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

Abstract

The invention provides novel bicyclic heterocyclic or heteroaryl 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-032PCTNOVEL 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 No. 63 / 692,651, filed September 9, 2024, the entire content 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 heterocyclic or heteroaryl 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-032PCTCancer 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 al. 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, whereinPatent ApplicationAtty. Docket No. ENTX-032PCTRing A is a substituted 5- or 6-membered heteroaryl group;Ring B is a substituted 6-membered aryl or heteroaryl group;X is N, NRb, O, S or CRa;Y is O, S, CRa, CRaRa, N or NRb;V is CRaor N;Q is CRaor N;Z isW is CRR6;R1is R1A, OR1A, SR1Aor NRR’, wherein R1 Ais 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;R5is H or unsubstituted or substituted Ci-Ce alkyl;R6is H, D, F, Ci-Ce alkyl, C3-C6 carbocyclic, C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic 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, Ci-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Raand Ra' is independently 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’ arePatent ApplicationAtty. Docket No. ENTX-032PCT 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, “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The termPatent ApplicationAtty. Docket No. ENTX-032PCT 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 an 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, thePatent ApplicationAtty. Docket No. ENTX-032PCT 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 in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, - COOH, -CH2CN, -O-C1-C6 alkyl, Ci-C6alkyl, -OCi-C6alkenyl, -OCi-C6alkynyl, -Ci-C6Patent ApplicationAtty. Docket No. ENTX-032PCT 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, -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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate,Patent ApplicationAtty. Docket No. ENTX-032PCT 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 isopropylamine, 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.

[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 aPatent ApplicationAtty. Docket No. ENTX-032PCT 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.

[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 solidPatent ApplicationAtty. Docket No. ENTX-032PCT 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 com 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 the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk ofPatent ApplicationAtty. Docket No. ENTX-032PCT 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. Tn 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.Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”Patent ApplicationAtty. Docket No. ENTX-032PCT

[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, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,Patent ApplicationAtty. Docket No. ENTX-032PCT ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Rx)3 , -ORX, - SRX, -OC(O)-RX, -N(RX)2, -C(O)RX, -C(O)ORX, -OC(O)N(RX)2, -C(O)N(RX)2, -N(RX)C(O)ORX, - N(RX)C(O)RX, -N(RX)C(O)N(RX)2, -N(RX)C(NRX)N(RX)2, -N(Rx)S(O)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, tri fluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 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-C6 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 include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,Patent ApplicationAtty. Docket No. ENTX-032PCT 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, pyridothiazole, 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, alkylcarbonyl, 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 partially unsaturated. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can bePatent ApplicationAtty. Docket No. ENTX-032PCT 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 moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 carbocyclyl groups include norbornyl (C7). Examples of C3-8 carbocyclyl groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-lH indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3 , -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tN(Ra)2(where t is 1 or 2), - P(=O)(Ra)(Ra), or -O-P(=O)(ORa)2where each Rais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl"Patent ApplicationAtty. Docket No. ENTX-032PCT 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- [1,4] 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-piperi dinonyl, 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], hexahydro- IH-pyrrolizinyl, hexahydro- lH-pyrrolo[2,l- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls,Patent ApplicationAtty. Docket No. ENTX-032PCT hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- thiopyranyl 1,1 -dioxide.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 profdes. 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 heteroaryl group;Ring B is a substituted 6-membered aryl or heteroaryl group;X is N, NRb, O, S or CRa;Y is O, S, CRa, CRaRa, N or NRb;V is CRaor N;Q is CRaor N;Z isPatent Application Atty. Docket No. ENTX-032PCT(II)W is CRR6;R1is R1A, OR1A, SR1Aor NRR’, wherein R1Ais 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;R?is H or unsubstituted or substituted Ci-Ce alkyl;R6is H, D, F, Ci-Ce alkyl, Cs-Ce carbocyclic, C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic 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?,-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Raand Ra' is independently 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), Ring A is a substituted 5-membered heteroaryl group.

[0053] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-032PCT(Uli) whereinX is N or CRa; andY is O, S, CRaRa' orNRb

[0054] In certain embodiments of (Illi), X is N.

[0055] In certain embodiments of (Illi), X is CRa. In certain embodiments, Rais H.

[0056] In certain embodiments of (Illi), Y is O.

[0057] In certain embodiments of (Illi), Y is S.

[0058] In certain embodiments of (Illi), Y is NRb. In certain embodiments, Rbis H. In certain embodiments, Rbis CH3.

[0059] In certain embodiments of (I), the compound has the structural formula:whereinX is O, S or NRb; andY is N or CRa.

[0060] In certain embodiments of (III2), Y is N.

[0061] In certain embodiments of (III2), Y is CRa. In certain embodiments, Rais H.

[0062] In certain embodiments of (ITI2), X is O.

[0063] In certain embodiments of (III2), X is S.

[0064] In certain embodiments of (III2), X is NRb. In certain embodiments, Rbis H. In certain embodiments, Rbis CH3.

[0065] In certain embodiments of (I), Ring A is a substituted 6-membered heteroaryl group.

[0066] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-032PCTwhereinX is N or CRa; andY is N or CRa

[0067] In certain embodiments of (IV), Y is CRa.

[0068] In certain embodiments of (IV), Y is N.

[0069] In certain embodiments of (IV), X is CRa. In certain embodiments, Rais H.

[0070] In certain embodiments of (IV), X is N.

[0071] In certain embodiments of (I) and (III)-(IV), Q is CRa. In certain embodiments, Rais H.

[0072] In certain embodiments of (I) and (III)-(IV), Q is N.

[0073] In certain embodiments of (I) and (III)-(IV), V is CRa. In certain embodiments, RaisH.

[0074] In certain embodiments of (I) and (III)-(IV), V is N.

[0075] In certain embodiments of (I) and (III)-(IV), R3is a halogen.

[0076] In certain embodiments of (I) and (III)-(IV), R3is a substituted or unsubstituted Ci-Ce alkyl.

[0077] In certain embodiments of (I) and (III)-(IV), R3is a substituted or unsubstituted Ci- C4 alkyl.

[0078] In certain embodiments of (I) and (III)-(IV), R3is C1-C4 alkyl substituted with 1-5 halogen.

[0079] In certain embodiments of (I) and (III)-(IV), R3is C2-C4 alkyl substituted with 1-3 halogen.

[0080] In certain embodiments of (I) and (III)-(IV), R3is a substituted or unsubstituted C2- C4 alkynyl.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0081] In certain embodiments of (I) and (III)-(IV), R1is OR1A. In certain embodiments, R1Ais substituted or unsubstituted 6-membered aryl or heteroaryl. In certain embodiments, R1Ais substituted or unsubstituted phenyl.

[0082] In certain embodiments of (I) and (III)-(IV), R5is H.

[0083] In certain embodiments of (I) and (III)-(IV), 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.

[0084] In certain embodiments of (I)-(IV), R7and R8are in a trans configuration:

[0085] In certain embodiments of (I)-(IV), R7and R8are in a cis configuration:

[0086] In certain embodiments

[0087] In certain embodiments of (I)-(IV), R8is H.

[0088] In certain embodiments of (I)-(IV), R9is Ci-Ce alkyl. In certain embodiments), R9isCH3. In certain embodiments), R9is CD3.

[0089] In another aspect, the invention generally relates to a compound having the structural formula:(IIIiA)Patent ApplicationAtty. Docket No. ENTX-032PCT or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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;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.

[0090] In certain embodiments of (IIIiA), Rbis H.

[0091] In certain embodiments of (IIIiA), Rbis methyl.

[0092] In yet another aspect, the invention generally relates to a compound having the structural formula:(IIIiB)Patent ApplicationAtty. Docket No. ENTX-032PCT or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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;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.

[0093] In yet another aspect, the invention generally relates to a compound having the structural formula:(IIIic) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;Patent ApplicationAtty. Docket No. ENTX-032PCTR3is 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 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.

[0094] 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, whereinV is CRaor N;Q is CRaor N;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,Patent ApplicationAtty. Docket No. ENTX-032PCT orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Cj-Ce alky], Ch-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.

[0095] In certain embodiments of (IIIiD), Rbis H.

[0096] In certain embodiments of (IIIiD), Rbis methyl.

[0097] In certain embodiments of (IIIiD), Rais H.

[0098] 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, whereinV is CRaor N;Q is CRaor N;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,Patent ApplicationAtty. Docket No. ENTX-032PCT orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Cj-Ce alky], Ch-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.

[0099] In certain embodiments of (IIl2A), Rbis H.

[0100] In certain embodiments of (IIIiA), Rbis methyl.

[0101] In yet another aspect, the invention generally relates to a compound having the structural formula:(III2B) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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,Patent ApplicationAtty. Docket No. ENTX-032PCT orNRR’, wherein said alkyl, alkenyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted;R9is Cj-Ce alky], 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.

[0102] 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, whereinV is CRaor N;Q is CRaor N;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;Patent ApplicationAtty. Docket No. ENTX-032PCTR9is Ct-C6alkyl, 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.

[0103] 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, whereinX is CRaor N;Y is CRaor N;V is CRaor N;Q is CRaor N;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 Ci-Ce alkyl, Cb-Ce carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Patent ApplicationAtty. Docket No. ENTX-032PCTRais 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.

[0104] In certain embodiments of (IVA), X is CRa. In certain embodiments, Rais H.

[0105] In certain embodiments of (IVA), X is N.

[0106] In certain embodiments of (IVA), Y is CRa. In certain embodiments, Rais H.

[0107] In certain embodiments of (IVA), Y is N.

[0108] In certain embodiments of (IIIiA)-(IVA), Q is CRa. In certain embodiments, Rais H.

[0109] In certain embodiments of (IIIiA)-(IVA), Q is N.

[0110] In certain embodiments of (IIIiA)-(IVA), V is CRa. In certain embodiments, Rais H.

[0111] In certain embodiments of (IIIrA)-(IVA), V is N.

[0112] In certain embodiments of (IIIiA)-(IVA), R9is CH3 or CD3.

[0113] In certain embodiments of (IIIiA)-(IVA), R3is a halogen.

[0114] In certain embodiments of (IIIiA)-(IVA), R3is C1-C4 alkyl substituted with 1-5 halogen.

[0115] In certain embodiments of (IIIiA)-(IVA), R3is substituted or unsubstituted C2-C4 alkynyl.

[0116] Non-limiting examples of compounds of the invention include those listed in Table 1.Patent ApplicationAtty. Docket No. ENTX-032PCTTable 1. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-032PCTPatent ApplicationAtty. Docket No. ENTX-032PCTPatent ApplicationAtty. Docket No. ENTX-032PCT

[0117] In certain embodiments, a compound disclosed herein has one or more deuterium atoms in place of hydrogen.

[0118] In certain embodiments, the compound has one deuterium atom in place of a hydrogen atom.

[0119] 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.

[0120] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0121] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0122] In certain embodiments, is in the form of a tablet. In certain embodiments, is in the form of a capsule.

[0123] 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.

[0124] 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.

[0125] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

[0126] In yet another aspect, the invention generally relates to a method for making a compound disclosed herein.

[0127] Compounds of the invention include deuterated versions of the disclosed compounds, for example, having one or more deuterium atoms in place of hydrogen.

[0128] 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.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0129] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0130] 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).

[0131] 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.

[0132] 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 ammoniumPatent ApplicationAtty. Docket No. ENTX-032PCT compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[0133] 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.

[0134] 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.

[0135] 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.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0136] In certain preferred embodiments, the compound is administered orally. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[0137] 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.

[0138] 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.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0139] 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.

[0140] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0141] 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.

[0142] 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,Patent ApplicationAtty. Docket No. ENTX-032PCT 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.

[0143] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0144] 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.

[0145] 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.

[0146] 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 furtherPatent ApplicationAtty. Docket No. ENTX-032PCT administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0147] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds, e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as provided in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0152] 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.

[0153] 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 (SU 11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis),Patent ApplicationAtty. Docket No. ENTX-032PCTOxaliplatin (Eloxatin®, Sanofi), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophy cins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L- norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone,Patent ApplicationAtty. Docket No. ENTX-032PCT dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, H E), 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; difhroromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0154] 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 andPatent ApplicationAtty. Docket No. ENTX-032PCT the like), immunotherapy agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0155] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cisand trcinsd somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0156] 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.

[0157] 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.

[0158] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,33S,18F, and36C1, respectively.

[0159] 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)Patent ApplicationAtty. Docket No. ENTX-032PCT 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.

[0160] 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.)

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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),Patent ApplicationAtty. Docket No. ENTX-032PCT 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.

[0166] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[0167] 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.

[0168] 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.

[0169] 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 andPatent ApplicationAtty. Docket No. ENTX-032PCT discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.Examples

[0170] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0171] 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.Patent ApplicationAtty. Docket No. ENTX-032PCTList of Abbreviations aq: aqueousAc = AcetylAcO = AcetateAc2O = Acetic anhydrideAIBN = a,a'-AzoisobyronitrileAll = AllylAlloc = AllyloxycarbonylAm = Amyl (Pentyl)Ar = ArylB2Pin2 = bis(pinacolato)diboronPatent ApplicationAtty. Docket No. ENTX-032PCT9-BBN = 9-BorabicyclononaneBHT = tert-ButylhydroxytolueneBINAP = 2,2'-Bis(diphenylphosphino)-l,l'-binaphthylBMS = Borane-methylsulphide complexBn = BenzylBoe = tert-Butoxy carbonylBOP = Bis(2-oxo-3-oxazolidinyl)phosphineBu or n-Bu = n-Butyl s-Bu or sBu = sec-Butyl t-Bu or tBu = tert-ButylBuOH = ButanolBz = BenzoylBzl = BenzylCAN = Ceric ammonium nitrate cataCXium A Pd G3 = mesylate [(di(l-adamantyl)-n-butylphosphine)-2-(2’-amino-1 , 1 ’biphenyl)]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 = DihydropiranPatent ApplicationAtty. Docket No. ENTX-032PCTDHQD = 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 azideDdpb = l,4-bis(diphenylphosphino)butaneDppe = l,2-bis(diphenylphosphino)ethaneDppf = l,2-bis(diphenylphosphino)ferrocene dppp = 1,3 -bi s(di phenyl phosphino)propaneDtbbpy = 4, 4’-di-tert-butyl-2,2’-dipyridylEA = Ethyl acetateEDC = l-Ethyl-3-(3-dimethylaminopropy)carbodiimideEDCI = l-Ethyl-3-(3-dimethylaminopropy)carbodiimide hydrochloride Eq = equivalentES-API = electrospray-atmospheric pressure ionization.ESI or ES = Electrospray ionizationEt = ethylEt2O = Diethyl etherEtOAc = Ethyl acetateFMOC = 9-FluorenylmethoxycarbonylPatent ApplicationAtty. Docket No. ENTX-032PCTHATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHMDS = HexamethyldisilazaneHMPA = HexamethylphosphoramideHOAt = 7-Aza-l-hydroxybenzotriazoleHOBt = 1 -HydroxybenzotriazoleHPLC = 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 ether m / z = mass divided by charge Na2SO4 = Sodium SulphateNaHMDS = Sodium bis(trimethylsilyl)amideNaCNBH3 = Sodium cyanoborohydrideNBS = N-BromosuccinimideNCS = N-ChlorosuccinimideNIS = N-IodosuccinimideNMM = N-MethylmorpholinePatent ApplicationAtty. Docket No. ENTX-032PCTNMO = N-Methylmorpholine-N-oxideNMP = N-MethylpyrrolidoneNMR = Nuclear magnetic resonanceNs = p-Nitrophenyl sulphonylPd(dppf)C12 = [1 , 1’ -bis(diphenylphosphino)ferrocene]dichloropalladiumPd(PPh3)4 = tetrakis(triphenylphosphine)palladiumPDC = Pyridinium dichlorochromatePCC = Pyridinium chlorochromatePE = Petroleum etherPh = PhenylPiv = Pivaloyl, 2,2-dimethylacetylPMB = p-MethoxybenzylPPA = Polyphosphoric acidPPTS = Pyridinium p-toluensulphonate n-Pr = n-PropylPr = Propyl i-Pr or iPr = iso-propiloPTC = Phase transfer catalystPTS A = p-Toluenesulphonic acidPv = Pivaloyl, 2,2-dimethylacetylPy = PyridineRed-Al® = Sodium bis(2-methoxyethoxy)aluminium hydrideRT = room temperatureSFC = supercritical fluid chromatographyPrep-SFC = Preparative SFCSEM = 2-(Trimethylsilyl)ethoxymethylTBAF = Tetrabutylammonium fluorideTBDMS = tert-ButyldimethylsilylTBDPS = tert-ButyldiphenylsilylTBHP = tert-ButylhydroperoxydeTBS = tert-ButyldimethylsilylPatent ApplicationAtty. Docket No. ENTX-032PCTTEA = Tri ethylamineTES = TriethylsilylTf = TrifluoromethanesulfonylTfO = TrifluoromethanesulfonateTI2O = Trifluoromethanesulfonyl anhydrideTfOH = Trifluoromethanesulfonic acidTFA = Trifluoroacetic acidTFAA = Trifluoroacetic anhydrideThexyl = 2,3 -dimethyl-2 -butylTHF = TetrahydrofuraneTHP = TetrahydropyranylTIPS = Triisopropyl silylTMEDA = N,N,N',N'-TetramethylethylendiamineTMG = TetramethylguanidineTMS = Trimethyl silylTol = p-ToluylTPAP = Tetra-n-propylammonium perruthenateTPS = TripropylsilylTr = Trityl, triphenylmethylTroc = 2,2,2-TrichloroethoxycarbonylTrt = Trityl, triphenylmethylTs = p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acidUV = ultravioletZ = BenzyloxycarbonyUV : ultra violet

[0172] General LCMS Method:Instrument: Shimadzu LCMS2020Reverse-phase column (Shim-Pack Scepter C 18, 33 x 3.0 mm, 3um)Patent ApplicationAtty. Docket No. ENTX-032PCTElution with A: H20 / 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).

[0173] General HPLC analytical method:Instrument: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281.Column: YMC-Triart C18, 250*20 mm, 5um; Welch Ultimate XB-C18, 250*21.2 mm, 5um.Detection wavelength: 220, 254 nM.Flow rate: 15ml / min-20ml / min;Run time: 8 min;Column temperature: 25 °C.

[0174] 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.Exemplary synthetic procedures:General synthetic route to build Z piece:

[0175] Z piece may be built via a 4-step sequence in the scheme below using synthetic chemistry and purification of the intermediates and products with methods known in the art:

[0176] Step A: Br or I intermediate with R1and R3in place could be subjected to palladium or copper catalyzed C-N coupling with (lS)-l-amino-l-R6-3-(R9-sulfanyl)propan-2-ol.

[0177] Step B: m-CPBA oxidation of sulfur to sulfone.

[0178] Step C: Mesylation of the alcohol.

[0179] Step D: Elimination of mesylate to form the double bond.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0180] In some embodiments, while R1= phenyl, R3= 1,1 -difluoroethyl, R6= cyclopropyl and R9= methyl, Z piece could be built in the general synthesis route below:Exemplary synthetic procedures for intermediates (lS)-l-amino-l-cyclopropyl-3-Patent ApplicationAtty. Docket No. ENTX-032PCT(methylthio)propan-2-ol (hydrochloride):

[0181] Step A: To a solution of 2-methylpropan-2-yl {[(lS)-l-cyclopropyl-2- hydroxyethyl]amino}methanoate (1 g, 4.97 mmol) in DCM (15 mL) was added DESS-MARTIN (3.16 g, 7.45 mmol) at 0 °C and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and filtered through celite. The filtrate was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (12 g column) using 0 - 16% EtOAc / PE to afford 2-methylpropan-2-yl {[(S)- cyclopropyl(formyl)methyl]amino}methanoate (830 mg, 83%) as a white solid.1H NMR (400 MHz, CDC13) 8 9.64 (s, 1H), 5.10 (s, 1H), 3.67 (s, 1H), 1.44 (s, 9H), 0.96 - 0.84 (m, 1H), 0.70 - 0.47 (m, 4H).

[0182] Step B: To a suspension of NaH (0.42 g, 10.54 mmol) in DMSO (28 mL) was added Trimethyl sulfoxonium iodide (2.33 g, 10.54 mmol) at room temperature under nitrogen and the mixture was stirred at room temperature for 20 minutes. A solution of 2-methylpropan-2- yl {[(S)-cyclopropyl(formyl)methyl]amino}methanoate (1.4 g, 7.03 mmol) in DMSO (5 mL) was added to the mixture at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford 2-methylpropan-2-yl {[(S)-cyclopropyl(oxiran-2-yl)methyl]amino}methanoate (2 g, crude) as a colorless oil, which was used to next step directly without further purification. LCMS (ESI): m / z 214 [M+H]+.

[0183] Step C: To a solution of 2-methylpropan-2-yl {[(S)-cyclopropyl(oxiran-2- yl)methyl]amino}methanoate (2 g, crude) in MeOH (15 mL) was added sodium methanethiolate (0.59 g, 8.40 mmol) at room temperature and the mixture was stirred at room temperaturePatent ApplicationAty. Docket No. ENTX-032PCT overnight. The mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel chromatography (12 g column) using 0 - 16% EtOAc / PE to afford 2- methylpropan-2-yl { [( 1 S)- 1 -cyclopropyl-2-hydroxy-3 - (methylsulfanyl)propyl]amino}methanoate (739 mg, 40%) as a colorless oil. LCMS (ESI): m / z 262 [M+H]+.

[0184] Step D: To a solution of tert-butyl (lS)-l-cyclopropyl-2-hydroxy-3- (methylthio)propyl)carbamate (1 g, 3.82 mmol) in EtOAc (3 mb) was added HCl / EtOAc (3 mL, 4M) at 0 °C and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to afford (lS)-l-amino-l-cyclopropyl-3- (methylthio)propan-2-ol hydrochloride (700 mg, 92%) as a white solid which was used directly for next step. LCMS (ESI): m / z 162 [M+H] ,Exemplary synthetic procedures for ExamplesExample 1: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenoxy-lH-pyrazolo [4,3-c] pyridin-3-aminePatent ApplicationAtty. Docket No. ENTX-032PCTExample 1

[0185] Step A: To a solution of 4,6-dichloro-lH-pyrazolo[4,3-c]pyridine (7 g, 37.43 mmol) and 3,4-dihydro-2H-pyran (6.4 mL, 74.52 mmol) in DCM (30 mL) was added p- Toluenesulfonic acid (0.64 g, 3.72 mmol) at 0 °C, the resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc twice, then the combined extracts were dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluted with a gradient of 0-10% EtOAc in petroleum ether to afford 4, 6-dichloro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridine (10.0 g, 99%) as a white solid. LCMS: ESI m / z 272 [M+H]+.

[0186] Step B: To a solution of 4, 6-dichloro-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazolo[4,3-c]pyridine (10.0 g, 36.90 mmol) and phenol (7.8 mL, 88.23 mmol) in DMF (100 mL) was added K2CO3 (18.3 g, 132.33 mmol), the resulting mixture was stirred at 80 °C overnight. The cooled mixture was poured into ice-water, extracted with EtOAc twice, thePatent ApplicationAtty. Docket No. ENTX-032PCT combined extracts were washed with brine, dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluted with a gradient of 0-10% EtOAc in petroleum ether to afford 6-chloro-4-phenoxy-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazolo[4,3-c]pyridine (11.3 g, 93 %) as a white solid. LCMS: ESI m / z 330 [M+H]+. ’H NVIR (400 MHz, CDCh) 5 7.86 (s, 1H), 7.45 - 7.41 (m, 2H), 7.28 (d, J= 0.8 Hz, 1H), 7.24 (d, J= 0.8 Hz, 3H), 5.63 (dd, J = 92, 2.8 Hz, 1H), 4.03 (dd, J = 12.8, 2.8 Hz, 1H), 3.77 - 3.71 (m, 1H), 2.48 - 2.40 (m, 1H), 2.09 (ddd, J= 13.2, 7.6, 4.0 Hz, 2H), 1.78 - 1.68 (m, 3H).

[0187] Step C: To a solution of 6-chloro-4-phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazolo[4,3-c]pyridine (11.3 g, 34.34 mmol) and tributyl(l-ethoxyvinyl)-X4-stannane (30.7 g, 84.91 mmol) in 1,4-dioxane (100 mL) was added Pd(PPha)4 (4.9 g, 4.25 mmol), the resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with H2O, extracted with EtOAc three times, the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated, to obtain the desired product 6-(l-ethoxyvinyl)-4-phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridine (14 g, crude) as a brown oil which was used directly for next step without purification. LCMS (ESI): m / z 366 [M+H]1.

[0188] Step D: A solution of product 6-( 1 -ethoxy vinyl)-4-phen oxy-1 -(tetrahy dro-2H-pyran- 2-yl)-lH-pyrazolo[4,3-c]pyridine (14 g, crude) in HC1 solution (2 N, 30 mL) and THF (15 mL) was stirred at room temperature for 2 hours. The aqueous layer was extracted with EtOAc, the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, eluted with a gradient of 0 to 20% EtOAc in petroleum ether. The desired fractions were evaporated to dryness to afford l-(4- phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridin-6-yl)ethan-l-one (9 g, 78%)as a colorless oil. LCMS (ESI): m / z 338 [M+H]+. ’H NMR (400 MHz, CDCh) 8 8.06 (s, 1H), 7.99 (s, 1H), 7.47 - 7.43 (m, 2H), 7.31 - 7.27 (m, 3H), 5.76 (dd, J = 9.6, 2.4 Hz, 1H), 4.07 (d, J = 10.4 Hz, 1H), 3.77 (dd, J= 11.2, 8.4 Hz, 1H), 2.49 (s, 4H), 2.16 - 2.06 (m, 2H), 1.77 (dd, J = 13.2, 5.6 Hz, 2H), 1.70 - 1.66 (m, 1H).

[0189] Step E: A solution of l-(4-phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3- c]pyridin-6-yl)ethan-l-one (9 g, 26.68 mmol) in DAST was stirred at 50 °C overnight. The reaction mixture was poured into ice-water, extracted with EtOAc, the combined extracts were washed with sat. NaHCOa and brine, dried over anhydrous Na2SO4, filtered and evaporated. ThePatent ApplicationAtty. Docket No. ENTX-032PCT crude product was purified by flash silica chromatography, elution with a gradient of 0-10% ethyl acetate in petroleum ether to afford 6-(l,l-difluoroethyl)-4-phenoxy-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazolo[4,3-c]pyridine (5.5 g, 57.4%) as a light yellow oil. LCMS (ESI): m / z 360 [M+H]+.

[0190] Step F: To a solution of 6-( 1 , l-difluoroethyl)-4-phenoxy-l-(tetrahydro-2H-pyran-2- yl)-lH-pyrazolo[4,3-c]pyridine (5.5 g, 15.30 mmol) in DCM (10 mL) was added TFA (50 mL), the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated and the residue was diluted with ice-water (30 mL), extracted with DCM (50 mL x 3), the combined organic phase was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by flash silica chromatography, elution with a gradient of 0-10% ethyl acetate in petroleum ether to afford 6- (l,l-difluoroethyl)-4-phenoxy-lH-pyrazolo[4,3-c]pyridine (3.6 g, 86%) as a white solid. LCMS (ESI): m / z 276 [M+H]+.

[0191] Step G: To a solution of 6-(l,l-difluoroethyl)-4-phenoxy-lH-pyrazolo[4,3-c]pyridine (2 g, 5.57 mmol) in DMF (30 mL) was added NIS (3.3 g, 14.53 mmol), the resulting mixture was stirred at 80 °C for 3 hours. The reaction mixture was diluted with ice-water (20 mL), extracted with EtOAc (30 mL x 3), the combined organic phase was washed by water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give the crude product which was purified by flash silica chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford 6-(l,l-difluoroethyl)-3-iodo-4-phenoxy-lH-pyrazolo[4,3-c]pyridine (2.2 g, 76%) as a light yellow oil. LCMS (ESI): m / z 402 [M+H]+.

[0192] Step H: To a solution of 6-(l,l-difluoroethyl)-3-iodo-4-phenoxy-lH-pyrazolo[4,3- c]pyridine (2.2 g, 5.48 mmol) and 3,4-dihydro-2H-pyran (0.94 mL, 10.97 mmol) in DCM (30 mL) was added p-Toluenesulfonic acid (0.09 g, 0.55 mmol), the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ice-water (20 mL), extracted with DCM (30 mL x 3), the combined organic phase was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 0 - 10 % ethyl acetate in petroleum ether) to afford 6-(l , 1- difluoroethyl)-3-iodo-4-phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridine (2.4 g, 90%) as a light yellow oil. LCMS (ESI): m / z 486 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0193] Step I: To a solution of 6-(l,l-difluoroethyl)-3-iodo-4-phenoxy-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazolo[4,3-c]pyridine (200 mg, 0.41 mmol) and (1S)-1 -amino- 1-cyclopropyl- 3 -(methyl sulfanyl)propan-2-ol (66 mg, 0.41 mmol) in Toluene (10 mL) was added Pd2(dba)s (38 mg, 0.04 mmol), XANT PHOS (48 mg, 0.08 mmol) and CS2CO3 (403 mg, 1.24 mmol) at room temperature. The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 6 hours under nitrogen. After cooled to room temperature, the reaction solution was diluted with EA (20 mL), washed with water and brine, dried over anhydrous Na2SC>4, concentrated in vacuum and the residue was purified by flash chromatography (silica gel, 0 ~ 12 % ethyl acetate in petroleum ether) to afford (1 S)-l -cyclopropyl- l-((6-(l, 1 -difluoroethyl)-4- phenoxy- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazolo[4,3 -c]pyridin-3 -yl)amino)-3 - (methylthio)propan-2-ol (10 mg, 5%) as a yellow oil. LCMS (ESI): m / z 519 [M+H]+.rH NMR (400 MHz, CDCI3) 8 7.41 (t, J= 8.0 Hz, 2H), 7.30 - 7.22 (m, 4H), 5.44 (dd, J= 9.6, 2.4 Hz, 1H), 5.19 (dd, J= 24.4, 7.6 Hz, 1H), 4.12 - 3.97 (m, 2H), 3.70 (dd, J= 15.2, 6.8 Hz, 1H), 3.28 - 3.16 (m, 1H), 2.84 (td, J= 14.0, 4.4 Hz, 1H), 2.72 (ddd, J= 13.6, 8.4, 2.4 Hz, 1H), 2.43 - 2.30 (m, 1H), 2.20 - 2.06 (m, 4H), 1.97 (d, J= 12.8 Hz, 1H), 1.80 (d, J= 18.4 Hz, 3H), 1.70 (d, J = 9.6 Hz, 3H), 1.28 (ddd, J = 12.8, 8.8, 4.8 Hz, 1H), 0.68 - 0.47 (m, 3H), 0.39 (ddd, J = 16.8, 10.4, 4.8 Hz, 1H).

[0194] Step J: To a solution of (lS)-l-cyclopropyl-l-((6-(l,l-difluoroethyl)-4-phenoxy-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylthio)propan-2-ol (90 mg, 0.17 mmol) in DCM (8 mL) was added m-CPBA (105 mg, 0.52 mmol), The reaction mixture was heated at 25 °C under N2 atmosphere for 2hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (50% EtOAc in PE) to afford (1S)-1- cyclopropyl- 1 -((6-( 1 , 1 -difluoroethyl)-4-phenoxy- 1 -(tetrahydro-2H-pyran-2-yl)- lH-pyrazolo[4,3 - c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-ol (70 mg, 73%) as a white solid. LCMS (ESI): m / z 551 [M+H]+.

[0195] Step K: To a solution of ( IS)- 1 -cyclopropyl- 1-((6-( 1,1 -difluoroethyl)-4-phenoxy- 1- (tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2- ol (70 mg, 0.13 mmol) in DCM (10 mL) was added TEA (38 mg, 0.38 mmol) and methanesulfonic anhydride (33 mg, 0.19 mmol), The reaction mixture was heated at 25 °C underPatent ApplicationAtty. Docket No. ENTX-032PCTNz for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with brine, dried over anhydrous NasSCL and filtered. The filtrate was concentrated to afford ( IS)- 1 -cyclopropyl- 1-((6-( 1,1 -difluoroethyl)-4- phenoxy- 1 -(tetrahydro-2H-pyran-2-yl)- lH-pyrazolo[4,3 -c]pyridin-3 -yl)amino)-3 - (methylsulfonyl)propan-2-yl methanesulfonate (25 mg, 31%) as a white solid. LCMS (ESI): m / z 629 [M+H]+.

[0196] Step L: To a solution of ( IS)- 1 -cyclopropyl- 1-((6-( 1,1 -difluoroethyl)-4-phenoxy- 1- (tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2- yl (25 mg, 0.040 mmol) in THF (3 mL) was added DBU (12 mg, 0.080 mmol), The reaction mixture was heated at 25 °C under N2 for 1 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (35% EtOAc in PE) to afford N-((S,E)-l-cyclopropyl-3- (methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4-phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazolo[4,3-c]pyri din-3 -amine (16 mg, 75%) as a white solid. LCMS (ESI): m / z 533 [M+H]+.

[0197] Step M: To a solution of N-((S,E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l- difluoroethyl)-4-phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-c]pyridin-3-amine (15 mg, 0.028 mmol) in DCM (5 mL) was added TFA (0.4 mL), The reaction mixture was stirred at 25 °C under N2 for 1 hours. The reaction mixture was concentrated and the crude product was purified by reverse phase purification (C18, MeCN / LLO, 0.1% FA modifier, 0 to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized afford (S,E)-N-(1- cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4-phenoxy-lH-pyrazolo[4,3- c]pyri din-3 -amine (3.0 mg, 23%) as a white solid. LCMS (ESI): m / z 449 [M+H]+.JH NMR (400 MHz, CDCI3) 8 7.48 - 7.41 (m, 2H), 7.32 - 7.26 (m, 3H), 7.23 (s, 1H), 7.09 (dd, J= 15.0, 4.6 Hz, 1H), 6.67 (dd, J= 15.0, 1.4 Hz, 1H), 5.06 (d, .7= 6.0 Hz, 1H), 3.83 (dt, J = 9.3, 4.6 Hz, 1H), 2.94 (s, 3H), 1.78 (t, J= 18.6 Hz, 3H), 1.16 - 1.07 (m, 1H), 0.77 - 0.65 (m, 2H), 0.57 - 0.43 (m, 2H).Example 2: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-4- phenoxyisoxazolo[4,5-c]pyridin-3-aminePatent ApplicationAtty. Docket No. ENTX-032PCT

[0198] Step A: To a stirring solution of methyl 2-amino-4,6-dichloronicotinate (15 g, 67.86 mmol) in pyridine hydrofluoride solution (150 mL) was added sodium nitrite (4.68 g, 67.86 mmol) by portions at 0 °C and the result solution was stirred 0 °C for 1 hour. The mixture was then quenched with NH4OH (300 mL), extracted with ethyl acetate, The organic extract wasPatent ApplicationAtty. Docket No. ENTX-032PCT washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with 6% ethyl acetate in petroleum ether to afford methyl 4,6-dichloro-2-fluoroni cotinate (13 g, 85%). LCMS (ESI): m / z 224 [M + H]~. 'H NMR (400 MHz, DMSO-c / 6) 5 8.03 (s, 1H), 3.95 (s, 3H).

[0199] Step B: To a solution of methyl 4,6-dichloro-2-fluoronicotinate (13 g, 58.03 mmol) in N, N-Dimethylformamide (100 mb) was added phenol (5 mb, 58.03 mmol) and potassium carbonate (16.04 g, 116.06 mmol). The resulting mixture was stirred at room temperature for 1 hour under nitrogen. The reaction mixture was poured into ice-water, extracted with ethyl acetate twice, then the combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel flash chromatography eluted with 0~6% ethyl acetate in petroleum ether to afford methyl 4,6-dichloro- 2-phenoxynicotinate (13 g, 75%). LCMS (ESI): m / z 298 [M+H]+.

[0200] Step C: To a solution of methyl 4,6-dichloro-2-phenoxynicotinate (13 g, 43.61 mmol) and tributyl(l-ethoxyvinyl)stannane (15.7 g, 43.60 mmol) in N, N-Dimethylformamide (130 mb) was added tetrakis(triphenylphosphine)palladium (2.5 g, 2.20 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 3 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with potassium fluoride solution, and the organic layer was separated. HC1 (500 mL, 6N) was added into the solution and stirred at room temperature for 4 hours, The organic phares was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluted with 4% ethyl acetate in petroleum ether to afford methyl 6-acetyl-4-chloro-2-phenoxynicotinate (5.7 g, 42%). LCMS (ESI): m / z 306 [M+H]+.

[0201] Step D: To a solution of methyl 6-acetyl-4-chloro-2-phenoxynicotinate (6.2 g, 20.28 mmol) in DCM (10 mL) was added DAST (10 mL) slowly at 0 °C. Then the reaction mixture was warmed to 50 °C and stirred at 50 °C for 3 hours. The cooled reaction mixture was diluted with DCM, washed with brine, and the organic layer was separated. The aqueous layer was extracted with DCM, the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 2% ethyl acetate in petroleum ether to affordPatent ApplicationAtty. Docket No. ENTX-032PCT methyl 4-chloro-6-(l,l-difluoroethyl)-2-phenoxynicotinate (6.0 g, 90%). LCMS (ESI): m / z 328 [M+H]+.

[0202] Step E: To a solution of methyl 4-chloro-6-(l,l-difluoroethyl)-2-phenoxynicotinate (6.0 g, 18.31 mmol) in DCM (60 mL) at -60 °C, was added diisobutylaluminium hydride (55.0 mL, 54.93 mmol, 1 mol / L in Toluene). The reaction was stirred at -60 °C for 0.5 hour. The reaction mixture was diluted with DCM, washed with brine, and the organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, fdtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 2% ethyl acetate in petroleum ether to afford (4-chloro-6-(l,l-difluoroethyl)-2-phenoxypyri din-3 -yl)m ethanol (2.8 g, 51%). LCMS (ESI): m / z 300[M+H]+.

[0203] Step F: To a stirred mixture of (4-chloro-6-( 1,1 -difluoroethyl)-2-phenoxypyri din-3 - yl)methanol (2.5 g, 8.34 mmol) in 1,2-di chloroethane (5 mL) was added manganese dioxide (7.25 g, 83.42 mmol). The mixture was stirred at 50 °C overnight. The reaction mixture was filtered and evaporated to afford 4-chloro-6-(l,l-difluoroethyl)-2-phenoxynicotinaldehyde (2 g, 80%) which was used directly for the next step. LCMS (ESI): m / z 298 [M+H]1.

[0204] Step G: To a solution of 4-chloro-6-(l,l-difluoroethyl)-2-phenoxynicotinaldehyde (2 g, 6.72 mmol) in methanol (25 mL) was added Hydroxylamine hydrochloride (470 mg, 6.72 mmol) and potassium carbonate (1.86 g, 13.44 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford (E)-4-chloro-6-(l,l-difluoroethyl)-2-phenoxynicotinaldehyde oxime (400 mg, 19%). LCMS (ESI): m / z 313 [M+H]+.Step H: To a solution of (E)-4-chloro-6-(l,l-difluoroethyl)-2-phenoxynicotinaldehyde oxime (400 mg, 1.28 mmol) in N, N-Dimethylformamide (5 mL) was added N-chlorosuccinimide (170.8 mg, 1.28 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over sodium sulfate and concentrated to afford (Z)-4-chloro-6-(l,l-difluoroethyl)-N-hydroxy-2-phenoxynicotinimidoyl chloride (440 mg, 99%) which was used directly for next step. LCMS (ESI): m / z 347[M+H]+.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0205] Step I: To a solution of (440 mg, 1.27 mmol) in dichloromethane (5 mL) was added (1S)-1 -amino- 1-cy cl opropyl-3-(methylthio)propan-2-ol (204 mg, 1.27 mmol) and triethylamine (0.53 mL, 3.80 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with di chloromethane, washed with H2O and brine, dried over sodium sulfate and concentrated to afford (Z)-4-chloro-N-((lS)-l-cyclopropyl-2-hydroxy-3- (methylthio)propyl)-6-(l, l-difluoroethyl)-N'-hydroxy-2-phenoxynicotinimidamide (500 mg, 83%). LCMS (ESI): m / z 472[M+H]+.

[0206] Step J: To a stirred mixture of (Z)-4-chloro-N-((lS)-l-cyclopropyl-2-hydroxy-3- (methylthio)propyl)-6-(l, l-difluoroethyl)-N'-hydroxy-2-phenoxynicotinimidamide (500 mg, 1.06 mmol) in N,N-Dimethylacetamide (8 mL) was added potassium carbonate (292 mg, 2.12 mmol) and the mixture was stirred at 70 °C for 1 hour. The cooled reaction mixture was diluted with ethyl acetate, washed with brine, and organic layer was separated. The aqueous layer was extracted with ethyl acetate, then the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, fdtered 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 ( 1 S)- 1 -cyclopropyl- 1 -((6-( 1 , 1 -difluoroethyl)-4-phenoxyisoxazolo[4,5-c]pyridin-3 - yl)amino)-3-(methylthio)propan-2-ol (300 mg, 65%). LCMS: (ESI) m / z 436 [M+H]+.

[0207] Step K: To a stirred mixture of (1 S)-l -cyclopropyl- 1-((6-( 1,1 -difluoroethyl)-4- phenoxyisoxazolo[4,5-c]pyridin-3-yl)amino)-3-(methylthio)propan-2-ol (150 mg, 0.34 mmol) in DCM (5 mL) was added 3 -chloroperoxybenzoic acid (174 mg, 0.86 mmol, 87%) and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with di chloromethane, and the organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 20-30% ethyl acetate in petroleum ether to afford ( 1 S)- 1 -cyclopropyl- 1 -((6-( 1 , 1 -difluoroethyl)-4-phenoxyisoxazolo[4,5-c]pyri din-3 -yl)amino)-3 - (methylsulfonyl)propan-2-ol (100 mg, 62%). LCMS (ESI): m / z 468 [M+H]+.

[0208] Step L: To a stirred mixture of ( IS)- 1 -cyclopropyl- l-((6-(l,l -difluoroethyl)-4- phenoxyisoxazolo[4,5-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-ol (100 mg, 0.21 mmol) in DCM (5 mL) was added triethylamine (430 mg, 4.28 mmol) and methanesulfonic anhydride (37.26 mg, 0.21 mmol). The mixture was stirred at room temperature for 1 hour. ThePatent ApplicationAtty. Docket No. ENTX-032PCT reaction mixture was diluted with DCM, washed with water and brine, and the organic layer was separated. The aqueous layer was extracted with DCM, the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated, The residue was purified by prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l- difhioroethyl)-4-phenoxyisoxazolo[4,5-c]pyridin-3-amine (18.8 mg, 16%). LCMS (ESI): m / z 450 [M+H]t1H NMR (400 MHz, CD3OD) 5 7.50 - 7.45 (m, 2H), 7.40 (s, 1H), 7.33 - 7.28 (m, 3H), 7.05 - 6.98 (m, 1H), 6.87 - 6.81 (m, 1H), 3.76 - 3.71 (m, 1H), 3.00 (s, 3H), 1.78 - 1.68 (m, 3H), 1.38 - 1.31 (m, 1H), 0.74 - 0.66 (m, 2H), 0.59 - 0.45 (m, 2H).Example 3: (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-l-methyl- 4-phenoxy-lH-pyrazolo[4,3-c]pyridin-3-amineExample 3

[0209] Step A: To a flask containing 6-(l,l-difluoroethyl)-4-phenoxy-lH-pyrazolo[4,3- c]pyridine (2.0 g, 7.27 mmol) in ACN (10 mL) was added l,3-Dibromo-5,5- dimethylhydantoin (208 mg, 0.73 mmol) at room temperature. The reaction was stirred at 70 °C for 2 hours. ThePatent ApplicationAtty. Docket No. ENTX-032PCT reaction solvent was evaporated under reduced pressure and the crude product was purified by silica gel flash chromatography eluted with a gradient of 10-30% EtOAc in petroleum ether to afford 3-bromo-6-(Ll-difluoroethyl)-4-phenoxy-lH-pyrazolo[4,3-c]pyridine (1.5 g, 58%). LCMS (ESI) m / z: 354 | M ■ H i .

[0210] Step B: To a solution of 3-bromo-6-(l,l-difluoroethyl)-4-phenoxy-lH-pyrazolo[4,3- c]pyridine (1.1 g, 3.11 mmol) and K2CO3 (1 3 g, 9.32 mmol) in ACN (10 mL) was added CH3I (881 mg, 6.21 mmol), the resulting mixture was stirred at 60 °C overnight. The cooled mixture was diluted with ice-water (20 mL), extracted with EtOAc (30 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 10 % ethyl acetate in petroleum ether to afford 3-bromo-6-(l,l-difluoroethyl)-l-methyl-4-phenoxy-lH- pyrazolo[4,3-c]pyridine (930 mg, 81%). LCMS (ESI): m / z 368 [M+H]+.

[0211] Step C: To a solution of 3-bromo-6-(l,l-difluoroethyl)-l-methyl-4-phenoxy-lH- pyrazolo[4,3-c]pyridine (1 g, 2.72 mmol) and (1 S)-l-amino-l-cyclopropyl-3-(methylsulfanyl)propan-2-ol (0.7 g, 4.07 mmol) in Toluene (10 mL) was added Xantphos (0.3 g, 0.54 mmol), Pd2(dba)3 (0.3 g, 0.27 mmol) and CS2CO3 (2.7 g, 8.15 mmol) at room temperature. The reaction mixture was purged with nitrogen three times, then heated to 100 °C and stirred at 100 °C for 4 h under nitrogen. The cooled mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over anhydrous Na2SO4, concentrated in vacuum and the residue was purified by silica gel flash chromatography eluted with 0 - 12% ethyl acetate in petroleum ether to afford ( 1 S)- 1 -cyclopropyl- 1 -((6-(l , 1 -difluoroethyl)- 1 -methyl-4-phenoxy- lH-pyrazolo[4,3 - c]pyridin-3-yl)amino)-3-(methylthio)propan-2-ol (55 mg, 4.5%). LCMS (ESI): m / z 449 [M+H]+

[0212] Step D: To a solution of (lS)-l-cyclopropyl-l-((6-(l,l-difluoroethyl)-l-methyl-4- phenoxy-lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylthio)propan-2-ol (40 mg, 0.09 mmol) in Acetone (3 mL) and Water (1.5 mL) was added Oxone (137 mg, 0.22 mmol), The reaction mixture was stirred at 25 °C under nitrogen for 0.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the crude product was purified by silica gel flash chromatography eluted with 50% EtOAc in petroleum ether to afford ( 1 S)- 1 -cyclopropyl- 1 -((6-( 1 , 1 -difluoroethyl)- 1 -methyl-4-phenoxy- lH-pyrazolo[4,3 -Patent ApplicationAtty. Docket No. ENTX-032PCT c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-ol (40 mg, 93 %). LCMS (ESI): m / z 481 [M+H]+.

[0213] Step E: To a solution of (l S)-l-cyclopropyl-l-((6-(l,l-difluoroethyl)-l-methyl-4- phenoxy-lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-ol (50 mg, 0.10 mmol) in DCM (5 mL) was added TEA (210 mg, 2.08 mmol) and Methanesulfonic anhydride (181 mg, 1.04 mmol). The reaction mixture was stirred at 25 °C under nitrogen for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated to afford ( 1 S)- 1 -cyclopropyl- 1 -((6-(l , 1 -difluoroethyl)- 1 -methyl-4-phenoxy- 1 H-pyrazolo[4,3 - c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-yl methanesulfonate (70 mg, 96 %). LCMS (ESI): m / z 559 [M+H]+.

[0214] Step F: To a solution of (lS)-l-cyclopropyl-l-((6-(l,l-difluoroethyl)-l-methyl-4- phenoxy-lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-yl methanesulfonate (60 mg, 0.11 mmol) in THF (5 mL) was added DBU (16 mg, 0.11 mmol), The reaction mixture was stirred at 25 °C under nitrogen for 5 min. The reaction mixture was concentrated and the crude product was purified by Prep-HPLC to afford (S, E)-N-(l- cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-l-methyl-4-phenoxy-lH- pyrazolo[4,3-c]pyri din-3 -amine (18.8 mg, 37.8%). LCMS (ESI): m / z 463 [M+H]+. 'HNMR (400 MHz, DMSO-c / r,) 8 7.53 - 7.43 (m, 2H), 7.42 (s, 1H), 7.34 - 7.32 (m, 2H), 7.29 - 7.27 (m, 1H), 6.93 (dd, J= 15.2, 5.6 Hz, 1H), 6.82 (d, J= 15.2 Hz, 1H), 6.11 (d, J= 8.4 Hz, 1H), 3.82 (s, 3H), 3.00 (s, 3H), 1.76 (t, J= 18.8 Hz, 3H), 1.35 - 1.22 (m, 1H), 0.62 - 0.49 (m, 2H), 0.49 - 0.26 (m, 2H).Example 4: (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(l,l-difluoroethyl)-2-methyl- 4-phenoxy-2H-pyrazolo[4,3-c]pyridin-3-aminePatent ApplicationAtty. Docket No. ENTX-032PCT

[0215] Step A: To a flask containing 3-bromo-6-(l,l-difluoroethyl)-4-phenoxy-lH- pyrazolo[4,3-c]pyridine (1.1 g, 3.11 mmol) and Trimethyloxonium tetrafluoroborate (700 mg, 4.66 mmol) in DCM (20 mb) at room temperature 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 10-30% ethyl acetate in petroleum ether to afford 3- bromo-6-(l,l-difluoroethyl)-2-methyl-4-phenoxy-2H-pyrazolo[4,3-c]pyridine (900 mg, 79%). LCMS (ESI) m / z: 368 [M+H]+.

[0216] Step B: To a solution of 3-bromo-6-(l,l-difluoroethyl)-2-methyl-4-phenoxy-2H- pyrazolo[4,3-c]pyridine (900 mg, 2.44 mmol) and (lS)-l-amino-l-cyclopropyl-3-(methylsulfanyl)propan-2-ol (0.6 g, 3.67 mmol) in Toluene (20 mb) was added Xant phos (0.3 g, 0.49 mmol), Pd2(dba)s (0.2 g, 0.24 mmol) and CS2CO3 (2.4 g, 7.33 mmol) at room temperature. The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 3 h under nitrogen. After cooled to room temperature, the reaction solution was diluted with EtOAc (20 mb), washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuum and the residue was purified by silica gel flash chromatography eluted with 0 - 12 % ethyl acetate in petroleum ether to afford (1 S)-l -cyclopropyl- 1-((6-( 1,1 -difluoroethyl)-2-methyl- 4-phenoxy-2H-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylthio)propan-2-ol (40 mg, 4%). LCMS (ESI): m / z 449 [M+H]+Patent ApplicationAtty. Docket No. ENTX-032PCT

[0217] Step C: To a solution of (lS)-l-cyclopropyl-l-((6-(l,l-difluoroethyl)-2-methyl-4- phenoxy-2H-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylthio)propan-2-ol (40 mg, 0.09 mmol) in Acetone (3 mL) and Water (1.5 mL) was added Oxone (137 mg, 0.22 mmol), The reaction mixture was heated at 25 °C under nitrogen for 0.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the crude product was purified by silica gel flash chromatography eluted with 50% ethyl acetate in petroleum ether to afford (1 S)-l -cyclopropyl- l-((6-(l, l-difluoroethyl)-2-methyl-4-phenoxy-2H-pyrazolo[4, 3- c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-ol (30 mg, 70%). LCMS (ESI): m / z 481 [M+H]+.

[0218] Step D: To a solution of (l S)-l-cyclopropyl-l-((6-(l,l-difhioroethyl)-2-methyl-4- phenoxy-2H-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-ol (30 mg, 0.06 mmol) in DCM (5 mL) was added TEA (0.17 mL, 1.25 mmol) and methanesulfonic anhydride (33 mg, 0.19 mmol). The reaction mixture was stirred at 25 °C under nitrogen for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated to afford ( 1 S)- 1 -cyclopropyl- 1 -((6-(l , 1 -difluoroethyl)-2-methyl-4-phenoxy-2,3 ,3 a,7a-tetrahydro- lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan-2-yl methanesulfonate (20 mg, 57%). LCMS (ESI): m / z 559 [M+H]+.

[0219] Step E: To a solution of (lS)-l-cyclopropyl-l-((6-(l,l-difluoroethyl)-2-methyl-4- phenoxy-2,3,3a,7a-tetrahydro-lH-pyrazolo[4,3-c]pyridin-3-yl)amino)-3-(methylsulfonyl)propan- 2-yl methanesulfonate (20 mg, 0.04 mmol) in THF (5 mL) was added DBU (6 mg, 0.04 mmol), The reaction mixture was stirred at 25 °C under nitrogen for 5 min. The reaction mixture was concentrated and the crude product was purified by Prep-HPLC to afford (S, E)-N-(l- cyclopropyl-3-(methylsulfonyl)allyl)-6-(l , 1 -difluoroethyl)-2-methyl-4-phenoxy-2H- pyrazolo[4,3-c]pyri din-3 -amine (7.9 mg, 48%). LCMS (ESI): m / z 463 [M+H]+. H NMR (400 MHz, DMSO-t / e) 8 7.46 - 7.40 (m, 2H), 7.28 - 7.22 (m, 3H), 7.16 (s, 1H), 6.90 (dd, J= 15.2, 5.0 Hz, 1H), 6.83 (d, J= 15.2 Hz, 1H), 6.37 (d, J= 9.2 Hz, 1H), 4.02 - 3.93 (m, 4H), 2.85 (s, 3H), 1.72 (t, J= 18.8 Hz, 3H), 1.25 - 1.16 (m, 1H), 0.59 - 0.45 (m, 2H), 0.33 - 0.19 (m, 2H).Exemplary In vitro WRN (500-1242) unwinding assayPatent ApplicationAty. Docket No. ENTX-032PCT

[0220] All compounds were initially prepared as 10 mM stocks in DMSO. The stock solution was then serially diluted 3 -fold in 100% DMSO to 10 concentrations. 200nL of each compound dilution was subsequently added to 384-well plate in duplicate. To each well, 10 pL of enzyme solution containing 8 nM WRN (500-1242) and ImM ATP in 1 * Assay buffer (50 mM Tris HC1 (pH 7.5), 2 mM MgCh, 100 mM NaCl, 0.003% BSA,0.01% Tween-20 and 1 mM DTT) was added, then centrifuged for 30s, and incubated at 28°C for 2h. To initiate each reaction, 10 pL of substrate solution containing fluorescence / quencher labeled double stranded DNA(SEQ No. 1 : 5 ’ -TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-BHQ2 3 ’ ,SEQ No. 2: 5’ TAMRA-GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTT-

[0221] TTTTTTTT-3’, final concentration at 20 nM) and 80nM Capture DNA (GAACGAACATCGGGTACG) was added to each well and centrifuged for 30s. All the reaction was incubated at 28°C for 30 minutes. 10 pL of EDTA with the final concentration at 10 mM was added to quench the reactions for endpoint measurement. After incubating at 28°C for 10 min, the fluorescence intensity was measured on Paradigm microplate reader using excitation and emission wavelength of 540 nm and 580 nm, respectively. The fluorescence values were converted to % inhibition (% inhibition = (Max-sample) / (Max-Min)*100). Min control represents full inhibition of unwinding activity, containing substrates and DMSO. Max control represents no inhibition of unwinding activity, containing enzyme, substrates and DMSO. IC50 fitting was carried out by using XLfit Excel add-in version 5.4.0.8.

[0222] Compounds having an IC50 less than or equal to 300 nM are represented as “A”; Compounds having an IC50 greater than 300 nM but less than or equal to 1 pM are represented as “B”; Compounds having an IC50 greater than 1 pM but less than 10 pM are represented as “C”; Compounds having an IC50 greater than or equal to 10 pM are represented as “D”. Data of the compounds are disclosed in Table 2.Table 2. WRN DNA Unwinding AssayPatent ApplicationAtty. Docket No. ENTX-032PCTExemplary method for detecting effect on cell proliferation

[0223] The colon carcinoma cell lines SW48 (RRID: CVCL 1724), HCT 116 (RRID: CVCL 0291), HCC70(CVCL 1270) and SW620 (RRID: CVCL 0547) were obtained from ATCC.

[0224] HCC70 cells were cultured in growth medium composed of RPMI-1640 (Invitrogen Cat# 11875135), 2 mM L-Glutamine (Invitrogen Cat# 35050061), IX Penicillin-Streptomycin (Invitrogen Cat# 15140122) and 10% fetal bovine serum (Biological Industries Cat# 040021A, Lot# 2144325). SW48 and SW620 cells were cultured in growth medium composed of DMEM (Invitrogen Cat 12430062), 1 mM sodium pyruvate (Invitrogen Cat# 11360070), 2 mM L- Glutamine (Invitrogen Cat# 35050061), IX Penicillin-Streptomycin (Invitrogen Cat# 15140122) and 10% fetal bovine serum (Biological Industries Cat# 040021A, Lot# 2144325). HCT 116 cells were cultured in growth medium composed of McCoys 5 A (Invitrogen Cat # 16600082), 2 mM L-Glutamine (Invitrogen Cat# 35050061), lx Penicillin-Streptomycin (Invitrogen Cat# 15140122) and 10% fetal bovine serum (Biological Industries Cat# 040021A, Lot# 2144325).). All cells were maintained at 37 °C in a humidified 5% CO2 incubator.

[0225] Trypsinized cells were seeded in 100 microliters growth medium at 4000 (SW48) or 5000 (HCC70, SW620) OR at 300(HCTl 16) cells / well into white, clear-bottom 96-well plates (Costar Cat# 3903). Duplicates were prepared for each compound treatment condition.Following overnight incubation at 37° C in a humidified 5% CO2 atmosphere, nine 3 -fold serial dilutions of a given compound stock (obtained at a concentration of 10 mM in DMSO and stored at -20°C) were dispensed directly into each of the triplicate assay plates using a HP 300D noncontact Digital Dispenser (TECAN). The final concentration of DMSO was normalized to 0.1% in all wells. 120 hours after compound addition, cellular ATP levels as a surrogate for cell viability was assessed following addition of 100 microliters CellTiterGIo (Promega Cat #G7573) reagent and luminescence quantification on ENVISION following a 10 incubation at room temperature.

[0226] For data analysis, the assay background signal that was determined in wells containing medium, but no cells, was subtracted from all other data points prior to further calculations. The extent of growth inhibition and potential cell kill was assessed by comparingPatent ApplicationAtty. Docket No. ENTX-032PCT the ATP levels (measured using CellTiterGIo, Promega) in compound-treated cells with those present at the time of compound addition. To this end, the following conditional concept was programmatically applied in XL-fit, an in-house software applying a multi-step decision tree to arrive at optimal concentration response curve fits. Data analysis was carried out using commercially available software XL-fit designed to determine IC50 values using 4- parameter fits. y = (A+((B-A) / (l+((C / x)AD)))); B DMSO; A:BLANK; C: IC50; D: HillSlope

[0227] Compounds having an IC50 less than or equal to 1 pM are represented as “AA”; Compounds having an IC50 greater than 1 pM but less than or equal to 2 pM are represented as “BB”; Compounds having an IC50 greater than 2 pM but less than 10 pM are represented as “CC”. The data of the compounds are listed in Table 3.Table 3. CTG HCT116 cell proliferation assay

[0228] 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.

[0229] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.Patent ApplicationAtty. Docket No. ENTX-032PCT

[0230] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and / or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[0231] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.Incorporation by Reference

[0232] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.Equivalents

[0233] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification andPatent ApplicationAtty. Docket No. ENTX-032PCT guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

Patent ApplicationAtty. Docket No. ENTX-032PCTWhat 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 heteroaryl group;Ring B is a substituted 6-membered aryl or heteroaryl group;X is N, NRb, O, S or CRa;Y is O, S, CRa, CRaRa, N or NRb;V is CRaor N;Q is CRaor N;Z isW is CRR6;R1is R1A, OR1A, SR1Aor NRR’, wherein R1Ais 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;Patent ApplicationAtty. Docket No. ENTX-032PCTR3is a halogen, Ci-Ce alkyl, Ci-Ce alkenyl, CI-CG 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;R5is H or unsubstituted or substituted Ci-Ce alkyl;R6is H, D, F, Cj-Ce alkyl, C3-C6 carbocyclic, C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted Cj-Ce alkyl;R8is H, D, or unsubstituted or substituted Ci-Ce alkyl;R9is C--C6 alkyl, C3-C6 carbocyclic or C2-C5 heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;Raand Ra' is independently 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, Ring A is a substituted 5-membered heteroaryl group.

3. The compound of claim 1 or 2, having the structural formula:whereinX is N or CRa; andY is O, S, CRaRa' or NRb.The compound of claim 3, wherein X is N.The compound of claim 3, wherein X is CRa.Patent ApplicationAtty. Docket No. ENTX-032PCT6. The compound of any one of claims 3-5, wherein Y is O.

7. The compound of any one of claims 3-5, wherein Y is S.

8. The compound of any one of claims 3-5, wherein Y is NRb.

9. The compound of claim 8, wherein Y is NH.

10. The compound of claim 8, wherein Y is NCH3.

11. The compound of claim 1 or 2, having the structural formula:whereinX is O, S or NRb; andY is N or CRa12. The compound of claim 11, wherein Y is N.

13. The compound of claim 11, wherein Y is CRa.

14. The compound of any one of claims 11-13, wherein X is O.

15. The compound of any one of claims 11-13, wherein X is S.

16. The compound of any one of claims 11-13, wherein X is NRb.

17. The compound of claim 16, wherein X is NH.

18. The compound of claim 16, wherein X is NCH3.

19. The compound of claim 1, wherein Ring A is a substituted 6-membered heteroaryl group.

20. The compound of claim 1 or 19, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-032PCT(IV) whereinX is N or CRa; andY is N or CRN21. The compound of claim 20, wherein Y is CRa.

22. The compound of claim 20, wherein Y is N.

23. The compound of any one of claims 20-22, wherein X is CRa.

24. The compound of any one of claims 20-22, wherein X is N.

25. The compound of any one of claims 1-24, wherein Q is CRa.

26. The compound of any one of claims 1-24, wherein Q is N.

27. The compound of any one of claims 1-26, wherein V is CRa.

28. The compound of any one of claims 1-26, wherein V is N.

29. The compound of any one of claims 1-28, wherein R3is a substituted or unsubstituted Ci- CG alkyl.

30. The compound of claim 29, wherein R3is a substituted or unsubstituted C1-C4 alkyl.

31. The compound of claim 30, wherein R3is a substituted or unsubstituted C2-C4 alkynyl.

32. The compound of claim 30, wherein R3is C1-C4 alkyl substituted with 1-5 halogen.

33. The compound of claim 32, wherein R3is C2-C4 alkyl substituted with 1-3 halogen.

34. The compound of any one of claims 1-33, wherein R1is OR1A.

35. The compound of claim 34, wherein R1Ais substituted or unsubstituted 6-membered aryl or heteroaryl.

36. The compound of claim 35, wherein R1Ais substituted or unsubstituted phenyl.

37. The compound of any one of claims 1-36, wherein R3is H.

38. The compound of any one of claims 1-37, wherein W is CRR6.

39. The compound of claim 38, wherein R is H.

40. The compound of claim 38 or 39, wherein R6is a Ci-Ce alkyl.

41. The compound of claim 38 or 39, wherein R6is a C3-C6 carbocyclic.

42. The compound of claim 41, wherein R6is cyclopropyl.

43. The compound of any one of claims 1-42, wherein R7and R8are in a trans configuration:Patent ApplicationAtty. Docket No. ENTX-032PCT44. The compound of any one of claims 1-42, wherein R7and R8are in a cis configuration:

45. The compound of any one of claims 1-44, wherein R7is H.

46. The compound of any one of claims 1-45, wherein R8is H.

47. The compound of any one of claims 1-46, wherein R9is Ci-Ce alkyl.

48. The compound of claim 47, wherein R9is CH3 or CD3.

49. A compound having the structural formula:(IIIiA) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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;Patent ApplicationAtty. Docket No. ENTX-032PCTR9is C;-C6alkyl, 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.

50. The compound of claim 49, wherein Rbis H.

51. The compound of claim 49, wherein Rbis methyl.

52. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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;Patent ApplicationAtty. Docket No. ENTX-032PCTR9is C=-C6alkyl, 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.

53. A compound having the structural formula:(III1C) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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 alky 4, 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 RPatent ApplicationAtty. Docket No. ENTX-032PCT and R’ are attached to the same N atom together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring.

54. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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, C ;-C(. 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.

55. The compound of claim 54, wherein Rbis H.Patent ApplicationAtty. Docket No. ENTX-032PCT56. The compound of claim 54, wherein Rbis methyl.

57. The compound of any one of claims 53-56, wherein Rais H.

58. A compound having the structural formula:(IIl2A) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;R3is a halogen, Ci-Cg 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 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;Rbis H or R; 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.

59. The compound of claim 58, wherein Rbis H.

60. The compound of claim 58, wherein Rbis methyl.Patent ApplicationAtty. Docket No. ENTX-032PCT61. A compound having the structural formula:(IIl2B) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;R3is a halogen, Ci-Cg alkyl, Ci-Cg 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.

62. A compound having the structural formula:Patent ApplicationAtty. Docket No. ENTX-032PCT(III2C) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinV is CRaor N;Q is CRaor N;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 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.

63. A compound having the structural formula:Patent ApplicationAtty. Docket No. ENTX-032PCTor a pharmaceutically acceptable form or an isotope derivative thereof, whereinX is CRaor N;Y is CRaor N;V is CRaor N;Q is CRaor N;R3is a halogen, Ci-Cg alkyl, Ci-Cg 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 ;-('(. 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.

64. The compound of claim 63, wherein X is CRa.

65. The compound of claim 63, wherein X is N.

66. The compound of any one of claims 63-65, wherein Y is CRa.

67. The compound of any one of claims 63-65, wherein Y is N.Patent ApplicationAtty. Docket No. ENTX-032PCT68. The compound of any one of claims 49-67, wherein Q is CRa.

69. The compound of any one of claims 49-67, wherein Q is N.

70. The compound of any one of claims 49-69, wherein V is CRa.

71. The compound of any one of claims 49-69, wherein V is N.

72. The compound of any one of claims 49-71, wherein R9is CH3 or CD3.

73. The compound of any one of claims 49-72, wherein R3is substituted or unsubstituted C2- C4 alkynyl.

74. The compound of any one of claims 49-73, wherein R3is C1-C4 alkyl substituted with 1-5 halogen.

75. A compound selected from Table 1.

76. The compound of any of claims 1-75, having one or more deuterium atoms in place of hydrogen.

77. A pharmaceutical composition comprising a compound according to any one of claims 1- 76 and a pharmaceutically acceptable excipient, carrier, or diluent.

78. The pharmaceutical composition of claim 77, being suitable for oral administration.

79. A unit dosage form comprising a pharmaceutical composition according to claim 77 or 78.

80. The unit dosage form of claim 79, being in the form of a tablet or capsule.

81. 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 1-76.

82. The method of claim 81, 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.

83. The method of claim 82, 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.

84. The method of any one of claims 81-83, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy,Patent ApplicationAtty. Docket No. ENTX-032PCT immunotherapy and hormonal therapy.

85. Use of a compound according to any one of claims 1-76, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

86. The use of claim 85, wherein the disease or disorder is cancer.

87. The use of claim 86, 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.

88. The use of claim 87, 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.

89. A method for making a compound of any one claims 1 -76.

Images