Novel bicyclic heteroaryl and heterocyclic compounds, and compositions and methods thereof

Abstract

The invention provides novel bicyclic heteroaryl and heterocyclic compounds and derivatives that inhibit Werner Syndrome ATP dependent helicase enzyme (WRN) activity. The invention also provides pharmaceutical compositions comprising compounds of the invention and methods thereof for treating various diseases and disorders associated with or related to WRN activity, such as various types of cancer.

Description

Patent ApplicationAtty. Docket No. ENTX-033PCTNOVEL BICYCLIC HETEROARYL AND HETEROCYCLIC COMPOUNDS, AND COMPOSITIONS AND METHODS THEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 692,653, filed September 9, 2024, and 63 / 783,055, filed April 3, 2025, 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 bicyclic heteroaryl and heterocyclic compounds and derivatives that inhibit Werner Syndrome ATP dependent helicase enzyme (WRN) activity. The invention also provides pharmaceutical compositions comprising compounds of the invention and methods thereof for treating various diseases and disorders associated with or related to WRN activity, such as various types of cancer.Background of the Invention

[0003] Werner syndrome helicase (WRN) is a member of the RecQ DNA helicase subfamily. RecQ helicases are considered genome caretakers as they are involved in multiple DNA processing steps including DNA replication, double-strand break repair, transcription and telomere maintenance. Defects in WRN, Bloom Syndrome RecQ Like Helicase (BLM) and RecQ Like Helicase 4 (RECQL4) give rise to human disease syndromes associated with developmental defects and cancer predisposition. Patients with Werner syndrome display a premature ageing phenotype including arteriosclerosis, type II diabetes and osteoporosis and are prone to develop tumors of mesenchymal origin, such as soft tissue sarcoma or osteosarcoma. WRN has been identified as a synthetic lethality vulnerability to cancer cells with high microsatellite instability status (MSI-H). In tumor cell lines, the co-occurrence of WRN inactivation and MSI leads to cell death and cell cycle arrest via the acquisition of double-strand breaks and chromosomal instability. (Croteau et al. 2014 Annual Review of Biochemistry 83:519-552; Yu et al. 1996 Science 272:258-262; Chu et al. 2009 Nature ReviewsPatent ApplicationAtty. Docket No. ENTX-033PCTCancer 9:644-654; Brosh, et al. 2013 Nature Reviews Cancer 13 :542-558; Oshima et al. 2017 Ageing Research Reviews 33 / 105-114; Goto et al. 2013 BioScience Trends 7: 13-22; Hickson, et al. 2003 Nature Reviews Cancer 3:169-178; Lauper etal. 2013 PLoS One 8:e59709; Lieb et al. 2019 eLife 8:e43333; Zimmer, et l. 2020 Cancers (Basel) 12(5): 1319.)

[0004] There is an ongoing need for potent and selective WRN inhibitors, in particular, compounds that are useful in treating diseases and disorders, such as various types of cancer, that are associated with WRN activity.Summary of the Invention

[0005] The invention provides novel WRN inhibitors that have been shown to exhibit favorable potency and selectivity profiles over known WRN inhibitors. The novel compounds selectively target, bind to and inhibit the activity of WRN. The compounds are also orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for treating various types of cancer, e.g., cancers characterized by microsatellite instability and / or defective DNA mismatch repair system.

[0006] Covalent inhibitors have made a major impact on human health. A covalent inhibitor selectively binds its target protein to form a covalent complex so as to affect the protein’s function. Via their reactive electrophilic warhead, a covalent inhibitor reacts with nucleophilic residues in binding pockets of a target protein, for example, through a nucleophilic addition or substitution reaction. Without wishing to be bound by the theory, compounds of the invention are selective covalent inhibitors of WRN.

[0007] 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,Patent ApplicationAtty. Docket No. ENTX-033PCT whereinRing A is a substituted 5- or 6-membered heterocyclic, aryl or heteroaryl group;Ring B is a substituted 5- or 6-membered heterocyclic, aryl or heteroaryl group;M is C or N;U is N or C;X is N, C(O) or CRa;Y is N or C;J is C or N;Q is CRa, N, NRb, C(O), O or S;V is CRa, N, NRb, C(O), O or S;Z isE is O or NR;W is CRR6;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R7is H, D, or unsubstituted or substituted Ci-Ce alkyl;R8is H, D, or unsubstituted or substituted Ci-Ce alkyl;R9is Ci-Ce alkyl, C -C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR;Rbis H or R; andPatent ApplicationAtty. Docket No. ENTX-033PCT each of R and R’ is independently selected from H, unsubstituted or substituted Ci-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0008] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0009] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0010] 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.

[0011] In yet another aspect, the invention generally relates to use of compounds disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0012] In yet another aspect, the invention generally relates to a method for making a compound disclosed herein.Definitions

[0013] 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.

[0014] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0015] 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,Patent ApplicationAtty. Docket No. ENTX-033PCT“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.

[0016] 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.

[0017] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0018] 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.

[0019] 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.

[0020] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0021] 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 affect the intended application including, but not limited to, disease treatment, as illustrated below.

[0022] In some embodiments, the amount is that effective for stop the progression or effect reduction of an inflammatory disease or disorder. In some embodiments, the amount is that effective for stop the progression or effect reduction of an immune system disorders. In some embodiments, the amount is that effective to stop the progression or effect reduction of anPatent ApplicationAtty. Docket No. ENTX-033PCT autoimmune disease or disorder. In some embodiments, the amount is that effective for stop the progression or effect reduction of a cardiovascular disease or disorder. 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. In some embodiments, the amount is that effective for stop the progression or effect reduction of PPD, depression, insomnia, sleep apnea, restless legs syndrome, and narcolepsy, emotional disorders, depression, schizophrenia, bipolar disorder, obsessive- compulsive disorder, and other anxiety disorders, behavioral and pharmacological syndrome of dementia, or neurodegenerative diseases. In some embodiments, the amount is that effective for stop the progression or effect reduction of Parkinson's disease (PD). In some embodiments, the amount is that effective for stop the progression or effect reduction of Alzheimer's disease (AD).

[0023] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. Such amount may be administered as a single dosage or according to a regimen. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age / existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0024] 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 to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e. a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used inPatent ApplicationAtty. Docket No. ENTX-033PCT the optional substitution of the described groups include, without limitation, halogen, oxo, CN, - COOH, -CH2CN, -O-CI-C6alkyl, 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-Ci-C6alkyl, -S(O)NHCI-C6alkyl, and S(O)N(CI-C6alkyl)2.

[0025] 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.

[0026] 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-Patent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0027] 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 isopropyl amine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0028] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0029] 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.

[0030] 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.

[0031] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0032] 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.

[0033] 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.

[0034] 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 thePatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.Patent ApplicationAtty. Docket No. ENTX-033PCTAdditionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

[0039] 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.

[0040] 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. By way of example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-4, C1-3, C1-2, C2-5, C2-4, C3-6, C3-5 and C4-6 alkyl groups.

[0041] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C1-6 (e.g., Ci, C2, C3, C4, C5 or Ce) alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, - isopentyl, 2-methylbutyl, 3 -methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2- methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,Patent ApplicationAtty. Docket No. ENTX-033PCT 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)a , -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)tN(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, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3 -hydroxypropyl, benzyl, and phenethyl.

[0042] 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- C6alkyl, 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 tetrahydrobenzoannulenyl.

[0043] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0044] 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 includePatent ApplicationAtty. Docket No. ENTX-033PCT acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothi azole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.“Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.

[0045] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkyl carbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZiZ2)carbonyl. The term "NZ1Z2" 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 NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0046] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0047] As used herein, the terms “cycloalkyl” and “carbocyclic” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partiallyPatent ApplicationAtty. Docket No. ENTX-033PCT unsaturated. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following 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, heteroarylPatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0048] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., O, N, S, P or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl include 2-hydroxy-aziridin-l-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2-dimethyl- tetrahydrofuran-3-yl, 3 -carboxy -morpholin-4-yl, l-cyclopropyl-4-methyl-piperazin-2-yl. 2- pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H- [l ,4]oxazine, etc.

[0049] As used herein, the terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fully saturated or partially unsaturated cyclic groups, for example, 3- to 7-membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered spirocyclic or tricyclic ring systems, which have at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. A heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-lH,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H, 3 'H- spiro[cyclopropane-l,2'-pyrrolizine], hexahydroPatent ApplicationAtty. Docket No. ENTX-033PCTIH-pyrrolizinyl, hexahydro- lH-pyrrolo[2,l- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- thi opy rany 1 1 , 1 -di oxi de .Detailed Description of the Invention

[0050] The invention is based in part on the discovery of novel WRN inhibitors that selectively bind to (e.g., covalently) and inhibit the activity of WRN. The novel compounds have been shown to exhibit favorable potency and selectivity profiles. The compounds exhibit superior DMPK profiles suitable for development into an orally administered therapeutic agent for treating cancer, e.g., cancers characterized by microsatellite instability and / or defective DNA mismatch repair system.

[0051] 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 substituted 5- or 6-membered heterocyclic, aryl or heteroaryl group;Ring B is a substituted 5- or 6-membered heterocyclic, aryl or heteroaryl group;M is C or N;U is N or C;X is N, C(O) or CRa;Y is N or C;J is C or N;Q is CRa, N, NRb, C(O), O or S;Patent ApplicationAtty. Docket No. ENTX-033PCTV is CRa, N, NRb, C(0), O or S;Z isE is O or NR;W is CRR6;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R7is H, D, or unsubstituted or substituted Ci-Ce alkyl;R8is H, D, or unsubstituted or substituted Cj-Ce alkyl;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR;Rbis H or R; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0052] In certain embodiments of (I), M is C and the compound has the structural formula (IA):Patent ApplicationAtty. Docket No. ENTX-033PCT

[0053] In certain embodiments of (IA), U is N and the compound has the structural formula:

[0054] In certain embodiments of (III), J is C and the compound has the structural formula:

[0055] In certain embodiments of (III), J is N and the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT

[0056] In certain embodiments of (IA), U is C and the compound has the structural formula:

[0057] In certain embodiments of (IV), J is C and the compound has the structural formula:

[0058] In certain embodiments of (IV), J is N and the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT

[0059] In certain embodiments of (I), M is N and the compound has the structural formula

[0060] In certain embodiments of (IB), U is N.

[0061] In certain embodiments of (IB), U is C.

[0062] In certain embodiments of (IB), J is N.

[0063] In certain embodiments of (IB), J is C.

[0064] In certain embodiments of (I)-(IB) and (III)-(IVb), Ring A is a 5 -membered heterocyclic group.

[0065] In certain embodiments of (I)-(IB) and (III)-(IVb), Ring A is a 5 -membered heteroaryl group.

[0066] In certain embodiments of (I)-(IB) and (III)-(IVb), Ring A is a 6-membered heterocyclic group.

[0067] In certain embodiments of (I)-(IB) and (III)-(IVb), Ring A is a 6-membered aryl or heteroaryl group.

[0068] In certain embodiments of (I)-(IB) and (III)-(I Vb), Ring B is a 5-membered heterocyclic group.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0069] In certain embodiments of (I)-(IB) and (III)-(IVb), Ring B is a 5-membered heteroaryl group.

[0070] In certain embodiments of (I)-(IB) and (III)-(IVb), Ring B is a 6-membered heterocyclic group.

[0071] In certain embodiments of (I)-(IB) and (III)-(IVb), Ring B is a 6-membered aryl or heteroaryl group.

[0072] In certain embodiments of (I), the compound has the structural formula:whereinG is N or CRa;Q is N, CRaor C(O);V is N, CRaor C(O); andT is N or CRa.

[0073] In certain embodiments of (I), the compound has the structural formula:whereinG is N or CRa;Q is N, CRaor C(O);Patent ApplicationAtty. Docket No. ENTX-033PCTV is N, CRaor C(O); and T is N or CRa.

[0074] In certain embodiments of (VA), Q is C(O) and the compound has the structural formula:

[0075] In certain embodiments of (VA), V is C(O) and the compound has the structural formula:

[0076] In certain embodiments of (I), the compound has the structural formula:whereinG is N or CRa;Patent ApplicationAtty. Docket No. ENTX-033PCTQ is N, C(0) or CRa,V is N, C(O) or CRa; andT is N or CRa

[0077] In certain embodiments of (VI), G is N or CRaand the compound has the structural formula:

[0078] In certain embodiments of (I), the compound has the structural formula:whereinG is N or CRa;Q is N or CRa;V is N or CRa, andT is N or CRa

[0079] In certain embodiments of (V)- (Vc), (VI)-(VIA) and (VII), G if present is N.

[0080] In certain embodiments of (V)- (Vc), (VI)-(VIA) and (VII), G if present is CRa. In certain embodiments, Rais H.

[0081] In certain embodiments of (V)- (Vc), (VI)-(VIA) and (VII), Q if present is N.

[0082] In certain embodiments of (V)- (Vc), (VI)-(VIA) and (VII), Q if present is CRa. In certain embodiments, Raif present is H.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0083] In certain embodiments of (I), the compound has the structural formula:whereinQ is O, S or NRb;V is N or CRa, andT is N or CRa

[0084] In certain embodiments of (VIII), Q is NRb. In certain embodiments, Rbis H. In certain embodiments, Rbis CH3.

[0085] In certain embodiments of (VIII), Q is O.

[0086] In certain embodiments of (VIII), Q is S.

[0087] In certain embodiments of (VIII), V is N.

[0088] In certain embodiments of (I), the compound has the structural formula:whereinQ is N or CRa:V is O, S or NRb; andT is N or CRa.

[0089] In certain embodiments of (IX), V is NRa.

[0090] In certain embodiments of (IX), V is O.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0091] In certain embodiments of (IX), V is S.

[0092] In certain embodiments of (IX), Q is N.

[0093] In certain embodiments of (I), the compound has the structural formula:whereinQ is N or CRa;V is N or CRa; andT is N or CRa

[0094] In certain embodiments of (I), the compound has the structural formula:whereinQ is O, S or NRb:V is N or CRa; andT is N or CRa.

[0095] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCTwhereinQ is N or CRa;V is O, S or NRb; andT is N or CRa.

[0096] In certain embodiments of (I), the compound has the structural formula:whereinQ is O, S or NRb;V is N or CRa; andT is N or CRa

[0097] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT whereinQ is N or CRa;V is O, S or NRb; andT is N or CRa

[0098] In certain embodiments of (XIb) and (XIIb), Q is CRa.

[0099] In certain embodiments of (XIb) and (XIIb), V is O.

[0100] In certain embodiments of (XIb) and (XIIb), V is S.

[0101] In certain embodiments of (XIb) and (XIIb), V is NRb.

[0102] In certain embodiments of (XIa) and (XIF), V is CRa.

[0103] In certain embodiments of (XIa) and (XIIa), Q is O.

[0104] In certain embodiments of (XIa) and (XIF), Q is S.

[0105] In certain embodiments of (XF) and (XIF), Q is NRb.

[0106] In certain embodiments of (I), the compound has the structural formula:whereinQ is N or CRa;V is N or CRa: andR ■ is R .

[0107] In certain embodiments of (XIII), R4is H.

[0108] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCTwhereinQ is N or CRa;V is N or CRa, andR:is Ra.

[0109] In certain embodiments of (I), the compound has the structural formula:whereinX is N or CRa;Q is N or CRa;V is N or CRa, andR" is Ra.

[0110] In certain embodiments of (XV), R4is H.

[0111] In certain embodiments of (XV), X is N.

[0112] In certain embodiments of (XV), X is CRa.

[0113] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCTwhereinX is N or CRa;Q is N or CRa;V is N or CRa, andT is N or CRa; andRais Rd

[0114] In certain embodiments of (XVI), R4is H.

[0115] In certain embodiments of (XVI), X is N.

[0116] In certain embodiments of (XVI), X is CRa.

[0117] In certain embodiments of (I), (III)-(VII) and (XIII)-(XVI), V is CRa.

[0118] In certain embodiments of (I), (III)-(VII) and (XIII)-(XVI), V is N.

[0119] In certain embodiments of (I), (III)-(VII) and (XIII)-(XVI), Q is CRa.

[0120] In certain embodiments of (I), (III)-(VII) and (XIII)-(XVI), Q is N.

[0121] In certain embodiments of (I), (III)-(VII), (VIII)-(XIIb) and (XVI), T is CRa.

[0122] In certain embodiments of (I), (III)-(VII), (VIII)-(XIIb) and (XVI), T is N.

[0123] In certain embodiments of (I) and (III)-(XVI), R3is a halogen.

[0124] In certain embodiments of (I) and (III)-(XVI), R3is a substituted or unsubstituted Ci-Ce alkyl.

[0125] In certain embodiments of (I) and (III)-(XVI), R3is a substituted or unsubstituted Ci-C4 alkyl.

[0126] In certain embodiments of (I) and (III)-(XVI), R3is C1-C4 alkyl substituted with 1, 2,3, 4 or 5 halogen (e.g., F, Cl).

[0127] In certain embodiments of (I) and (III)-(XVI), R3is C2-C4 alkyl substituted with 1, 2 or 3 halogen (e.g., F, Cl).Patent ApplicationAtty. Docket No. ENTX-033PCT

[0128] In certain embodiments of (I) and (III)-(XVI), R3is a substituted or unsubstituted C2- C4 alkynyl.

[0129] In certain embodiments of (I) and (III)-(XVI), R1is a substituted or unsubstituted 6- membered aryl or heteroaryl.

[0130] In certain embodiments of (I) and (III)-(XVI), W is CRR6. In certain embodiments, R is H. In certain embodiments, R6is a Ci-Ce alkyl. In certain embodiments, R6is a C3-C6 carbocyclic. In certain embodiments, R6is cyclopropyl.

[0131] In certain embodiments is:

[0132] In certain embodiments of (I)-(XVI), E is NR and Z is:

[0133] In certain embodiments of (I)-(XVI), E is NH and Z is:

[0134] In certain embodiments of (I)-(XVI), R7and R8are in a trans configuration:

[0135] In certain embodiments of (I)-(XVI), R7and R8are in a cis configuration:Patent ApplicationAtty. Docket No. ENTX-033PCT

[0136] In certain embodiments of (I)-(XVI), E is NR and -S(O)(NR)R9is characterized by the following chirality:

[0137] In certain embodiments of (I)-(XVI), E is NR and -S(O)(NR)R9is characterized by the following chirality:

[0138] In certain embodiments of (I)-(XVI), R7is H.

[0139] In certain embodiments of (I)-(XVI), R8is H.

[0140] In certain embodiments of (I)-(XVI), R9is Ci-Ce alkyl.

[0141] In certain embodiments of (I)-(XVI), R9is CH3.

[0142] In certain embodiments of (I)-(XVI), R9is CD3.

[0143] In another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;Patent ApplicationAtty. Docket No. ENTX-033PCTT is CRaor N;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R4is Rs;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0144] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;Patent Application Atty. Docket No. ENTX-033PCTV is CRaor N;T is CRaor N;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Q- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0145] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;Patent ApplicationAtty. Docket No. ENTX-033PCTV is CRaor N;T is CRaor N;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Q- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0146] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;Patent Application Atty. Docket No. ENTX-033PCTV is CRaor N;T is CRaor N;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Q- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0147] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;Patent ApplicationAtty. Docket No. ENTX-033PCTV is CRaor N;T is CRaor N;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Q- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R';is Ra;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0148] In certain embodiments of (Ia)-(Ie), Q is CRa.

[0149] In certain embodiments of (Ia)-(Ie), Q is N.

[0150] In certain embodiments of (Ia)-(Ie), V is CRa.

[0151] In certain embodiments of (Ia)-(Ie), V is N.

[0152] In yet another aspect, the invention generally relates to a compound having the structural formula:Patent Application Atty. Docket No. ENTX-033PCT cn or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;T is CRaor N;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, C>,- C10 aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Cj-C6alkyl, Cs-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0153] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof,Patent ApplicationAtty. Docket No. ENTX-033PCT whereinE is O or NR;T is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, C&- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cs-Cs carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, Ch-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0154] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Patent Application Atty. Docket No. ENTX-033PCTQ is NRb, O or S;V is CRaor N;T is N or CRa;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, C&- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cs-Cs carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, Ch-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0155] In certain embodiments of (Ih), Q is NRa.

[0156] In certain embodiments of (Ih), Q is O.

[0157] In certain embodiments of (Ih), Q is S.

[0158] In certain embodiments of (Ih), V is N.

[0159] In yet another aspect, the invention generally relates to a compound having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT(r) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is NRb, O or S;T is N or CRa;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cs-Cs carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, Ci-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR;Rbis H or R; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0160] In certain embodiments of (I1), Q is NRa.

[0161] In certain embodiments of (f), Q is O.

[0162] In certain embodiments of (I1), Q is S.

[0163] In certain embodiments of (I1), V is N.

[0164] In yet another aspect, the invention generally relates to a compound having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCTor a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;T is N or CRa;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cs-Cs carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Cj-Ce alkyl, ( ;-Cbcarbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0165] In yet another aspect, the invention generally relates to a compound having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCTor a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is NRb;V is CRaor N;T is N or CRa;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, C&- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cb-Cs carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-C6alkyl, Cs-C6 carbocyclic or C2-C5 heterocyclic, wherein said alky], carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR;Rbis H or R; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0166] In certain embodiments of (Ij) and (Ik), V is N.

[0167] In certain embodiments of (I>) and (Ik), V is CRa.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0168] In certain embodiments of (I>) and (Ik), T is CRa.

[0169] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;R1is selected from Ci-Cg alkyl, Cs-Cg carbocyclic, 4- to 6-membered heterocyclic, Cg- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Cg alkyl, Ci-Cg alkenyl, Ci-Cg alkynyl, Cb-Cg carbocyclic, 4- to 6- membered heterocyclic, Cg-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R4is Ra;R9is Ci-Cg alkyl, Cj-Cg carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted Ci-g alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0170] In yet another aspect, the invention generally relates to a In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R4is RyR9is Cj-Ce alkyl, Cs-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0171] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R4is RyR9is Cj-Ce alkyl, Cs-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0172] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;T is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, C&- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0173] In yet another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;T is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, C&- Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6- membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

[0174] In certain embodiments of (I’)-(IP), Q is CH.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0175] In certain embodiments of (I*)-(IP), Q is N.

[0176] In certain embodiments of (I*)-(IP), V is CH.

[0177] In certain embodiments of (I1)-(IP), V is N.

[0178] In certain embodiments of (Ia)-(IP), R9is CH3 or CD3.

[0179] In certain embodiments of (Ia)-(IP), R1is substituted or unsubstituted phenyl.

[0180] In certain embodiments of (Ia)-(IP), R3is C1-C4 alkyl substituted with 1, 2, 3, 4 or 5 halogen (e.g., F, Cl).

[0181] In certain embodiments of (Ia)-(IP), R3is substituted or unsubstituted C2-C4 alkynyl.

[0182] In certain embodiments of (Ia)-(IP), E is O.

[0183] In certain embodiments of (Ia)-(IP), E is NR.

[0184] In certain embodiments of (Ia)-(IP), E is NH.

[0185] Non-limiting examples of compounds of the invention include those listed in Table 1.Table 1. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-O33PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent Application Atty . Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCTPatent ApplicationAtty. Docket No. ENTX-033PCT

[0186] In certain embodiments, a compound disclosed herein has one or more deuterium atoms in place of hydrogen.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0187] In certain embodiments, the compound has one deuterium atom in place of a hydrogen atom.

[0188] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0189] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0190] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0191] In certain embodiments, is in the form of a tablet. In certain embodiments, is in the form of a capsule.

[0192] 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.

[0193] In certain embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer and thyroid cancer.

[0194] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

[0195] In yet another aspect, the invention generally relates to a method for making a compound disclosed herein.

[0196] Compounds of the invention include deuterated versions of the disclosed compounds, for example, having one or more deuterium atoms in place of hydrogen.

[0197] 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.

[0198] 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 mixturesPatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0199] 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).

[0200] 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.

[0201] 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 comprisePatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0202] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[0203] 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.

[0204] Any appropriate route of administration can be employed, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalational, buccal, intraperitoneal, rectal, intrapleural, and intrathecal administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[0205] 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 anPatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0206] 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.

[0207] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0208] 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.

[0209] 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 andPatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0210] 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 diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0211] 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.

[0212] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing aPatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0213] 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.

[0214] 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.

[0215] Methods of treatment disclosed herein may be employed in combination with or in addition to other therapies. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0216] 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,Patent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0217] 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.

[0218] 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.

[0219] In certain embodiments, the method disclosed herein is in combination with one or more of immune check point blockade, co-signaling of T cells, and tumor targeting antibody therapies.

[0220] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0221] 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.

[0222] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesPatent ApplicationAtty. Docket No. ENTX-033PCT including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L- norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, di deoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin;Patent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0223] Examples of the second (or further) agent or therapy may include, but are not limited to, immunotherapies (e.g. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonist, cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab and the like), mitosis inhibitors e.g., paclitaxel, vincristine, vinblastine and the like), alkylating agents (e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and the like), anti-metabolites (e.g., methotrexate, 5-FU and the like), intercalating anticancer agents, (e.g., actinomycin, anthracycline, bleomycin, mitomycin-C and the like), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide and the like), immunotherapy agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0224] 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.Patent ApplicationAtty. Docket No. ENTX-033PCTAdditional 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.

[0225] 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.

[0226] 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.

[0227] 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,lyN,18O,170,31P,32P,35S,18F, and36C1, respectively.

[0228] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.Patent Application Atty. Docket No. ENTX-033PCT

[0229] Further, substitution of normally abundant hydrogen ('H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. Benefits may also be obtained from replacement of normally abundant12C with13C. (See, WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.)

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] Compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0235] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may bePatent ApplicationAtty. Docket No. ENTX-033PCT 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.

[0236] 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.

[0237] 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.

[0238] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps thatPatent ApplicationAtty. Docket No. ENTX-033PCT 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

[0239] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0240] 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.List of Abbreviations aq: aqueousAc = AcetylAcO = AcetateAc2O = Acetic anhydrideAIBN = a,a'-AzoisobyronitrileAll = AllylAlloc = AllyloxycarbonylAm = Amyl (Pentyl)Ar = ArylB2Pin2 = bis(pinacolato)diboron9-BBN = 9-BorabicyclononaneBHT = tert-ButylhydroxytolueneBINAP = 2,2'-Bis(diphenylphosphino)-l,T-binaphthylBMS = Borane-methylsulphide complexBn = BenzylBoc = tert-Butoxy carbonylBOP = Bis(2-oxo-3-oxazolidinyl)phosphineBu or n-Bu = n-Butyl s-Bu or sBu = sec-ButylPatent ApplicationAtty. Docket No. ENTX-033PCT 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 ’ bipheny l)]palladium(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 azodi carb oxy lateDHP = DihydropiranDHQD = DihydroquinidineDIBAL = Diisobutylaluminium hydrideDIBAL-H = Diisobutylaluminium hydrideDIC = 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 = DiisopropylamineDPPA = Diphenylphosphoryl azidePatent ApplicationAtty. Docket No. ENTX-033PCTDdpb = 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 = equivalentES-API = electrospray-atmospheric pressure ionization.ESI or ES = Electrospray ionizationEt = ethylEt2O = Diethyl etherEtOAc = Ethyl acetateFMOC = 9-FluorenylmethoxycarbonylHATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHMDS = HexamethyldisilazaneHMPA = HexamethylphosphoramideHO At = 7-Aza-l -hydroxybenzotriazoleHOBt = 1-Hydroxybenzotri azoleHPLC = high pressure liquid chromatographyIP A = Isopropyl alcoholIm = ImidazoleKHMDS = Potassium bis(trimethylsilyl)amideKO Ac = Potassium acetateLAH = Lithium aluminium hydrideLDA = Lithium diisopropylamideLHMDS = Lithium bis(trimethylsilyl)amideMCPBA = meta-chloroperoxybenzoic acidMe = MethylMeCN = AcetonitrileMeOH = MethanolMOM = MethoxymethylMg = magnesiumMS = Molecular sievesMs = MethanesulphonylMTBE = Methyl tert-butyl etherPatent ApplicationAtty. Docket No. ENTX-033PCT m / z = mass divided by chargeNa2SO4 = Sodium SulphateNaHMDS = Sodium bis(trimethylsilyl)amideNaCNBH3 = Sodium cyanoborohydrideNBS = N-BromosuccinimideNCS = N-ChlorosuccinimideNIS = N-IodosuccinimideNMM = N-MethylmorpholineNMO = N-Methylmorpholine-N-oxideNMP = N-MethylpyrrolidoneNMR = Nuclear magnetic resonanceNs = p-Nitrophenyl sulphonylPd(dppf)C12 = [1, r-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-ButyldiphenylsilylTBHP = tert-ButylhydroperoxydePatent ApplicationAtty. Docket No. ENTX-033PCTTBS = tert-ButyldimethylsilylTEA = TriethylamineTES = Tri ethyl silylTf = TrifluoromethanesulfonylTfO = TrifluoromethanesulfonateTf2O = Trifluoromethanesulfonyl anhydrideTfOH = Trifluoromethanesulfonic acidTFA = Trifluoroacetic acidTFAA = Trifluoroacetic anhydrideThexyl = 2,3 -dimethyl-2 -butylTHF = TetrahydrofuraneTHP = TetrahydropyranylTIPS = Triisopropyl silylTMEDA = N,N,N',N'-TetramethylethylendiamineTMG = TetramethylguanidineTMS = TrimethylsilylTol = p-ToluylTPAP = Tetra-n-propylammonium perruthenateTPS = Tripropyl silylTr = Trityl, triphenylmethylTroc = 2,2,2-TrichloroethoxycarbonylTrt = Trityl, triphenylmethylTs = p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acidUV = ultravioletZ = BenzyloxycarbonyUV: ultra violet

[0241] General LCMS Method :Instrument: Shimadzu LCMS2020Reverse-phase column (Shim-Pack Scepter C 18, 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).

[0242] General HPLC analytical method:Instrument: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281.Patent ApplicationAtty. Docket No. ENTX-033PCTColumn: YMC-Triart Cl 8, 250*20 mm, 5um; Welch Ultimate XB-C18, 250*21.2 mm, 5um.Detection wavelength: 220, 254 nM.Flow rate: 15ml / min-20ml / min;Run time: 8 min;Column temperature: 25 °C.

[0243] General prep-HPLC purification method:Instrument: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281.Column: YMC-Triart Cl 8, 250*20 mm, 5um; Welch Ultimate XB-C18, 250*21.2 mm, 5um.Elution with A: H2O; B: MeCN;Flow rate: 15ml / min - 20ml / min.Modifier: 0.1% FA; 0.1% TFA; NH4HCO3; NH4OH.Run time: 15 min~ 30min;Detection wavelength: 220, 254 nM.Column temperature: 25 °C.

[0244] XH NMR SpectroscopyNMR spectra were run with Bruker Ultrashield TM400 (400 MHz), Bruker UltrashieldTM400 Plus (400 MHz), Bruker Ultrashi el dTM600 (600 MHz) and Bruker AscendTM400 (400 MHz) 15 spectrometers, all with and without tetramethylsilane as an internal standard. Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (single), d (double), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), br (broad).Exemplary chiral prep-SFC conditions and methods for isomers separation:

[0245] Method 1:Instrument: Waters Thar 80 preparative SFCColumn: ChiralPakC-IG, 250><30mm I.D., 5pmMobile phase: A for CO2 and B for MEOH ( 0.1% 7mol / L NH3 in MeOH)Gradient: B 40%Flow rate: 60mL / minBack pressure: 100 barColumn temperature: 35 °CPatent ApplicationAtty. Docket No. ENTX-033PCTWavelength: 220nmRun time: 13 minCycle-time: 13minInjection volume: 3mLNumber of injection needles: 9Eluted time: 2H

[0246] Method 2:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak AD, 250><30mm I.D., 5 pmMobile phase: A for CO2 and B for MEOHGradient: B 25%Flow rate: 60 mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220 nmCycle-time: 10 minInjection volume: 1.5 mLNumber of injection needles: 4Eluted time: 2 H

[0247] Method 3:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak AD, 250x30mm I.D., 5pmMobile phase: A for CO2 and B for MEOH (0.1% 7mol / L NH3 in MeOH)Gradient: B 40%Flow rate: 60mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220nmCycle-time: 8 minInjection volume: 3 mLNumber of injection needles: 5Patent ApplicationAty. Docket No. ENTX-033PCTEluted time: 2 H

[0248] Method 4:Instrument: Waters Thar 80 preparative SFCColumn: ChiralPak C-IG, 250><30mm I.D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 50%Flow rate: 60 mL / minBack pressure: 100 barColumn temperature: 35°CWavelength: 220nmRun time: 16minCycle-time: 16minInjection volume: 4.2 mLNumber of injection needles: 3Eluted time: 2H

[0249] Method 5:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak IC, 250x30mm I.D., 5pmMobile phase: A for CO2 and B for MEOHGradient: B 35%Flow rate: 60mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220nmCycle-time: lOminEluted time: 2H

[0250] Method 6:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak IC, 250x30mm I.D., 5pmMobile phase: A for CO2 and B for MEOH+0.1%NH3H2OGradient: B 30%Patent ApplicationAty. Docket No. ENTX-033PCTFlow rate: 60mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 10 minEluted time: 3H

[0251] Method ?:Instrument: Waters Thar 80 preparative SFCColumn: ChiralPak IG, 250><20mm I D., 5pmMobile phase: A for CO2 and B for MeOH (0.1% 7mol / L NH3 in MeOH)Gradient: B 50%Flow rate: 30mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmRun time: 10 minCycle-time: 7 minInjection volume: 1 mNumber of injection needles: 10Eluted time: 2H

[0252] Method 8:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralCel OZ, 250x20mm I.D., 5pmMobile phase: A for CO2 and B for MEOH (0.1% 7mol / L NH3 in MeOH)Gradient: B 40 %Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 20 minPatent ApplicationAtty. Docket No. ENTX-033PCTInjection volume: 1.5 mLNumber of injection needles: 9Eluted time: 4H

[0253] Method 9:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralCel OZ, 250><20mm I D., 5 pmMobile phase: A for CO2 and B for MEOH (0.1% 7mol / L NH3 in MeOH)Gradient: B 40 %Flow rate: 40mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 20 minInjection volume: 1.5 mLNumber of injection needles: 9Eluted time: 4HExemplary synthetic procedures:General synthetic route I for pyridone or pyridazinone fused bicyclic examples:

[0254] Warhead Z piece could be installed to pyridone or pyridazinone fused bicyclic intermediate (Int-I) bearing R1, R3and other substituents vial a three-step-sequence in the Scheme I below using synthetic chemistry and purification of the intermediates and products with methods known in the art of synthetic organic chemistry:Patent ApplicationAtty. Docket No. ENTX-033PCTScheme Iyridazinone with ethyl 2-bromo(or other leaving groups)-2-R6-acetate (step 1), followed by a reduction of the ester to aldehyde (step 2), then an olefination of the aldehyde to form Michael acceptor, which could be achieved via an olefination reaction, i.e., Horner-Wadsworth-Emmons Reaction with phosphorus ylides ((R9- sulfonyl)methyl)phosphonate or ((R9-sulfonimidoyl)methyl)phosphonate (step 3).

[0256] In some embodiments, warheads could be introduced via the olefine metathesis showing in the step 2 of Scheme II below:Scheme IIlnt-1

[0257] In some embodiments, the enantiomers are obtained through chiral resolution (Scheme III), i.e., prep-HPLC or prep-SFC with chiral column from racemic compounds. In some embodiments, chiral sulfoximine compounds could be separated through chiral resolution i.e., prep-HPLC or prep-SFC with chiral column from mixed compounds.Scheme III

[0258] In some embodiments, installation of exemplary warhead Z piece, R1and R3on Int-II could be installed in various sequences depending on the availability of reagents andPatent ApplicationAtty. Docket No. ENTX-033PCT exploration of these pieces. For example, warhead Z piece could be introduced before R1and R3groups, which is described in the General synthetic for Int-II in the Scheme IV below. Halides (Br or I) or other leaving groups could be optionally (steps 2 and 4 once needed) introduced to the para-position of the carbonyl in ring A pyridone or pyridazinone, and the desired position on the fused ring B sequentially, which gives handles to introduce R1andR3via cross coupling reactions, sequentially and respectively, meaning sequences of steps 2-3 and 4-5 can be switched.General synthetic route for Int-II:Scheme IV

[0259] In some embodiments, pyridone fused bicyclic core are constructed via a ring closure chemistry of “carboxylic acid - enoate” intermediate (Int-III) with amine bearing warhead Z piece (Int-IV) to form the pyridone. This synthetic method can introduce Z piece with active stereochemistry directly while using the desired enantiomer of the amine, which is described in the Scheme VI below:General synthetic route II for pyridone fused bicyclic examples:Exemplary synthetic procedures for intermediates:Patent ApplicationAtty. Docket No. ENTX-033PCTInt-IV: (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine 4-methylbenzenesulfonic acid (R6is cyclopropyl, R9= methyl)

[0260] Step A: To a solution of tert-butyl (S)-(l-cyclopropyl-2-hydroxyethyl)carbamate (1.7 g, 8.4 mmol) in DCM (25 mL) was added Dess-Martin periodinane (7.2 g, 16.9 mmol). The reaction was stirred at 25 °C for 2 hours under N2 atmosphere. The reaction was diluted with icewater, extracted with DCM (40 mL x 3), The organic layer was separated, washed with sat. NaHCO3 and brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by flash column chromatography eluted with 0-10% ethyl acetate in petroleum ether to afford tertbutyl (S)-(l-cyclopropyl-2-oxoethyl)carbamate, 1-1 (1.2 g, 71%) as a colorless oil.

[0261] Step B: To a solution of 1-1 (1.2 g, 6.0 mmol) in THF (15 mL) was added diethyl [(methyldioxo-L6-sulfanyl)methyl]phosphonate (1.25 g, 5.4 mmol) and K^CCh (2.5 g, 18.0 mmol). The reaction was stirred at 60 °C for 3 hours under N2 atmosphere. The reaction was diluted with ice-water, extracted with EtOAc (20 mL x 3) The organic layer was separated, washed with brine and concentrated. The residue was purified by flash column chromatography eluted with 0-25% ethyl acetate in petroleum ether to afford tert-butyl (S,E)-(l-cyclopropyl-3- (methylsulfonyl)allyl)carbamate, 1-2 (1.2 g, 72%) as a white solid.

[0262] LCMS (ESI): m / z 276 [M+H]+. 'HNMR (400 MHz, CDC13) 8 6.93 (dd, J = 15.2, 4.8 Hz, 1H), 6.52 (dd, J = 15.2, 1.6 Hz, 1H), 4.75 (brs, 1H), 3.68 (brs, 1H), 2.95 (s, 3H), 1.45 (s, 9H), 0.95 - 0.82 (m, 1H), 0.70 - 0.55 (m, 2H), 0.49 - 0.29 (m, 2H).

[0263] Step C: To a solution of 1-2 (70 mg, 0.254 mmol) in MeCN (6 mL) was added TsOH (52 mg, 0.305 mmol). The reaction was stirred at 60 °C for 3 hours under N2 atmosphere. The reaction was concentrated to afford (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine 4- methylbenzenesulfonic acid, 1-3 (50 mg, 56%) as a white solid which was used directly for next step without purification. LCMS (ESI): m / z 176 [M+H]+Exemplary synthetic procedures for Examples:Example 1: (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[4,3-d]pyrimidin-5(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCTExample 2: (S,E)-6-(l-cyclopropyl-3-(methylsuIfonyI)allyI)-2-(l,l-difluoroethyl)-8- phenylpyrido[4,3-d]pyrimidin-5(6H)-oneExample 3: (R,E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[4,3-d]pyrimidin-5(6H)-one

[0264] Step A: To a solution of methyl 2-chloro-4-methylpyrimidine-5-carboxylate (5 g, 26.88 mmol) and tributyl(l -ethoxy vinyl)stannane (11.6 g, 32.16 mmol) in N,N- Dimethylformamide (5 mb) was added tetrakis(triphenylphosphine)palladium (2.18 g, 1.89 mmol). The reaction mixture was stirred at 100 °C for 3 hours under nitrogen. Then the cooled reaction mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. To the organic layer was added 2 AHC1 (10 mb) and the mixture was stirred at room temperature for 0.5 hour. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 10-15% ethyl acetate in petroleum ether toPatent ApplicationAtty. Docket No. ENTX-033PCT afford methyl 2-acetyl-4-methylpyrimidine-5-carboxylate (4 g, 77%). LCMS (ESI): m / z 195 [M + H]+.

[0265] Step B: A mixture of methyl 2-acetyl-4-methylpyrimidine-5-carboxylate (3 g, 15.45 mmol) in DAST (20 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 10-15% ethyl acetate in petroleum ether to afford methyl 2-(l,l-difluoroethyl)-4-methylpyrimidine-5-carboxylate (3.0 g, 90%). LCMS (ESI): m / z 217 [M+H]+

[0266] Step C: A mixture of methyl 2-(l,l-difluoroethyl)-4-methylpyrimidine-5-carboxylate (1.0 g, 4.63 mmol) and l,l-di-tert-butoxy-N,N-dimethylmethanamine (CAS# 36805-97-7; 4.69 g, 23.13 mmol) in DMA (10 mL) was stirred at 100 °C for 2 hours. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography, eluted with a gradient of 10-15% ethyl acetate in petroleum ether to afford methyl (E)-2-(l, l-difluoroethyl)-4-(2- (dimethylamino)vinyl)pyrimidine-5-carboxylate (1.0 g, 80%). LCMS (ESI): m / z 272 [M+H]+

[0267] Step D: A mixture of methyl (E)-2-(l,l-difluoroethyl)-4-(2-(dimethylamino)vinyl)pyrimidine-5-carboxylate (1.0 g, 3.66 mmol) and NH4OAC (2.82 g, 36.59 mmol) in EtOH (10 mL) was stirred at 100 °C for 8 hours under nitrogen. The reaction mixture was diluted with H2O, extracted with DCM. The combined organic layer was washed with water and brine, dried over anhydrous Na2 SO4, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% MeOH in DCM to afford 2-(l,l-difluoroethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (700 mg, 91%). LCMS (ESI): m / z 212 [M+H]+

[0268] Step E: To a stirred mixture of 2-(l,l-difluoroethyl)pyrido[4,3-d]pyrimidin-5(6H)- one (700 mg, 3.31 mmol) in acetonitrile (10 mL) was added NBS (708 mg, 3.98 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% MeOH in DCM to afford 8-bromo-2-Patent ApplicationAtty. Docket No. ENTX-033PCT(l,l-difluoroethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (800 mg, 83%). LCMS (ESI): m / z 290 [M+H]+

[0269] Step F: To a mixture of 8-bromo-2-(l,l-difluoroethyl)pyrido[4,3-d]pyrimidin-5(6H)- one (800 mg, 2.76 mmol), phenylboronic acid (504 mg, 4.14 mmol), K3PO4 (878 mg, 4.14 mmol) in dioxane (10 mL) and H2O (1 m ) was added PdCh(dtbpf) (CAS# 95408-45-0; 0.14 g, 0.21 mmol). Then the reaction mixture was stirred at 100 °C for 4 hours under nitrogen. The cooled reaction mixture was diluted with H2O, extracted with DCM. The combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 to 10% MeOH in DCM to afford 2-(l,l-difluoroethyl)-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one (700 mg, 88%). LCMS (ESI): m / z 288 [M+H]+.

[0270] Step G: To a stirred mixture of 2-(l,l-difluoroethyl)-8-phenylpyrido[4,3- d]pyrimidin-5(6H)-one (600 mg, 2.09 mmol) in N,N-Dimethylformamide (15 mL) were added 1- cyclopropylprop-2-en-l -ol (2.05 mg, 20.9 mmol) and CMBP (2.5 g, 10.4 mmol; in Toluene). The reaction mixture was stirred at 100 °C for 4 hours and then diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford 6-(l- cyclopropylallyl)-2-(l, l-difluoroethyl)-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one (180 mg, 23%). LCMS (ESI): m / z 368 [M+H]+.

[0271] Step H: A mixture of 6-(l-cyclopropylallyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[4,3-d]pyrimidin-5(6H)-one (180 mg, 0.49 mmol), (methylsulfonyl)ethene (520 mg, 4.90 mmol) and Hovey da-grubbs 2nd(CAS# 301224-40-8; 61 mg, 0.10 mmol) in DCE (10 mL) was stirred at 90 °C for 4 hours. The cooled reaction mixture was diluted with H2O, extracted with DCM. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (Cl 8, MeCN / TLO, 0.1% ammonium bicarbonate modifier, 0 to 70% gradient, 30 min run) to afford (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrido[4,3- d]pyrimidin-5(6H)-one (2.1 mg, 1%). LCMS (ESI): m / z 446 [M+H]+. 'H NMR (400 MHz, DMSO-cL) 5 9.69 (s, 1H), 8.34 (s, 1H), 7.70 (d, J= 8.0 Hz, 2H), 7.50 (t, J= 7.2 Hz, 2H), 7.42 (t, J= 7.2 Hz, 1H), 7.06 (dd, J= 15.2, 4.4 Hz, 1H), 6.97 (d, J= 15.2 Hz, 1H), 4.82 (dd, J= 10.0, 4.4Patent ApplicationAtty. Docket No. ENTX-033PCTHz, 1H), 3.03 (s, 3H), 2.04 (t, J= 19.2 Hz, 3H), 1.86 - 1.82 (m, 1H), 0.86 - 0.82 (m, 1H), 0.74 - 0.67 (m, 1H), 0.61 - 0.57 (m, 1H), 0.44 - 0.36 (m, 1H).

[0272] Step I: (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[4,3-d]pyrimidin-5(6H)-one was purified by chiral prep-SFC method 1 to give (S,E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrido[4,3- d]pyrimidin-5(6H)-one LCMS (ESI): m / z 446 [M+H]+. 'H NMR (400 MHz, DMSO-tfc) 8 9.69 (s, 1H), 8.34 (s, 1H), 7.70 (d, J= 8.0 Hz, 2H), 7.50 (t, J= 7.2 Hz, 2H), 7.42 (t, J= 7.2 Hz, 1H), 7.06 (dd, J= 15.2, 4.4 Hz, 1H), 6.97 (d, J= 15.2 Hz, 1H), 4.82 (dd, J= 10.0, 4.4 Hz, 1H), 3.03 (s, 3H), 2.04 (t, J= 19.2 Hz, 3H), 1.86 - 1.82 (m, 1H), 0.86 - 0.82 (m, 1H), 0.74 - 0.67 (m, 1H), 0.61 - 0.57 (m, 1H), 0.44 - 0.36 (m, 1H). And (R,E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)- 2-(l,l-difluoroethyl)-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one LCMS (ESI): m / z 446 [M+H]+. 'HNMR (400 MHz, DMSO-tC) 8 9.69 (s, 1H), 8.34 (s, 1H), 7.70 (d, J= 8.0 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.42 (t, J= 7.2 Hz, 1H), 7.06 (dd, J= 15.2, 4.4 Hz, 1H), 6.97 (d, J= 15.2 Hz, 1H), 4.82 (dd, J= 10.0, 4.4 Hz, 1H), 3.03 (s, 3H), 2.04 (t, J = 19.2 Hz, 3H), 1 .86 - 1 .82 (m, 1H), 0.86 - 0.82 (m, 1H), 0.74 - 0.67 (m, 1H), 0.61 - 0.57 (m, 1H), 0.44 - 0.36 (m, 1H).Example 4: (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenylisoquinolin-l(2H)-oneExample 5: (R,E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenylisoquinolin-l(2H)-oneExample 6: (S,E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenylisoquinolin-l(2H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0273] Step A: To a stirred mixture of 6-bromoisoquinolin-l(2H)-one (4.50 g, 20.08 mmol) in acetonitrile (50 mL) was added N-Iodosuccinimide (4.52 g, 20.08 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 20-50% ethyl acetate in petroleum ether to afford 6- bromo-4-iodoisoquinolin-l(2H)-one (5.0 g, 71%). LCMS (ESI): m / z 350, 352 [M+H]+.

[0274] Step B: To a stirred mixture of 6-bromo-4-iodoisoquinolin-l(2H)-one (1.0 g, 2.86 mmol) in N,N-Dimethylformamide (15 mL) were added ethyl 2-bromo-2-cyclopropylacetate (0.59 g, 2.86 mmol) and potassium carbonate (1.18 g, 8.57 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filteredPatent ApplicationAtty. Docket No. ENTX-033PCT and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-30% ethyl acetate in petroleum ether to afford ethyl 2-(6-bromo-4-iodo-l- oxoisoquinolin-2(lH)-yl)-2-cyclopropylacetate (1.0 g, 73%). LCMS (ESI): m / z 476, 478 [M+H]+.1H NMR (400 MHz, DMSO-c / 6) 5 8.17 (s, 1H), 8.12 (d, J= 8.4 Hz, 1H), 7.80 (d, J= 1.8 Hz, 1H), 7.76 (dd, J= 8.4, 1.8 Hz, 1H), 4.32 (d, J= 10.2 Hz, 1H), 4.14 (q, J= 7.2 Hz, 2H), 1.72 - 1.68 (m, 1H), 1.17 (t, J= 7.2 Hz, 3H), 0.86 - 0.79 (m, 1H), 0.65 - 0.61 (m, 1H), 0.58 - 0.52 (m, 1H), 0.35 - 0.31 (m, 1H).

[0275] Step C: To a mixture of ethyl 2-(6-bromo-4-iodo-l-oxoisoquinolin-2(lH)-yl)-2- cyclopropylacetate (1.0 g, 2.10 mmol), phenylboronic acid (0.26 g, 2.10 mmol), cesium carbonate (1.71 g, 5.25 mmol) in dioxane (2 mL) and H2O (0.4 mb) was added bis(triphenylphosphine)palladium(II) Dichloride (0.15 g, 0.21 mmol). Then the reaction mixture was stirred at 50 °C for 6 hours under nitrogen. The cooled reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 to 50% ethyl acetate in petroleum ether to afford ethyl 2-(6-bromo-l-oxo-4-phenylisoquinolin-2(lH)-yl)-2-cyclopropylacetate (0.5 g, 55%). LCMS (ESI): m / z 426, 428 [M+H]+.

[0276] Step D: To a solution of ethyl 2-(6-bromo-l-oxo-4-phenylisoquinolin-2(lH)-yl)-2- cyclopropylacetate (400 mg, 0.94 mmol) and tributyl(l-ethoxyvinyl)stannane (440 mg, 1.22 mmol) in N,N-Dimethylformamide (5 mL) was added tetrakis(triphenylphosphine)palladium (100 mg, 0.09 mmol). The reaction mixture was stirred at 100 °C for 3 hours under nitrogen. Then the cooled reaction mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. To the organic layer was added 10 mL 6 N HC1 and the mixture was stirred at room temperature for 4 hours. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-30% ethyl acetate in petroleum ether to afford ethyl 2-(6-acetyl-l-oxo-4-phenylisoquinolin-2(lH)-yl)-2-cyclopropylacetate (270 mg, 73%). LCMS (ESI): m / z 390 [M + H]+.

[0277] Step E: A mixture of ethyl 2-(6-acetyl-l-oxo-4-phenylisoquinolin-2(lH)-yl)-2- cyclopropylacetate (270 mg, 0.69 mmol) in DAST (2 mL) was stirred at 50 °C for 18 hours. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer wasPatent ApplicationAtty. Docket No. ENTX-033PCT washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0~5% ethyl acetate in petroleum ether to afford ethyl 2-cy cl opropyl-2-(6-( 1,1 -difluoroethyl)- l-oxo-4- phenylisoquinolin-2(lH)-yl)acetate (210 mg, 73%). LCMS (ESI): m / z 412 [M+H]+.

[0278] Step F: To a solution of ethyl 2-cy clopropyl-2-(6-( 1,1 -difluoroethyl)- l-oxo-4- phenylisoquinolin-2(lH)-yl)acetate (210 mg, 0.51 mmol) in dichloromethane (2 mL), was added DIBAL -H (1.53 mL, 1.53 mmol, 1.0 M in toluene) at -60 °C. The reaction was stirred at this temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 20 % ethyl acetate in petroleum ether to afford 2-cyclopropyl-2-(6-(l,l-difluoroethyl)-l-oxo-4-phenylisoquinolin-2(lH)- yl)acetaldehyde (150 mg, 79%). LCMS (ESI): m / z 368 [M + H]+.JH NMR (400 MHz, DMSO- d6) 5 9.71 (s, 1H), 8.42 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 8.4 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.58 - 7.53 (m, 2H), 7.49 (d, J= 7.6 Hz, 3H), 4.26 (d, J= 10.0 Hz, 1H), 2.01 - 1.95 (m, 3H), 1.69 - 1.63 (m, 1H), 0.85 - 0.83 (m, 1H), 0.71 - 0.67 (m, 1H), 0.51 - 0.40 (m, 2H).

[0279] Step G: To a mixture of sodium hydride (7 mg, 0.16 mmol, 60% in oil) in THF (2 mL) was added diethyl ((methylsulfonyl)methyl)phosphonate (19 mg, 0.08 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, then cooled to -60 °C and 2-cyclopropyl-2-(6-(l,l- difluoroethyl)-l-oxo-4-phenylisoquinolin-2(lH)-yl)acetaldehyde (30 mg, 0.08 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at -60 °C for another 1 hour and then quenched with saturated solution of ammonium chloride, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified Prep-HPLC to afford (E)-2-(l-cyclopropyL3- (methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4-phenylisoquinolin-l(2H)-one (17.9 mg, 49%). LCMS (ESI): m / z 444 [M+H]+. 'H NMR (400 MHz, MeOD- / ) 8 8.48 (d, J= 8.8 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.56 - 7.53 (m, 1H), 7.52 - 7.45 (m, 5H), 7.15 - 7.09 (m, 1H), 6.89 - 6.82 (m, 1H), 4.97 - 4.93 (m, 1H), 3.00 (s, 3H), 1.89 (t, J= 18.4 Hz , 3H), 1.68 - 1.59 (m, 1H), 0.96 - 0.89 (m, 1H), 0.70 - 0.63 (m, 2H), 0.52 - 0.45 (m, 1H).

[0280] Step H: (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenylisoquinolin-l(2H)-one (50 mg, 0.11 mmol) was purified by chiral prep-SFC method 2 to give (R,E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4-phenylisoquinolin-Patent ApplicationAtty. Docket No. ENTX-033PCT l(2H)-one (12.3 mg, 27.7 pmol, 24%) LCMS (ESI): m / z 444 [M+H]+. ’HNMR (400 MHz, MeOD-6 / 4) 5 8.52 (d, J= 8.8 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.56 - 7.53 (m, 1H), 7.52 - 7.45 (m, 5H), 7.15 - 7.09 (m, 1H), 6.89 - 6.82 (m, 1H), 4.97 - 4.93 (m, 1H), 3.00 (s, 3H), 1.89 (t, .7= 18.4 Hz , 3H), 1.68 - 1.59 (m, 1H), 0.96 - 0.89 (m, 1H), 0.70 - 0.63 (m, 2H), 0.52 - 0.45 (m, 1H).And (S,E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4-phenylisoquinolin- l(2H)-one(15.5 mg, 34.9 pmol, 31%). LCMS (ESI): m / z 444 [M+H]+. ’HNMR (400 MHz, MeOD-t / 4) 5 8.52 (d, 1H), 7.74 - 7.69 (m, 2H), 7.56 - 7.53 (m, 1H), 7.52 - 7.43 (m, 5H), 7.15 - 7.08 (m, 1H), 6.89 - 6.81 (m, 1H), 4.97 - 4.93 (m, 1H), 3.00 (s, 3H), 1.89 (t, J= 18.4 Hz , 3H), 1.68 - 1.60 (m, 1H), 0.95 - 0.89 (m, 1H), 0.70 - 0.63 (m, 2H), 0.52 - 0.45 (m, 1H).Example 7: (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0281] Step A: To a solution of methyl 2,6-dichloronicotinate (3 g, 14.56 mmol) and tributyl(l -ethoxy vinyl)stannane (5.3 g, 14.56 mmol) in N,N-Dimethylformamide (5 mL) was added tetrakis(triphenylphosphine)palladium (1.7 g, 1.46 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. Then the cooled reaction mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. To the organic layer was added 2 N HC1 (10 mL) and the mixture was stirred at room temperature for 0.5 hours. The organic layer was separated and washed with water and brine, dried over anhydrous TsfeSCU, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 10-15% ethyl acetate in petroleum ether to afford methyl 6-acetyl-2-chloronicotinate (2.3 g, 74%). LCMS (ESI): m / z 214.1 [M + H]+.

[0282] Step B: A mixture of methyl 6-acetyl-2-chloroni cotinate (2.3 g, 10.77 mmol) in DAST (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 10-15% ethyl acetate in petroleum ether to afford methyl 2-chl oro-6-( 1,1 -difluoroethyl )nicotinate (1.8 g, 71%). LCMS (ESI): m / z 235.8 [M + H]T1H NMR (400 MHz, CDCh) 8 8.26 (d, J= 7.8 Hz, 1H), 7.66 (d, J= 7.8 Hz, 1H), 3.98 (s, 3H), 2.03 (t, J= 18.4 Hz, 3H).

[0283] Step C: A mixture of methyl 2-chloro-6-( 1,1 -difluoroethyl )nicotinate (1.3 g, 5.52 mmol), (l-phenylvinyl)boronic acid (980 mg, 6.62 mmol), Pd(dppf)C12 (404 mg, 0.55 mmol) and K3PO4 (2.9 g, 13.79 mmol) in THF (10 mL) and H2O (1 mL) was stirred at 80 °C for 3 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford methyl 6-(l,l-difluoroethyl)-2-(l-phenylvinyl)nicotinate (900 mg, 54%). LCMS (ESI): m / z 304.1 [M + H]T 'H NMR (400 MHz, CDCh) 8 8.08 (d, J= 8.2 Hz, 1H), 7.63 (d, J= 8.2 Hz, 1H), 7.24 - 7.16 (m, 5H), 5.75 (d, J= 1.0 Hz, 1H), 5.56 (d, J= 1.0 Hz, 1H), 3.43 (s, 3H), 1.98 (t, J= 18.8 Hz, 3H).

[0284] Step D: A mixture of methyl 6-(l,l-difluoroethyl)-2-(l-phenylvinyl)nicotinate (900 mg, 2.97 mmol) in MeOH (10 mL) and DCM (10 mL) was cooled to -60 °C. O3 was pumpedPatent ApplicationAtty. Docket No. ENTX-033PCT into the solution for 1 hour while stirring. The mixture was quenched with dimethyl sulfide, diluted with H2O, extracted with DCM. The organic layer was washed with brine, dried over Na SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford methyl 2- benzoyl-6-(l, l-difluoroethyl)nicotinate (500 mg, 55%). LCMS (ESI): m / z 306.1 [M + H]+.

[0285] Step E: To a stirred mixture of methyl 2-benzoyl-6-(l,l-difluoroethyl)ni cotinate (180 mg, 0.59 mmol) in EtOH (3 mL) was added hydrazine (0.10 mL, 3.15 mmol). The mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 20 - 30% EtOAc in petroleum ether to afford 2-(l,l-difluoroethyl)-8-phenylpyrido[2,3- d]pyridazin-5(6H)-one (120 mg, 71%). LCMS (ESI): m / z 288.1 [M + H]+. 'H NMR (400 MHz, CDCI3) 5 10.75 (s, 1H), 8.92 (d, J= 8.4 Hz, 1H), 8.09 (d, J= 8.4 Hz, 1H), 8.00 - 7.95 (m, 2H), 7.55 - 7.48 (m, 3H), 2.06 (t, J= 18.8 Hz, 3H).

[0286] Step F: To a stirred mixture of 2-(l,l-difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin- 5(6H)-one (100 mg, 0.35 mmol) in DMF (2 mL) were added ethyl 2-bromo-2-cyclopropylacetate (72 mg, 0.35 mmol) and K2CO3 (120 mg, 0.87 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-water, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 15 - 35% EtOAc in petroleum ether to afford ethyl 2-cyclopropyl-2-(2- (l,l-difluoroethyl)-5-oxo-8-phenylpyrido[2,3-d]pyridazin-6(5H)-yl)acetate (140 mg, 97%).LCMS (ESI): m / z 414.1 [M + H]+.

[0287] Step G: To a stirred mixture of ethyl 2-cyclopropyl-2-(2-(l,l-difhioroethyl)-5-oxo-8- phenylpyrido[2,3-d]pyridazin-6(5H)-yl)acetate (40 mg, 0.10 mmol) in DCM (2 mL) was added DIBAL -H (0.2 mL, 0.2 mmol, 1 M in Toluene) at -60 °C under nitrogen. The mixture was stirred at -60 °C for 1 hour. Then the cooled reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 20 - 25% EtOAc in petroleum ether to afford 2-Patent ApplicationAtty. Docket No. ENTX-033PCT cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrido[2,3-d]pyridazin-6(5H)- yl)acetaldehyde (20 mg, 56%). LCMS (ESI): m / z 370.1 [M + H]+.

[0288] Step H: To a solution of diethyl ((methylsulfonyl)methyl)phosphonate (13 mg, 0.05 mmol) in THF (1 mL) was added NaH (4 mg, 0.10 mmol, 60% in oil) at 0 °C. The mixture was stirred at 0 °C for 1 hours, then cooled to -10 °C and 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5- oxo-8-phenylpyrido[2,3-d]pyridazin-6(5H)-yl)acetaldehyde (20 mg, 0.05 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at -10 °C for another 1 hour and then quenched with saturated solution of ammonium chloride, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified Prep-HPLC (YMC-C18, 20% - 95% MeCN in water with 0.1% FA) to afford (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one.(0.7 mg, 3%). LCMS (ESI): m / z 446.1 [M + H]+. 'H NMR (400 MHz, MeOD-tA) 8 8.93 (d, J= 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.54 - 7.48 (m, 3H), 7.26 - 7.14 (m, 1H), 7.03 - 6.88 (m, 1H), 5.18 - 5.08 (m, 1H), 3.00 (s, 3H), 2.05 (t, J= 18.8 Hz, 3H), 1.73 - 1.69 (m, 1H), 0.91 - 0.85 (m, 1H), 0.72 - 0.49 (m, 3H).Example 8: (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenylphthalazin-l(2H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0289] Step A: A mixture of l-(3-bromo-4-iodophenyl)ethan-l-one (8.0 g, 24.6 mmol) and Pd(dppf)C12 (360 mg, 0.49 mmol) in EtOH (50 mL) was stirred at 50 °C overnight under carbon monoxide. After cooling to room temperature, the reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% EtOAc in petroleum ether to afford ethyl 4-acetyl-2-bromobenzoate (6.6 g, 99%). LCMS (ESI): m / z 271, 273 [M + H]+.

[0290] Step B: A mixture of ethyl 4-acetyl-2-bromobenzoate (650 mg, 2.4 mmol) in DAST (5 mL) was stirred at 60 °C overnight. After cooling to room temperature, the reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford ethyl 2-bromo-4-(l,l-difluoroethyl)benzoate (600 mg, 85%). LCMS (ESI): m / z 293, 295 [M + H]+.

[0291] Step C: A mixture of ethyl 2-bromo-4-(l,l-difluoroethyl)benzoate (200 mg, 0.68 mmol), (1 -phenyl vinyl)boronic acid (101 mg, 0.68 mmol), Pd(dppf)C12 (50 mg, 0.07 mmol) and K3PO4 (430 mg, 2.0 mmol) in THF (5 mL) and H2O (1 mL) was stirred at 80 °C overnight under nitrogen. After cooling to room temperature, the reaction mixture was diluted with H2O,I l lPatent ApplicationAtty. Docket No. ENTX-033PCT extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% EtOAc in petroleum ether to afford ethyl 4-(l,l-difluoroethyl)-2-(l-phenylvinyl)benzoate (200 mg, 93%). LCMS (ESI): m / z 317 [M + H]+.

[0292] Step D: A mixture of ethyl 4-(l,l-difluoroethyl)-2-(l-phenylvinyl)benzoate (200 mg, 0.63 mmol) in DCM (5 mL) and MeOH (1 mL) was cooled to -60 °C. O3 was pumped into the solution for 30 mins while stirring. The mixture was quenched with dimethyl sulfide, diluted with H2O, extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford ethyl 2-benzoyl-4-(l,l-difluoroethyl)benzoate (200 mg, crude). LCMS (ESI): m / z 319 [M + H]+.

[0293] Step E: To a stirred mixture of ethyl 2-benzoyl-4-(l,l-difluoroethyl)benzoate (200 mg, 0.63 mmol) in EtOH (3 mL) was added hydrazine (0.10 mL, 3.15 mmol). The mixture was stirred at 80 °C overnight. The reaction mixture was concentrated, and the residue was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 6-(l,l-difluoroethyl)-4-phenylphthalazin-l(2H)-one (150 mg, crude). LCMS (ESI): m / z 287 [M + H]-.

[0294] Step F: To a stirred mixture of 6-(l,l-difluoroethyl)-4-phenylphthalazin-l(2H)-one (100 mg, 0.35 mmol) in DMA (5 mL) were added ethyl 2-bromo-2-cyclopropylacetate (72 mg, 0.35 mmol) and CS2CO3 (341 mg, 1.05 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-water, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 20% EtOAc in petroleum ether to afford ethyl 2-cyclopropyl-2-(6-(l,l- difluoroethyl)-l-oxo-4-phenylphthalazin-2(lH)-yl)acetate (130 mg, 90%). LCMS (ESI): m / z 413 [M + H]+.

[0295] Step G: To a stirred mixture of ethyl 2-cyclopropyl-2-(6-( 1,1 -difluoroethyl)- l-oxo-4- phenylphthalazin-2(lH)-yl)acetate (200 mg, 0.48 mmol) in DCM (2 mL) was added DIBAL-H (1.1 mL, 1.1 mmol, 1 M in Toluene) at -60 °C under nitrogen. The mixture was stirred at -60 °C for 1.5 hours. Then the cooled reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4,Patent ApplicationAtty. Docket No. ENTX-033PCT filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 15% EtOAc in petroleum ether to afford 2-cyclopropyl-2-(6-(l,l- difluoroethyl)-l-oxo-4-phenylphthalazin-2(lH)-yl)acetaldehyde (20 mg, 11%). LCMS (ESI): m / z 369 [M + H]+.

[0296] Step H: To a solution of diethyl ((methylsulfonyl)methyl)phosphonate (35 mg, 0.16 mmol) in THF (5 mL) was added NaH (7 mg, 0.16 mmol, 60% in oil) at 0 °C. The mixture was stirred at 0 °C for 1 hour, then cooled to -60 °C and 2-cyclopropyl-2-(6-(l,l-difluoroethyl)-l- oxo-4-phenylphthalazin-2(lH)-yl)acetaldehyde (20 mg, 0.13 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at -60 °C for another 1 hour and then quenched with saturated solution of ammonium chloride, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- (l,l-difluoroethyl)-4-phenylphthalazin-l(2H)-one (7.1 mg, 12%), LCMS (ESI): m / z 445 [M+H]+. ‘HNMR (400 MHz, MeOD-< ) 8 8.55 (d, J= 8.4 Hz, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.93 (s, 1H), 7.68 - 7.55 (m, 5H), 7.16 (dd, J= 15.2, 5.4 Hz, 1H), 6.91 (dd, J= 15.2, 1.4 Hz, 1H), 5.14 - 5.10 (m, 1H), 2.99 (s, 3H), 1.95 (t, J= 18.4 Hz, 3H), 1.72 - 1.59 (m, 1H), 0.96 - 0.78 (m, 1H), 0.71 - 0.45 (m, 3H).Example 9: (E)-5-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-7- phenylthiazolo [5,4-c] pyr idin-4(5H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0297] Step A: To a suspension of 2,4-dibromothiazole-5-carboxylic acid (5 g, 17.4 mmol) in and K2CO3 (3.6 g, 26.1 mmol) DMF (50 mL) was added CH3I (3.0 g, 20.9 mmol). The mixture was stirred at room temperature for Ihour. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford methyl 2,4-dibromothiazole-5-carboxylate (5 g, 95.3%). LCMS (ESI): m / z 301.9, 302.9 [M+H]+.

[0298] Step B: To a flask containing methyl 2,4-dibromothiazole-5-carboxylate (4.5 g, 14.9 mmol) and tributyl(l-ethoxyvinyl)-X4-stannane (5.4 g, 14.9 mmol) in dioxane (50 mL) wasPatent ApplicationAtty. Docket No. ENTX-033PCT added Pd(dppf)C12 (540 mg, 0.74 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was quenched with KF solution (20 mL) and extracted with EtOAc three times, The combined extracts were concentrated in vacuo. The residue was dissolved in THF (30 mL) and was added 4 N HC1 (30 mL). The mixture was stirred at room temperature for 2 hours, then neutralized with NaHCCh solution. The resulting mixture was extracted with EtOAc twice, then the combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluted with a gradient of 0-50% EtOAc in petroleum ether to afford methyl 2-acetyl-4-bromothiazole-5-carboxylate (2.5 g, 63.3%). LCMS (ESI): m / z 265, 267 [M+H]+.

[0299] Step C: A solution of methyl 2-acetyl-4-bromothiazole-5-carboxylate (2.5 g, 9.5 mmol) in DAST (50 mL) was stirred at 60 °C for 16 hours. The cooled mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% EtOAc in petroleum ether to afford methyl 4-bromo-2-(l,l-difluoroethyl)thiazole-5-carboxylate (2.5 g, 92.7%) . LC / MS (ESI) m / z: 285 [M + H]+.

[0300] Step D: To a mixture of methyl 4-bromo-2-(I,I-difluoroethyl)thiazole-5-carboxylate (2.5 g, 8.74 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.6g, 13.11 mmol), Pd(dppf)C12 (930 mg, 1.3 mmol) in dioxane (25 mL) and H2O (5 mL) was added K3PO4 (5.56 g, 26.22 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 2 hours under nitrogen. The cooled reaction mixture was diluted with FEO, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluted with a gradient of 0 to 10 % EtOAc in petroleum ether to afford methyl (E)-2-(l,I-difluoroethyl)-4-(2-ethoxyvinyl)thiazole-5-carboxylate (2.4 g, 99%). LC / MS (ESI) m / z: 278 [M + H]+.

[0301] Step E: To a solution of methyl (E)-2-(l,l-difluoroethyl)-4-(2-ethoxyvinyl)thiazole-5- carboxylate (110 mg, 0.39 mmol) in THF (5 mL) was added a solution of Lithium hydroxide monohydrate (47 mg, 1.98 mmol) in H2O (5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ice-water and acidified with 1 N HCI to pH = 4,Patent ApplicationAtty. Docket No. ENTX-033PCT extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo, to give (E)-2-(l,l-difluoroethyl)-4-(2- ethoxyvinyl)thiazole-5-carboxylic acid (75 mg, 72%) . LCMS (ESI): m / z 264 [M + H]+.

[0302] Step F: To a mixture of (E)-2-(l,l-difluoroethyl)-4-(2-ethoxyvinyl)thiazole-5- carboxylic acid (75 mg, 0.28 mmol) in DMF (3 mL) was added NH4C1 (158 mg, 2.8 mmol), HATU (159 mg, 0.42 mmol) and DIEA (67 mg, 0.52 mmol), the result solution was stirred at 25 °C for 1 h. The mixture diluted with water, extracted with EtOAc (10 mL x 3), the organic layer was separated, washed with brine, dried with Na2SO4 and concentrate. The residue was purified by flash silica gel chromatography, eluted with a gradient of 0 to 10 % EtOAc in petroleum ether to afford (E)-2-(l,l-difluoroethyl)-4-(2-ethoxyvinyl)thiazole-5-carboxamide (45 mg, 60%). LCMS (ESI): m / z 263 [M + H]+.

[0303] Step G: A mixture of (E)-2-(l,l-difluoroethyl)-4-(2-ethoxyvinyl)thiazole-5- carboxamide (45 mg, 0.17 mmol) and TFA (1 ml) in dioxane (4 ml) was stirred at 80 °C for 2 hours. The cooled mixture diluted with water, extracted with EtOAc (10 mL x 3), the organic layer was separated, washed with brine, dried with Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography, eluted with a gradient of 0 to 10 % MeOH in DCM to afford 2-(l,l-difluoroethyl)thiazolo[5,4-c]pyridin-4(5H)-one (20 mg, 54%). LC / MS (ESI) m / z: 217 [M + H]+.

[0304] Step H: To a solution of 2-(l,l-difluoroethyl)thiazolo[5,4-c]pyridin-4(5H)-one (90 mg, 0.42 mmol) in DMF (2 mL), was added NBS (74.1 mg, 0.42 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O, extracted with EtOA. The organic was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluted with a gradient of 0-10% MeOH in DCM to afford 7-bromo-2-(l,l- difluoroethyl)thiazolo[5,4-c]pyridin-4(5H)-one (100 mg, 81.4%). LC / MS (ESI) m / z: 295, 297 [M + H]+.

[0305] Step I: To a mixture of 7-bromo-2-( 1,1 -difluoroethyl )thiazolo[5,4-c]pyridin-4(5H)- one (120 mg, 0.41 mmol), phenylboronic acid (74.4 mg, 0.61 mmol), Pd(dppf)C12 (29.8 mg, 0.04 mmol) in dioxane (5 mL) and H2O (1 mL) was added K3PO4 (216 mg, 1.02 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 2 hours under nitrogen. The cooled reaction mixture was diluted with H2O, extracted with EtOAc. ThePatent ApplicationAtty. Docket No. ENTX-033PCT combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluted with a gradient of 0 to 10 % MeOH in DCM to afford 2-(l,l-difluoroethyl)-7- phenylthiazolo[5,4-c]pyridin-4(5H)-one (110 mg, 93%) . LC / MS (ESI) m / z: 293 [M + H]+.

[0306] Step J:To a solution of 2-(l,l-difluoroethyl)-7-phenylthiazolo[5,4-c]pyridin-4(5H)- one (120 mg, 0.41 mmol) and ethyl 2-bromo-2-cyclopropylacetate (102 mg, 0.49 mmol) in N,N- dimethylacetamide (2 m ) was added CS2CO3 (201 mg, 0.62 mmol). The reaction was stirred at rt for 1 hour. The cooled reaction mixture was diluted with H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford ethyl 2-cyclopropyl-2-(2-(l, 1- difhioroethyl)-4-oxo-7-phenylthiazolo[5,4-c]pyridin-5(4H)-yl)acetate (100 mg, 58%). LCMS (ESI): m / z 419 [M + H]+.

[0307] Step K: To a solution of ethyl 2-cyclopropyl-2-(2-(l ,l -difluoroethyl)-4-oxo-7- phenylthiazolo[5,4-c]pyridin-5(4H)-yl)acetate (100 mg, 0.24 mmol) in an anhydrous DCM (2 mL) was added Diisobutylaluminium hydride (0.53 mL, 0.53 mmol, 1.0 M in toluene) at -78 °C. the stirring was continued at -78 °C for 2 h. The mixture was poured into a stirred solution of aqueous NH4CI, extracted with DCM twice. The combined extracts were dried over anhydrous MgSCE, filtered and evaporated. The crude product was purified by flash silica chromatography, eluted with a gradient 0% to 20% EtOAc in petroleum ether to afford 2- cyclopropyl-2-(2-(l,l-difluoroethyl)-4-oxo-7-phenylthiazolo[5,4-c]pyridin-5(4H)- yl)acetaldehyde (25 mg, 28%). LCMS (ESI): m / z 375 [M + H]+.

[0308] Step L: To a solution of diethyl [(methyldioxo-X6-sulfanyl)methyl]phosphonate (11.1 mg, 0.05 mmol) in an anhydrous tetrahydrofuran (2 mL) was added sodium hydride (3.2 mg, 0.08 mmol, 60% dispersion in mineral oil) at 0 °C. the mixture was stirred at 0 °C for 30 minutes, then cooled to -60 °C. 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-4-oxo-7- phenylthiazolo[5,4-c]pyridin-5(4H)-yl)acetaldehyde (15 mg, 0.04 mmol) in 1 ml THF was added. The mixture was stirred at -60°C for 1 hour, and then quenched with saturated solution of ammonium chloride, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (Cl 8, acetonitrile / EEO, 0.1% trifluoroacetic acid modifier, 5% to 95%Patent ApplicationAtty. Docket No. ENTX-033PCT gradient, 30 min run) to afford (E)-5-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-7-phenylthiazolo[5,4-c]pyridin-4(5H)-one (1.7 mg, 9%). LCMS (ESI): m / z 451 [M + H]+. 'H NMR (400 MHz, Methanol-A) 8 7.91 (s, 1H), 7.75 (d, J= 7.6 Hz, 2H), 7.50 - 7.38 (m, 3H), 7.15 (dd, J= 15.2, 4.6 Hz, 1H), 6.8815.2 Hz, 1H), 4.96 (dd, J= 9.2, 4.0 Hz,1H), 3.01 (s, 3H), 2.15 (t, J= 18.8 Hz, 3H), 1.75 - 1.68 (m, 1H), 0.97 - 0.90 (m, 1H), 0.72 - 0.68 (m, 2H), 0.53 - 0.48 (m, 1H).Example 10: (R,E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenyl- l,6-naphthyridin-5(6H)-oneExample 11: (S,E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenyl- l,6-naphthyridin-5(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0309] Step A: To a solution of methyl 6-bromo-2-methylnicotinate (5 g, 21.73 mmol) and tributyl(l -ethoxy vinyl)stannane (10.2 g, 28.25 mmol) in dioxane (50 mL) was added Pd(PPhs)4 (2.5 g, 2.17 mmol). The reaction mixture was purged with nitrogen three times, then stirred at 100 °C under nitrogen overnight. The cooled mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution, further washed with water and brine, dried over anhydrous Na SO4, filtered, and concentrated to afford methyl 6-(l -ethoxy vinyl)-2-methylnicotinate (6 g, crude). LCMS (ESI): m / z 222 [M+H]+.

[0310] Step B: To a solution methyl 6-(l -ethoxy vinyl)-2-methylnicotinate (6 g, 18.98 mmol) in THF (20 mL) was added 2 A HCI (50 mL, 100 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. The mixture was poured into a stirred solution of sat.NaHCCL solution, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-20% EtOAc in petroleum ether to afford methyl 6-acetyl-2-methylnicotinate (3 g, 82%). LCMS (ESI): m / z 194 [M+H]+

[0311] Step C: A solution of methyl 6-acetyl-2-methylnicotinate (3 g, 15.53 mmol) in DAST (20 mL) was stirred at 50 °C overnight. The cooled reaction mixture was diluted with EtOAc,Patent ApplicationAtty. Docket No. ENTX-033PCT poured into ice-water and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-15 % EtOAc in petroleum ether to afford methyl 6- (l,l-difluoroethyl)-2-methylnicotinate (2 g, 59%). LCMS (ESI): m / z 216 [M+H]+. 'H NMR (400 MHz, CDC13) 8 8.28 (d, J= 8.1 Hz, 1H), 7.54 (d, J= 8.1 Hz, 1H), 3.94 (s, 3H), 2.86 (s, 3H), 2.01 (t, J= 18.7 Hz, 3H).

[0312] Step D: To a sealed tube containing methyl 6-(l,l-difluoroethyl)-2-methylnicotinate (2 g, 9.29 mmol) in DMA (20 mL) was added 1 , 1 -di-tert-butoxy-N, N-dimethylmethanamine (CAS#: 36805-97-7, 9.4 g, 46.47 mmol). The resulting mixture was stirred at 100 °C for 16 hours. The cooled reaction mixture was diluted with EtOAc and water, and two layers were separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0~20 % EtOAc in petroleum ether to afford methyl (E)-6-(l,l-difluoroethyl)-2-(2- (dimethylamino)vinyl)nicotinate (1.4 g, 56%). LCMS (ESI) m / z: 271 [M+H] ' . 'H NMR (400 MHz, CDCI3) 6 8.12 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 12.7 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.31 (d, J= 12.7 Hz, 1H), 3.88 (s, 3H), 2.98 (s, 6H), 2.04 - 1.92 (m, 3H).

[0313] Step E: To a solution of methyl (E)-6-(l, l-difluoroethyl)-2-(2- (dimethylamino)vinyl)nicotinate (1.4 g, 5.18 mmol) in EtOH (10 mL) was added ammonium hydroxide (5 mL, 5.18 mmol) and ammonium acetate (4 g, 51.8 mmol). The mixture was stirred at 90 °C for 4 hours under nitrogen. The cooled mixture was diluted with water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 3-30 % EtOAc in petroleum ether to afford 2-(l, 1 -difluoroethyl)- 1,6- naphthyridin-5(6H)-one (1 g, 92 %). LCMS (ESI) m / z: 211 [M+H]+.

[0314] Step F: To a solution of 2-(l, 1 -difluoroethyl)- l,6-naphthyridin-5(6H)-one (900 mg, 4.28 mmol) in MeCN (10 mL) was added N-Bromosuccinimide (686 mg, 3.85 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solvent was evaporated under reduced pressure and the crude product was purified by silica gel flash chromatography, elutedPatent ApplicationAtty. Docket No. ENTX-033PCT with a gradient of 10-30 % EtOAc in petroleum ether to afford 8-bromo-2-(l,l-difluoroethyl)-1.6-naphthyridin-5(6H)-one (640 mg, 52%). LCMS (ESI) m / z: 289 [M+H]+.

[0315] Step G: To a mixture of 8-bromo-2-( 1,1 -difluoroethyl)- l,6-naphthyridin-5(6H)-one (600 mg, 2.08 mmol), phenylboronic acid (253 mg, 2.08 mmol), K2CO3 (287 mg, 2.08 mmol) in dioxane (10 mL) and water (2 mL) was added Pd(dtbpf)Ch (134 mg, 0.2 mmol). The reaction mixture was purged with nitrogen three times, then stirred at 100 °C under nitrogen for 6 hours. The cooled mixture was diluted with water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous M SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-30 % EtOAc in petroleum ether to afford 2-(l,l-difluoroethyl)-8-phenyl-l,6-naphthyridin-5(6H)-one (500 mg, 84%). LCMS (ESI) m / z: 287 [M+H]+.

[0316] Step H: To a solution of 2-(l,l-difluoroethyl)-8-phenyl-l,6-naphthyridin-5(6H)-one (270 mg, 0.94 mmol) in DMF (15 mL) were added ethyl 2-bromo-2-cyclopropylacetate (390 mg, 1 .89 mmol) and K2CO3 (325 mg, 2.36 mmol). The result mixture was stirred at 25 °C for 2 hours. The reaction was diluted with water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluted with 0-40% ethyl acetate in petroleum ether to afford ethyl 2-cyclopropyl-2-(2-( 1 , 1 -difluoroethyl)-5-oxo-8-phenyl- 1 ,6-naphthyridin-6(5H)- yl)acetate (220 mg, 56%). LCMS (ESI): m / z 413 [M+H]+.

[0317] Step I: To a solution of ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenyl-1.6-naphthyridin-6(5H)-yl)acetate (220 mg, 0.53 mmol) in DCM (5 mL) was added DIBAL-H (1.6 mL, 1.60 mmol, 1 M in DCM) under -60 °C. The reaction was stirred at -60 °C under nitrogen for 1 hour. The reaction was diluted with DCM and then poured into ice-water. The organic layer was separated, washed with brine and dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with 0- 40% ethyl acetate in petroleum ether to afford the product 2-cyclopropyl-2-(2-(l,l- difhioroethyl)-5-oxo-8-phenyl-l,6-naphthyridin-6(5H)-yl)acetaldehyde (140 mg, 71 %) as a white solid. LCMS (ESI): m / z 369 [M+H]+.

[0318] Step J: To a suspension of NaH (23 mg, 0.60 mmol, 60% in oil) in anhydrous THF (40 mL) was added diethyl ((methylsulfonyl)methyl)phosphonate (75 mg, 0.33 mmol) dropwise at 0 °C under nitrogen. The white suspension was stirred at 0 °C for 1 hour, then cooled to -Patent ApplicationAtty. Docket No. ENTX-033PCT60 °C. A solution of 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenyl-l,6-naphthyridin- 6(5H)-yl)acetaldehyde (110 mg, 0.30 mmol) in THF (4 mL) was slowly added into the mixture and stirred at -60 °C for another 1 hour. The reaction was poured into ice-water, extracted with EtOAc. The organic extract was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-32% EtOAc in petroleum ether to afford the crude products and further purified by chiral prep-SFC method 3 to afford the desired product (R, E)-6- (l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difhioroethyl)-8-phenyl-l,6-naphthyridin-5(6H)- one (21 mg, 15 %) LCMS (ESI): m / z 445 [M+H]+. 'H NMR (400 MHz, DMSO-cL) 8 8.82 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 7.4 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.42 - 7.40 (m, 1H), 7.07 (dd, J= 15.2, 4.8 Hz, 1H), 6.94 (d, J= 15.2 Hz, 1H), 4.87 - 4.83 (m, 1H), 3.03 (s, 3H), 2.00 (t, J= 19.2 Hz, 3H), 1.84 - 1.82 (m, 1H), 0.85 - 0.75 (m, 1H), 0.74 - 0.66 (m, 1H), 0.64 - 0.54 (m, 1H), 0.42 - 0.34 (m, 1H). And (S, E)-6-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenyl-l,6-naphthyridin-5(6H)-one (22 mg, 16 %). LCMS (ESI): m / z 445 [M+H]+. ’HNMR (400 MHz, DMSO-t / 6) 8 8.82 (d, J= 8.4 Hz, 1H), 8.05 (s, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 1A Hz, 2H), 7.52 - 7.46 (m, 2H), 7.42 - 7.40 (m, 1H), 7.07 (dd, J= 15.2, 4.8 Hz, 1H), 6.94 (d, J= 15.2 Hz, 1H), 4.87 - 4.83 (m, 1H), 3.03 (s, 3H), 2.00 (t, J= 19.2 Hz, 3H), 1.84 - 1.82 (m, 1H), 0.85 - 0.75 (m, 1H), 0.74 - 0.66 (m, 1H), 0.64 - 0.54 (m, 1H), 0.42 - 0.34 (m, 1H).Example 12: (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenylthieno[2,3-c]pyridin-7(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCTExample 12

[0319] Step A: To a stirred mixture of 5-bromothiophene-3-carbaldehyde (20 g, 104 mmol) in pyridine (250 mL) was added malonic acid (12 g, 115 mmol) and piperidine (2.7 g, 31 mmol). The mixture was stirred at 110 °C for 6 hours. The cooled mixture was neutralized with 2 A' IICI to pH = 3~ 4, the precipitate was filtered and the filter cake was washed with H2O, dried under reduce pressure to afford (E)-3-(5-bromothiophen-3-yl)acrylic acid (20 g, crude), which was used directly without further purification.rH NMR (400 MHz, DMSO y) 5 7.93 (d, J= 1.2 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.49 (d, J= 16.0 Hz, 1H), 6.37 (d, J= 16.0 Hz, 1H).Patent ApplicationAtty. Docket No. ENTX-033PCT

[0320] Step B: To a stirred mixture of (E)-3-(5-bromothiophen-3-yl)acrylic acid (22 g, crude) in DCM (200 mL) were added TEA (39 mL, 283.2 mmol) and diphenyl azidophosphonate (52 g, 188 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford (E)-3-(5-bromothiophen-3- yl)acryloyl azide (24 g, crude) which was used directly without further purification.

[0321] Step C: A solution of (E)-3-(5-bromothiophen-3-yl)acryloyl azide (24 g, crude) in dioxane (100 mL) was added into a stirred mixture of (phenyloxy )benzene phenylbenzene (157 mL) at 230 °C. The mixture was stirred at this temperature for 1 hour. The cooled mixture was dilute with hexane, the precipitate was filtered and the filter cake was washed with hexane and further purified by silica gel flash chromatography, eluted with a gradient of 0-20% MeOH in DCM to afford 2-bromothieno[2,3-c]pyridin-7(6H)-one (1.8 g, 9%). LCMS (ESI): m / z 230 [M+H]+.

[0322] Step D: To a stirred mixture of 2-bromothieno[2,3-c]pyridin-7(6H)-one (1 .8 g, 7.8 mmol) in dioxane (50 mL) was added tributyl(l -ethoxy vinyl)stannane (3.4 g, 9.4 mmol) and Pd(PPh3)2C12 (550 mg, 0.78 mmol). The reaction mixture was purged with nitrogen three times, then stirred at 100 °C under nitrogen overnight. The cooled mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. The organic layer was separated, washed with brine and concentrated. The residue was dissolved in THF (20 mL), 3 1VHC1 solution (20 mL) was added into the mixture and stirred at room temperature for another 1 hour, then neutralized with sat. aqueous NaHCCh solution. The resulting mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous MgSOa, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-100% EtOAc in petroleum ether to afford 2-acetylthieno[2,3-c]pyridin-7(6H)-one (1.7 g, 43%). LCMS (ESI): m / z 194 [M+H]-.

[0323] Step E: To a mixture of 2-acetylthieno[2,3-c]pyridin-7(6H)-one (1.7 g, 8.8 mmol) in DMF (20 mL) were add NBS (1.6 g, 8.8 mmol). The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with EtOAc, washed with water, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-100% ethylPatent ApplicationAtty. Docket No. ENTX-033PCT acetate in petroleum ether to afford 2-acetyl-4-bromothieno[2,3-c]pyridin-7(6H)-one (2 g, 83%). LCMS (ESI): m / z 272, 274 [M+H]+.

[0324] Step F: To a suspension of 2-acetyl-4-bromothieno[2,3-c]pyridin-7(6H)-one (1 g, 3.6 mmol) and ethyl 2-bromo-2-cyclopropylacetate (1.5 g, 7.4 mmol) in MeCN (30 mb) was added K2CO3 (1.0 g, 7.4 mmol). The resulting mixture was stirred at 50 °C under nitrogen overnight. The cooled mixture was diluted with EtOAc, washed with water, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford ethyl 2-(2-acetyl-4-bromo-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-2- cyclopropylacetate (400 mg, 27%). LCMS (ESI): m / z 398, 400 [M+H]+.

[0325] Step G: A solution of ethyl 2-(2-acetyl-4-bromo-7-oxothieno[2,3-c]pyridin-6-yl)-2- cyclopropylacetate (400 mg, 1.0 mmol) in DAST (5 mL) was stirred at 50 °C overnight. The cooled mixture was poured into ice-water, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 2-10% MeOH in DCM to afford ethyl 2-(4-bromo-2-(l,l-difluoroethyl)-7-oxothieno[2,3-c]pyridin- 6(7H)-yl)-2-cyclopropylacetate (340 mg, 80%). LCMS (ESI): m / z 420, 422 [M+H]+.

[0326] Step H: To a mixture of ethyl 2-(4-bromo-2-(l,l-difluoroethyl)-7-oxothieno[2,3- c]pyridin-6(7H)-yl)-2-cyclopropylacetate (50 mg, 0.12 mmol), phenylboronic acid (21 mg, 0.18 mmol) and K3PO4 (63 mg, 0.3 mmol) in anhydrous dioxane (3 mL) was added 1, l'-Bis(di-t- butylphosphino)ferrocene palladium dichloride (8 mg, 0.01 mmol). The reaction mixture was purged with nitrogen three times and stirred at 100 °C under nitrogen overnight. The cooled mixture was poured into ice-water, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-15% EtOAc in petroleum ether to afford ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-7-oxo-4- phenylthieno[2,3-c]pyridin-6(7H)-yl)acetate (40 mg, 80%). LCMS (ESI): m / z 418 [M+H]+.

[0327] Step I: To a mixture of ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-7-oxo-4- phenylthieno[2,3-c]pyridin-6(7H)-yl)acetate (40 mg, 0.1 mmol) in DCM (3 mL) was added DIBAL-H (0.3 mL, 0.29 mmol, 1 M in DCM) at -60 °C. The resulting mixture was stirred at -Patent ApplicationAtty. Docket No. ENTX-033PCT60 °C for 1 hour. The reaction was diluted with DCM and then poured into ice-water. The organic layer was separated, washed with brine and dried over anhydrous MgSCL, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford 2-cyclopropyl-2-(2-(l,l- difluoroethyl)-7-oxo-4-phenylthieno[2,3-c]pyridin-6(7H)-yl)acetaldehyde (10 mg, 28%). LCMS (ESI): m / z 374 [M+H]+.

[0328] Step J: To a mixture of NaH (3 mg, 0.05 mmol, 60% in oil) in THF (2 m ) was added diethyl ((methyl sulfonyl)methyl)phosphonate (7 mg, 0.03 mmol) at 0 °C and the mixture was stirred at this temperature for 1 hour. Then cooled to -60 °C, a solution of 2-cyclopropyl-2- (2-(l,l-difluoroethyl)-7-oxo-4-phenylthieno[2,3-c]pyridin-6(7H)-yl)acetaldehyde (10 mg, 0.03 mmol) in THF (2 mL) was added into the above mixture and the reaction was stirred at -60 °C for 1 hour. The reaction was poured into ice-water, extracted with EtOAc. The organic extract was washed with water and brine, dried over anhydrous MgSCU, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford (E)-6-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4-phenylthieno[2,3-c]pyridin-7(6H)-one (2.4 mg, 20%). LCMS (ESI): m / z 450 [M+H]1.1H NMR (400 MHz, CDCh) 8 7.53 - 7.48 (m, 2H), 7.47 - 7.39 (m, 4H), 7.28 (s, 1H), 7.10 (dd, J= 15.2, 4.4 Hz, 1H), 6.53 (dd, J= 15.2, 1.6 Hz, 1H), 5.18 - 5.10 (m, 1H), 2.96 (s, 3H), 2.03 (t, J= 18.0 Hz, 3H), 1.40 - 1.34 (m, 1H), 0.97 - 0.91 (m, 1H), 0.69 - 0.67 (m, 2H), 0.56 - 0.54 (m, 1H).Example 13: (S, E)-5-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-7- phenylthiazolo[4,5-c]pyridin-4(5H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0329] Step A: To a solution of ethyl 2,5-dibromothiazole-4-carboxylate (5 g, 15.8 mmol) and tributyl(l -ethoxy vinyl)stannane (8.6 g, 23.8 mmol) in dioxane (80 mb) was added Pd(PPha)2C12 (1.1 g, 1.6 mmol). The reaction mixture was purged with nitrogen three times, then stirred at 100 °C under nitrogen overnight. The cooled mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. The organic layer was separated, washed with brine and concentrated. The residue was dissolved in THF (30 m ), 6 AHC1 (30 mb) was added into the solution and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and water. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-5% ethyl acetate in petroleum ether toPatent ApplicationAtty. Docket No. ENTX-033PCT afford ethyl 2-acetyl-5-bromothiazole-4-carboxylate (2.1 g, 47%). LCMS (ESI): m / z 278, 280 [M+H]+.

[0330] Step B: A solution of ethyl 2-acetyl-5-bromothiazole-4-carboxylate (1.8 g, 6.5 mmol) in DAST (15 mL) was stirred at 50 °C for 16 hours. The cooled reaction solution was diluted with EtOAc and then poured into ice-water. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-5% ethyl acetate in petroleum ether to afford ethyl 5-bromo-2-(l,l-difluoroethyl)thiazole-4-carboxylate (1.6 g, 82%). LCMS (ESI): m / z 300, 302 [M+H]+.

[0331] Step C: A mixture of N'-(2-methoxy-l-phenylethylidene)-4- methylbenzenesulfonohydrazide (Ref: Chemistry A European Journal, 2009, vol. 15, 48, 13291- 13294+13273,' 128 mg, 0.4 mmol), ethyl 5-bromo-2-(l,l-difluoroethyl)thiazole-4-carboxylate (110 mg, 0.37 mmol), PdCh(MeCN)2 (9 mg, 0.04 mmol), 1,3-Bis(diphenylphosphino)propane (30 mg, 0.07 mmol) and CS2CO3 (286 mg, 0.88 mmol) was stirred at 90 °C under nitrogen for 3 hours. The cooled mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0-12% ethyl acetate in petroleum ether to afford ethyl (E)-2-(l,l-difluoroethyl)-5-(2- methoxy-l-phenylvinyl)thiazole-4-carboxylate (26 mg, 20%). LCMS (ESI): m / z 354 [M+H]+.

[0332] Step D: To a solution of ethyl (E)-2-(l, l-difluoroethyl)-5-(2 -methoxy- 1- phenylvinyl)thiazole-4-carboxylate (26 mg, 0.07 mmol) in THF and H2O (4 mL, 3: 1) was added LiOH (10 mg, 0.22 mmol). The reaction was stirred at 50 °C for 2 hours. The cooled mixture was poured into ice-water and adjusted to pH = 3~4 with 2 AHC1. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford (E)-2-(l,l-difluoroethyl)-5-(2-methoxy-l- phenylvinyl)thiazole-4-carboxylic acid (20 mg, crude) which was used directly for the next step. LCMS (ESI): m / z 326 [M+H]+.

[0333] Step E: To a solution of (E)-2-( 1,1 -difhioroethyl)-5-(2-m ethoxy- 1- phenylvinyl)thiazole-4-carboxylic acid (80 mg, crude) in DCM (6 mL) was added (S, E)-l- cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (51 mg, 0.30 mmol), HATU (112 mg, 0.30 mmol) and DIEA (126 mg, 0.98 mmol). The mixture was stirred at 25 °C for 3 hours. Then the reaction was diluted with DCM, washed with water and brine, dried over anhydrous Na2SC>4,Patent ApplicationAtty. Docket No. ENTX-033PCT filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-50% ethyl acetate in petroleum ether to afford N-((S, E)-l-cyclopropyl-3- (methylsulfonyl)allyl)-2-( 1 , 1 -difluoroethyl)-5-((E)-2-m ethoxy- 1 -phenylvinyl)thiazole-4- carboxamide (40 mg, 21%). LCMS (ESI): m / z 483 [M+H]+.

[0334] Step F: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-5-((E)-2-methoxy-l-phenylvinyl)thiazole-4-carboxamide (30 mg, 0.06 mmol) in dioxane (2 mL) was added HC1 (0.5 mL, 4 AT in dioxane). The mixture was stirred at 25°C for 3 hours. The reaction was concentrated and the residue was purified by Prep-HPLC to afford (S, E)-5-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-7-phenylthiazolo[4,5- c]pyridin-4(5H)-one (2.5 mg, 8%). LCMS (ESI): m / z 451 [M+H]+.1H NMR (400 MHz, Methanol-tii) 5 7.88 (s, 1H), 7.67 - 7.61 (m, 2H), 7.57 - 7.51 (m, 2H), 7.49 - 7.44 (m, 1H), 7.14 (dd, J= 15.2, 4.7 Hz, 1H), 6.88 (dd, J= 15.2, 1.8 Hz, 1H), 5.05 - 4.97 (m, 1H), 3.01 (s, 3H), 2.20 (t, J= 18.8 Hz, 3H), 1.76 - 1.64 (m, 1H), 0.98 - 0.89 (m, 1H), 0.75 - 0.64 (m, 2H), 0.54 - 0.45 (m, 1H).Example 14: (E)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-7-(l,l-difluoroethyl)-l- phenylisoquinolinePatent ApplicationAtty. Docket No. ENTX-033PCTExample 14

[0335] Step A: A mixture of 7-bromo-l,3-dichloroisoquinoline (5 g, 18.0 mmol), tributyl(l- ethoxyvinyl)stannane (7.17 g, 19.9 mmol) and Pd(PPhs)4 (1.04 g, 0.9 mmol) in dioxane (60 mL) was stirred at 100 °C under nitrogen overnight. The cooled reaction mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. The organic layer was separated and 6 AHC1 was added into the solution. The mixture was stirred at room temperature for 1 hour. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-30% ethyl acetate in petroleum ether to afford 1 -( 1 ,3- dichloroisoquinolin-7-yl)ethan-l-one (3.75 g, 86%). LCMS (ESI): m / z 240 [M+H]+.

[0336] Step B: A mixture of l-(l,3-dichloroisoquinolin-7-yl)ethan-l-one (3.75 g, 15.6 mmol), phenylboronic acid (1.9 g, 15.62 mmol), cesium fluoride (4.8 g, 31.3 mmol) and Pd(PPh3)4 (0.9 g, 0.78 mmol) in 1,2-dimethoxy ethane (50 mL) was stirred at 90 °C under nitrogen overnight. Then the cooled reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-30% ethyl acetate in petroleum ether to afford l-(3-chloro-l-phenylisoquinolin-7-yl)ethan-l-one (2 g, 46%). LCMS (ESI): m / z 282 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0337] Step C: A solution of l-(3-chloro-l-phenylisoquinolin-7-yl)ethan-l-one (2 g, 7.1 mmol) in DAST (20 mL) was stirred at 60 °C for 48 hours. The cooled reaction mixture was poured into ice-water, extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford 3-chloro-7-(l,l-difluoroethyl)-l-phenylisoquinoline (2 g, 93%). LCMS (ESI): m / z 304 [M+H]t

[0338] Step D: To a solution of 3-chloro-7-(l,l-difluoroethyl)-l-phenylisoquinoline (210 mg, 0.69 mmol) in N, N-Dimethylformamide (7 mL) were added 2-cyclopropyl-2-oxoacetic acid (473 mg, 4.15 mmol), Ir[dF(Me)ppy]2(dtbbpy)PF6 (14 mg, 0.01 mmol, CAS# 1335047-34-1), Nickel(II) chloride ethylene glycol dimethyl ether complex (30 mg, 0.14 mmol), 4,4'-di-tert- butyl-2,2'-bipyridine (37 mg, 0.14 mmol) and Li2COa (102 mg, 1.38 mmol). The reaction mixture was purged with nitrogen three times, then stirred and irradiated with 18W blue LED (450 nm) with a fan placed above for cooling. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-30% ethyl acetate in petroleum ether to afford cyclopropyl(7-(l,l-difluoroethyl)-l-phenylisoquinolin-3- yl)methanone (60 mg, 26%). LCMS (ESI): m / z 338 [M+H]+.

[0339] Step E: To a solution of (methoxymethyl)triphenylphosphonium chloride (1.2 g, 3.56 mmol) in THF (20 mL) was added Sodium bis(trimethylsilyl)amide (3.56 mL, 3.56 mmol, 1.0 M in hexane) dropwise at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 hours. Then a solution of cyclopropyl(7-(l,l-difluoroethyl)-l-phenylisoquinolin-3-yl)methanone (400 mg, 1.19 mmol) in THF (4 mL) was added dropwise. The mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford (Z)-3-(l-cyclopropyl-2-methoxyvinyl)-7-(l,l-difluoroethyl)- 1 -phenylisoquinoline (100 mg, 23%). LCMS (ESI): m / z 366 [M+H]+.

[0340] Step F: To a solution of (Z)-3 -( 1-cy cl opropyl-2-methoxyvinyl)-7-( 1,1 -difluoroethyl )- 1 -phenylisoquinoline (40 mg, 0.11 mmol) in acetone (2 mL) were added ChlorotrimethylsilanePatent ApplicationAtty. Docket No. ENTX-033PCT(26 mg, 0.16 mmol) and Nal (25 mg, 0.16 mmol). The reaction was stirred at 25 °C for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated to afford 2-cyclopropyl-2-(7-(l,l-difluoroethyl)-l- phenylisoquinolin-3-yl)acetaldehyde (40 mg, crude). LCMS (ESI): m / z 352 [M + H]+.

[0341] Step G: To a solution of diethyl ((methylsulfonyl)methyl)phosphonate (26 mg, 0.11 mmol) in THF (2 mL) was added NaH (14 mg, 0.34 mmol, 60% in oil) at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours under nitrogen. The mixture was cooled to -60 °C and a solution of 2-cy cl opropyl-2-(7-(l, 1 -difluoroethyl)-! -phenylisoquinolin-3-yl)acetaldehy de (40 mg, crude) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (E)-3-(l- cyclopropyl-3-(methylsulfonyl)allyl)-7-(l,l-difluoroethyl)-l-phenylisoquinoline (0.7 mg, 1%). LCMS (ESI): m / z 428 [M+H]+. 'H NMR (400 MHz, Methanol-^) 8 8.16 (s, 1H), 8.12 - 8.10 (m, 1H), 7.93 - 7.87 (m, 2H), 7.71 - 7.66 (m, 2H), 7.63 - 7.59 (m, 3H), 7.31 (dd, J= 15.2, 7.0 Hz, 1H), 6.78 (dd, 7= 15.2, 1.2 Hz, 1H), 4.88 - 4.87 (m, 1H), 2.98 (s, 3H), 1.99 - 1.90 (m, 3H), 1.54 - 1.43 (m, 1H), 0.85 - 0.75 (m, 1H), 0.66 - 0.59 (m, 1H), 0.49 - 0.39 (m, 2H).Example 15: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- (cyclopropyldifluoromethyl)-4-phenylisoquinolin-l(2H)-one and Example 16: (R, E)-2-(l- cyclopropyl-3-(methylsulfonyl)allyl)-6-(cyclopropyldifluoromethyl)-4-phenylisoquinolin- l(2H)-onePatent ApplicationAtty. Docket No. ENTX-033PCTExample 15 Example 16

[0342] Step A: To a solution of ethyl 2-(6-bromo-l-oxo-4-phenylisoquinolin-2(lH)-yl)-2- cyclopropylacetate (750 mg, 1.76 mmol) and 2-cyclopropyl-2-oxoacetic acid (1.2 g, 10.6 mmol) in DMF (27 mL) were added Nickel (II) chloride ethylene glycol dimethyl ether complex (10 mg, 0.05 mmol), Lithium carbonate (35 mg, 0.47 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (90 mg, 0.35 mmol) and Ir[dF(Me)ppy]2(dtbbpy)PFe (5 mg, 0.04 mmol, CAS#: 1335047-34-1). The reaction mixture was purged with nitrogen three times, then irradiated with 18W blue LED (450 nm) with a fan placed above for cooling and stirred at room temperature for 2 hours under nitrogen. The reaction was poured into ice-water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous MgSCL, filtered and evaporated. The residue was purified by silica gel flash chromatography eluted with 0-30% ethyl acetate in petroleum ether to afford ethyl 2-(6-(cyclopropanecarbonyl)-l-oxo-4-phenylisoquinolin-2(lH)- yl)-2-cyclopropylacetate (360 mg, 49%). LCMS (ESI): m / z 416.4 [M+H]+. *H NMR (400 MHz, DMSO-tL) 5 8.46 (d, J= 8.4 Hz, 1H), 8.21 (d, J= 8.4 Hz, 1H), 8.12 (s, 1H), 7.72 (s, 1H), 7.58 - 7.47 (m, 5H), 4.43 (d, J= 10.2 Hz, 1H), 4.17 (q, J= 7.2 Hz, 2H), 2.84 - 2.78 (m, 1H), 1.79 - 1.71 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H), 1.10 - 1.04 (m, 4H), 0.85 - 0.80 (m, 1H), 0.68 - 0.55 (m, 2H), 0.40 - 0.38 (m, 1H).

[0343] Step B: A solution of ethyl 2-(6-(cyclopropanecarbonyl)-l-oxo-4-phenylisoquinolin- 2(lH)-yl)-2-cyclopropylacetate (470 mg, 1.13 mmol) in DAST (8 mL) was stirred at 65 °C forPatent ApplicationAtty. Docket No. ENTX-033PCT72 hours. The cooled reaction mixture was diluted with EtOAc, poured into ice-water and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-30% ethyl acetate in petroleum ether to afford ethyl 2-cyclopropyl-2-(6-(cyclopropyldifluoromethyl)- l-oxo-4-phenylisoquinolin-2(lH)-yl)acetate (200 mg, 40%). LCMS (ESI): m / z 438.4 [M+H]+. ’HNMR (400 MHz, DMSO-oL) 8 8.42 (d, J= 8.4 Hz, 1H), 7.75 - 7.70 (m, 3H), 7.60 - 7.53 (m, 2H), 7.52 - 7.46 (m, 3H), 4.43 (d, J= 10.2 Hz, 1H), 4.17 (q, J= 12 Hz, 2H), 3.07- 2.99 (m, 1H), 1.76 - 1.71 (m, 1H), 1.19 (t, J= 12 Hz, 3H), 0.85 - 0.80 (m, 1H), 0.68 - 0.62 (m, 5H), 0.58 - 0.53 (m, 1H), 0.41 - 0.34 (m, 1H).

[0344] Step C: To a solution of ethyl 2-cyclopropyl-2-(6-(cyclopropyldifluoromethyl)-l- oxo-4-phenylisoquinolin-2(lH)-yl)acetate (200 mg, 0.46 mmol) in DCM (10 mL) was added DIBAL-H (1.37 mL, 1.37 mmol, 1.0 M in DCM) at -60 °C. The reaction was stirred at -60 °C for 1 hour. The reaction was diluted with DCM and then poured into ice-water. The organic layer was separated, washed with brine and dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-30 % ethyl acetate in petroleum ether to afford 2-cyclopropyl-2-(6-(cyclopropyldifluoromethyl)-l-oxo- 4-phenylisoquinolin-2(lH)-yl)acetaldehyde (140 mg, 77%). LCMS (ESI): m / z 394.4 [M+H]+.

[0345] Step D: To a suspension of sodium hydride (47 mg, 1.18 mmol, 60 % in oil) in THF (2 mL) at 0 °C was added diethyl ((methylsulfonyl)methyl)phosphonate (91 mg, 0.39 mmol). The reaction was stirred at 0 °C for 30 minutes. The mixture was cooled to -60 °C and a solution of 2-cyclopropyl-2-(6-(cyclopropyldifluoromethyl)-l-oxo-4-phenylisoquinolin-2(lH)- yl)acetaldehyde (155 mg, 0.39 mmol) in THF (5 mL) was added dropwise into the mixture. The resulting mixture was stirred at this temperature for another 1 hour. The reaction mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous M SO4, filtered and concentrated in vacuo. The crude product was purified by Prep-HPLC to afford (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- (cyclopropyldifluoromethyl)-4-phenylisoquinolin-l(2H)-one (125 mg, 67%). LCMS (ESI): m / z 470.5 [M+H]+. ’H NMR (400 MHz, Methanol-^) 8 8.51 (d, J= 8.8 Hz, 1H), 7.76 - 7.74 (m, 2H), 7.56 - 7.52 (m, 2H), 7.51 - 7.46 (m, 4H), 7.12 (dd, J= 15.2, 4.6 Hz, 1H), 6.86 (dd, J =Patent ApplicationAtty. Docket No. ENTX-033PCT15.2, 1.6 Hz, 1H), 4.98 - 4.94 (m, 1H), 3.01 (s, 3H), 1.69 - 1.60 (m, 1H), 1.58- 1.51 (m, 1H), 0.96 - 0.89 (m, 1H), 0.71 - 0.63 (m, 6H), 0.53 - 0.46 (m, 1H).

[0346] Step E: (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- (cyclopropyldifluoromethyl)-4-phenylisoquinolin-l(2H)-one (125 mg, 0.27 mmol) was separated by chiral prep-SFC method 4 to give (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- (cyclopropyldifluoromethyl)-4-phenylisoquinolin-l(2H)-one. LCMS (ESI): m / z 470.5 [M+H]+. ’HNMR (400 MHz, Methanol-^) 8 8.51 (d, J= 8.8 Hz, 1H), 7.76 - 7.74 (m, 2H), 7.56 - 7.52 (m, 2H), 7.51 - 7.46 (m, 4H), 7.12 (dd, J= 15.2, 4.6 Hz, 1H), 6.86 (dd, J= 15.2, 1.6 Hz, 1H), 4.98 - 4.94 (m, 1H), 3.01 (s, 3H), 1.69 - 1.60 (m, 1H), 1.58- 1.51 (m, 1H), 0.96 - 0.89 (m, 1H), 0.71 - 0.63 (m, 6H), 0.53 - 0.46 (m, 1H). And (R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)- 6-(cyclopropyldifluoromethyl)-4-phenylisoquinolin-l(2H)-one. LCMS (ESI): m / z 470.5 [M+H]+. 'H NMR (400 MHz, Methanol-^) 8 8.51 (d, J= 8.8 Hz, 1H), 7.76 - 7.74 (m, 2H), 7.56 - 7.52 (m, 2H), 7.51 - 7.46 (m, 4H), 7.12 (dd, J= 15.2, 4.6 Hz, 1H), 6.86 (dd, J= 15.2, 1.6 Hz, 1H), 4.98 - 4.94 (m, 1H), 3.01 (s, 3H), 1.69 - 1.60 (m, 1H), 1.58- 1.51 (m, 1H), 0.96 - 0.89 (m, 1H), 0.71 - 0.63 (m, 6H), 0.53 - 0.46 (m, 1H).Example 17: (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-3-fluoro- 4-phenylthieno[2,3-c]pyridin-7(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT step GF F Example 17

[0347] Step A: To a solution of methyl 4-fluorothiophene-2-carboxylate (3 g, 18.7 mmol) and FeBr.3 (6.64 g, 22.5 mmol) in CCU (20 mL) was added Br2 (30 g, 187.3 mmol) and the mixture was stirred at 60 °C for 16 hours. The mixture was poured into ice-water and quenched with saturated aq. Na2S20a solution. The mixture was extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% ethyl acetate in petroleum ether to afford methyl 3,5-dibromo-4- fluorothiophene-2-carboxylate (3.3 g, 55%). 'H NMR (400 MHz, CDCI3) 8 3.91 (s, 3H).

[0348] Step B: A mixture of methyl 3,5-dibromo-4-fluorothiophene-2-carboxylate (1 g, 3.15 mmol), tributyl(l-ethoxyvinyl)stannane (1.2 g, 3.3 mmol) and Pd(PPh3)2Ch (158 mg, 0.3 mmol) in dioxane (20 mL) was stirred at 100 °C under nitrogen overnight. The cooled reaction mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. The organic layer was separated and 6 N HC1 was added into the solution. The mixture was stirred at room temperature for 1 hour. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford methyl 5-acetyl-3-bromo-4-fluorothiophene-2-carboxylate (500 mg, 56%). LCMS (ESI): m / z 282 [M+H]+.

[0349] Step C: A solution of methyl 5-acetyl-3-bromo-4-fluorothiophene-2-carboxylate (500 mg, 1.78 mmol) in DAST (5 mL) was stirred at 50 °C overnight. The cooled reaction mixture was diluted with EtOAc, poured into ice-water and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-10% EtOAc in petroleum ether to affordPatent ApplicationAtty. Docket No. ENTX-033PCT methyl 3-bromo-5-(l,l-difluoroethyl)-4-fluorothiophene-2-carboxylate (400 mg, 74%). LCMS (ESI): m / z 304 [M+H]+. ’H NMR (400 MHz, CDC13) 5 3.93 (s, 3H), 2.07 (t, J= 18.4 Hz, 3H).

[0350] Step D: A mixture of N'-(2-methoxy-l-phenylethylidene)-4- methylbenzenesulfonohydrazide (174 mg, 0.55 mmol), methyl 3-bromo-5-(l,l-difluoroethyl)-4- fluorothiophene-2-carboxylate (138 mg, 0.46 mmol), PdCh(MeCN)2 (11.8 mg, 0.05 mmol), 1,3- Bis(diphenylphosphino)propane (37.6 mg, 0.09 mmol) and CS2CO3 (445 mg, 1.37 mmol) in dioxane (8 mL) was stirred at 90 °C under nitrogen for 2 hours. The cooled mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 12% ethyl acetate in petroleum ether to afford methyl (E)-5-(l,l-difluoroethyl)-4-fluoro-3-(2-methoxy-l- phenylvinyl)thiophene-2-carboxylate (30 mg, 18%). LCMS (ESI): m / z 357 [M+H]+.

[0351] Step E: To a solution of methyl (E)-5-(l,l-difluoroethyl)-4-fluoro-3-(2-methoxy-l- phenylvinyl)thiophene-2-carboxylate (30 mg, 0.08 mmol) in THF and H2O (4 mL, 3:1) was added LiOH (8.8 mg, 0.21 mmol). The reaction was stirred at 50 °C for 2 hours. The cooled mixture was poured into ice-water and adjusted to pH = 3~4 with 2 AHC1. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford (E)-5-(l,l-difluoroethyl)-4-fluoro-3-(2-methoxy-l- phenylvinyl)thiophene-2-carboxylic acid (15 mg, crude) which was used directly for next step. LCMS (ESI): m / z 343 [M+H]+.

[0352] Step F: To a solution of (E)-5-(l,l-difluoroethyl)-4-fluoro-3-(2-methoxy-l- phenylvinyl)thiophene-2-carboxylic acid (15 mg, crude) in DCM (3 mL) was added (S, E)-l - cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (12 mg, 0.06 mmol), HATU (45 mg, 0.12 mmol) and DIEA (16 mg, 0.12 mmol). The mixture was stirred at 25 °C for 1 hour. Then the reaction was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by Perp-TLC to afford N-((S, E)-l - cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-4-fluoro-3-((E)-2-methoxy-l- phenylvinyl)thiophene-2-carboxamide (10 mg, 46%). LCMS (ESI): m / z 500 [M+H]+.

[0353] Step G: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l- difluoroethyl)-4-fluoro-3-((E)-2-m ethoxy- l-phenylvinyl)thiophene-2-carboxamide (20 mg, 0.06 mmol) in dioxane (3 mL) was added HC1 (1 mL, 4 M in dioxane). The mixture was stirred at 25°C for 3 hours. The reaction was concentrated and the residue was purified by Prep-HPLC toPatent ApplicationAtty. Docket No. ENTX-033PCT afford (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-3-fluoro-4- phenylthieno[2,3-c]pyridin-7(6H)-one (3.8 mg, 20%). LCMS (ESI): m / z 468 [M+H]+. ’H NMR (400 MHz, Methanol^) 8 7.57 (s, 1H), 7.50 - 7.39 (m, 5H), 7.10 (dd, J= 15.3, 4.7 Hz, 1H), 6.86 (dd, 15.3, 1.8 Hz, 1H), 4.94 - 4.89 (m, 1H), 3.01 (s, 3H), 2.16 - 2.02 (m, 3H), 1.69 - 1.60 (m, 1H), 0.98 - 0.87 (m, 1H), 0.71 - 0.62 (m, 2H), 0.52 - 0.45 (m, 1H).Example 18: (S, E)-5-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-7- phenylthieno[3,2-c]pyridin-4(5H)-oneadded methyl 2 -bromothiophene-3 -carboxylate (1 g, 4.5 mmol), followed by acetyl chloride (0.64 mL, 9.0 mmol) under nitrogen at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction was poured into ice-water, extracted with DCM. The organic extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford methyl 5- acetyl-2-bromothiophene-3-carboxylate (1.1 g, 92%). LCMS (ESI): m / z 263, 265 [M+H]+.

[0355] Step B: A solution of methyl 5-acetyl-2-bromothiophene-3-carboxylate (1.1 g, 4.2 mmol) in DAST (10 mL) was stirred at 60 °C for 16 hours. The cooled mixture was diluted with EtOAc and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried overPatent ApplicationAtty. Docket No. ENTX-033PCT anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 3% EtOAc in petroleum ether to afford methyl 2- bromo-5-(l,l-difluoroethyl)thiophene-3-carboxylate (800 mg, 67%) as a white solid. LCMS (ESI): m / z 285, 287 [M+H]+.JH NMR (400 MHz, DMSO r,) 8 7.69 (s, 1H), 3.83 (s, 3H), 2.11 (t, J= 18.8 Hz, 3H).

[0356] Step C: A mixture of N-{[(lZ)-2-methoxy-l-phenylethylidene]amino}-4- methylbenzenesulfonamide (223 mg, 0.7 mmol), methyl 2-bromo-5-(l,l- difluoroethyl)thiophene-3-carboxylate (200 mg, 0.7 mmol), PdC12(MeCN)2 (45 mg, 0.14 mmol), 1,3-Bis(diphenylphosphino)propane (57 mg, 0.14 mmol) and CS2CO3 (457 mg, 1.4 mmol) in dioxane (10 mL) was stirred at 90 °C under nitrogen for 3 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% ethyl acetate in petroleum ether to afford methyl (E)-5-(l,l-difluoroethyl)-2-(2-methoxy-l- phenylvinyl)thiophene-3-carboxylate (100 mg, 42%). LCMS (ESI): m / z 339 [M+H]+.

[0357] Step D: To a solution of methyl methyl (E)-5-(l,l-difluoroethyl)-2-(2-methoxy-l- phenylvinyl)thiophene-3-carboxylate (100 mg, 0.3 mmol) in THF (3 mL), MeOH (3 mL) and H2O (1 mL) was added LiOH (37 mg, 0.9 mmol). The reaction mixture was stirred at 50 °C for 16 hours. The cooled mixture was poured into ice-water and adjusted to pH = 3~4 with 2 AHC1. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford (E)-5-(l,l-difluoroethyl)-2-(2- methoxy-l-phenylvinyl)thiophene-3 -carboxylic acid (90 mg, crude) which was used directly for next step. LCMS (ESI): m / z 325 [M+H]+.

[0358] Step E: To a stirred mixture of (E)-5-(l,l-difluoroethyl)-2-(2-methoxy-l- phenylvinyl)thiophene-3-carboxylic acid (50 mg, 0. 15 mmol) in DCM (10 mL) was added (S, E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (40 mg, 0.23 mmol), HATH (87 mg, 0.23 mmol) and DIEA (96 mg, 0.75 mmol) and the result mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford a crude products N-((S, E)- 1 -cy clopropyl-3 -(methylsulfonyl)allyl)-5-( 1 , 1 -difluoroethyl)-2-((E)-2-methoxy- 1 - phenylvinyl)thiophene-3-carboxamide (50 mg, crude) which was used directly for next step. LCMS (ESI): m / z 482 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0359] Step F: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l- difhioroethyl)-2-((E)-2-methoxy-l-phenylvinyl)thiophene-3 -carboxamide (50 mg, 0.10 mmol) in dioxane (3 mL) was added HC1 (1 mL, 4 M in dioxane) under 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous Na2SCL, filtered and evaporated. The residue was purified Prep-HPLC to afford (S, E)-5-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-7-phenylthieno[3,2-c]pyridin-4(5H)-one (2.1 mg, 4%). LCMS (ESI): m / z 450 [M+H]+. 'H NMR (400 MHz, DMSC ,) 8 7.93 (s, 1H), 7.92 (s, 1H), 7.71 - 7.63 (m, 2H), 7.59 - 7.52 (m, 2H), 7.50 - 7.44 (m, 1H), 7.05 (dd, J= 15.3, 5.0 Hz, 1H), 6.88 (d, J= 15.3 Hz, 1H), 4.91 - 4.81 (m, 1H), 3.04 (s, 3H), 2.18 (t, J= 18.7 Hz, 3H), 1.86 - 1.73 (m, 1H), 0.85 - 0.75 (m, 1H), 0.72 - 0.63 (m, 1H), 0.62 - 0.51 (m, 1H), 0.42 - 0.30 (m, 1H).Example 19: (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)alIyl)-2- (cyclopropyldifluoromethyl)-8-phenyl-l,6-naphthyridin-5(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCTExample 19

[0360] Step A: To a solution of ethyl 6-bromo-2-chloronicotinate (1 g, 3.8 mmol), 2-(l- cyclopropylvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.8 g, 4.2 mmol) and K2CO3 (1.6 g, 11.34 mmol) in dioxane (15 mL) and H2O (2 mb) was added Pd(dppf)Ch (280 mg, 0.38 mmol). The reaction mixture was purged with nitrogen three times, then stirred at 80 °C under nitrogen for 3 hours. The cooled reaction mixture was diluted with EtOAc, washed with water, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford ethyl 2-chloro-6-(l-cyclopropylvinyl)nicotinate (700 mg, 73%). LCMS (ESI): m / z 252, 254 [M+H]+.

[0361] Step B: A solution of ethyl 2-chloro-6-( l-cyclopropylvinyl)nicotinate (700 mg, 2.78 mmol) in DCM (10 mL) and MeOH (2 mL) was cooled to -65 °C. O3 was pumped into the solution for 10 mins while stirring. Then the reaction was quenched with dimethyl sulfide, diluted with H2O, extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford ethyl 2- chloro-6-(cyclopropanecarbonyl)nicotinate (600 mg, 85%). LCMS (ESI): m / z 254, 256 [M+H]+.

[0362] Step C: A solution of ethyl 2-chloro-6-(cyclopropanecarbonyl)nicotinate (600 mg, 2.4 mmol) in DAST (5 mL) was stirred at 60 °C for 16 hours. The cooled reaction mixture was diluted with EtOAc and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 15 - 20% EtOAc in petroleum ether to affordPatent ApplicationAtty. Docket No. ENTX-033PCT ethyl 2-chloro-6-(cyclopropyldifluoromethyl)nicotinate (340 mg, 52%). LCMS (ESI): m / z 276, 278 [M+H]t

[0363] Step D: A mixture of N'-(2-methoxy-l-phenylethylidene)-4- methylbenzenesulfonohydrazide (496 mg, 1.6 mmol), ethyl 2-chloro-6- (cyclopropyldifluoromethyl)nicotinate (340 mg, 1.3 mmol), PdCh(MeCN)2 (33 mg, 0.13 mmol), 1,3-Bis(diphenylphosphino)propane (107 mg, 0.26 mmol) and CS2CO3 (1270 mg, 3.9 mmol) in dioxane (10 mL) was stirred at 90 °C under nitrogen for 6 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% ethyl acetate in petroleum ether to afford ethyl (E)-6-(cyclopropyldifluoromethyl)-2-(2-methoxy-l- phenylvinyl)nicotinate (75 mg, 16%). LCMS (ESI): m / z 374 [M+H]+.

[0364] Step E: To a solution of ethyl (E)-6-(cy clopropyldifluoromethyl)-2-(2 -methoxy- 1- phenylvinyl)nicotinate (75 mg, 0.2 mmol) in THF, MeOH and H2O (7 mL, 3:3: 1) was added LiOH (42 mg, 1 .0 mmol). The reaction was stirred at 40 °C for 6 hours. The cooled mixture was poured into ice- water and adjusted to pH = 3~4 with 2 N HC1. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford (E)-6-(cyclopropyldifluoromethyl)-2-(2 -methoxy- 1- phenylvinyl)nicotinic acid (70 mg, crude) which was used directly for next step. LCMS (ESI): m / z 346 [M+H]+

[0365] Step F: To a solution of (E)-6-(cyclopropyldifluoromethyl)-2-(2-methoxy-l- phenylvinyl)nicotinic acid (70 mg, crude) in DCM (6 mL) was added (S, E)-l-cyclopropyl-3- (methylsulfonyl)prop-2-en-l -amine (53 mg, 0.30 mmol), HATU (112 mg, 0.30 mmol) and DIEA (126 mg, 0.98 mmol) and the mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 40% ethyl acetate in petroleum ether to afford N-((S, E)-l-cyclopropyL3- (methylsulfonyl)allyl)-6-(cyclopropyldifluoromethyl)-2-((E)-2-methoxy-l- phenylvinyl)nicotinamide (55 mg, 54%). LCMS (ESI): m / z 503 [M+H]+.

[0366] Step G: To a solution of N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6- (cyclopropyldifluoromethyl)-2-((E)-2-methoxy-l-phenylvinyl)nicotinamide (55 mg, 0.06 mmol) in MeCN (6 mL) was added Hydriodic acid (0.2 mL, cata.). The mixture was stirred at 25°C forPatent ApplicationAtty. Docket No. ENTX-033PCT6 hours. The reaction was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford (S, E)-6-(l -cyclopropyl -3-(methylsulfonyl)allyl)-2-(cy cl opropyldifluoromethyl)-8-phenyl- 1,6- naphthyridin-5(6H)-one (16.4 mg, 32%). LCMS (ESI): m / z 471 [M+H]+. 'H NMR (400 MHz, DMSO-tA) 5 8.81 (d, J= 8.3 Hz, 1H), 8.04 (s, 1H), 7.83 (d, J= 8.3 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.52 - 7.44 (m, 2H), 7.42 - 7.35 (m, 1H), 7.06 (dd, J= 15.2, 4.8 Hz, 1H), 6.93 (dd, J= 15.2, 1.2 Hz, 1H), 4.91 - 4.77 (m, 1H), 3.03 (s, 3H), 1.88 - 1.74 (m, 2H), 0.82 - 0.76 (m, 1H), 0.72 - 0.65 (m, 5H), 0.63 - 0.53 (m, 1H), 0.43 - 0.33 (m, 1H).Example 20: (S, E)-5-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-7- phenylthiazolo[5,4-c]pyridin-4(5H)-oneExample 20

[0367] Step A: To a mixture of methyl 2,4-dibromothiazole-5-carboxylate (2.1 g, 7.0 mmol), Potassium Vinyltrifluoroborate (89.0 mg, 0.66 mmol), Pd(dppf)C12 (500 mg, 0.70 mmol) in dioxane (30 mb) and H2O (3 mL) was added K2CO3 (2.9 g, 21.1 mmol). The reaction mixture was purged with nitrogen three times and stirred at 90 °C under nitrogen for 3 hours. The cooled reaction mixture was diluted with water, extracted with EtOAc. The combined extracts werePatent ApplicationAtty. Docket No. ENTX-033PCT washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 10 - 15% EtOAc in petroleum ether to afford methyl 4-bromo-2-vinylthiazole-5-carboxylate (1.05 g, 60%). LCMS (ESI): m / z 248, 250 [M+H]+.

[0368] Step B: A solution of methyl 4-bromo-2-vinylthiazole-5-carboxylate (1.2 g, 4.8 mmol) in MeOH (10 mb) and DCM (10 m ) was cooled to -65 °C. O3 was pumped into the solution for 1 hour while stirring. The reaction was quenched with dimethyl sulfide, diluted with H2O, extracted with DCM. The organic phase was washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 20 - 30% EtOAc in petroleum ether to afford methyl 4-bromo-2-formylthiazole-5-carboxylate (750 mg, 62%). LCMS (ESI): m / z 250, 252 [M+H]+.

[0369] Step C: To a solution of methyl 4-bromo-2-formylthiazole-5-carboxylate (750 mg, 3.0 mmol) in THF (10 mb) were added Ethylmagnesium bromide (4.5 mb, 4.5 mmol, 1.0 M in THF) at -65 °C. The reaction mixture was stirred at -65 °C for 3 hours. The reaction mixture was quenched with NH4CI solution (3 mb) at 0 °C, extracted with EtOAc. The organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 15 - 20% EtOAc in petroleum ether to afford methyl 4-bromo-2-(l- hydroxypropyl)thiazole-5-carboxylate (300 mg, 36%). LCMS (ESI): m / z 280, 282 [M+H]+.JH NMR (400 MHz, DMSO-r / 6) 5 6.51 (d, J= 5.3 Hz, 1H), 4.83 - 4.74 (m, 1H), 3.83 (s, 3H), 1.92 - 1.82 (m, 1H), 1.74 - 1.63 (m, 1H), 0.94 - 0.84 (m, 3H).

[0370] Step D: To a solution of methyl 4-bromo-2-(l-hydroxypropyl)thiazole-5-carboxylate (300 mg, 1.1 mmol) in DCM (3 mL) was added Dess-Martin periodinane (908 mg, 2.1 mmol) at 0 °C . The reaction was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was washed with NaHCOs solution, further washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 15 - 25% EtOAc in petroleum ether to afford methyl 4-bromo-2-propionylthiazole-5-carboxylate (240 mg, 81%). LCMS (ESI): m / z 278, 280 [M+H]+.

[0371] Step E: A solution of methyl 4-bromo-2-propionylthiazole-5-carboxylate (240 mg, 0.86 mmol) in DAST (4 mL) was stirred at room temperature for 1.5 hours. The reaction mixturePatent ApplicationAtty. Docket No. ENTX-033PCT was diluted with EtOAc and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 15 - 20% EtOAc in petroleum ether to afford methyl 4-bromo-2-(l,l-difluoropropyl)thiazole-5-carboxylate (230 mg, 89%). LCMS (ESI): m / z: 300, 302 [M+H]+. 'H NMR (400 MHz, DMSO-ofe) 8 3.88 (s, 3H), 2.47 - 2.34 (m, 2H), 1.04 - 0.97 (m, 3H).

[0372] Step F: A mixture of N'-(2-methoxy-l-phenylethylidene)-4- methylbenzenesulfonohydrazide (229 mg, 0.72 mmol), methyl 4-bromo-2-(l,l- difluoropropyl)thiazole-5-carboxylate (180 mg, 0.60 mmol), PdCh(MeCN)2 (15.6 mg, 0.06 mmol), 1,3-Bis(diphenylphosphino)propane (49.5 mg, 0.12 mmol) and CS2CO3 (445 mg, 1.37 mmol) in 1,4-dioxane (5 mL) was stirred at 90 °C under nitrogen for 2 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 10 - 15% EtOAc in petroleum ether to afford methyl (E)-2-(l,l-difluoropropyl)-4-(2-methoxy-l- phenylvinyl)thiazole-5-carboxylate (40 mg, 19%). LCMS (ESI): m / z 354 [M+H]1.

[0373] Step G: To a solution of methyl (E)-2-(l,l-difluoropropyl)-4-(2-methoxy-l- phenylvinyl)thiazole-5-carboxylate (40 mg, 0.11 mmol) in THF (4 mL) and H2O (0.4 mL) was added LiOH (12 mg, 0.28 mmol). The reaction was stirred at 40 °C for 2 hours. The cooled mixture was neutralized with 2 N HC1 solution, extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford (E)-2- (l,l-difluoropropyl)-4-(2-methoxy-l-phenylvinyl)thiazole-5-carboxylic acid (30 mg, crude) which was used directly for next step. LCMS (ESI): m / z 340 [M+H]+.

[0374] Step H: To a stirred mixture of (E)-2-(l,l-difluoropropyl)-4-(2-methoxy-l- phenylvinyl)thiazole-5-carboxylic acid (30 mg, 0.09 mmol) in DCM (3 mL) was added (S, E)-l- cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (17 mg, 0.1 mmol), HATU (67 mg, 0.18 mmol) and DIEA (57 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by perp-TLC to afford N-((S, E)- 1 -cy cl opropyl-3 -(methyl sulfony l)ally l)-2-( 1 , 1 -difluoropropyl )-4-((E)-2-meth oxy- 1 - phenylvinyl)thiazole-5-carboxamide (30 mg, 68%). LCMS (ESI): m / z 497 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0375] Step I: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoropropyl)-4-((E)-2-methoxy-l-phenylvinyl)thiazole-5-carboxamide (20 mg, 0.04 mmol) in dioxane (3 mL) was added HC1 (1 mL, 4 M in dioxane). The mixture was stirred at 25°C for 2 hours. The reaction was concentrated and the residue was purified by Prep-HPLC to afford (S, E)-5-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-7-phenylthiazolo[5,4- c]pyridin-4(5H)-one (9.6 mg, 51%). LCMS (ESI): m / z 465 [M+H]+. Tl NMR (400 MHz, Methanol-^) 8 7.92 (s, 1H), 7.77 - 7.71 (m, 2H), 7.50 - 7.44 (m, 2H), 7.43 - 7.38 (m, 1H), 7.15 (dd, J = 15.3, 4.7 Hz, 1H), 6.88 (dd, J= 15.3, 1.8 Hz, 1H), 5.00 - 4.93 (m, 1H), 3.01 (s, 3H), 2.53 - 2.41 (m, 2H), 1.75 - 1.66 (m, 1H), 1.12 - 1.07 (m, 3H), 0.99 - 0.91 (m, 1H), 0.73 - 0.64 (m, 2H), 0.53 - 0.45 (m, 1H).Example 21: (S,E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenylthieno[2,3-c]pyridin-7(6H)-oneExample 22: R,E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenylthieno [2 ,3-c] pyridin-7(6H)-oneExample 22 Example 21

[0376] Step A: (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenylthieno[2,3-c]pyridin-7(6H)-one (80 mg, 0.18 mmol) was purified by chiral prep-SFC method 5 to afford the desired product (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-4-phenylthieno[2,3-c]pyridin-7(6H)-one (25.2 mg, 31 %). LCMS (ESI): m / z 450 [M+H]+. 6 7.84 (s, 1H), 7.62 (s, 1H), 7.58 - 7.51 (m, 4H), 7.47 - 7.43 (t, J= 7.2 Hz, 1H), 7.05 (dd, J= 15.2, 5.2 Hz, 1H), 6.89 (d, J= 15.2 Hz, 1H),4.88 - 4.84 (m, 1H), 3.04 (s, 3H), 2.15 (t, J = 18.8 Hz, 3H), 1.84 - 1.75 (m, 1H), 0.84 - 0.75 (m, 1H), 0.67 - 0.65 (m, 1H), 0.59 - 0.52 (m, 1H), 0.37 - 0.35 (m, 1H). And (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-Patent ApplicationAtty. Docket No. ENTX-033PCT difluoroethyl)-4-phenylthieno[2,3-c]pyridin-7(6H)-one (27.7 mg, 35 %). LCMS (ESI): m / z 450 [M+H]+. *H NMR (400 MHz, DMSO-rA) 8 7.84 (s, 1H), 7.62 (s, 1H), 7.58 - 7.51 (m, 4H), 7.47 - 7.43 (t, ,7 = 7.2 Hz, 1H), 7.05 (dd, J= 15.2, 5.2 Hz, 1H), 6.89 (d, J= 15.2 Hz, 1H),4.88 - 4.84 (m, 1H), 3.04 (s, 3H), 2.15 (t, J= 18.8 Hz, 3H), 1.84 - 1.75 (m, 1H), 0.84 - 0.75 (m, 1H), 0.67 - 0.65 (m, 1H), 0.59 - 0.52 (m, 1H), 0.37 - 0.35 (m, 1H).Example 23: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenylph thalaz in- 1 (2H)-oneExample 24: (R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenylphthalazin-l(2H)-oneExample 23 Example 24

[0377] Step A: (E)-2-( 1 -cyclopropyl-3 -(methylsulfonyl)allyl)-6-( 1 , 1 -difluoroethyl)-4- phenylphthal azin- l(2H)-one (80 mg, 0.18 mmol) was purified by chiral prep-SFC method 6 to afford (S, E)-2-(l -cyclopropyl-3 -(methyl sulfonyl)allyl)-6-( 1 , 1 -difluoroethyl)-4- phenylphthalazin-l(2H)-one (24.3 mg, 30%) LCMS (ESI): m / z 445 [M+H]+. 'H NMR (400 MHz, DMSO-17) 8 8.52 (d, J= 8.2 Hz, 1H), 8.11 (d, J= 8.2 Hz, 1H), 7.84 (s, 1H), 7.69 - 7.60 (m, 5H), 7.10 - 6.87 (m, 2H), 5.10 - 5.06 (m, 1H), 3.03 (s, 3H), 2.01 (t, J= 19.0 Hz, 3H), 1.68 - 1.50 (m, 1H), 0.82 - 0.63 (m, 2H), 0.60 - 0.48 (m, 1H), 0.42 - 0.38 (m, 1H). And (R, E)-2-(l- cyclopropyl-3 -(methyl sulfonyl)allyl)-6-( 1 , 1 -difluoroethyl)-4-phenylphthalazin- 1 (2H)-one (22.3 mg, 28%) LCMS (ESI): m / z 445 [M+H]+. 'H NMR (400 MHz, DMSO-tL) 8 8.52 (d, J= 8.2 Hz, 1H), 8.11 (d, J= 8.2 Hz, 1H), 7.84 (s, 1H), 7.69 - 7.60 (m, 5H), 7.10 - 6.87 (m, 2H), 5.10 - 5.06 (m, 1H), 3.03 (s, 3H), 2.01 (t, J= 19.0 Hz, 3H), 1.68 - 1.50 (m, 1H), 0.82 - 0.63 (m, 2H), 0.60 - 0.48 (m, 1H), 0.42 - 0.38 (m, 1H).Patent ApplicationAtty. Docket No. ENTX-033PCTExample 25: (E)-3-chloro-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenylthieno[2,3-c]pyridin-7(6H)-oneExample 25

[0378] Step A: To a solution of 2-oxo-l,2-dihydropyridine-4-carbonitrile (1.0 g, 8.3 mmol) in CH3CN (15 mL) was added NBS (3.1 g, 17.5 mmol) and the mixture was stirred at 65 °C overnight. The cooled reaction mixture was poured into water and extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous ISfeSC , filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford 3,5-dibromo-2-oxo-l,2- dihydropyridine-4-carbonitrile (500 mg, 22%). LCMS (ESI): m / z 279 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0379] Step B: To a solution of 3,5-dibromo-2-oxo-l,2-dihydropyridine-4-carbonitrile (500 mg, 1.8 mmol) in z-PrOH (5 mb) was added methyl 2-mercaptoacetate (210 mg, 1.98 mmol) and K2CO3 (746 mg, 5.4 mmol). The result mixture was stirred at 65 °C overnight. The cooled reaction mixture was filtered and the filter cake was washed with water. The aqueous layer was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% MeOH in DCM to afford methyl 3-amino-4- bromo-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (300 mg, 55%). LCMS (ESI): m / z 303, 305 [M+H]+.

[0380] Step C: To a solution of methyl 3-amino-4-bromo-7-oxo-6,7-dihydrothieno[2,3- c]pyridine-2-carboxylate (300 mg, 0.99 mmol) in dioxane (5 mL) was added phenylboronic acid (121 mg, 0.99 mmol), Pd(dtbpf)C12 (50 mg, 0.1 mmol) and K3PO4 (630 mg, 2.97 mmol). The mixture was stirred at 100 °C under nitrogen overnight. The cooled reaction mixture was poured into water and extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% MeOH in DCM to afford methyl 3- amino-7-oxo-4-phenyl-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (200 mg, 67%). LCMS (ESI): m / z 301 [M+H]+.

[0381] Step D: To a solution of methyl 3-amino-7-oxo-4-phenyl-6,7-dihydrothieno[2,3- c]pyridine-2-carboxylate (200 mg, 0.67 mmol) in CH3CN (5 mL) was added tert-butyl nitrite (137 mg, 1.33 mmol) and Copper(I) chloride (330 mg, 3.33 mmol), the result mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% MeOH in DCM to afford methyl 3-chloro-7-oxo-4-phenyl-6,7- dihydrothieno[2,3-c]pyridine-2-carboxylate (100 mg, 47%). LCMS (ESI): m / z 320 [M+H]+.

[0382] Step E: To a solution of methyl 3-chloro-7-oxo-4-phenyl-6H-thieno[2,3-c]pyridine- 2-carboxylate (100 mg, 0.3 mmol) in THF (3 mL) and H2O (2 mL) was added LiOH (40 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was neutralized with 2 A HCI solution, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford thePatent ApplicationAtty. Docket No. ENTX-033PCT product 3-chloro-7-oxo-4-phenyl-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (90 mg, 94%) which was used directly for next step. LCMS (ESI): m / z 306 [M+H]+.

[0383] Step F: To a solution of 3-chloro-7-oxo-4-phenyl-6,7-dihydrothieno[2,3-c]pyridine- 2-carboxylic acid (90 mg, 0.3 mmol) in CH3CN (3 mL) was added DIEA (190 mg, 1.47 mmol) and HATU (224 mg, 0.59 mmol) and the result mixture was stirred at room temperature for 10 mins. Then N, O-dimethylhydroxylamine (18 mg, 0.3 mmol) was added into the mixture and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% MeOH in DCM to afford 3-chloro-N-methoxy- N-methyl-7-oxo-4-phenyl-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (100 mg, 97%). LCMS (ESI): m / z 349 [M+H]+.

[0384] Step G: To a solution of 3-chloro-N-methoxy-N-methyl-7-oxo-4-phenyl-6H- thieno[2,3-c]pyridine-2-carboxamide (100 mg, 0.29 mmol) in THF (5 mL) was added methylmagnesium bromide (0.86 mL, 0.86 mmol, \M in THF) at -60 °C under nitrogen. The result mixture was stirred at -60 °C for 30 mins and warmed to -20 °C and stirred at -20 °C for another 30 mins. The reaction mixture was quenched by sat. NH4CI solution at 0 °C and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% MeOH in DCM to afford 2-acetyL3-chloro-4- phenylthieno[2,3-c]pyridin-7(6H)-one (70 mg, 80%). LCMS (ESI): m / z [M+H]+.

[0385] Step H: To a suspension of 2-acetyl-3-chloro-4-phenylthieno[2,3-c]pyridin-7(6H)- one (70 mg, 0.23 mmol) and K2CO3 (64 mg, 0.46 mmol) in DMA (3 mL) was added ethyl 2- bromo-2-cyclopropylacetate (48 mg, 0.23 mmol). The result mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4. filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% MeOH in DCM to afford ethyl 2-(2-acetyl-3-chloro-7-oxo-4- phenylthieno[2,3-c]pyridin-6(7H)-yl)-2-cyclopropylacetate (80 mg, 80%). LCMS: 430 [M+H]+.

[0386] Step I: A solution of ethyl 2-(2-acetyl-3-chloro-7-oxo-4-phenylthieno[2,3-c]pyridin- 6(7H)-yl)-2-cyclopropylacetate (80 mg, 0.19 mmol) in DAST (3 mL) was stirred at 60 °C for 18Patent ApplicationAtty. Docket No. ENTX-033PCT hours. The cooled reaction mixture was diluted with EtOAc and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% MeOH in DCM to afford ethyl 2-(3-chloro-2-(l,l-difluoroethyl)-7-oxo-4- phenylthieno[2,3-c]pyridin-6(7H)-yl)-2-cyclopropylacetate (50 mg, 59%). LCMS (ESI): m / z 452 [M+H]+.

[0387] Step J: To a solution of ethyl 2-(3 -chi oro-2-( 1,1 -difluoroethyl )-7-oxo-4- phenylthieno[2,3-c]pyridin-6(7H)-yl)-2-cyclopropylacetate (50 mg, 0.11 mmol ) in DCM (2 mL) was added DIBAL-H (0.11 mL, 0.22 mmol, 2.0 M in DCM) at -60 °C under nitrogen. The result reaction was stirred at -60 °C for 1 hour. The reaction mixture was quenched by sat. NH4CI solution at 0 °C and extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% MeOH in DCM to afford 2-(3-chloro- 2-(l,l-difluoroethyl)-7-oxo-4-phenylthieno[2,3-c]pyridin-6(7H)-yl)-2-cyclopropylacetaldehyde (30 mg, 66%). LCMS (ESI): m / z 408 [M + H]1.

[0388] Step K: To a mixture of sodium hydride (7 mg, 0.16 mmol, 60% in oil) in THF (2 mL) was added diethyl ((methylsulfonyl)methyl)phosphonate (19 mg, 0.08 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, then cooled to -60 °C and a solution of 2-(3-chloro-2- (l,l-difluoroethyl)-7-oxo-4-phenylthieno[2,3-c]pyridin-6(7H)-yl)-2-cyclopropylacetaldehyde (30 mg, 0.07 mmol) in THF (2 mL) was added into the mixture dropwise. The mixture was stirred at -60 °C for another 1 hour and then quenched with saturated solution of ammonium chloride, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified Prep- HPLC to afford (E)-3-chloro-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenylthieno[2,3-c]pyridin-7(6H)-one (1.5 mg, 4%). LCMS (ESI): m / z 484 [M+H]+. 'HNMR (400 MHz, DMSO-tL) 8 7.56 - 7.34 (m, 5H), 7.25 - 7.21 (m, 1H), 6.02 - 5.70 (m, 1H), 4.25 - 4.23(m, 2H), 3.09 (s, 3H), 2.17 -2.07(m, 3H), 1.28 - 1.18 (m, 1H), 0.89 - 0.73 (m, 2H), 0.72 - 0.53 (m, 1H), 0.53 - 0.41 (m, 1H).Patent ApplicationAtty. Docket No. ENTX-033PCTExample 26: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenyl-2,7-naphthyridin-l(2H)-one

[0389] Step A: To a mixture of methyl 6-bromo-4-chloronicotinate (900 mg, 3.59 mmol) and tributyl(l -ethoxy vinyl)stannane (1.43 g, 3.95 mmol) in DMF (20 mL) was added Pd(PPha)4 (415 mg, 0.36 mmol). The reaction mixture was purged with nitrogen for three times and stirred at 100 °C under nitrogen for 16 hours. The cooled mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. The organic layer was separated, washed with brine and concentrated. The residue was dissolved in THF (9 mL), 6 A HO (9 mL) was added into the solution and stirred at room temperature for another 1 hour. The mixture was neutralized with NaHCCL solution, extracted with EtOAc twice. Then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% EtOAc in petroleum ether to afford methyl 6-acetyl-4-chloronicotinate (450 mg, 57%). LCMS (ESI) m / z: 214 [M+H]+.

[0390] Step B: A solution of methyl 6-acetyl-4-chloronicotinate (450 mg, 2.11 mmol) in DAST (10 mL) was stirred at 50 °C for 16 hours. The cooled mixture was diluted with EtOAc and poured into ice-water, neutralized with NaHCOs solution, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered andPatent ApplicationAtty. Docket No. ENTX-033PCT concentrated in vacuo. The crude product was purified by silica gel flash chromatography, eluted with a gradient 0 - 20 % EtOAc in petroleum ether to afford methyl 4-chloro-6-(l,l- difluoroethyl)nicotinate (450 mg, 91%). LCMS (ESI): m / z 236[M+H]+.

[0391] Step C: A mixture of methyl 4-chloro-6-(l,l-difluoroethyl)nicotinate (250 mg, 1.06 mmol), N-{[(lZ)-2-methoxy-l-phenylethylidene]amino}-4-methylbenzenesulfonamide (372 mg, 1.17 mmol), Pd2(dba)3 (97 mg, 0.11 mmol), X-phos (101 mg, 0.21 mmol) and / -BuOLi (204 mg, 2.55 mmol) in dioxane (5 mL) was stirred at 90 °C under nitrogen for 2 hours. The cooled mixture was diluted with H2O, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30 % EtOAc in petroleum ether to afford methyl (E)-6-(l,l-difluoroethyl)-4-(2-methoxy-l- phenylvinyl)nicotinate (45 mg, 13%). LCMS (ESI) m / z: 334 [M+H]+.

[0392] Step D: A mixture of methyl (E)-6-(l,l-difluoroethyl)-4-(2-methoxy-l- phenylvinyl)nicotinate (45 mg, 0.13 mmol) and (S, E)-l-cyclopropyl-3-(methylsulfonyl)prop-2- en-l-amine (35 mg, 0.2 mmol) in HO Ac (2 mL) was stirred at 110 °C for 16 hours. The cooled mixture was diluted with H2O, extracted with EtOAc, the combined extracts were washed with NaHCOs solution, further washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by prep-HPLC to afford (S, E)-2-(l- cyclopropyl-3 -(methylsulfonyl)allyl)-6-( 1 , 1 -difluoroethyl)-4-phenyl-2,7-naphthyridin- 1 (2H)-one (3 mg, 5%). LCMS (ESI) m / z: 445 [M+H]+. 'H NMR (400 MHz, MeOD-t4) 8 9.56 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.58 - 7.46 (m, 5H), 7.12 (dd, J= 15.3, 4.7 Hz, 1H), 6.91 (dd, 15.3, 1.7 Hz, 1H), 4.96 - 4.91 (m, 1H), 3.01 (s, 3H), 1.99 (t, J= 18.8 Hz, 3H), 1.71 - 1.59 (m, 1H), 0.98 - 0.86 (m, 1H), 0.73 - 0.61 (m, 2H), 0.55 - 0.45 (m, 1H).Example 27: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-5-fluoro- 4-phenylisoquinolin-l(2H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0393] Step A: To a solution of 4-chl oro-3 -fluorobenzoic acid (3 g, 17.2 mmol) in THF (30 mb) was added LDA (18.9 mL, 37.8 mmol, 2 Alin THF) dropwise at -60 °C. The result reaction was stirred at -60°C for 1 hour under nitrogen. Then a solution of l,2-dibromo-l,l,2,2- tetrachloroethane (8.9 g, 27.5 mmol) in THF (30 mL) was added into the reaction mixture at - 60 °C. The reaction was allowed to warm to room temperature and stirred at room temperature for 16 hours under nitrogen. The reaction was poured into sat. NH4CI solution at 0 °C, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford 2- bromo-4-chloro-3 -fluorobenzoic acid (3.6 g, 82%). LCMS (ESI): m / z 251, 253 [M-H]‘.

[0394] Step B: To a solution of 2-bromo-4-chloro-3-fluorobenzoic acid (3.2 g, 12.6 mmol) in DMF (25 mL) was added K2CO3 (5.2 g, 37.8 mmol) and CH3I (2.3 g, 16.4 mmol) and the mixture was stirred at 25°C for 2 hours. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous Na SC , filtered andPatent ApplicationAtty. Docket No. ENTX-033PCT concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% ethyl acetate in petroleum ether to afford methyl 2-bromo-4-chl oro-3 - fluorobenzoate (3 g, 88%). LCMS (ESI): m / z 267, 268 [M+H]+.

[0395] Step C: A mixture of N'-(2-methoxy-l-phenylethylidene)-4- methylbenzenesulfonohydrazide (1.3 g, 4.1 mmol), methyl 2-bromo-4-chloro-3-fluorobenzoate (1 g, 3.7 mmol), PdC12(MeCN)2 (0.1 g, 0.37 mmol), dppf (0.4 g, 0.75 mmol) and CS2CO3 (3.6 g, 11.2 mmol) in dioxane (30 mb) was stirred at 90 °C under nitrogen for 3 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 6% ethyl acetate in petroleum ether to afford methyl 4-chl oro-3 -fluoro-2-(2-methoxy-l- phenylvinyl)benzoate (180 mg, 15%). LCMS (ESI): m / z 321, 323 [M+H]+.

[0396] Step D: A mixture of methyl 4-chloro-3-fluoro-2-(2-methoxy-l- phenylvinyl)benzoate (160 mg, 0.50 mmol), tributyl(l -ethoxy vinyl)stannane (270 mg, 0.75 mmol) and Pd( / -Bu3P)2 (25 mg, 0.05 mmol) in DMA (7 mb) was stirred at 120 °C under nitrogen for 5 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 6% ethyl acetate in petroleum ether to afford methyl (E)-4-(l-ethoxyvinyl)-3-fluoro-2-(2-methoxy-l-phenylvinyl)benzoate (90 mg, 50%). LCMS (ESI): m / z 357 [M+H]+.

[0397] Step E: To a solution of methyl (E)-4-(l -ethoxy vinyl)-3-fluoro-2-(2 -methoxy- 1- phenylvinyl)benzoate (90 mg, 0.25 mmol) in THF / MeOH / PEO 3:3: 1 (7 mb) was added NaOH (20 mg, 0.51 mmol) and the result mixture was stirred at 25°C for 16 hours. The mixture was poured into ice water and acidified to pH = 3~4 with 2AHC1. The mixture was extracted with EtOAc. washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford (E)-4-acetyl-3-fluoro-2-(2-methoxy-l-phenylvinyl)benzoic acid (70 mg, 80%). LCMS (ESI): m / z 315 [M+H]+.

[0398] Step F: To a solution of (E)-4-acetyl-3-fluoro-2-(2-methoxy-l-phenylvinyl)benzoic acid (70 mg, 0.22 mmol) in DCM (5 mb) was added (S, E)-l-cyclopropyl-3- (methylsulfonyl)prop-2-en- 1 -amine (50 mg, 0.29 mmol), HATU (423 mg, 1.11 mmol) and DIEA (143 mg, 1.11 mmol). The reaction was stirred at 25°C for 1 hour. The reaction was diluted with DCM and water. The organic layer was separated, washed with brine, dried over anhydrousPatent ApplicationAtty. Docket No. ENTX-033PCTNa2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-60% ethyl acetate in petroleum ether to afford 4- acetyl-N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-3-fluoro-2-((E)-2-methoxy-l- phenylvinyl)benzamide (45 mg, 42%). LCMS (ESI): m / z 472 [M+H]+.

[0399] Step G: To a solution of 4-acetyl-N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-3- fluoro-2-((E)-2-methoxy-l-phenylvinyl)benzamide (45 mg, 0.10 mmol) in MeCN (4 mL) was added HI (24 mg, 0.19 mmol) at 0 °C. The reaction was stirred at 25°C for 16 hours under nitrogen. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with water and brine, dried over anhydrous NazSCU, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 60% ethyl acetate in petroleum ether to afford (S, E)-6-acetyl-2-(l-cyclopropyl-3- (methylsulfonyl)allyl)-5-fluoro-4-phenylisoquinolin-l(2H)-one (30 mg, 71%). LCMS (ESI): m / z 440 [M+H]+.

[0400] Step H: A solution of (S, E)-6-acetyl-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- fluoro-4-phenylisoquinolin-l(2H)-one (30 mg, 0.07 mmol) in DAST (4 mL) was stirred at 50 °C for 16 hours. The cooled reaction solution was diluted with EtOAc and poured into ice-water. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Pre-HPLC to afford (S, E)-2-(l- cyclopropyl-3 -(methylsulfonyl)allyl)-6-( 1 , 1 -difluoroethyl)-5-fluoro-4-phenylisoquinolin- 1 (2H)- one (11.5 mg, 36%). LCMS (ESI): m / z 462 [M+H]+. 'H NMR (400 MHz, MeOD-cL) 5 8.33 (d, J = 8.6 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.44 - 7.38 (m, 5H), 7.35 (s, 1H), 7.09 (dd, J = 15.2, 4.6 Hz, 1H), 6.86 (d, .7= 15.2 Hz, 1H), 4.91 - 4.88 (m, 1H), 3.00 (s, 3H), 1.93 (t, .7= 18.7 Hz, 3H), 1.65 - 1.55 (m, 1H), 0.94 - 0.85 (m, 1H), 0.68 - 0.61 (m, 2H), 0.52 - 0.43 (m, 1H).Example 28: (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-8- phenyl-l,6-naphthyridin-5(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCTExample 28

[0401] Step A: A mixture of ethyl 6-bromo-2-chloronicotinate (1 g, 3.8 mmol), 2- oxobutanoic acid (0.58 g, 5.7 mmol), Ir[dF(Me)ppy]2(dtbbpy)PFe (0.38 g, 0.38 mmol), NiCh- DME (0.17 g, 0.76 mmol), dtbbpy (0.2 g, 0.76 mmol) and Li CCh (0.56 g, 7.6 mmol) in DMF (15 mL) was purged with nitrogen three times, then stirred at room temperature and irradiated with 24 W blue LED (450 nm) for 3 hours. The reaction mixture was diluted with H2O, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford ethyl 2- chloro-6-propionylnicotinate (400 mg, 21%). LCMS (ESI): m / z 242, 244 [M+H]+.

[0402] Step B: A solution of ethyl 2-chloro-6-propionylnicotinate (400 mg, 0.83 mmol) in DAST (5 mL) was stirred at 50 °C for 16 hours. The reaction mixture was diluted with EtOAc and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% EtOAc in petroleum ether to afford ethyl 2- chloro-6-(l,l-difluoropropyl)nicotinate (120 mg, 54%). LCMS (ESI): m / z 264, 265 [M+H]+.

[0403] Step C: A mixture of N'-(2-methoxy-l-phenylethylidene)-4- methylbenzenesulfonohydrazide (144 mg, 0.46 mmol), ethyl 2-chloro-6-(l, l- difluoropropyl)nicotinate (120 mg, 0.46 mmol), PdCh(MeCN)2 (11 mg, 0.05 mmol), dppp (37 mg, 0.09 mmol) and CS2CO3 (295 mg, 0.91 mmol) in dioxane (7 mL) was stirred at 90 °C under nitrogen for 3 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 6% ethyl acetate in petroleum ether to afford ethylPatent ApplicationAtty. Docket No. ENTX-033PCT6-(l,l-difluoropropyl)-2-(2-methoxy-l-phenylvinyl)nicotinate (30 mg, 18%). LCMS (ESI): m / z 362 [M+H]

[0404] Step D: To a solution of ethyl 6-(l,l-difluoropropyl)-2-(2-methoxy-l- phenylvinyl)nicotinate (30 mg, 0.08 mmol) in THF / MeOHFEO 3:3: 1 (7 mL) was added LiOH (10 mg, 0.25 mmol) and the result mixture was stirred at 25°C for 2 hours. The mixture was poured into ice- water, neutralized with 2 N HC1 solution, extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous ISfeSCU, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% EtOAc in petroleum ether to afford 6-(l,l-difluoropropyl)-2-(2-methoxy-l-phenylvinyl)nicotinic acid (15 mg, 54%). LCMS (ESI): m / z 334 [M+H]+.

[0405] Step E: To a solution of 6-(l, 1-difluoropropy l)-2-(2-m ethoxy- 1- phenylvinyl)nicotinic acid (15 mg, 0.04 mmol) in DCM (5 mL) was added (S, E)-l-cyclopropyl- 3 -(methyl sulfonyl)prop-2-en-l -amine (11 mg, 0.07 mmol), HATU (25 mg, 0.07 mmol) and DIEA (29 mg, 0.22 mmol). The reaction was stirred at 25°C for 1 hour. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous ISfeSCL, filtered and evaporated. The residue was purified Prep-HPLC to afford N-((S, E)-l-cyclopropyl-3- (methylsulfonyl)allyl)-6-(l,l-difluoropropyl)-2-(2-methoxy-l-phenylvinyl)nicotinamide (13 mg, 58%). LCMS (ESI): m / z 491 [M+H]+.

[0406] Step F: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l, l- difluoropropyl)-2-(2-methoxy-l-phenylvinyl)nicotinamide (13 mg, 0.03 mmol) in MeCN (3 mL) was added HI (0.3 mL) at 0°C. The mixture was stirred at 25°C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The reaction was purified by Prep-HPLC to afford (S, E)-6-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-( 1 , 1 -difluoropropyl)-8-phenyl- 1 ,6-naphthyridin-5(6H)-one (2 mg, 16%). LCMS (ESI): m / z 451 [M+H]+. 'H NMR (400 MHz, MeOD-t / ,) 8 8.86 (d, J= 8.4 Hz, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.82 (s, 1H), 7.66 - 7.62 (m, 2H), 7.47 - 7.43 (m, 2H), 7.41 - 7.38 (m, 1H), 7.14 (dd, J= 15.2, 4.6 Hz, 1H), 6.89 (dd, J= 15.2, 1.7 Hz, 1H), 4.97 - 4.91 (m, 1H), 3.01 (s, 3H), 2.37 - 2.25 (m, 2H), 1.72 - 1.65 (m, 1H), 0.98 - 0.94 (m, 3H), 0.93 - 0.90 (m, 1H), 0.72 - 0.65 (m, 2H), 0.52 - 0.46 (m, 1H).Example 29: (S, E)-6-benzyl-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenyl-5, 6,7,8- tetrahydro-2,6-naphthyridin-l(2H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0407] Step A: To a solution of ethyl l-benzyl-3-oxopiperidine-4-carboxylate (2 g, 7.65 mmol) in DMF (20 mL) was added NaH (0.46 g, 11.48 mmol, 60% suspension in paraffin oil) by portions at 0 °C. The result mixture was stirred at 0 °C under nitrogen for 1 hour. Then 1,1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.01 g, 8.42 mmol) was added into the mixture and the result mixture was stirred at 25 °C under nitrogen for another 1 hour. The reaction mixture was poured into ice-water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford ethyl l-benzyl-5- (((trifluoromethyl)sulfonyl)oxy)-l,2,3,6-tetrahydropyridine-4-carboxylate (500 mg, 17%).LCMS (ESI): m / z 394 [M+H]+.

[0408] Step B: To a solution of ethyl l-benzyl-5-(((trifluoromethyl)sulfonyl)oxy)-l,2,3,6- tetrahydropyridine-4-carboxylate (500 mg, 1.27 mmol) in dioxane (10 mL) was added (E)-N'-(2- methoxy-l-phenylethylidene)-4-methylbenzenesulfonohydrazide (486 mg, 1.53 mmol), dppf (143.49 mg, 0.25 mmol), CS2CO3 (1.24 g, 3.81 mmol) and bis(acetonitrile) palladium chloride (33 mg, 0.13 mmol). The result mixture was stirred at 90 °C under nitrogen for 3 hours. The cooled mixture was diluted with H2O, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30 % EtOAc in petroleum ether to afford ethyl (E)-l-benzyl-5-(2-methoxy-l-phenylvinyl)- l,2,3,6-tetrahydropyridine-4-carboxylate (300 mg, 63%). LCMS (ESI): m / z 378 [M+H]1.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0409] Step C: To a solution of ethyl (E)-l-benzyl-5-(2-methoxy-l-phenylvinyl)-l,2,3,6- tetrahydropyridine-4-carboxylate (100 mg, 0.26 mmol) in THF (3 mb) and H2O (1 mL) was added hydroxylithium hydrate (111 mg, 2.65 mmol). The mixture was stirred at 60 °C for 3 hours. The cooled mixture was poured into ice-water, acidified with 2 AHC1, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford (E)-l-benzyl-5-(2-methoxy-l-phenylvinyl)-l, 2,3,6- tetrahydropyridine-4-carboxylic acid (15 mg, 16%). LCMS (ESI): m / z 350 [M+H]+.

[0410] Step D: To a solution of (E)-l-benzyl-5-(2-methoxy-l-phenylvinyl)-l, 2,3,6- tetrahydropyridine-4-carboxylic acid (15 mg, 0.04 mmol) in DCM (3 mL) was added (S, E)-l- cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (16 mg, 0.06 mmol), DIEA (28 mg, 0.21 mmol) and HATU (25 mg, 0.06 mmol). The mixture was stirred at 25°C for 1 hour. The mixture was diluted with H2O, extracted with DCM, the combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30 % EtOAc in petroleum ether to afford l-benzyl-N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((E)-2-methoxy-l- phenylvinyl)-l,2,3,6-tetrahydropyridine-4-carboxamide (20 mg, 92%). LCMS (ESI): m / z 507 [M+H]+.

[0411] Step E: To a solution of l-benzyl-N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)- 5-((E)-2-methoxy-l-phenylvinyl)-l,2,3,6-tetrahydropyridine-4-carboxamide (20 mg, 0.04 mmol) in MeCN (2 mL) was added HI (0.2 mL). The mixture was stirred at 25 °C under nitrogen for 12 hours. The mixture was diluted with H2O, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified Prep-HPLC to afford (S, E)-6-benzyL2-(l-cyclopropyl-3- (methylsulfonyl)allyl)-4-phenyl-5,6,7,8-tetrahydro-2,6-naphthyridin-l(2H)-one (2.5 mg, 13%). LCMS (ESI): m / z 475 [M+H]+. 'H NMR (400 MHz, DMSO-tfe) 5 7.78 (s, 1H), 7.54 - 7.19 (m, 10H), 7.04 - 6.94 (m, 1H), 6.93 - 6.81 (m, 1H), 4.79 - 4.58 (m, 1H), 4.57 - 4.23 (m, 2H), 4.08 - 3.81 (m, 1H), 3.73 - 3.38 (m, 3H), 3.04 (s, 3H), 2.93 - 2.68 (m, 2H), 1.78 - 1.67 (m, 1H), 0.81 - 0.70 (m, 1H), 0.65 - 0.45 (m, 2H), 0.37 - 0.21 (m, 1H).Example 30: (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(ethyl(methyl)amino)-8- phenyl-l,6-naphthyridin-5(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCTI Example 30

[0412] Step A: To a stirred mixture of methyl 2,6-dichloronicotinate (1 g, 4.8 mmol) in DMF (8 mL) was added N-methylethanamine (0.3 g, 4.8 mmol), TEA (1.4 g, 14.6 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The reaction mixture was purified by reverse phase chromatography (MeCN / EEO, 0.2% formic acid modifier, 20% to 40% gradient, 30 min run) to afford methyl 2- chloro-6-(ethyl(methyl)amino)nicotinate (200 mg, 18%). LCMS (ESI): m / z 229, 231 [M+H]+. 'l l NMR (400 MHz, DMSO-c / 6) 5 7.95 (d, J= 8.9 Hz, 1H), 6.63 (d, J= 8.9 Hz, 1H), 3.74 (s, 3H), 3.60 - 3.51 (m, 2H), 3.02 (s, 3H), 1.12 - 1.04 (m, 3H).

[0413] Step B: To a mixture of N'-(2 -methoxy- l-phenylethylidene)-4- methylbenzenesulfonohydrazide (334 mg, 1.05 mmol), methyl 2-chloro-6- (ethyl(methyl)amino)nicotinate (200 mg, 0.87 mmol), PdC12(MeCN)2 (23 mg, 0.09 mmol), 1,3- Bis(diphenylphosphino)propane (49 mg, 0.12 mmol) and CS2CO3 (855 mg, 2.62 mmol) in 1,4- dioxane (5 mL) was stirred at 90 °C under nitrogen for 2 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 10 - 15% EtOAc in petroleum ether to afford methyl (E)-6-(ethyl(methyl)amino)-2-(2-m ethoxy- 1- phenylvinyl)nicotinate (80 mg, 28%). LCMS (ESI): m / z 327 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 8 7.76 (d, J= 8.9 Hz, 1H), 7.19 -7.18 (m, 4H), 7.13 - 7.03 (m, 1H), 6.54 (d, J= 8.9 Hz, 1H), 6.51 (s, 1H), 3.72 (s, 3H), 3.59 - 3.54 (m, 2H), 3.29 (s, 3H), 3.02 (s, 3H), 1.09 - 1.03 (m, 3H).

[0414] Step C: A solution of methyl 6-(ethyl(methyl)amino)-2-(2-methoxy-l- phenylvinyl)nicotinate (50 mg, 0.15 mmol) and (S, E)-l-cyclopropyl-3-(methylsulfonyl)prop-2- en-l-amine (40 mg, 0.23 mmol) in Tol / HOAc (2 / 0.3) (7 mL) was stirred at 110 °C for 16 hours.Patent ApplicationAtty. Docket No. ENTX-033PCTThe cooled mixture was poured into ice-water. Extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Pre-HPLC to afford (S, E)-6-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(ethyl(methyl)amino)-8-phenyl-l,6-naphthyridin-5(6H)-one (3 mg, 4%). LCMS (ESI): m / z 438 [M+H]+. 1H NMR (400 MHz, MeOD-r / v) 5 8.30 (d, J= 9.2 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.59 (s, 1H), 7.43 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 7.11 (dd, J= 15.2, 4.6 Hz, 1H), 6.86 (d, J= 9.2 Hz, 1H), 6.80 (dd, J= 15.2, 1.6 Hz, 1H), 4.92 - 4.88 (m, 1H), 3.63 (q, J= 7.0 Hz, 2H), 3.11 (s, 3H), 3.01 (s, 3H), 1.65 - 1.57 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H), 0.94 - 0.88 (m, 1H), 0.69 - 0.61 (m, 2H), 0.51 - 0.43 (m, 1H).Example 31: (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido [4,5-d] pyridazin-5(6H)-oneExample 32: (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido [4,5-d] pyridazin-5(6H)-onePatent ApplicationAtty. Docket No. ENTX-033PCTExample 31 Example 32

[0415] Step A: To a solution of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (1.0 g, 4.3 mmol) in 1,4-dioxane (10 mL) was added (l-phenylvinyl)boronic acid (636 mg, 4.3 mmol), Pd(PPhs)4 (249 mg, 0.21 mmol) and K2CO3 (594 mg, 4.3 mmol). The reaction mixture was purged with nitrogen three times, then stirred at 60 °C overnight. The cooled reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, eluted with a gradient of 0 - 10% EtOAc in petroleum ether to afford ethyl 2-(m ethyl sulfanyl)-4- (l-phenylvinyl)pyrimidine-5-carboxylate (1.0 g, 77%). LCMS (ESI): m / z 301 [M+H]T

[0416] Step B: To a solution of ethyl 2-(methylsulfanyl)-4-(l-phenylvinyl)pyrimidine-5- carboxylate (750 mg, 2.50 mmol) in THF (15 mL) was added tributyl(l -ethoxy vinyl)stannane (1.36 g, 3.75 mmol) and Pd(PPhs)4 (290 mg, 0.25 mmol) and Copper(I) thiophene-2-carboxylate (950 mg, 5.0 mmol). The reaction mixture was purged with nitrogen three times, and stirred at 70 °C for 2 hours under nitrogen. The cooled reaction mixture was quenched with KF solution, extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF (6 mL), 2AHC1 solution (6 mL) was added into the solution and stirred at room temperature for 1 hour. The mixture was neutralized with NaHCOs solution, extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flashPatent ApplicationAtty. Docket No. ENTX-033PCT silica gel chromatography eluted with 0 - 30% EtOAc in petroleum ether to afford ethyl 2-acetyl- 4-(l-phenylvinyl)pyrimidine-5-carboxylate (200 mg, 27%). LCMS (ESI): m / z 297 [M+H]+.

[0417] Step C: A solution of ethyl 2-acetyl-4-(l-phenylvinyl)pyrimidine-5-carboxylate (260 mg, 0.88 mmol) in DAST (2 mb) was stirred at 60 °C for 1 hour. The cooled reaction mixture was poured into ice-water, extracted with DCM, The organic phase was washed with water and brine, dried over NaaSOi, filtered and concentrated. The residue was purified by flash silica gel chromatography eluted with 0 - 10% EtOAc in petroleum ether to afford ethyl 2-(l, 1- difluoroethyl)-4-(l-phenylvinyl)pyrimidine-5-carboxylate (130 mg, 46%) as a white solid. LCMS (ESI): m / z 319 [M+H]+.

[0418] Step D: A solution of ethyl 2-(l,l-difluoroethyl)-4-(l-phenylvinyl)pyrimidine-5- carboxylate (100 mg, 0.31 mmol) in DCM (3 mL) and MeOH (1 mL) was cooled to -65 °C. O3 was pumped into the solution for 10 mins while stirring. Then the reaction was quenched with dimethyl sulfide, diluted with H2O, extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% EtOAc in petroleum ether to afford ethyl 4-benzoyl-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate (100 mg, 99%). LCMS (ESI): m / z 321 [M+H]+.

[0419] Step E: A mixture of ethyl 4-benzoyl-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate (120 mg, 0.37 mmol) and hydrazine (0.12 mL, 1.87 mmol) in ethanol (2 mL) was stirred at 60 °C for 2 hours. The reaction mixture was evaporated under reduced pressure and the crude product was purified by silica gel flash chromatography, eluted with a gradient of 10 - 50% EtOAc in petroleum ether to afford 2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (45 mg, 42%). LCMS (ESI) m / z:289 [M+H]+.

[0420] Step F: To a solution of 2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin- 5(6H)-one (45 mg, 0.16 mmol) in N, N-dimethylmethanamide (2 mL) was added ethyl 2-bromo- 2-cyclopropylacetate (48 mg, 0.23 mmol) and K^CO (43mg, 0.31 mmol). The result mixture was stirred at 25 °C for 2 hours. The reaction was diluted with water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluted with 0 - 40% EtOAc in petroleum ether to afford ethyl 2-cyclopropyl-2-(2-( 1,1 -difluoroethyl )-5-oxo-8- phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetate (51 mg, 79%). LCMS (ESI): m / z 415 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0421] Step G: To a solution of 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8- phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetate (51 mg, 0.13 mmol) in anhydrous DCM (2 mL) was added DIBAL-H (0.25 mL, 0.25 mmol, 1 mol / L in DCM) at -78 °C. The result mixture was stirred at -78 °C for 2 hours. The mixture was poured into a stirred solution of aqueous NH4CI solution, extracted with DCM twice. The combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient 0 - 20% EtOAc in petroleum ether to afford 2-cy cl opropyl-2-(2-( 1, 1 -difluoroethyl )-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)- yl)acetaldehyde (45 mg, 95%). LCMS (ESI): m / z 371[M+H]+.

[0422] Step H: To a solution of diethyl [(methyldioxo-X6-sulfanyl)methyl]phosphonate (34 mg, 0.15 mmol) in anhydrous THF (2 mL) was added NaH (10 mg, 0.24 mmol, 60%, dispersion in Paraffin Liquid) at 0 °C. The mixture was stirred at 0 °C for 20 min, then cooled to -60 °C. A solution 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)- yl)acetaldehyde (45 mg, 0.12 mmol) in 1 ml THF was added into the mixture and stirred at - 60 °C for another 1 hour. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient 0 - 20% EtOAc in petroleum ether to afford (E)-6-(l- cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin- 5(6H)-one (8 mg, 15%). LCMS (ESI): m / z 447[M+H]+.

[0423] Step I: (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one (8 mg, 0.018 mmol) was further purified by chiral prep-SFC method 7 to afford (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (3.6 mg, 45%). LCMS (ESI): m / z 447[M+H]+H NMR (400 MHz, MeOD-4 / 7) 5 9.88 (s, 1H), 8.09 - 8.07 (m, 2H), 7.57 - 7.48 (m, 3H), 7.17 (dd, J= 15.2, 5.1 Hz, 1H), 6.98 (d, J= 15.2 Hz, 1H), 5.15 - 5.12 (m, 1H), 3.00 (s, 3H), 2.09 (t, J= 18.4 Hz, 3H), 1.79 - 1.61 (m, 1H), 0.89 - 0.86 (m, 1H), 0.69 - 0.63 (m, 2H), 0.62 - 0.54 (m, 1H).

[0424] and (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one (3.2 mg, 140%). LCMS (ESI): m / z 447[M+H]+. 'H NMR (400 MHz, MeOD-tL) 5 9.88 (s, 1H), 8.09 - 8.07 (m, 2H), 7.53 - 7.51 (m, 3H), 7.16 (dd, JPatent ApplicationAty. Docket No. ENTX-033PCT= 15.2, 5.1 Hz, 1H), 6.99 (d, J= 15.2 Hz, 1H), 5.16- 5.12 (m, 1H), 3.00 (s, 3H), 2.09 (t, J= 18.4 Hz, 3H), 1.75 - 1.63 (m, 1H), 0.92 - 0.83 (m, 1H), 0.72 - 0.60 (m, 2H), 0.60 - 0.51 (m, 1H).Example 33: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoropropyl)-4- phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dione

[0425] Step A: To a solution of methyl 5-bromo-2-oxo-lH-pyridine-4-carboxylate (3 g, 12.9 mmol) and K2CO3 (3.6 g, 25.9 mmol) in DMF (30 mL) was added 3 -bromo-3, 3 -difluoroprop- 1- ene (2.2 g, 14.2 mmol) at 25°C. The result mixture was stirred at 80°C for 3 hours under nitrogen. The cooled mixture was diluted with EtOAc and water. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0 - 15% ethyl acetate in petroleum ether to afford methyl 5-bromo-l-(l,l-difluoroallyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (250 mg, 6%). LCMS (ESI): m / z 308, 310 [M+H]+.

[0426] Step B: To a solution of methyl 5-bromo-l-(l,l-difluoroallyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (250 mg, 1.1 mmol) in THF (5 mL) was added PtCE (100 mg, 0.4Patent ApplicationAtty. Docket No. ENTX-033PCT mmol) at 25°C. The result mixture was stirred at 25°C for 2 hours under H2 atmosphere using a balloon. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 25% ethyl acetate in petroleum ether to afford methyl 5-bromo-l-(l,l-difluoropropyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (150 mg, 45%). LCMS (ESI): m / z 310, 312 [M+H]+.

[0427] Step C: A mixture of methyl 5-bromo-l-(l,l-difluoropropyl)-2-oxopyridine-4- carboxylate (150 mg, 0.48 mol), N'-(2-m ethoxy- 1 -phenylethylidene)-4- methylbenzenesulfonohydrazide (184 mg, 0.58 mol), dppf (53 mg, 0.01 mol) and CS2CO3 (472 mg, 1.45 mol) in 1,4-dioxane (3 mL) was added bis(acetonitrile) palladium chloride (12.6 mg, 0.005 mol). The reaction resulting mixture was purged with nitrogen three times, then stirred at 90 °C for 3 h. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 -15 % ethyl acetate in petroleum ether to afford methyl (E)-l-(l,l- difluoropropyl)-5-(2-methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (140 mg, 80%). LCMS (ESI): m / z 364 [M+H]+.

[0428] Step D: A mixture of methyl (E)-l-(l,l-difluoropropyl)-5-(2-methoxy-l- phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (140 mg, 0.5 mmol) in THF (4 mL) and H2O (2 mL) was added NaOH (90 mg, 2.3 mmol). The reaction was stirred at 25 °C for 1 hour. The cooled mixture was acidified with 2 / VHC1 to pH= 3~4, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated to afford (E)-l-(l,l-difluoropropyl)-5-(2-methoxy-l-phenylvinyl)-2-oxo-l,2- dihydropyridine-4-carboxylic acid (120 mg, 76%). LCMS (ESI): m / z 350 [M+H]+.

[0429] Step E: To a solution of (E)-l-(l,l-difluoropropyl)-5-(2-methoxy-l-phenylvinyl)-2- oxo-l,2-dihydropyridine-4-carboxylic acid (50 mg, 0.1 mmol), (IS, 2E)-l-cyclopropyl-3- (methyldioxo-k6-sulfanyl)prop-2-en-l -amine (37 mg, 0.2 mmol) and HATU (81 mg, 0.2 mmol) in DCM (5 mL) was added DIEA (92 mg, 0.7 mmol). The reaction was stirred at 25°C for 30 minutes under nitrogen. The reaction was diluted with DCM, washed with water and brine, dried over Na2SC>4, filtered and concentrated to afford N-((S, E)-l-cyclopropyl-3- (methylsulfonyl)allyl)- 1 -( 1 , 1 -difluoropropy l)-5 -((E)-2-methoxy- 1 -pheny lvinyl)-2-oxo- 1,2- dihydropyridine-4-carboxamide (65 mg, 90%) which was used directly for next step. LCMS (ESI): m / z 507 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0430] Step F: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-l-(l,l- difluoropropyl)-5-((E)-2-m ethoxy- 1 -phenylvinyl)-2-oxo- 1 ,2-dihy dropyridine-4-carboxamide (65 mg, 0.1 mmol) in MeCN (4 m ) was added HI (1 drop, cata.) at 0 °C. The reaction was stirred at 25°C for 1 hour under nitrogen. The mixture was poured into ice-water, quenched with saturated Na2S20.3 solution, extracted with EtOAc twice. The combined extracts were washed with saturated NaHCCh solution, further washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 60% ethyl acetate in petroleum ether, and further purified by prep- HPLC to afford (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoropropyl)-4- phenyl-2,6-dihydro-2,6-naphthyri dine- 1,7-dione (15 mg, 25%). LCMS (ESI): m / z 475 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 8 7.80 (s, 1H), 7.60 - 7.43 (m, 5H), 7.21 (s, 1H), 7.12 (s, 1H), 6.97 - 6.95 (m, 2H), 4.69 (d, J= 10.0 Hz, 1H), 3.05 (s, 3H), 2.78 - 2.60 (m, 2H), 1.78 - 1.60 (m, 1H), 0.92 (t, J= 7 A Hz, 3H), 0.82 - 0.71 (m, 1H), 0.65 - 0.51 (m, 2H), 0.36 - 0.32 (m, 1H).Example 34: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoropropyl)-4- phenyl-2,6-dihydro-2,6-naphthyridine-l, 5-dionePatent ApplicationAtty. Docket No. ENTX-033PCT

[0431] Step A: To a mixture of 2,3-dichloropyridine-4-carboxylic acid (5.0 g, 26 mmol) in MeOH (100 mL) were add sodium methanolate (7.0 g, 130 mmol) at 0 °C. The result mixture was stirred at reflux overnight. The cooled mixture poured into ice-water and acidified with 2N HC1 solution to pH=3- 4, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous NasSCE, filtered and evaporated to afford 3 -chi oro-2 - methoxyisonicotinic acid (4.5 g, 92%), which was used directly without further purification. LCMS (ESI): m / z 188 [M+H]+.

[0432] Step B: To a mixture of 3-chloro-2-methoxyisonicotinic acid (6.6 g, 35 mmol) and K2CO3 (14.6 g, 105 mmol) in DMF (80 mL) were added CH3I (12.5 g, 87 mmol). The result mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into ice-water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% ethyl acetate in petroleum ether to afford methyl 3-chloro-2-methoxypyridine-4-carboxylate (6 g, 84%). LCMS (ESI): m / z 202 [M+H]+.

[0433] Step C: To a solution of methyl 3-chloro-2-methoxypyridine-4-carboxylate (3 g, 14.9 mmol) in MeCN (30 mL) was added TMSI (10.5 g, 74.4 mmol) at 0 °C. The result mixture was stirred at 25 °C overnight. The reaction mixture was diluted with EtOAc and H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc, then the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 5% ethyl acetate in petroleum ether to afford methyl 3-chloro-2-oxo-lH-pyridine-4-carboxylate (2.7 g, 96%). LCMS (ESI): m / z 188 [M+H]T

[0434] Step D: To a mixture of methyl 3-chloro-2-oxo-lH-pyridine-4-carboxylate (2 g, 10.7 mmol) and K2CO3 (2.9 g, 21.3 mmol) in MeCN (20 mL) were added 3 -bromo-3, 3 -difluoroprop-Patent ApplicationAtty. Docket No. ENTX-033PCT1-ene (1.8 g, 11.7 mmol). The result mixture was stirred at 80 °C overnight. The cooled mixture was diluted with H2O, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl 3-chloro-l-(l,l-difluoroallyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (110 mg, 4%). LCMS (ESI): m / z 264 [M+H]+.

[0435] Step E: To a solution of methyl 3-chloro-l-(l,l-difluoroallyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (90 mg, 0.34 mmol) in 2,2,2-trifluoroethan-l-ol (2 mL) was added Rhodium(I) tris(triphenylphosphine) chloride (27 mg, 0.03 mmol). The mixture was purged with hydrogen three times, then stirred at 25 °C under hydrogen for 1 hour. The reaction mixture was filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl 3-chloro-l-(l,l-difluoropropyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (70 mg, 77%). LCMS (ESI): m / z 266 [M+H]+.

[0436] Step F: To a mixture of methyl 3-chloro-l-(l,l-difluoropropyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (80 mg, 0.30 mmol) in dioxane (3 mL) were add N-{ [(lZ)-2- methoxy-l-phenylethylidene]amino}-4-methylbenzenesulfonamide (115 mg, 0.36 mmol), bis(acetonitrile) palladium chloride (7.8 mg, 0.03 mmol), dppf (34 mg, 0.06 mmol) and CS2CO3 (294 mg, 0.90 mmol). The result mixture was purged with nitrogen three times, then stirred at 90 °C for 3 hours. The cooled mixture was diluted with H2O, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl (E)-l-(l,l-difluoropropyl)- 3-(2-methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (50 mg, 45%) LCMS (ESI): m / z 364 [M+H]+.

[0437] Step G: To a mixture of methyl (E)-l-(l,l-difluoropropyl)-3-(2-methoxy-l- phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (30 mg, 0.08 mmol) in THF (2 mL) and H2O (2 mL) were added NaOH (16 mg, 0.4 mmol) at 0 °C. The result mixture was stirred at 25 °C for 1 hour. The mixture was poured into ice-water and acidified with 2AHC1 to pH = 3 -4, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated to afford (E)-l-(l,l-difluoropropyl)-3-(2-Patent ApplicationAtty. Docket No. ENTX-033PCT methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid (25 mg, 86 %) which was used directly for next step. LCMS (ESI): m / z 350 [M+H]

[0438] Step H: To a mixture of (E)-l-(l,l-difluoropropyl)-3-(2-methoxy-l-phenylvinyl)-2- oxo-l,2-dihydropyridine-4-carboxylic acid (25 mg, 0.07 mmol) in DCM (2 mL) were added (IS, 2E)-l-cyclopropyl-3-(methyldioxo-X6-sulfanyl)prop-2-en-l -amine (18.8 mg, 0.11 mmol), HATU (41 mg, 0.11 mmol) and DIEA (46 mg, 0.36 mmol) . The result mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into ice-water, extracted with DCM twice. The combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated to afford N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-l-(l,l-difluoropropyl)-3- ((E)-2-methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxamide (30 mg, 82%) which was used directly for next step. LCMS (ESI): m / z 507 [M+H]+.

[0439] Step I: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-l-(l,l- difluoropropyl)-3 -((E)-2-m ethoxy- 1 -phenylvinyl)-2-oxo- 1 ,2-dihy dropyridine-4-carboxamide (50 mg, 0.10 mmol) in MeCN (3 mL) were add HI (0.1 mL, cata.)' at 0 °C. The result mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by prep-HPLC to afford (S, E)-2-(l- cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoropropyl)-4-phenyl-2,6-dihydro-2,6- naphthyridine-1, 5-dione (6.4 mg, 13%). LCMS: ESI m / z 475 [M + H]+. 'H NMR (400 MHz, CDCI3) 8 7.54 (d, J = 7.8 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.27 - 7.26 (m, 1H), 7.26 - 7.25 (m, 1H), 7.13 (s, 1H), 7.09 - 7.01 (m, 2H), 6.55 (dd, J = 15.2, 1.6 Hz, 1H), 5.01 - 4.99 (m, 1H), 2.96 (s, 3H), 2.64 - 2.54 (m, 2H), 1.33 - 1.25 (m, 1H), 0.98 (t, J= 1A Hz, 3H), 0.94 - 0.88 (m, 1H), 0.75 - 0.60 (m, 2H), 0.57 - 0.45 (m, 1H).Example 35: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoro-2- hydroxyethyl)-4-phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dionePatent ApplicationAtty. Docket No. ENTX-033PCT

[0440] Step A: To a solution of methyl 5-bromo-2-oxo-l,2-dihydropyridine-4-carboxylate (5.00 g, 21.6 mmol) in THF (50 mL) was added NaH (1.3 g, 32.3 mmol, 60% dispersion in mineral oil) by portions at 0 °C. The result mixture was stirred for 30 min. A solution of methyl carb onochlori date (3 g, 32.3 mmol) in THF (10 mL) was added into the mixture. The result mixture was stirred at room temperature for another 1 hour. The reaction mixture was poured into ice-water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, fdtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 20% ethyl acetate in petroleum ether to afford methyl 5-bromo-2-((methoxycarbonyl)oxy)isonicotinate (5 g, 79%). LCMS (ESI): m / z 290 [M+H]+.

[0441] Step B: To a mixture of methyl 5-bromo-2-((methoxycarbonyl)oxy)isonicotinate (14 g, 48.3 mmol) and KF (11.0 g, 193 mmol) in anhydrous EtOAc (500 mL) were addedPatent ApplicationAtty. Docket No. ENTX-033PCT(bromodifluoromethyl)trimethylsilane (29.4 g, 144.8 mmol) dropwise. The result mixture was stirred at 40 °C overnight. The reaction mixture was poured into ice-water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 20% ethyl acetate in petroleum ether to afford methyl 5-bromo-l- (l,l-difluoro-2-methoxy-2-oxoethyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (1.9 g, 11 %). LCMS (ESI): m / z 340 [M+H]+.

[0442] Step C: To a solution of methyl 5-bromo-l-(l,l-difluoro-2-methoxy-2-oxoethyl)-2- oxo-l,2-dihydropyridine-4-carboxylate (900 mg, 2.65 mmol) in MeOH (10 mL) were added NaBEU (502 mg, 13.2 mmol) by portions at 0 °C. The result mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into ice-water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl 5 -bromo- 1-( 1,1 -di fluorolhydroxy ethyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (100 mg, 12%). LCMS (ESI): m / z 312 [M+H]1.

[0443] Step D: To a mixture of methyl 5-bromo-l-(l,l-difluoro-2-hydroxyethyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (300 mg, 0.96 mmol) and IH-imidazole (196 mg, 2.9 mmol) and DMAP (12 mg, 0.10 mmol) in DCM (10 mL) was added TBSC1 (290 mg, 1.92 mmol). The r result mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with DCM and H2O, the organic layer was separated. The aqueous layer was extracted with DCM, then the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl 5-bromo-l-(2-((tert- butyldimethylsilyl)oxy)- 1 , 1 -difluoroethyl)-2-oxo-l ,2-dihydropyridine-4-carboxylate (400 mg, 97%). LCMS (ESI): m / z 426 [M+H]+.

[0444] Step E: To a mixture of methyl 5-bromo-l-(2-((tert-butyldimethylsilyl)oxy)-l,l- difluoroethyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (500 mg, 1.17 mmol) in dioxane (10 mL) were added N-{[(lE)-2-methoxy-l-phenylvinyl]amino}-4-methylbenzenesulfonamide (448 mg, 1.41 mmol), bis(acetonitrile) palladium chloride (30. mg, 0.12 mmol), dppf (129 mg, 0.23 mmol) and CS2CO3 (L lg, 3.5 mmol). The result mixture was purged with nitrogen three times,Patent ApplicationAtty. Docket No. ENTX-033PCT then stirred at 90 °C for 3 hours. The cooled mixture was diluted with H2O, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl (E)-l-(2-((tert- butyldimethylsilyl)oxy)- 1 , 1 -difluoroethyl)-5-(2-methoxy- 1 -phenylvinyl)-2-oxo- 1 ,2- dihydropyridine-4-carboxylate (350 mg, 62 %). LCMS (ESI): m / z 480 [M+H]+.

[0445] Step F: To a solution of methyl (E)-l-(2-((tert-butyldimethylsilyl)oxy)-l,l- difluoroethyl)-5-(2 -methoxy- l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (300 mg, 0.63 mmol) in THF (5 mL) were added TBAF (0.65 mL, 0.63 mmol, Imol / L in THF). The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with H2O, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl (E)-l -(1 , 1 -difluoro-2-hydroxyethyl)-5-(2-methoxy-l -phenylvinyl)-2-oxo-l ,2- dihydropyridine-4-carboxylate (200 mg, 87 %). LCMS (ESI): m / z 366 [M+H]+.

[0446] Step G: To a mixture of methyl (E)-l-(l, l-difhioro-2-hydroxy ethyl )-5-(2-m ethoxy- 1- phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (130 mg, 0.36 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH (74 mg, 1.8 mmol). The result mixture was stirred at 20 °C for 1 hour. The mixture was poured into ice-water and acidified with 2 .V HCI to pH=3 -4, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated to afford (E)-l-(l,l-difluoro-2-hydroxyethyl)-5-(2- methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid (120 mg, 95%) which was used directly for next step without further purification. LCMS (ESI): m / z 352 [M+H]+.

[0447] Step H: To a mixture of (E)-l-(l,l-difluoro-2-hydroxyethyl)-5-(2-methoxy-l- phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid (50 mg, 0.14 mmol) in DCM (2 mL) were added (IS, 2E)-l-cy cl opropyl-3-(m ethyldi oxo-X6-sulfanyl)prop-2-en-l -amine (37 mg, 0.21 mmol), HATU (81 mg, 0.21 mmol) and DIEA (91 mg, 0.71 mmol). The result mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with DCM, washed water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 70% ethyl acetate in petroleum ether to afford N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-l-(l,l-difluoro-2-hydroxyethyl)-5-((E)-Patent ApplicationAtty. Docket No. ENTX-033PCT2-methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxamide (20 mg, 27%). LCMS (ESI): m / z 509 [M+H]+.

[0448] Step I: To a solution of N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-l-(l,l- difluoro-2-hydroxyethyl)-5-((E)-2-methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4- carboxamide (10 mg, 0.02 mmol) in ACN (2 m ) were added HI (1 drop, cata). The result mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with EtOAc, water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by prep-HPLC to afford (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoro-2- hydroxyethyl)-4-phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dione (2.2 mg, 21 %). LCMS (ESI): m / z 477 [M+H]+. 'HNMR (400 MHz, DMSO-r / 6) 5 7.75 (s, 1H), 7.56 - 7.50 (m, 2H), 7.50 - 7.45 (m, 3H), 7.19 (s, 1H), 7.11 (s, 1H), 6.96 -6.95 (m, 2H), 4.69 (dd, J= 10.0, 2.1 Hz, 1H), 4.25 (t, J= 12.4 Hz, 2H), 3.04 (s, 3H), 1.67 - 1.65 (m, 1H), 0.78 - 0.71 (m, 1H), 0.65 - 0.53 (m, 2H), 0.34 - 0.31 (m, 1H).Example 36: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dione

[0449] Step A: To a mixture of methyl 5-bromo-l-(l,l-difluoro-2-hydroxyethyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (200 mg, 0.47 mmol), PPI13 (924 mg, 3.52 mmol) and 1H-Patent ApplicationAtty. Docket No. ENTX-033PCT imidazole (240 mg, 3.52 mmol) in THF (5 mL) was added a solution of I2 (895 mg, 3.52 mmol) in THF (2 mL) at 0°C. The result mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with EtOAc and water, The organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a with a gradient of 0 - 40% ethyl acetate in petroleum ether to afford methyl 5-bromo-l-(l, l-difluoro-2-iodoethyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (440 mg, 59%). LCMS (ESI): m / z 422 [M+H]+.

[0450] Step B: To a mixture of methyl 5-bromo-l-(l,l-difluoro-2-iodoethyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (400 mg, 0.95 mmol) in toluene (5 mL) was added tributyl stannane (310 mg, 1.9 mmol) and AIBN (27 mg, 0.09 mmol). The result mixture was stirred at 110°C under nitrogen overnight. The cooled reaction mixture was diluted with EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl 5 -bromo- 1-( 1,1- difluoroethyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (130 mg, 46%). LCMS (ESI): m / z 296 [M+H]+. 'H NMR (400 MHz, DMSO ) 5 8.05 (s, 1H), 6.84 (s, 1H), 3.86 (s, 3H), 2.25 (t, J = 17.5 Hz, 3H).

[0451] Step C: To a mixture of methyl 5-bromo-l-(l,l-difluoroethyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (80 mg, 0.27 mmol) in dioxane (5 mL) were add N-{[(lE)-2- methoxy-l-phenylvinyl]amino]-4-methylbenzenesulfonamide (103 mg, 0.32 mmol), bis(acetonitrile) palladium chloride (7.0 mg, 0.03 mmol), dppf (31 mg, 0.05 mmol) and CS2CO3 (264 mg, 0.81 mmol). The result mixture was purged with nitrogen three times, then stirred at 90 °C for 3 hours. The cooled mixture was diluted with H2O, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford methyl (E)-l-(l,l-difluoroethyl)-5- (2-m ethoxy- l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (80 mg, 84%). LCMS (ESI): m / z 350 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0452] Step D: To a mixture of methyl (E)-l-(l,l-difluoroethyl)-5-(2-methoxy-l- phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylate (80 mg, 0.23 mmol) in THF (2 mL) and H2O (2 mL) were added Li OH (48 mg, 1.1 mmol) The result mixture was stirred at 20 °C for 1 hour. The mixture was diluted with ice- water and acidified with 2N HC1 to pH=3 - 4, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated to afford (E)-l-(l,l-difluoroethyl)-5-(2-methoxy-l- phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid (70 mg, 91%) which was used directly for next step. LCMS (ESI): m / z 336 [M+H]+.

[0453] Step E: To a solution of (E)-l-(l,l-difluoroethyl)-5-(2-m ethoxy- l-phenylvinyl)-2- oxo-l,2-dihydropyridine-4-carboxylic acid (80 mg, 0.24 mmol), (lS,2E)-l-cyclopropyl-3- (methyldioxo-X6-sulfanyl)prop-2-en-l -amine (63 mg, 0.36 mmol) and HATU (136 mg, 0.36 mmol) in DCM (5 mL) was added DIEA (154 mg, 1.19 mmol). The reaction was stirred at 25°C for 30 minutes. The reaction was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-l-(l,l- difluoroethyl)-5-((E)-2-methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxamide (60 mg, 51.1%). LCMS (ESI): m / z 493 [M+H]+.

[0454] Step F: To a solution ofN-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-l-(l,l- difluoroethyl)-5-((E)-2-methoxy-l-phenylvinyl)-2-oxo-l,2-dihydropyridine-4-carboxamide (60 mg, 0.12 mmol) in MeCN (4 mL) was added HI (15.6 mg, 0.12 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 hour. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with brine and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified Prep-HPLC to afford (S, E)-2-(l-cyclopropyl-3- (methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4-phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dione (19.2 mg, 34%). LCMS (ESI): m / z 461 [M+H]+. ’HNMR ((400 MHz, CDCh) 8 7.87 (s, 1H), 7.55 (s, 1H), 7.51 - 7.45 (m, 3H), 7.37 - 7.34 (m, 2H), 7.02 (dd, J= 15.2, 4.4 Hz, 1H), 6.63 - 6.58 (m, 2H), 4.96 - 4.91 (m, 1H), 2.97 (s, 3H), 2.33 (t, J= 17.0 Hz, 3H), 0.94 - 0.82 (m, 2H), 0.72 - 0.66 (m, 1H), 0.63 - 0.58 (m, 1H), 0.55 - 0.49 (m, 1H).Example 37: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoropropyl)-4- phenyl-2,5,6,8-tetrahydro-2,6-naphthyridine-l,7-dionePatent ApplicationAtty. Docket No. ENTX-033PCTExample 37

[0455] Step A: To a flask containing (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- (l,l-difluoropropyl)-4-phenyl-2,6-dihydro-2,6-naphthyridine- 1,7-dione (170 mg, 0.36 mmol) in Toluene (5 mL) was added AIBN (6 mg, 0.04 mmol) and tributyl stannane (104 mg, 0.36 mmol). The reaction mixture was purged with nitrogen for three times and stirred at 110 °C under nitrogen for 1 hour. The reaction was cooled to room temperature and the solvent was evaporated. The crude product was purified by Pre-HPLC to afford (S, E)-2-(l-cyclopropyl-3- (methylsulfonyl)allyl)-6-(1,l-difluoropropyl)-4-phenyl-2,5,6,8-tetrahydro-2,6-naphthyridine-l,7- dione (9.4 mg, 5.5%). LCMS (ESI): m / z 477 [ XI H | . H NMR (400 MHz, DMSO-de) 8 7.79 (s, 1H), 7.52 - 7.37 (m, 5H), 6.99 (dd, J= 15.2, 5.6 Hz, 1H), 6.88 (dd, J= 15.2, 1.2 Hz, 1H), 4.72 (dd, J= 10.0, 5.2 Hz, 1H), 4.48 (s, 2H), 3.51 (s, 2H), 3.04 (s, 3H), 2.51 - 2.45 (m, 2H), 2.07 (s, 1H), 1.71 - 1.69 (m, 1H), 0.88 (t, J= 7.6 Hz, 3H), 0.75- 0.75 (m, 1H), 0.63 - 0.50 (m, 2H), 0.33 - 0.31 (m, 1H).Example 38: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenyl-2,5,6,8-tetrahydro-2,6-naphthyridine-l,7-dionePatent ApplicationAtty. Docket No. ENTX-033PCT

[0456] Step A: To a suspension of (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l- difluoro-2-hydroxyethyl)-4-phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dione (100 mg, 0.21 mmol) in anhydrous THF (10 mL) was added I2 (80 mg, 0.31 mmol) and IH-imidazole (21 mg, 0.31 mmol) dropwise under nitrogen at 0 °C. then PPh3 (81 mg, 0.31 mmol) was slowly added at 0 °C. The resulting solution was stirred at 25 °C for 1 hour. The cooled mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoro-2-iodoethyl)-4-phenyl- 2, 6-dihydro-2,6-naphthyridine- 1,7-dione (100 mg, 81%). LCMS (ESI): m / z 587 [M+H]+.

[0457] Step B: To a suspension of (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l- difluoro-2-iodoethyl)-4-phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dione (100 mg, 0.17 mmol) in anhydrous Tol (10 mL) was added AIBN (5.59 mg, 0.03 mmol) Tributyltin hydroxide (157 mg, 0.51 mmol) The resulting solution was stirred at 110 °C for 2 hours. The reaction mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Prep-HPLC to afford (S, E)-2-(l-cyclopropyl-3-(m ethyl sulfonyl)allyl)-6-( 1,1- difluoroethyl)-4-phenyl-2,5,6,8-tetrahydro-2,6-naphthyridine-l,7-dione (2.7 mg, 3%). LCMS (ESI): m / z 463 [M+H]+. 'H NMR (400 MHz, CDCI3) 5 7.50 - 7.43 (m, 3H), 7.27 (s, 1H), 7.26 - 7.25 (m, 1H), 7.24 - 7.23 (m, 1H), 7.02 (dd, J= 15.2, 4.4 Hz, 1H), 6.53 (dd, J= 15.2, 1.6 Hz, 1H), 5.03 - 5.01 (m, 1H), 4.45 (s, 2H), 3.64 (s, 2H), 2.97 (s, 3H), 2.19 (t, J= 17.6 Hz, 3H), 0.95 - 0.89 (m, 1H), 0.73 - 0.59 (m, 2H), 0.54 - 0.47 (m, 1H).Example 39: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenyl-6-(l,l,2- trifluoroethyl)-2,6-dihydro-2,6-naphthyridine-l, 7-dionePatent ApplicationAtty. Docket No. ENTX-033PCTExample 39

[0458] Step A: A solution of methyl 5-bromo-l-(l,l-difluoro-2-hydroxyethyl)-2-oxo-l,2- dihydropyridine-4-carboxylate (500 mg, 1.60 mmol) in DAST (10 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with EtOAc and poured into ice-water. The organic layer was separated, and the aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 15 - 20% EtOAc in petroleum ether to afford methyl 5 -brom o-2-oxo-l-( 1,1,2- trifluoroethyl)-l,2-dihydropyridine-4-carboxylate (200 mg, 40%). LCMS (ESI): m / z: 300, 302 [M+H]+.1H NMR (400 MHz, CDCh) 5 7.75 (s, 1H), 6.88 (s, 1H), 5.19 (dt, J = 45.7, 10.9 Hz, 2H), 3.95 (s, 3H).

[0459] Step B: A mixture of N'-(2-m ethoxy- 1 -phenylethylidene)-4- methylbenzenesulfonohydrazide (243 mg, 0.76 mmol), methyl 5-bromo-2-oxo-l-(l,l,2- trifluoroethyl)-l,2-dihydropyridine-4-carboxylate (200 mg, 0.64 mmol), PdC12(MeCN)2 (16.5 mg, 0.06 mmol), 1,3-Bis(diphenylphosphino)propane (72 mg, 0.13 mmol) and CS2CO3 (622 mg, 1.9 mmol) in 1,4-dioxane (10 mL) was stirred at 90 °C under nitrogen for 2 hours. The cooled mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 10 -Patent ApplicationAtty. Docket No. ENTX-033PCT15% to afford methyl (E)-5-(2-methoxy-l-phenylvinyl)-2-oxo-l-(l,l,2-trifluoroethyl)-l,2- dihydropyridine-4-carboxylate (110 mg, 47%). LCMS (ESI): m / z 367 [M+H]+.

[0460] Step C: To a solution of methyl (E)-5-(2-methoxy-l-phenylvinyl)-2-oxo-l-(l,l,2- trifluoroethyl)-l,2-dihydropyridine-4-carboxylate (110 mg, 0.3 mmol) in MeOH (5 mb) and H2O (2 mL) was added NaOH (60 mg, 1.5 mmol). The reaction was stirred at 40 °C for 3 hours. The cooled mixture was neutralized with 2 A HCI solution, extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous ISfeSCU, fdtered and concentrated to afford (E)-5-(2-methoxy- 1 -phenylvinyl)-2-oxo- 1 -(1 , 1 ,2-trifluoroethyl)- 1 ,2-dihydropyridine-4- carboxylic acid (100 mg, 98%) which was used directly for next step. LCMS (ESI): m / z 354 [M+H]+.

[0461] Step D: To a stirred mixture of (E)-5-(2-methoxy-l-phenylvinyl)-2-oxo-l-(l,l,2- trifluoroethyl)-l,2-dihydropyridine-4-carboxylic acid (100 mg, 0.28 mmol) in DCM (10 mL) were added (S, E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (59.5 mg, 0.34 mmol), HATU (162 mg, 0.42 mmol) and DIEA (183 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 20 - 30% EtOAc in petroleum to afford N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((E)-2-methoxy-l-phenylvinyl)-2-oxo-l- (l,l,2-trifluoroethyl)-l,2-dihydropyridine-4-carboxamide (140 mg, 97%). LCMS (ESI): m / z 511 [M+H]+.

[0462] Step E: To a stirred mixture of N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5- ((E)-2-methoxy- 1 -phenylvinyl)-2-oxo- 1 -( 1 , 1 ,2-trifluoroethyl)- 1 ,2-dihydropyridine-4- carboxamide (30 mg, 0.06 mmol) in MeCN (5 mL) was added HI (cata.). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, and organic layer was separated and dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by Prep-HPLC to afford (S, E)-2-(l-cyclopropyl-3- (methylsulfonyl)allyl)-4-phenyl-6-(l,l,2-trifluoroethyl)-2,6-dihydro-2,6-naphthyridine-l, 7-dione (4.1 mg, 15%). LCMS (ESI): m / z 479 [M+H]+. ‘H NMR (400 MHz, CDCI3) 8 7.83 (s, 1H), 7.56 (s, 1H), 7.53 - 7.46 (m, 3H), 7.36 (dd, J= 7.8, 1.6 Hz, 2H), 7.05 - 6.99 (m, 1H), 6.65 - 6.58 (m, 2H), 5.37 - 5.14 (m, 2H), 4.92 (dd, J= 8.9, 4.2 Hz, 1H), 2.97 (s, 3H), 1.28 - 1.24 (m, 1H), 0.94 - 0.88 (m, 1H), 0.74 - 0.65 (m, 1H), 0.65 - 0.57 (m, 1H), 0.56 - 0.49 (m, 1H).Patent ApplicationAtty. Docket No. ENTX-033PCTExample 41: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenyl-6-(l,l,2- trifluoroethyl)-2,5,6,8-tetrahydro-2,6-naphthyridine-l,7-dioneExample 41

[0463] Step A: To a solution of (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenyl- 6-(l,l,2-trifluoroethyl)-2,6-dihydro-2,6-naphthyridine-l, 7-dione (70 mg, 0.15 mmol) in anhydrous Tol (5 mL) was added AIBN (6 mg, 0.03 mmol) and tributyl stannane (138 mg, 0.45 mmol). The result solution was stirred at 110 °C for 2 hours. The cooled mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Prep- HPLC to afford (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenyl-6-(l,l,2- trifluoroethyl)-2,5,6,8-tetrahydro-2,6-naphthyridine-l,7-dione (2.3 mg, 3%). LCMS (ESI): m / z 481 [M+H]+. 'H NMR (400 MHz, CDCh) 8 7.47 - 7.45 (m, 3H), 7.28 - 7.26 (m, 2H), 7.24 - 7.21 (m, 1H), 7.02 (dd, J= 15.0, 3.8 Hz, 1H), 6.54 (d, J= 15.4 Hz, 1H), 5.18 - 5.13 (m, 1H), 5.09 - 4.95 (m, 2H), 4.48 (s, 2H), 3.66 (s, 2H), 2.97 (s, 3H), 1.36 - 1.33 (m, 1H), 0.92 - 0.90 (m, 1H), 0.74 - 0.61 (m, 2H), 0.56 - 0.46 (m, 1H).Example 42: (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-7-fluoro- 4-phenylisoquinolin-l(2H)-onePatent ApplicationAtty. Docket No. ENTX-033PCT

[0464] Step A: To a mixture of methyl 2-amino-4-bromo-5-fluorobenzoate (1 g, 4.03 mmol) and tributyl(l -ethoxy vinyl)stannane (2.18 g, 6.05 mmol) in DMF (20 mL) was added Pd(PPhs)4 (415 mg, 0.36 mmol). The reaction mixture was purged with nitrogen for three times and stirred at 100 °C under nitrogen for 16 hours. The cooled mixture was diluted with EtOAc, washed with aqueous potassium fluoride solution. The organic layer was separated, washed with brine and concentrated. The residue was dissolved in THF (30 mL), 4 .V HCI (30 mL) was added into the solution and stirred at room temperature for another 1 hour. The mixture was neutralized with NaHCCh solution, extracted with EtOAc twice. Then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% EtOAc in petroleum ether to afford methyl 4-acetyl-2-amino-5-fluorobenzoate (700 mg, 82%). LCMS (ESI): m / z 212 [M+H]+.

[0465] Step B: To a mixture of methyl 4-acetyl-2-amino-5-fluorobenzoate (100 mg, 0.47 mmol) and CuB (211 mg, 0.95 mmol) in MeCN (5 mL) was added tert-butyl nitrite (98 mg,Patent ApplicationAtty. Docket No. ENTX-033PCT0.95 mmol). The result mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, The organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% EtOAc in petroleum ether to afford methyl 4-acetyl-2-bromo-5-fluorobenzoate (60 mg, 46%). LCMS (ESI): m / z 276 [M+H]+.

[0466] Step C: A mixture of methyl 4-acetyl-2-bromo-5-fluorobenzoate (1 g, 3.64 mmol) in DAST (15 mL) was stirred at 60 °C for 18 hours. The reaction mixture was diluted with EtOAc, poured into ice-water, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0- 10 % ethyl acetate in petroleum ether to afford methyl 2-bromo-4-(l,l-difluoroethyl)-5-fluorobenzoate (600 mg, 56%). LCMS (ESI): m / z 298 [M+H]+.

[0467] Step D: To a mixture of methyl 2-bromo-4-(l,l-difluoroethyl)-5-fluorobenzoate (600 mg, 2.02 mmol) in 1,4-dioxane (100 mL) was added (E)-N'-(2 -m ethoxy- 1 -phenylethylidene)-4- methylbenzenesulfonohydrazide (964 mg, 3.03 mmol), bis(acetonitrile) palladium chloride (52 mg, 0.2 mmol), dppf (166 mg, 0.3 mmol) and CS2CO3 (1.9 g, 6.06 mmol). The reaction resulting mixture was purged with nitrogen three times, then stirred at 90 °C for 3 h. The cooled reaction was poured into water, extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, elution with a gradient of 0 - 10% ethyl acetate in petroleum ether to afford methyl (E)-4-(l,l-difluoroethyl)-5-fluoro-2-(2-methoxy-l-phenylvinyl)benzoate (500 mg, 70%). LCMS (ESI): m / z 350 [M+H]+.

[0468] Step E: To a mixture of methyl (E)-4-(I,l-difluoroethyl)-5-fluoro-2-(2-methoxy-l- phenylvinyl)benzoate (500 mg, 1.42 mmol) in MeOH (8 mL) and H2O (30 mL) was added a solution of NaOH (285 mg, 7.14 mmol) in H2O (20 mL) at 0 °C. The reaction was stirred at 50 °C overnight. The cooled mixture was acidified with 2 AHC1 to pH= 3~4, extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated to afford (E)-4-(l,l-difluoroethyl)-5-fluoro-2-(2 -methoxy- 1- phenylvinyl)benzoic acid (450 mg, 95 %), which was used directly without further purification. LCMS (ESI): m / z 337 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-033PCT

[0469] Step F: To a stirred mixture of (E)-4-(l,l-difluoroethyl)-5-fluoro-2-(2-methoxy-l- phenylvinyl)benzoic acid (150 mg, 0.09 mmol) in DCM (10 mL) were added (S,E)-1- cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (86 mg, 0.49 mmol), HATU (220.5 mg, 0.58 mmol) and DIEA (172.9 mg, 1.34 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with brine, and organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous ISfeSC , filtered and evaporated. The crude product was purified by preparation of thin layer chromatography, elution with a gradient of 20 to 30% EtOAc in petroleum to afford N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(l,l-difluoroethyl)-5-fluoro-2-((E)-2- methoxy- l-phenylvinyl)benzamide (180 mg, 82%). LCMS (ESI): m / z 494 [M+H]+.

[0470] Step B: To a stirred mixture of N-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-4- (l,l-difluoroethyl)-5-fluoro-2-((E)-2-methoxy-l-phenylvinyl)benzamide (100 mg, 0.2 mmol) in MeCN (5 mL), were added HI (0.5 mL, cata.) at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by Prep-HPLC to afford (S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-7- fluoro-4-phenylisoquinolin-l(2H)-one (61.1 mg, 65%). LCMS (ESI): m / z 462 [M+H]+. 'H NMR (400 MHz, CDC13) 8 8.21 (d, J= 11.0 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.56 - 7.44 (m, 3H), 7.43 - 7.37 (m, 2H), 7.13 (s, 1H), 7.09 (dd, J= 15.2, 4.4 Hz, 1H), 6.55 (dd, J= 15.2, 1.8 Hz, 1H), 5.18 - 5.03 (m, 1H), 2.96 (s, 3H), 2.08 - 1.92 (t, J= 18.6 Hz, 3H), 1.40 - 1.28 (m, 1H), 0.98 - 0.87 (m, 1H), 0.75 - 0.62 (m, 2H), 0.57 - 0.48 (m, 1H).Example 43: 2-((lS, E)-l-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-6-(l,l- difluoropropyl)-4-phenyl-2,6-dihydro-2,6-naphthyridine-l, 7-dionePatent ApplicationAtty. Docket No. ENTX-033PCT

[0471] Step A: To a solution of diethyl ((S-methylsulfonimidoyl)methyl)phosphonate (7.4 g, 32.15 mmol) in THF (80 mL) was added LiHMDS (33 mL, 32.15 mmol, 1 mol / L in Hexane) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of benzyl (S)-(l-cyclopropyl-2-oxoethyl)carbamate (5 g, 21.43 mmol) in THF (10 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixtu...

Claims

Patent ApplicationAtty. Docket No. ENTX-033PCTWhat 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 substituted 5- or 6-membered heterocyclic, aryl or heteroaryl group;Ring B is a substituted 5- or 6-membered heterocyclic, aryl or heteroaryl group;M is C or N;U is N or C;X is N, C(O) or CRa;Y is N or C;J is C or N;Q is CRa, N, NRb, C(O), O or S;V is CRa, N, NRb, C(O), O or S;Z isE is O or NR;W is CRR6;Patent Application Atty. Docket No. ENTX-033PCTR1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cb-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R7is H, D, or unsubstituted or substituted C j -Ce alkyl;R8is H, D, or unsubstituted or substituted Ci-Ce alkyl;R9is C=-C6 alkyl, Cb-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR;Rbis H or R; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

2. The compound of claim 1, wherein M is C, having the structural formula:

3. The compound of claim 2, wherein U is N, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT4. The compound of claim 3, wherein J is C, having the structural formula:

5. The compound of claim 3, wherein J is N, having the structural formula:

6. The compound of claim 2, wherein U is C, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT7. The compound of claim 6, wherein J is C, having the structural formula:

8. The compound of claim 6, wherein J is N, having the structural formula:

9. The compound of claim 1, wherein M is N, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT10. The compound of claim 9, wherein U is N.

11. The compound of claim 9, wherein U is C.

12. The compound of any one of claims 9-11, wherein J is N.

13. The compound of any one of claims 9-11, wherein J is C.

14. The compound of any one of claims 1-13, Ring A is a 5-membered heterocyclic group.

15. The compound of any one of claims 1-13, Ring A is a 5-membered heteroaryl group.

16. The compound of any one of claims 1-13, Ring A is a 6-membered heterocyclic group.

17. The compound of any one of claims 1-13, Ring A is a 6-membered aryl or heteroaryl group.

18. The compound of any one of claims 1-17, Ring B is a 5-membered heterocyclic group.

19. The compound of any one of claims 1 -17, Ring B is a 5-membered heteroaryl group.

20. The compound of any one of claims 1-17, Ring B is a 6-membered heterocyclic group.

21. The compound of any one of claims 1-17, Ring B is a 6-membered aryl or heteroaryl group.

22. The compound of claim 1, having the structural formula:whereinPatent ApplicationAtty. Docket No. ENTX-033PCTG is N, C(0) or CRa;Q is N, CRaor C(O);V is N, CRaor C(O); andT is N or CRa23. The compound of claim 1, having the structural formula:whereinG is N or CRa;Q is N, CRaor C(O);V is N, CRaor C(O); andT is N or CRa24. The compound of claim 23, wherein Q is C(O), having the structural formula:

25. The compound of claim 23, wherein V is C(O), having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT26. The compound of claim 1, having the structural formula:whereinG is N or CRa;Q is N, C(O) or CRa:V is N, C(O) or CRa; and T is N or CRa.

27. The compound of claim 26, wherein G is N or CRa, having the structural formula:

28. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCTwhereinG is N or CRa;Q is N or CRa;V is N or CRa; andT is N or CRa29. The compound of claim 28, wherein G is N.

30. The compound of claim 28, wherein G is CRa.

31. The compound of any one of claims 22-30, wherein Ra, if present, is H.

32. The compound of claim 1, having the structural formula:whereinQ is O, S or NRb,V is N or CRa; andT is N or CRaThe compound of claim 32, wherein Q is NRb.The compound of claim 32, wherein Q is O.The compound of claim 32, wherein Q is S.Patent ApplicationAtty. Docket No. ENTX-033PCT36. The compound of any one of claims 32-35, wherein V is N.

37. The compound of claim 1, having the structural formula:whereinQ is N or CRa;V is O, S or NRb; andT is N or CRN38. The compound of claim 37, wherein V is NRa.

39. The compound of claim 37, wherein V is O.

40. The compound of claim 37, wherein V is S.

41. The compound of any one of claims 37-40, wherein Q is N.

42. The compound of claim 1, having the structural formula:whereinQ is N or CRa;V is N or CRa; andT is N or CRa.

43. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCTwhereinQ is O, S or NRb,V is N or CRa; andT is N or CRa44. The compound of claim 1, having the structural formula:whereinQ is N or CRa;V is O, S or NRb; andT is N or CRa.

45. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT whereinQ is O, S or NRb;V is N or CRa; andT is N or CRa46. The compound of claim 1, having the structural formula:whereinQ is N or CRa;V is O, S or NRb, andT is N or CRa.

47. The compound of any one of claims 44 or 46, wherein Q is CRa.

48. The compound of claim 47, wherein V is O.

49. The compound of claim 47, wherein V is S.

50. The compound of claim 47, wherein V is NRb.

51. The compound of any one of claims 43 or 45, wherein V is CRa.

52. The compound of claim 51, wherein Q is O.

53. The compound of claim 51, wherein Q is S.

54. The compound of claim 51, wherein Q is NRb.

55. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-033PCT(XIII) whereinQ is N or CRa,V is N or CRa; andR.1is R:'56. The compound of claim 55, wherein R4is H.

57. The compound of claim 1, having the structural formula:whereinQ is N or CRa;V is N or CRa; andPJ is R‘.

58. The compound of claim 1, having the structural formula:whereinX is N or CRa;Q is N or CRa;V is N or CRa; andPR is R ‘.Patent ApplicationAtty. Docket No. ENTX-033PCT59. The compound of claim 58, wherein R4is H.

60. The compound of claim 58 or 59 wherein X is N.

61. The compound of claim 58 or 59, wherein X is CRa.

62. The compound of claim 1, having the structural formula:whereinX is N or CRa;Q is N or CRa;V is N or CRa; andT is N or CRa, and 4 is Ra.

63. The compound of claim 62, wherein R4is H.

64. The compound of claim 62 or 63, wherein X is N.

65. The compound of claim 62 or 63, wherein X is CRa.

66. The compound of any one of claims 1-31 and 55-65, wherein V is CRa.

67. The compound of any one of claims 1-31 and 55-65, wherein V is N.

68. The compound of claim 66 or 67, wherein Q is CRa.

69. The compound of claim 66 or 67, wherein Q is N.

70. The compound of any one of claims 22-54 and 62-69, wherein T is CRa.

71. The compound of any one of claims 22-54 and 62-69, wherein T is N.

72. The compound of any one of claims 1-71, wherein R3is a substituted or unsubstituted Ci-C7> alkyl.

73. The compound of claim 72, wherein R3is a substituted or unsubstituted C1-C4 alkyl74. The compound of claim 73, wherein R3is C1-C4 alkyl substituted with 1-5 halogen.

75. The compound of claim 74, wherein R3is C2-C4 alkyl substituted with 1-3 halogen.Patent ApplicationAtty. Docket No. ENTX-033PCT76. The compound of claim 75, wherein R3is a substituted or unsubstituted C2-C4 alkynyl.

77. The compound of claim 75, wherein R3is a halogen.

78. The compound of any one of claims 1-77, wherein R1is a substituted or unsubstituted 6- membered aryl or heteroaryl.

79. The compound of any one of claims 1-78, wherein W is CRR6.

80. The compound of claim 79, wherein R is H.

81. The compound of claim 79 or 80, wherein R6is a Ci-Ce alkyl.

82. The compound of claim 79 or 80, wherein R6is a C3-C6 carbocyclic.

83. The compound of claim 82, wherein R6is cyclopropyl.

84. The compound of any one of claims 1-83, wherein E is O and Z is:

85. The compound of any one of claims 1-83, wherein E is NR and Z is:

86. The compounds of claim 85, wherein E is NH and Z is:

87. The compound of any one of claims 84-86, wherein R7and R8are in a trans configuration:

88. The compound of any one of claims 84-86, wherein R7and R8are in a cis configuration:Patent Application Atty. Docket No. ENTX-033PCT89. The compound of claim 87 or 88, wherein E is NR and -S(O)(NR)R9is characterized by the following chirality:

90. The compound of claim 87 or 88, wherein E is NR and -S(O)(NR)R9is characterized by the following chirality:

91. The compound of any one of claims 1-90, wherein R7is H.

92. The compound of any one of claims 1-91, wherein R8is H.

93. The compound of any one of claims 1-92, wherein R9is Ci-Ce alkyl.

94. The compound of claim 93, wherein R9is CH3 or CD3.

95. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;Patent ApplicationAtty. Docket No. ENTX-033PCTV is CRaor N;T is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R1is R3;R9is Cs-Ce alkyl, Cj-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

96. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;Patent Application Atty. Docket No. ENTX-033PCTV is CRaor N;T is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is C=-C6 alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted Ci-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

97. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;Patent Application Atty. Docket No. ENTX-033PCTT is CRaor N,R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, C?-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyd, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

98. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;T is CRaor N,Patent ApplicationAtty. Docket No. ENTX-033PCTR1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cb-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is C-.-Ce alkyl, (b-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

99. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;T is CRaor N,Patent Application Atty. Docket No. ENTX-033PCTR1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cb-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R4is Ra;R9is Ci-Ce alkyl, C?-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

100. The compound of any one of claims 95-99, wherein Q is CRa.

101. The compound of any one of claims 95-99, wherein Q is N.

102. The compound of any one of claims 95-101, wherein V is CRa.

103. The compound of any one of claims 95-101, wherein V is N.

104. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinPatent Application Atty. Docket No. ENTX-033PCTE is O or NR;T is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is C=-C6 alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted Ci-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

105. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;T is CRaor N,Patent Application Atty. Docket No. ENTX-033PCTR1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cb-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is C-.-Ce alkyl, (b-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

106. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is NRb, O or S;V is CRaor N;T is N or CRa;Patent Application Atty. Docket No. ENTX-033PCTR1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cb-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is C-.-Ce alkyl, (b-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

107. The compound of claim 106, wherein Q is NRa.

108. The compound of claim 106, wherein Q is O.

109. The compound of claim 106, wherein Q is S.

110. The compound of any one of claims 106-109, wherein V is N.11 1. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Patent ApplicationAtty. Docket No. ENTX-033PCTQ is CRaor N;V is NRb, O or S;T is N or CRa;R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Cs-Ce alkyl, Cj-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR;Rbis H or R; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

112. The compound of claim 111, wherein Q is NRa.

113. The compound of claim 111, wherein Q is O.

114. The compound of claim 111, wherein Q is S.

115. The compound of any one of claims 110-118, wherein V is N.

116. A compound having the structural formula:Patent Application Atty. Docket No. ENTX-033PCT(Ij) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;T is N or CRa;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is ( ■-('(. alkyl,carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

117. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof,Patent ApplicationAtty. Docket No. ENTX-033PCT whereinE is O or NR;Q is NRb;V is CRaor N;T is N or CRa,R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Cs alkynyl, Cs-Cg carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, Ch-Cg carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR;Rbis H or R; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

118. The compound of claim 116 or 117, wherein V is N.

119. The compound of claim 116 or 117, wherein V is CRa.

120. The compound of any one of claims 95-119, wherein T is CRa.

121. A compound having the structural formula:Patent Application Atty. Docket No. ENTX-033PCT(I1) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Q is CRaor N;V is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Cg alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R4is R3;R9is ( ■-('(. alkyl, (R-C(. carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

122. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof,Patent ApplicationAtty. Docket No. ENTX-033PCT whereinE is O or NR;Q is CRaor N;V is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R4is Ra;R9is Ci-Ce alkyl, Cs-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

123. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Patent Application Atty. Docket No. ENTX-033PCTQ is CRaor N;V is CRaor N;R1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R1is R3;R9is Cs-Ce alkyl, Cj-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Rais H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

124. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;Patent Application Atty. Docket No. ENTX-033PCTT is CRaor N,R1is selected from Ci-Ce alkyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C8 carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Ci-Ce alkyl, C?-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyd, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

125. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinE is O or NR;T is CRaor N;Patent ApplicationAtty. Docket No. ENTX-033PCTR1is selected from Ci-Ce alkyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Cs-Cs carbocyclic, 4- to 6-membered heterocyclic, Ce-Cio aryl, 5- to 6-membered heteroaryl, bicyclic heteroaryl, OR, SR, or NRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is C-.-Ce alkyl, Cs-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted; each Rais independently H, R, halogen, CN or OR; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

126. The compound of any one of claims 121-125, wherein R4is H.

127. The compound of any one of claims 121-126, wherein Q is CH.

128. The compound of any one of claims 121-126, wherein Q is N.

129. The compound of any one of claims 121-128, wherein V is CH.

130. The compound of any one of claims 121-128, wherein V is N.

131. The compound of any one of claims 95-130, wherein R9is CH3 or CD3.

132. The compound of any one of claims 95-131, wherein R1is substituted or unsubstituted phenyl.

133. The compound of any one of claims 95-132, wherein R3is C1-C4 alkyl substituted with 1- 5 halogen.

134. The compound of any one of claims 95-132, wherein R3is substituted or unsubstituted C2-C4 alkynyl.

135. The compound of any one of claims 95-134, wherein E is O.

136. The compound of any one of claims 95-134, wherein E is NR.

137. The compounds of claim 136, wherein E is NH.

138. A compound selected from Table 1.

139. The compound of any of claims 1-138, having one or more deuterium atoms in place ofPatent ApplicationAtty. Docket No. ENTX-033PCT hydrogen.

140. A pharmaceutical composition comprising a compound according to any one of claims 1- 139 and a pharmaceutically acceptable excipient, carrier, or diluent.

141. The pharmaceutical composition of claim 140, being suitable for oral administration.

142. A unit dosage form comprising a pharmaceutical composition according to claim 140 or 141.

143. The unit dosage form of claim 142, being in the form of a tablet or capsule.

144. 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 according to any one of claims 1-139.

145. The method of claim 144, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer and thyroid cancer.146 The method of claim 145, wherein the cancer is selected from uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adenoid cystic carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma and endocervical adenocarcinoma.

147. The method of any one of claims 144-146, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

148. Use of a compound according to any one of claims 1-139, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

149. The use of claim 148, wherein the disease or disorder is cancer.

150. The use of claim 149, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer and thyroid cancer.151 The use of claim 150, wherein the cancer is selected from uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma,Patent ApplicationAtty. Docket No. ENTX-033PCT adenoid cystic carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma and endocervical adenocarcinoma.

152. A method for making a compound of any one claims 1-139.

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