26)the like), immunotherapic agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0211] 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.

[0212] 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.

[0213] 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.

[0214] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically -labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively.

[0215] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C)62SUBSTITUTE SHEET (RULE 26)labeled compounds are particularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[0216] Further, substitution of normally abundant hydrogen (1H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. Benefits may also be obtained from replacement of normally abundant12C with13C. (See, WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.)

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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),63SUBSTITUTE 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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 and64SUBSTITUTE 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

[0226] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0227] 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 Compounds65SUBSTITUTE SHEET (RULE 26)66SUBSTITUTE SHEET (RULE 26)67SUBSTITUTE SHEET (RULE 26)68SUBSTITUTE SHEET (RULE 26)69SUBSTITUTE SHEET (RULE 26)70SUBSTITUTE SHEET (RULE 26)71SUBSTITUTE SHEET (RULE 26)72SUBSTITUTE SHEET (RULE 26)73SUBSTITUTE SHEET (RULE 26)74SUBSTITUTE SHEET (RULE 26)75SUBSTITUTE SHEET (RULE 26)76SUBSTITUTE SHEET (RULE 26)77SUBSTITUTE SHEET (RULE 26)78SUBSTITUTE SHEET (RULE 26)19SUBSTITUTE SHEET (RULE 26)80SUBSTITUTE SHEET (RULE 26)81SUBSTITUTE SHEET (RULE 26)82SUBSTITUTE SHEET (RULE 26)83SUBSTITUTE SHEET (RULE 26)84SUBSTITUTE SHEET (RULE 26)85SUBSTITUTE SHEET (RULE 26)86SUBSTITUTE SHEET (RULE 26)87SUBSTITUTE SHEET (RULE 26)88SUBSTITUTE SHEET (RULE 26)89SUBSTITUTE SHEET (RULE 26)Exemplary Synthetic ProceduresList of Abbreviations aq: aqueousAc = AcetylAcO = AcetateAciO = Acetic anhydrideAIBN a,a'-AzoisobyronitrileAll = AllylAlloc = AllyloxycarbonylAm = Amyl (Pentyl)Ar = ArylB2Pin2 = bis(pinacolato)diboron90SUBSTITUTE SHEET (RULE 26)9-BBN = 9-BorabicyclononaneBHT = tert-ButylhydroxytolueneBINAP = 2,2'-Bis(diphenylphosphino)-l,l'-binaphthylBMS = Borane-methylsulphide complexBn = BenzylBoc = tert-Butoxy carbonylBOP = Bis(2-oxo-3-oxazolidinyl)phosphineBu or n-Bu = n-Butyl s-Bu or sBu = sec-Butyl t-Bu or tBu = tert-ButylBuOH = ButanolBz = BenzoylBzl = BenzylCAN = Ceric ammonium nitrate cataCXium A Pd G3 = mesylate [(di(l-adamantyl)-n-butylphosphine)-2-(2’ -amino- 1 , 1 ’biphenyl)Jpalladium(II)CBS = Corey -Bashki-ShibatCbz = BenzyloxycarbonylCbzCl = Benzyl chloroformate oxCod = CyclooctadieneCp = CyclopentadienylCSA = Camphorsulphonic acidDABCO = 1,4-Diazabicyclo[2.2.2]octane, TriethylendiamineDAST = Diethylaminosulphur trifluoride dba = DibenzylideneacetoneDBU = l,8-Diazabyciclo[5.4.0]undec-7-eneDCC = 1,3 -DicyclohexylcarbodiimideDCM = DichloromethaneDDQ = 2,3-Dichloro-5,6-dicyano-l,4-benzoquinoneDEAD = Diethyl azodicarboxylateDHP = Dihydropiran91SUBSTITUTE SHEET (RULE 26)DHQD = DihydroquinidineDIBAL = Diisobutylaluminium hydrideDIBAL-H = Diisobutylaluminium hydrideDIG = DiisopropylcarbodiimideDIPEA = DiisopropylethylamineDMA = N,N-DimethylacetamideDMAC = N,N-DimethylacetamideDMAP = 4-DimethylaminopyridineDME = 1,2-Dimethoxy ethaneDMF = N,N-DimethylformamideDMP = Dess-Martin periodinaneDMPU = l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pirimidoneDMS = DimethylsulphideDMSO = DimethylsulphoxideDPA = DiisopropylamineDPP A = Diphenylphosphoryl azideDdpb = l,4-bis(diphenylphosphino)butaneDppe = l,2-bis(diphenylphosphino)ethaneDppf = 1 ,2-bi s(diphenylphosphino)ferrocene dppp = l,3-bis(diphenylphosphino)propaneDtbbpy = 4, 4’-di-tert-butyl-2,2’ -dipyridylEA = Ethyl acetateEDC = l-Ethyl-3-(3-dimethylaminopropy)carbodiimideEDCI = l-Ethyl-3-(3-dimethylaminopropy)carbodiimide hydrochlorideEq = equivalentESI or ES = Electrospray ionizationEt = ethylEt2O = Diethyl etherEtOAc = Ethyl acetateFMOC = 9-Fluorenylmethoxycarbonyl92SUBSTITUTE SHEET (RULE 26)HATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- bjpyridinium 3 -oxide hexafluorophosphateHMDS = HexamethyldisilazaneHMPA = HexamethylphosphoramideHOAt = 7-Aza-l-hydroxybenzotriazoleHOBt = 1 -HydroxybenzotriazoleHPLC = high pressure liquid chromatographyIP A = Isopropyl alcoholIm = ImidazoleKHMDS Potassium bis(trimethylsilyl)amideKOAc Potassium acetateLAH = Lithium aluminium hydrideLDA = Lithium diisopropyl ami deLHMDS = Lithium bis(trimethylsilyl)amideMCPBA = meta-chloroperoxybenzoic acid Me = MethylMeCN = AcetonitrileMeOH = MethanolMOM = MethoxymethylMg = magnesiumMS = Molecular sievesMs = MethanesulphonylMTBE = Methyl tert-butyl ether m / z = mass divided by charge NaiSCL = Sodium SulphateNaHMDS = Sodium bis(trimethylsilyl)amide NaCNBHs = Sodium cyanoborohydride NBS = N-BromosuccinimideNCS = N-ChlorosuccinimideNIS = N-IodosuccinimideNMM = N-Methylmorpholine93SUBSTITUTE SHEET (RULE 26)NMO = N-Methylmorpholine-N-oxideNMP = N-MethylpyrrolidoneNMR = Nuclear magnetic resonanceNs = p-Nitrophenyl sulphonylPd(dppf)C12 = [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladiumPd(PPh3)4 = tetrakis(triphenylphosphine)palladiumPDC = Pyridinium dichlorochromatePCC = Pyridinium chlorochromatePE = Petroleum etherPh = PhenylPiv = Pivaloyl, 2,2-dimethylacetylPMB = p-MethoxybenzylPPA = Polyphosphoric acidPPTS = Pyridinium p-toluensulphonate n-Pr = n-PropylPr = Propyl i-Pr or iPr = iso-propiloPTC = Phase transfer catalystPTS A = p-Toluenesulphonic acidPv = Pivaloyl, 2,2-dimethylacetylPy = PyridineRed-Al® = Sodium bis(2-methoxyethoxy)aluminium hydrideRT = room temperatureSFC = supercritical fluid chromatographyPrep-SFC = Preparative SFCSEM = 2-(Trimethylsilyl)ethoxymethylTBAF = Tetrabutylammonium fluorideTBDMS = tert-ButyldimethylsilylTBDPS = tert-Butyldiphenyl silylTBHP = tert-Butylhydroperoxyde94SUBSTITUTE SHEET (RULE 26)TBS = tert-ButyldimethylsilylTEA = Tri ethylamineTES = TriethylsilylTf = TrifluoromethanesulfonylTfO = TrifluoromethanesulfonateTf2O = Trifluoromethanesulfonyl anhydrideTfOH = Trifluoromethanesulfonic acidTFA = Trifluoroacetic acidTFAA = Trifluoroacetic anhydrideThexyl = 2,3-dimethyl-2-butylTHF = TetrahydrofuraneTHP = TetrahydropyranylTIPS = TriisopropylsilylTMEDA = N,N,N',N'-TetramethylethylendiamineTMG = TetramethylguanidineTMS = TrimethylsilylTol = p-ToluylTPAP = Tetra-n-propylammonium perruthenateTPS = TripropylsilylTr = Trityl, triphenylmethylTroc = 2,2,2-TrichloroethoxycarbonylTrt = Trityl, triphenylmethylTs = p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acidUV = ultravioletZ = BenzyloxycarbonyUV: ultra violetGeneral LCMS Method:95SUBSTITUTE SHEET (RULE 26)

[0228] 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:

[0229] 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:

[0230] Prep-SFC conditions for Example 29 and 30:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak IB, 250x21.2mm I D., 5 pmMobile phase: A for CO2 and B for MeOHGradient: B 25%Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220 nmCycle-time: 3 minEluted time: 2 H

[0231] 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 / minBack pressure: 100 barColumn temperature: 35°C96SUBSTITUTE SHEET (RULE 26)Wavelength: 220 nmCycle-time: 12 minEluted time: 2 H

[0232] 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 / minBack pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm Cycle-time: 3.2 min Eluted time: 2 H

[0233] Prep-SFC conditions for Example 42 and 43:Instrument: SHIMADZU PREP SOLUTION SECColumn: ChiralPak IH, 150><20mm I.D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 30%Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220nmCycle-time: 8 minEluted time: 2 H

[0234] Prep-SFC conditions for Example 57 and 58:Instrument: Waters Thar 80 preparative SECColumn: ChiralPak IA, 250x21.2 mm I D., 5 pmMobile phase: A for CO2 and B for MeOH (MeOH, neutral)Gradient: B 40 %Flow rate: 30 mL / min97SUBSTITUTE SHEET (RULE 26)Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nmCycle-time: 15 min Eluted time: 2 H

[0235] Prep-SFC conditions for Example 64 and 65:Preparative SFC separation methodInstrument: SHIMADZU PREP SOLUTION SFCColumn: (R,R)-WHELK, 250x30mm I D., 5 pmMobile phase: A for CO2 and B for MeOHGradient: B 50%Flow rate: 60 mL / minBack pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nmCycle-time: 10 min Eluted time: 2 H

[0236] 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 / minBack pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nmCycle-time: 10 min Eluted time: 3 H

[0237] Prep-SFC conditions for Example 87 and 88:Instrument: SHIMADZU PREP SOLUTION SECColumn: ChiralPak IH, 150><20mm I.D., 5pm98SUBSTITUTE SHEET (RULE 26)Mobile phase: A for CO2 and B for MEOH+0.1%NH3H2OGradient: B 50%Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220nmCycle-time: 7minEluted time: 4 H

[0238] Prep-SFC conditions for Example 125 and 126Instrument: Waters Thar 80 preparative SFC Column: (R,R)-WHELK, 250x30 mm I D., 5 pm Mobile phase: A for CO2and B for MeOH Gradient: B 40%Flow rate: 60 mL / minBack pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nmCycle-time: 15 min Eluted time: 2 H

[0239] Prep-SFC conditions for Example 134 and 135:Instrum ent: Waters Thar 80 preparative SFCColumn: ChiralPak C-IG, 250x30mm I D., 5pmMobile phase: A for CO2 and B for MeOHGradient: B 30%Flow rate:60mL / minBack pressure: 100 bar Column temperature: 35°C Wavelength: 220 nmCycle-time: 15 min Eluted time: 3H

[0240] Prep-SFC conditions for Examples 141 - 144:99SUBSTITUTE SHEET (RULE 26)Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak IH, 150><20mm I.D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 10%Flow rate: 40mL / minBack pressure: 100 bar Column temperature: 35°C Wavelength: 220nmCycle-time: 20 min Eluted time: 3 H

[0241] Prep-SFC conditions for Example 145 and 146:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak IH, 150x20mm I.D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 10%Flow rate: 40mL / minBack pressure: 100 bar Column temperature: 35°C Wavelength: 220nmCycle-time: 10 min Eluted time: 3 H

[0242] Prep-SFC conditions for Example 147 and 148:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak AS, 250x20mm I D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 15%Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220nmCycle-time: lOmin100SUBSTITUTE SHEET (RULE 26)Eluted time: 2H

[0243] 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 / minBack pressure: 100 bar Column temperature: 35°C Wavelength: 220 nmCycle-time: 13 min Eluted time: 2 H

[0244] Prep-SFC conditions for Example 151 and 152:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak IH, 150x20mm I.D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 15%Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220nmCycle-time: lOminEluted time: 3H

[0245] Prep-SFC conditions for Example 154 and 155:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak AS, 250x20mm I D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 15%Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35°C101SUBSTITUTE SHEET (RULE 26)Wavelength: 220nmCycle-time: lOminEluted time: 2H

[0246] Prep-SFC conditions for Example 156 and 157:Instrument: SHIMADZU PREP SOLUTION SECColumn: ChiralPak AS, 250x20mm I D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 10%Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220nmCycle-time: 15minEluted time: 2H

[0247] Prep-SFC conditions for Example 158 and 159:Instrument: SHIMADZU PREP SOLUTION SECColumn: ChiralCel OX, 250x20mm I D., 5pmMobile phase: A for CO2 and B for MeOH Gradient: B 20 %Flow rate: 40mL / minBack pressure: 100 bar Column temperature: 35°C Wavelength: 220 nmCycle-time: 15 min Eluted time: 3 HSynthetic procedure:Example 1 N-(3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-benzo[e]isoindol-4-yl)-3- fluoro-5-(trifluoromethyl)benzamide102SUBSTITUTE SHEET (RULE 26)

[0248] 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]").

[0249] 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-2,5-103SUBSTITUTE 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)benzamide (500 mg, 13%). LCMS: m / z 525.0 ([M-H]").

[0250] 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)benzamide (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-(trifluoromethyl)benzamide (42.8 mg, 11%). LCMS: m / z 655.1 ([M-H]").

[0251] 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]isoindol-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-(trifluoromethyl)benzamide (9 mg, 18%). LCMS: m / z 651.0 ([M-H]").

[0252] 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 (8.1104SUBSTITUTE 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.XH 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-tetrahydropyrrolo[3,4- f|isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0253] 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).105SUBSTITUTE SHEET (RULE 26)

[0254] 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).

[0255] 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]+ 1H 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).

[0256] 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]+

[0257] 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 by106SUBSTITUTE 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).

[0258] 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-methoxyphenyl) 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]+

[0259] 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]+

[0260] 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]+107SUBSTITUTE SHEET (RULE 26)

[0261] 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-tetrahydropyrrolo[3,4- f]isoquinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7.3 mg, 0.014 mmol, 60%). LCMS: m / z 534 [M + H]+ XH 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-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide108SUBSTITUTE SHEET (RULE 26)

[0262] 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).

[0263] 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).

[0264] 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).109SUBSTITUTE SHEET (RULE 26)

[0265] 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]").XH 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).

[0266] 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]").

[0267] 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]").

[0268] 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 by110SUBSTITUTE 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]").

[0269] 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-(trifluoromethyl)benzamide (30 mg, 56%). LCMS: m / z 546.0 ([M-H]").

[0270] 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]').1H 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)benzamide111SUBSTITUTE SHEET (RULE 26)

[0271] 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 column112SUBSTITUTE 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).

[0272] 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]+).

[0273] 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).

[0274] 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-methylbenzenesulfonamide (1.0 g, 57%).LCMS: m / z 565.8 ([M -H]").113SUBSTITUTE SHEET (RULE 26)

[0275] Step E: To a solution of N-(4-bromo-6-chloro-3-((2-chloro-5- fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (560 mg, 0.98 mmol, 1.0 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-methylbenzenesulfonamide (310 mg, 55%). LCMS: m / z 563.7 ([M -H]").

[0276] 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)methanone (80 mg, 56%) as a yellow solid. LCMS: m / z 411.9 ([M +H]+).

[0277] 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]+).

[0278] 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-5-114SUBSTITUTE SHEET (RULE 26)fluorophenyl)-3-hydroxy-2,3-dihydro-lH-benzo[e]isoindol-l-one (38 mg, curde). LCMS: m / z 374.9 ([M-H]").

[0279] 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-(trifluoromethyl)benzamide (58 mg, curde). LCMS: m / z 564.9 ([M-H]").

[0280] 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-(trifluoromethyl)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-(trifluoromethyl)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-tetrahydro-lH- pyirolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide115SUBSTITUTE SHEET (RULE 26)

[0281] 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]isoquinoline-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)-dione (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).

[0282] 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]+.

[0283] 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)116SUBSTITUTE 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-lH-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]+.

[0284] 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-pyrrolo[4,3-f]isoquinolin-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.037 mmol) in TFA (4 mL) was added triethylsilane (1 mL, 6.192 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under vacuum to give N-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-7-methyl-l,6-dioxo-2,3-dihydro-lH-pyrrolo[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]+

[0285] Step E: To a solution ofN-[3-(2-chloro-5-fluorophenyl)-2-[(4- methoxyphenyl)methyl]-7-methyl-l,6-dioxo-2,3-dihydro-lH-pyrrolo[3,4-f]isoquinolin-4-yl]-5- fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.034 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (11.2 mg, 0.075 mmol). The reaction mixture was stirred at 70 °C for 1 hour. The cooled reaction mixture was concentrated and the residue was purified by 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]isoquinolin-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)benzamido)-8-oxo- l,6,7,8-tetrahydropyrrolo[3,4-g]indazole-3-carboxamide117SUBSTITUTE SHEET (RULE 26)

[0286] 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]").

[0287] 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-tetrahydropyrrolo[3,4-g]indazole-3- carboxamide (65 mg, crude). LCMS: m / z 374.0 ([M-H]").

[0288] 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),118SUBSTITUTE 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-tetrahydropyrrolo[3,4-g]indazole-3- carboxamide (110 mg, crude). LCMS: m / z 563.9 ([M-H]").

[0289] 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-tetrahydropyrrolo[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)benzamide119SUBSTITUTE SHEET (RULE 26)

[0290] 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]+.

[0291] 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]+.

[0292] 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-X6-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 column120SUBSTITUTE 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-methylbenzenesulfonamide (3.5 g, 8.29 mmol, 31%). LCMS: m / z 422 / 424 [M + H]+.

[0293] 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-methylbenzenesulfonamide (1.60 g, 2.90 mmol, 41%). LCMS: m / z 552 / 554 [M + H]+.

[0294] 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-methylbenzenesulfonamide (1.00 g, 1.82 mmol, 72%). LCMS: m / z 550 / 552 [M + H]+.

[0295] 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-methylbenzenesulfonamide121SUBSTITUTE SHEET (RULE 26)(1.20 g, cmde). The residue was not purified and will be used directly. LCMS: m / z 497 [M + H]+.

[0296] 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-dihydro-lH-benzo[e]isoindol-4-yl]- 4-methylbenzenesulfonamide (600 mg, 1.17mmol, 48%). LCMS: m / z 513 [M - H]".

[0297] 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-methylbenzenesulfonamide (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-dihydro- lH-benzo[e]isoindol-l-one (450 mg, 1.25 mmol, 92%). LCMS: m / z 359 [M- H]".

[0298] 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]".

[0299] 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-(trifluoromethyl)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 saturated122SUBSTITUTE 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 (400MHz, 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-tetrahydropyrrolo[3,4- g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide123SUBSTITUTE SHEET (RULE 26)

[0300] 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]+.

[0301] 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]+.

[0302] 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]+.

[0303] 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 resulting124SUBSTITUTE 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]+.

[0304] 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]+.

[0305] 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]+.

[0306] 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 Na2SO4 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]+.

[0307] 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 H2O (25 mL) was added LiOH / H2O (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]“.

[0308] 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, 2.47125SUBSTITUTE 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-methoxybenzyl)-5-nitro-l / / -indazole-7- carboxamide (1.2 g, 1.78 mmol, 72%). LCMS: m / z 664 [M + H]“.

[0309] 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-nitro-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-methoxybenzyl)-5-nitro-6,7- dihydropyrrolo[3,4-g]indazol-8(lf / )-one (430 mg, 0,673 mmol, 41%). LCMS: m / z 561 [M + H]+.

[0310] 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-dihydropyrrolo[3,4-g]indazol-8(l / / )-one (230 mg, 0.355 mmol, 47%). LCMS: m / z 531 [M + H]+.

[0311] 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 / )-one (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-TLC126SUBSTITUTE 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-tetrahydropyrrolo[3,4-g]indazol-5- yl)-3-fluoro-5 (trifluoromethyl)benzamide (30 mg, 0.037 mmol, 28%). LCMS: m / z 721 [M + H]+.

[0312] 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-(trifluoromethyl)benzamide (50 mg, 0.071 mmol, crude). LCMS: m / z 705 [M + H]+.

[0313] 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-tetrahydropyrrolo[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-(trifluoromethyl)benzamide127SUBSTITUTE SHEET (RULE 26)

[0314] 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).

[0315] 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]+).

[0316] 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,128SUBSTITUTE 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]+).

[0317] 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]-).

[0318] 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]").

[0319] 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 (10.3129SUBSTITUTE SHEET (RULE 26)mg, three steps yield 21%). LCMS: m / z 544.0 ([M-H]"). 'H NMR (400 MHz, DMSO-d6): 510.51 (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, J8.8, 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)benzamide130SUBSTITUTE SHEET (RULE 26)

[0320] 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]+.

[0321] 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]+.

[0322] 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]+.

[0323] 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-8-131SUBSTITUTE 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]+.

[0324] 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]+.

[0325] 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]+.

[0326] 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 1132SUBSTITUTE 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]+.

[0327] 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-tetrahydropyrrolo[4,3-h] quinolin- 6-yl]-5-fluoro-3-(trifluoromethyl) benzamide (11.1 mg, 0.021 mmol, 91%) as a white solid. LCMS: m / z 534 [M + H]+. 1H NMR (400 MHz, DMSO-d6) 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)benzamide133SUBSTITUTE SHEET (RULE 26)

[0328] 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)amino)-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]+.

[0329] Step B: A solution of 7-bromo-l-(2-chloro-5-fluorophenyl)-4-((3,4- dimethylbenzyl)amino)-2-(4-methoxybenzyl)-l,2-dihydro-3H-pyrrolo[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-methoxyphenyl)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]+.

[0330] 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-dihydro-7H-pyrrolo[4,3-1345UB5TITUTE 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]+.

[0331] 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)benzamide (230 mg, 0.358 mmol, 42%) as a yellow oil. LCMS: m / z 627 [M + H]+.

[0332] Step E: To a solution of N-[7-(2-chloro-5-fluorophenyl)-8-[(4- methoxyphenyl)methyl]-9-oxo-8,9-dihydro-7H-pyrrolo[4,3-c]imidazo[3,2-a]pyridin-6-yl]-3- fluoro-5-(trifluoromethyl)benzamide (150 mg, 0.239 mmol) in TFA (2 mL) was added triethylsilane (0.2 mL) and trifluoromethanesulfonic acid (0.2 mL) at 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-fluoro-5-(trifluoromethyl)benzamide (31.6 mg, 0.062 mmol, 26%). LCMS: m / z 507.0 [M + H]+.XH 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)benzamide135SUBSTITUTE SHEET (RULE 26)

[0333] Step A: To a solution of PBn (19.5 mL, 207 mmol) in CHCL (85 mL) was addedDMT (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.

[0334] 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.136SUBSTITUTE SHEET (RULE 26)

[0335] 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-X6-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]+.

[0336] 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)naphthalen-2-yl)-4- methylbenzenesulfonamide (800 mg, 1.40 mmol, 56%) as a yellow solid. LCMS: m / z 568.0 [M+H]+.

[0337] Step E: To a solution of N-(4-bromo-7-chloro-3-((2-chloro-5- fluorophenyl)(hydroxy)methyl)naphthalen-2-yl)-4-methylbenzenesulfonamide (700 mg, 1.23 mmol) in DCM (6 mL) 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-naphthyl}-4- methylbenzenesulfonamide (400 mg, 0.705 mmol, 57%) as a yellow solid. LCMS: m / z 566 [M+H]+.

[0338] Step F: To a solution of N-{4-bromo-7-chloro-3-[(2-chloro-5- fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (400 mg, 0.705137SUBSTITUTE 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]+.

[0339] 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]".

[0340] 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-methylbenzenesulfonamide (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]+

[0341] 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%)138SUBSTITUTE 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]+

[0342] 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-(trifluoromethyl)benzamide139SUBSTITUTE SHEET (RULE 26)

[0343] 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]+).

[0344] 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)methanone (400 mg, 50 %) as a red solid. LCMS: m / z 507.8, 509.9 ([M+H]+).

[0345] 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-dicarbonitrile (60 mg, 57%) as a yellow oil. LCMS: m / z 354.1 ([M+H]+).

[0346] 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, 6,7,8-140SUBSTITUTE SHEET (RULE 26)tetrahydropyrrolo[3,4-g]indazole-3-carbonitrile (100 mg, crude) as a yellow oil. LCMS: m / z 369.8 ([M-H]").

[0347] 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]").

[0348] 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]").JH 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-(trifluoromethyl)benzamide141SUBSTITUTE SHEET (RULE 26)

[0349] 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]+).

[0350] 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]+).

[0351] 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 to142SUBSTITUTE SHEET (RULE 26)give 5-amino-6-(2-chloro-5-fluorophenyl)-6-hydroxy-l-methyl-6,7-dihydropyrrolo[3,4- g]indazol-8(lH)-one (100 mg, 78%) as a yellow oil. LCMS: m / z 345.0 ([M-H]").

[0352] 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]").

[0353] 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-(trifluoromethyl)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-tetrahydropyrrolo[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]").1H 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)benzamide143SUBSTITUTE SHEET (RULE 26)

[0354] 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-carboxamide (2.8 g, 7.87 mmol, 93%) as a yellow solid. LCMS: m / z 357 [M+2+H] .

[0355] 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% in144SUBSTITUTE 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]+.

[0356] 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]+.

[0357] 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]pyridin-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]+.

[0358] 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-pyrrolo[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 column145SUBSTITUTE 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]+.

[0359] 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]pyridin-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-oxo-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]+.

[0360] 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]pyridin-7-yl]-3-fluoro-5- (trifluoromethyl)benzamide (130 mg, 0.209 mmol), potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (74.3 mg, 0.313 mmol), Pd(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]pyridin-4- yl]methyl}amino)methanoate (40 mg, 56 pmol, 27%) as a brown solid. LCMS: m / z 733 [M+H]+.

[0361] Step H: A solution of 2-methylpropan-2-yl ({[l-(2-chloro-5-fhiorophenyl)-7-({[3- fluoro-5-(trifluoromethyl)phenyl]carbonyl]amino)-2-[(4-methoxyphenyl)methyl]-3-oxo-2,3- dihydro-lH-pyrrolo[4,3-c]pyridin-4-yl]methyl}amino)methanoate (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-146SUBSTITUTE SHEET (RULE 26)lH-pyrrolo[4,3-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide (13 mg, 21 pmol, 100%) as a brown solid. LCMS: m / z 633 [M+H]+.

[0362] 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]pyridin-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-pyrrolo[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]+.

[0363] 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]imidazo[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)benzamide147SUBSTITUTE SHEET (RULE 26)

[0364] 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 / z318.19 [M+H]+.

[0365] 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 reaction1485UB5TITUTE 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]+.

[0366] 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)methanol (3.2 g, 8.320 mmol, 90%) as a yellow solid. LCMS: m / z 384.60 [M+H]+.

[0367] 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]+.

[0368] 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]+.149SUBSTITUTE SHEET (RULE 26)

[0369] 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]+.

[0370] 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-pyrrolo[4,3-h]isoquinolin-l-one (130 mg, 0.263 mmol, 60%) as a white solid. LCMS: m / z ESI 493.92 [M+H]+.

[0371] Step H: To a solution of 3-(2-chloro-5-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}-3-hydroxy-2,3-dihydro-lH-pyrrolo[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]+.

[0372] 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 to150SUBSTITUTE 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-(trifluoromethyl)benzamide (40 mg, 0.034 mmol, 56%) as a yellow solid. LCMS: m / z 707.94 [M+H]+.

[0373] 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-(trifluoromethyl)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]+.LH 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]triazolo[l,5- a]pyrrolo[3,4-c]pyridin-6-yl]-5-fliioro-3-(trifliioromethyl)benzamide151SUBSTITUTE SHEET (RULE 26)

[0374] 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]+

[0375] Step B: A solution of 7-bromo-l-(2-chloro-5-fluorophenyl)-4-[(2,4- dimethoxyphenyl)amino]-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-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]+

[0376] 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 crude152SUBSTITUTE SHEET (RULE 26)compound 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 (1.1 g, 2.07 mmol, 99%) as a yellow solid. LCMS: m / z 533.1 [M+2+H]+

[0377] 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)methylidene]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]+

[0378] 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)methyl]-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]+

[0379] 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]pyrrolo[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-(2-153SUBSTITUTE 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]".

[0380] 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]triazolo[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]+ JH 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)benzamide154SUBSTITUTE SHEET (RULE 26)

[0381] 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.

[0382] 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.

[0383] 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]+155SUBSTITUTE SHEET (RULE 26)

[0384] 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]+

[0385] 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]+

[0386] 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]+

[0387] 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]+

[0388] 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 mixture156SUBSTITUTE 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]+

[0389] 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]+

[0390] 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-(trifluoromethyl)benzamide (0.8 g, 1.25 mmol, 64%) as a yellow oil. LCMS: m / z 654.12 [M + H]+

[0391] 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-157SUBSTITUTE SHEET (RULE 26)oxo-2, 3-dihydro-lH-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (7 mg, 0.014 mmol, 43%). LCMS: m / z 518.12 [M + H]+.JH NMR (400 MHz, CDC13) 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)benzamide158SUBSTITUTE SHEET (RULE 26)

[0392] 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).

[0393] 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]+.

[0394] 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 residue159SUBSTITUTE 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]+.

[0395] 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-methylbenzenesulfonamide (600 mg, 0.98 mmol, 59%) as a yellow solid. LCMS: m / z 614 [M + H]+

[0396] Step E: To a solution of N-{4,8-dibromo-3-[(2-chloro-5- fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesulfonamide (600 mg, 0.98 mmol) in DCM (10 mL) 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-methylbenzenesulfonamide (250 mg, 0.409 mmol, 25%) as a yellow oil.

[0397] 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. The160SUBSTITUTE 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]+.

[0398] 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]+.

[0399] 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-methylbenzenesulfonamide (60 mg, 0.11 mmol) in TFA (2 mL) at room temperature was added triethylsilane (0.2 mL). The mixture was stirred at 70 °C for 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-methylbenzenesulfonamide (50 mg, 0.09 mmol, 81%) as a yellow solid. LCMS: m / z 559 / 561 [M + H]".

[0400] 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]isoindol-l-one (45 mg, 0.11 mmol, 100 %), which was directly used in the next step. LCMS: m / z 405 / 407 [M + H]+.161SUBSTITUTE SHEET (RULE 26)

[0401] 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-(trifluoromethyl)benzamide (38 mg, 0.06 mmol, 57%) as a yellow solid.

[0402] 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-(trifluoromethyl)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)benzamide162SUBSTITUTE SHEET (RULE 26)

[0403] 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.

[0404] 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]thiazole-4-carboxylate (2.6 g, 8.46 mmol, 21%) as a white solid.

[0405] 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]+163SUBSTITUTE SHEET (RULE 26)

[0406] 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]+

[0407] 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]+

[0408] 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-dihydro-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]+

[0409] 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]isoindol-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 was164SUBSTITUTE 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]+

[0410] 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]isoindol-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]+

[0411] 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-fluorobenzamide165SUBSTITUTE SHEET (RULE 26)

[0412] 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]+.

[0413] 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,166SUBSTITUTE 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]+.

[0414] 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-fluorobenzamide (50 mg, 0.05 mmol, 15%) as a yellow solid. LCMS: m / z 634 [M + H]+.

[0415] 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]+.

[0416] 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-tetrahydropyrrolo[4,3-g]indazol-5-yl]-5-167SUBSTITUTE 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-tetrahydropyrrolo[4,3- g] indazol-5-yl] benzo [d] [1,2] thiazole-3-carboxamide

[0417] 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]+

[0418] 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,168SUBSTITUTE 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

[0419] 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)169SUBSTITUTE 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).

[0420] 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).

[0421] 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).

[0422] 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)methyl]-2-naphthyl}-4-170SUBSTITUTE SHEET (RULE 26)methylbenzenesulfonamide (790 mg, 1.38 mmol, 80%) as a white solid. LCMS: m / z 568 [M - H]+.

[0423] Step E: To a solution of N-{4-bromo-8-chloro-3-[(2-chloro-5- fluorophenyl)(hydroxy)methyl]-2-naphthyl}-4-methylbenzenesulfonamide (790 mg, 1.38 mmol) in DCM (50 mL) was added Dess-Martin (1.17 g, 2.77 mmol). The 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]+

[0424] Step F: To a solution of N-{4-bromo-8-chloro-3-[(2-chloro-5- fluorophenyl)carbonyl]-2-naphthyl}-4-methylbenzenesulfonamide (250 mg, 0.441 mmol) in NMP (10 mL) was added CuCN (59.2 mg, 0.661 mmol). The reaction mixture was stirred at 150 °C for 1 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]+

[0425] 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]isoindol-4-yl]-4- methylbenzenesulfonamide (110 mg, 0.207 mmol, 62%) as a brown solid. LCMS: m / z 528.9 [M - H]+.

[0426] 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-methylbenzenesulfonamide (110 mg, 0.207 mmol) in IF A (4 mL) was added triethylsilane (1 mL, 6.19 mmol). The mixture was stirred at171SUBSTITUTE 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]+.

[0427] 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]+

[0428] 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]+ JHNMR (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)benzamide172SUBSTITUTE SHEET (RULE 26)

[0429] 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]quinoline 6-oxide (400 mg, 0.597 mmol, 76%) as a white solid. LCMS: m / z 770.11 [M + H]+

[0430] Step B: To a solution of 3-(2-chloro-5-fluorophenyl)-4-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-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.

[0431] 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-5-173SUBSTITUTE 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

[0432] To a solution of N-(6-amino-3-(2-chloro-5-fluorophenyl)-7-hydroxy-l-oxoisoindolin- 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)benzamide174SUBSTITUTE SHEET (RULE 26)

[0433] 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-carboxamide (40 g, 128.551 mmol, 99%) as a yellow solid. LCMS: m / z 313.0 [M+2+H]+

[0434] 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%).

[0435] To a solution of 4,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridine-2-carboxamide (15 g, 48.207 mmol) in THF (200 mL) was added NaH (2.89 g, 72.3 mmol, 60% in mineral oil)175SUBSTITUTE 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.

[0436] 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]+

[0437] 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]

[0438] 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 in176SUBSTITUTE 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-dimethoxyphenyl)methyl]amino}-6- [(4-methoxyphenyl)methyl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one (300 mg, 0.515 mmol, 23%) as a white solid. LCMS: m / z 582.2 [M+H]+

[0439] 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-dihydro-5H-pyrrolo[4,3-b]pyridin-7- one (230 mg, 0.532 mmol, 93.9%) as a yellow solid. LCMS: m / z 432.0 [M+H]+

[0440] 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-pyrrolo[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]+

[0441] 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-2,3-177SUBSTITUTE SHEET (RULE 26)dihydro-lH-pyrrolo[4,3-b]imidazo[2,3-f]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide (65 mg, 0.101 mmol, 46%) as a brown oil. LCMS: m / z 627.1 [M+H]+

[0442] 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]imidazo[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-tetrahydropyrrolo[4,3- g]indazol-5-yl]-3-fluoro-5-(trifluoromethyl)benzamide178SUBSTITUTE SHEET (RULE 26)

[0443] Step A: To a solution of 6-fluoro-7-(methoxycarbonyl)-lH-indazole-5-carboxylate (1.60 g, 6.75 mmol) in MeOH (10 mL) / H2O (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 Na2SC>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]-.

[0444] 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 Na2SC>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]+.

[0445] 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 Na2SC>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)methyl]-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]+.

[0446] 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 with179SUBSTITUTE 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]indazol-8-one (30 mg, 0.066 mmol, 91%) as yellow solid. LCMS: m / z 453 [M + H]+.

[0447] 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)methyl]-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)benzamide (30 mg crude, 0.047 mmol, 70%) as yellow solid. LCMS: m / z 799 [M + H]+.

[0448] 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-(trifluoromethyl)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-tetrahydropyrrolo[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]+.

[0449] 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-(trifluoromethyl)benzamide (2 mg, 0.004180SUBSTITUTE 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)benzamide

[0450] 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 compound1815UB5TITUTE 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)methanoate (330 mg, 0.604 mmol, 27%) as a brown solid. LCMS: m / z 546 [M+H]+.

[0451] 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]+.

[0452] Step C: A solution of 2-methylpropan-2-yl ({[5-(2-chloro-5-fluorophenyl)-4-({[3- fluoro-5-(trifluoromethyl)phenyl]carbonyl}amino)-6-[(4-methoxyphenyl)methyl]-7-oxo-6,7- 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)benzamide (38 mg, 62 pmol, 98%) as a brown solid. LCMS: m / z 617 [M+H]+.

[0453] 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-methoxyphenyl)methyl]-7- oxo-6, 7-dihydro-5H-pyrrolo[4,3-b]pyridin-4-yl]-5-fluoro-3-(trifluoromethyl)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-(trifluoromethyl)benzamide (40 mg, 64 pmol, 98%) as a crude product and used directly for next step. LCMS: m / z 627 [M+H]+.182SUBSTITUTE SHEET (RULE 26)

[0454] Step E: To a solution of N-[6-(2-chloro-5-fluorophenyl)-7-[(4- methoxyphenyl)methyl]-8-oxo-7,8-dihydro-6H-pyrrolo[4,3-b]imidazo[4,3-f]pyridin-5-yl]-5- fluoro-3-(trifluoromethyl)benzamide (40 mg, 64 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)benzamide (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-(trifluoromethyl)benzamide and Example 30 (7?)- / V-(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

[0455] 7V-(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 (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-(trifluoromethyl)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-(trifluoromethyl)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).183SUBSTITUTE SHEET (RULE 26)Example 31 N-(3-(2-chloro-5-fluorophenyl)-7-methoxy-l-oxo-2,3-dihydro-lH-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-pyrrolo[3,4-f]quinolin-4-yl)-3- fluoro-5-(trifluoromethyl)benzamide

[0456] 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]+

[0457] 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,184SUBSTITUTE 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).

[0458] 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-(trifluoromethyl)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-(trifluoromethyl)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)benzamide185SUBSTITUTE SHEET (RULE 26)

[0459] 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]+.

[0460] 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]+.

[0461] 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-fluorocyclohexa-l,5- dienyl)methanone (1.2 g, 3.10 mmol, 80%) as a white solid. LCMS: m / z 385 [M+H]+.186SUBSTITUTE SHEET (RULE 26)

[0462] 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]+.

[0463] 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-carbonitrile (75 mg, 0.157 mmol, 35%) as an orange solid. LCMS: m / z 479 [M + H]+.

[0464] Step F: To a solution of 5-[(2-chloro-5-fluorophenyl)carbonyl]-6-{[(2,4- dimethoxyphenyl)methyl]amino}-l-methylindazole-4-carbonitrile (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]+.

[0465] 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 reaction187SUBSTITUTE 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,

[0466] 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)benzamide (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-(trifluoromethyl)benzamide

[0467] 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, 0.890188SUBSTITUTE 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]+

[0468] 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-tetrahydropyrrolo[4,3-g]indazol-8- one (150 mg crude) as a yellow solid. LCMS: m / z 483 [M + H]+

[0469] 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-(trifluoromethyl)benzamide (40 mg, 0.059 mmol, 57%) as a yellow solid. LCMS: m / z 673 [M + H]+

[0470] 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. The189SUBSTITUTE 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-tetrahydropyrrolo[4,3- g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide (4.9 mg, 0.009 mmol, 20%). LCMS: m / z537 [M + H]+.XH 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)benzamide190SUBSTITUTE SHEET (RULE 26)

[0471] 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]+.

[0472] 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]+.

[0473] 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]+.

[0474] 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-{[(2,4-191SUBSTITUTE 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]+.

[0475] 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]+.

[0476] Step F: To a stirred solution of 7-(2-chloro-5-fluorophenyl)-6-{[(2,4- dimethoxyphenyl)methyl]amino}-7-hydroxy-8,9-dihydro-7H-pyrrolo[4,3-h]quinolin-9-one (100 mg, 0.21 mmol) in TFA (3 mL, 39.1 mmol) 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]+.

[0477] 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-fluoro-3- (trifluoromethyl)phenyl]carbonyl}-5-(trifluoromethyl)benzamide (100 mg, 0.14 mmol, 66%) as a white solid. LCMS: m / z 328 [M+H]+.

[0478] 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-(trifluoromethyl)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,192SUBSTITUTE 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-(trifluoromethyl)benzamide (25 mg, 0.047 mmol, 33%) as a white solid. LCMS: m / z 534 [M+H]+.

[0479] Step I: To a stirred solution of N-[7-(2-chloro-5-fluorophenyl)-7-hydroxy-9-oxo-8,9- dihydro-7H-pyrrolo[4,3-h]quinolin-6-yl]-5-fluoro-3-(trifluoromethyl)benzamide (25 mg, 0.047 mmol) in TFA (3 mL, 39 mmol) was added 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-AL(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-tetrahydropyirolo[3,4-g]indazol-5-yl)-5- fluorobenzamide

[0480] 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-(2-193SUBSTITUTE SHEET (RULE 26)chloro-5-fluorophenyl)-3-cyano-8-oxo-l,6,7,8-tetrahydropyrrolo[3,4-g]indazol-5-yl)-5- fluorobenzamide (15.1 mg, 0.03 mmol, 27.5%). LCMS: m / z 498 [M + H]+.JH 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-tetrahydro-lH- pyrrolo[3,4-h]quinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamideExample 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

[0481] 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 (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= 7.6194SUBSTITUTE 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-tetrahydropyrrolo[4,3- g] indazol-5-yl] benzo[d] [1,2] thiazole-3 -carboxamide (24.2 mg, 0.048 mmol). LCMS: m / z 503 [M + H]+. '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

[0482] Step A: To a solution of 3-(2-chloro-5-fluorophenyl)-4-({[5-fluoro-3- (trifluoromethyl)phenyl]carbonyl}amino)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-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)benzamide (60 mg, 0.090 mmol, 30%) as a white solid. LCMS: m / z 669.11 [M + H]+

[0483] 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-5-1955UB5TITUTE 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]+.JH 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-(trifluoromethyl)benzamide and Example 43 (R)-N -(6-(2-chloro-5-fluorophenyl)-3-cyano-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0484] N-(6-(2-chloro-5-fluorophenyl)-3-cyano-2-methyl-8-oxo-2, 6,7,8- tetrahydropyrrolo[3,4-g]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (90 mg) was separated by 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]+.XH 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-dihydro-6H- pyrrolo[4,3-g]indazol-5-yl]-5-fluoro-3-(trifluoromethyl)benzamide196SUBSTITUTE SHEET (RULE 26)

[0485] 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]+.

[0486] 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)...

Claims

What is claimed is:CLAIMS1. A compound having the structural formula I:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 5- or 6-membered aromatic ring, substituted with 0-6 Ras;R1is ZB-RB;R2is Zc-Rc;V is C or N;W is C or N;X is N, CH or CRx;Rxis Zx-Rx; each of ZB, Zcand Zxis 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 Ci-4 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 RBand Rcindependently 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 Rb, Rcor Rx, respectivelyRxis deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, - S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(0)NRR’, -401SUBSTITUTE SHEET (RULE 26)C(O)N(R)OR, -OC(O)R, -0C(0)NRR’, -N(R)C(0)0R, -N(R)C(O)R, -N(R)C(0)NRR’, - N(R)C(NR)NRR’, -N(R)S(O)2NRR’, or -N(R)S(O)2R; each of Ra, Rb, Rcand Rxis independentlyH, deuterium, oxo, halogen, -CN, -NO2, -OR, -SR, -NRR’, -S(O)2R, - S(O)2NRR’, -S(O)R, -S(O)NRR’, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(0)NRR’, - C(O)N(R)OR, -OC(O)R, -OC(O)NRR’, -N(R)C(0)0R, -N(R)C(O)R, -N(R)C(0)NRR’, - N(R)C(NR)NRR’, -N(R)S(O)2NRR’ or -N(R)S(O)2R; or an optionally substituted group selected from Ci-6 alkyl or 4- to 6- membered carbocyclic ring, provided that at least one Rais not H such that Ring A is substituted; each of R and R’ is independently selected from H, unsubstituted or substituted Ci-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 z is 1, 2, 3, 4, 5 or 6.

2. The compound of claim 1, wherein Ring A is a 5-membered aromatic ring, substituted with 1-4 Ras, having the structural formula Ia:wherein each of Y1, Y2and Y3is independently CH, N, NH, 0, S or C(0), provided that at least one of Y1, Y2and Y3is not N orNH and at least one of Y1, Y2and Y3is C or CH.

3. The compound of claim 1, wherein Ring A is a 6-membered aromatic ring, substituted with 1-4 Ras, having the structural formula Ii>:402SUBSTITUTE SHEET (RULE 26)wherein each of Y1, Y2, Y3and Y4is independently CH, N, NH, 0, S or C(0), provided that at least two of Y1, Y2, Y3and Y4is not N or NH and at least two of Y1, Y2, Y3and Y4is C or CH.

4. The compound of any one of claims 1-3, whereinRBis 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, 0 and S, substituted with 0-3 Rb’s; andRcis Ring C, a 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl ring with 0-4 ring heteroatoms independently selected from N, 0 and S, substituted with 0-3 Rc’s, having the structural formula Ic:wherein j is 0, 1, 2, 3, 4, 5 or 6; andAr is 0, 1, 2, 3, 4, 5 or 6.

5. The compound of claim 4, wherein ZBis NH-C(O) and Zcis a single bond, having the structural formula la:403SUBSTITUTE SHEET (RULE 26)6. The compound of claim 4, wherein ZBis C(0)-NH and Zcis a single bond, having the structural formula Ie:

7. The compound of any one of claims 1-6, wherein V is C and W is N, and the bond therebetween is a single bond.

8. The compound of any one of claims 1-6, wherein V is N and W is C, and the bond therebetween is a single bond.

9. The compound of any one of claims 1-6, wherein V is C and W is C, and the bond therebetween is a double bond.

10. The compound of any one of claims 1, 2, 4-6 and 9, wherein Ring A is selected from:

11. The compound of claim 10, wherein each of Y1and Y2is NH, optionally substituted with Ra.

12. The compound of any one of claims 1, 2, 4-6 and 9, wherein Ring A is selected from:404SUBSTITUTE SHEET (RULE 26)13. The compound of claim 12, wherein Y1and Y2is NH.

14. The compound of claim 12, wherein Ring A is selected from: whereinRais H, optionally substituted Ci-6 alkyl, or an optionally substituted 4- to 6- membered carbocyclic ring; andRais 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, NRSO2R’3, 4- to 6-membered carbocyclic or heterocyclic; provided that for at least one of Raand Rais not H.

15. The compound of claim 14, wherein Rais selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C2H5, CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH3, CH(OH)CF3, CH2OH, CH2CN, CH2NH2, CH2N(CH3)2, CH2OCHF2, CH2OCF3, NHCH3, isopropyl, cyclopropyl, CCH, CHCH2, QT-azetidine, CN, OCHF2, SO2CH3, NHSO2CH3, CH2-cyclopropyl, difluoro-propyl and trifluoro-propyl.

16. The compound of claim 15, wherein Rais selected from CH2CH2F, CH2CHF2, CH2CF3, CH2-cyclopropyl, difluoro-propyl and trifluoro-propyl.

17. The compound of claim 12, wherein Ring A is selected from:whereinRais H, Cl, F, CN, CH3or CD3; and405SUBSTITUTE SHEET (RULE 26)Rais H, CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN, provided that for each structure at least one of Raand Rais not H.

18. The compound of claim 17, wherein Rais CH2CHF2 or CH2CF3.

19. The compound of claim 17 or 18, wherein Rais H.

20. The compound of claim 17 or 18, wherein Rais CH3 or CD3.

21. The compound of claim 17 or 18, wherein Rais Cl, F or CN.

22. The compound of any one of claims 1, 2, 4-6 and 8, wherein Ring A is selected from:

23. The compound of any one of claims 1, 2, 4-6 and 8, wherein Ring A is selected from:

24. The compound of any one of claims 1, 2 and 4-7, wherein Ring A is selected from:

25. The compound of any one of claims 1, 2 and 4-7, wherein Ring A is selected from:

26. The compound of any one of claims 22-25, wherein each of Y1and Y2is CH.

27. The compound of any one of claims 1, 2, 4-6 and 9, wherein Ring A is selected from:406SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, C1-C4 alkyl and C1-C4 alkoxy.

28. The compound of claim 27, wherein Rais not H.

29. The compound of any one of claims 1, 3-6 and 9, wherein Ring A is selected from:

30. The compound of any one of claims 1, 3-6 and 9, wherein Ring A is selected from:407SUBSTITUTE SHEET (RULE 26)31. The compound of any one of claims 1, 3-6 and 9, wherein Ring A is selected from:

32. The compound of any one of claims 1, 3-6 and 9, wherein Ring A is selected from:408SUBSTITUTE SHEET (RULE 26)33. The compound of any one of claims 29-32, wherein Rais not H.

34. The compound of claim any one of 1-33, wherein X is CH.

35. The compound of claim any one of 1-33, wherein X is CRX.

36. The compound of claim any one of 1-33, wherein X is N.

37. The compound of any one of claims 1-36, wherein Ring B is a substituted or unsubstituted 5- or 6-membered monocyclic carbocyclyl or heterocyclic.

38. The compound of any one of claims 1-36, wherein Ring B is a substituted or unsubstituted 5- or 6-membered monocyclic aryl or heteroaryl ring.

39. The compound of any one of claims 1-36, wherein Ring B is a substituted or unsubstituted 8- to 10-membered bicyclic carbocyclyl or heterocyclic.

40. The compound of any one of claims 1-36, wherein Ring B is a substituted or unsubstituted 8- to 10-membered bicyclic aryl or heteroaryl ring.

41. The compound of any one of claims 1-36, wherein Ring B is selected from:409SUBSTITUTE SHEET (RULE 26)42. The compound of any one of claims 1-36, wherein Ring B is selected from:

43. The compound of any one of claims 1-36, wherein Ring B is selected from:

44. The compound of any one of claims 1-36, wherein Ring B is selected from:

45. The compound of claim 44, wherein Ring B is:

46. The compound of any one of claims 1-36, wherein Ring B is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.410SUBSTITUTE SHEET (RULE 26)47. The compound of claim 46, wherein Ring B is a substituted or unsubstituted phenyl.

48. The compound of claim 46, wherein Ring B is a substituted or unsubstituted pyridyl.

49. The compound of claim 46, wherein Ring B is a substituted or unsubstituted pyridazinyl.

50. The compound of claim 46, wherein Ring B is a substituted or unsubstituted pyrazinyl.

51. The compound of any one of claims 1-5 and 7-49, wherein ZBis NH-C(O).

52. The compound of any one of claims 1-51, wherein Ring C is a substituted or unsubstituted phenyl, pyridyl, pyridazinyl or pyrazinyl.

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

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

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

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

57. The compound of claim 47 or 53, wherein each of Ring B and Ring C is independently a substituted or unsubstituted phenyl.

58. The compound of any one of claims 1-57, wherein Ring C is selected from:

59. The compound of claim 58, wherein Ring C is:

60. The compound of claim 1, having the structural formula If:411SUBSTITUTE SHEET (RULE 26)wherein at least one Rais selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN.

61. The compound of claim 60, having the structural formula Ig:

62. The compound of claim 61, having the structural formula Ig<wherein Ring A is selected from:412SUBSTITUTE SHEET (RULE 26)63. The compound of claim 62, wherein Ring A is64. The compound of claim 62, wherein Ring A is:

65. The compound of claim 63 or 64, wherein Rais selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN.

66. The compound of claim 65, wherein Rais CH2CHF2 or CH2CF3.

67. The compound of any one of claims 63-66, wherein Rais H.

68. The compound of any one of claims 63-66, wherein Rais Cl, F, CN, CH3 or CD3.

69. The compound of claim 62, wherein Ring A is:

70. The compound of claim 69, wherein Rais selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C2H5, CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH3, CH(OH)CF3, CH2OH, CH2CN, CH2NH2, CH2N(CH3)2, CH2OCHF2, CH2OCF3, NHCH3, isopropyl, cyclopropyl, CCH, CHCH2, CH2-azetidine, CN, OCHF2, SO2CH3, NHSO2CH3, CFF-cyclopropyl, difluoro-propyl and trifluoro-propyl.413SUBSTITUTE SHEET (RULE 26)71. The compound of claim 70, wherein Rais selected from CH2CH2F, CH2CHF2, CH2CF3, CFL-cyclopropyl, difluoro-propyl and trifluoro-propyl.

72. The compound of claim 71, wherein Rais H or CH3.

73. The compound of claim 1, having the structural formula h:

74. The compound of claim 73, having the structural formula L:

75. The compound of any one of claims 61-72 and 74, having the following chirality in R1:

76. The compound of any one of claims 61-72 and 74, having the following chirality in R1:414SUBSTITUTE SHEET (RULE 26)77. The compound of claim 1, having the structural formula Ij :

78. The compound of claim 77, having the structural formula Ik:

79. The compound of claim 77 or 78, wherein X is CH.

80. The compound of claim 1, having the structural formula Ik*:415SUBSTITUTE SHEET (RULE 26)wherein Ring A is selected from:

81. The compound of claim 80, wherein Ring A is82. The compound of claim 80, wherein Ring A is:

83. The compound of claim 81 or 82, wherein Rais selected from CH2CH3, CD2CD3, CH2CHF2, CH2CF3 and CH2CN.

84. The compound of claim 80, wherein Rais selected from CH2CH2F, CH2CHF2, CH2CF3, CFF-cyclopropyl, difluoro-propyl and trifluoro-propyl.

85. The compound of any one of claims 81-84, wherein Rais H.

86. The compound of any one of claims 81-84, wherein Rais Cl, F, CN, CH3 or CD3.416SUBSTITUTE SHEET (RULE 26)87. The compound of claim 80, wherein Ring A is:

88. The compound of claim 87, wherein Rais selected from H, F, Cl, NH2, OH, CH3, CHF2, CH2F, C2H5, CH2CH2F, CH2CHF2, CH2CF3, CHFCF3, CH2CH2OH, CH(OH)CH3, CH(OH)CF3, CH2OH, CH2CN, CH2NH2, CH2N(CH3)2, CH2OCHF2, CH2OCF3, NHCH3, isopropyl, cyclopropyl, CCH, CHCH2, CH2-azetidine, CN, OCHF2, SO2CH3, NHSO2CH3, CFF-cyclopropyl, difluoro-propyl and trifluoro-propyl.

89. The compound of claim 88, wherein Rais selected from CH2CH2F, CH2CHF2, CH2CF3, CH2-cyclopropyl, difluoro-propyl and trifluoro-propyl.

90. The compound of any one of claims 87-89, wherein Rais H or CH3.

91. The compound of claim 1, having the structural formula II92. The compound of claim 91, having the structural formula Im:

93. The compound of any one of claims 1-92, having the following chirality at the carbon to417SUBSTITUTE SHEET (RULE 26)which R2is bond:

94. The compound of any one of claims 1-92, having the following chirality at the carbon to which R2is bond:

95. A compound having a structural formula selected from:418SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy; and each Rais independently H or an optionally substituted C1-6 alkyl, provided that at least one of Raand Rais not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

96. A compound having a structural formula selected from:420SUBSTITUTE SHEET (RULE 26)421SUBSTITUTE SHEET (RULE 26)422SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy; and each Rais independently H or an optionally substituted C1-6 alkyl, provided that at least one of Raand Rais not H, each Rais H, halo, optionally substituted C1-6 alkyl, NRR’, CN, optionally substituted C2-6 alkyne, optionally substituted C2-6 substituted alkene, optionally substituted C1-6 alkoxyl, SO2R, NRSO2R 3, 4- to 6-membered carbocyclic or heterocyclic, or a pharmaceutically acceptable form or an isotope derivative thereof.

97. The compound of claim 96, having the following chirality in R1:

98. The compound of claim 96, having the following chirality in R1:

99. The compound of claim 97 or 98, wherein at least one of Raand Ra, if present, is CH2CH3, CD2CD3, CH2CHF2, CH2CF3 or CH2CN.

100. The compound of claim 99, wherein at least one of Raand Ra, if present, is CH2CHF2 or423SUBSTITUTE SHEET (RULE 26)CH2CF3.

101. A compound having a structural formula selected from:424SUBSTITUTE SHEET (RULE 26)425SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, provided that at least one Rais not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

102. A compound having a structural formula selected from:426SUBSTITUTE SHEET (RULE 26)427SUBSTITUTE SHEET (RULE 26)428SUBSTITUTE SHEET (RULE 26)wherein each Rais independently selected from H, halo, CN, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, provided that at least one Rais not H, or a pharmaceutically acceptable form or an isotope derivative thereof.

103. The compound of claim 102, having the following chirality in R1:

104. The compound of claim 102, having the following chirality in R1:

105. The compound of any one of claims 95-104, having the following chirality at the carbon to which R2is bond:429SUBSTITUTE SHEET (RULE 26)106. The compound of any one of claims 95-104, having the following chirality at the carbon to which R2is bond:

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

108. The compound of any of claims 1-107, having one or more hydrogen atoms is replaced by deuterium atoms.

109. The compound of any of claims 1-108, having one hydrogen atom is replaced by a deuterium atom.

110. A pharmaceutical composition comprising a compound according to any one of claims 1- 109 and a pharmaceutically acceptable excipient, carrier, or diluent.

111. The pharmaceutical composition of claim 110, being suitable for oral administration.

112. A unit dosage form comprising a pharmaceutical composition according to claim 110 or 111.

113. The unit dosage form of claim 112, being in the form of a tablet or capsule.

114. A method for inhibiting cellular proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of claims 1-109.

115. A method for inhibiting phosphoinositide 3 -kinase a (PI3Ka) activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-109.

116. A method for treating a disease or disorder mediated by phosphoinositide 3-kinase a (PI3Ka), comprising administering to a subject in need thereof a therapeutically effective430SUBSTITUTE SHEET (RULE 26)amount of the compound according to any one of claims 1-109.

117. The method of claim 116, wherein the disease or disorder is a cellular proliferative disease.

118. A method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1-109.

119. The method of claim 118, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

120. The method of claim 118 or 119, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, gastric cancer, bile duct cancer, and a hematologic malignancy.

121. The method of any one of claims 118-120, wherein the subject has a mutated class IA PI3K pl l0a.

122. The method of any one of claims 118-120, wherein the subject has at least one of the following PI3Ka mutations: H1047R, E542K, and E545K.

123. The method of any one of claims 118-122, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

124. Use of the compound according to any one of claims 1-109, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

125. The use of claim 124, wherein the disease or disorder is a cellular proliferative disease.

126. The use of claim 125, wherein the disease or disorder is cancer.

127. The use of claim 126, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

128. The use of claim 126, wherein the cancer is selected from the group consisting of ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, small and non-small cell lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma,431SUBSTITUTE SHEET (RULE 26)bladder urothelial cancer, gastric carcinomas, bile duct cancer, hepatocellular carcinoma, thyroid carcinoma, and a hematologic malignancy.

129. The use of claim 126, wherein the cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas.432SUBSTITUTE SHEET (RULE 26)

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