WRN inhibitors and compositions and methods thereof

Abstract

The invention provides novel 5-membered heteroaryl derivatives of quinolinones 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

WRN INHIBITORS AND COMPOSITIONS AND METHODS THEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 669,116, filed July 9, 2024, 63 / 682,893, filed August 14, 2024, and 63 / 689,270, filed August 30, 2024, the entire content of each of which is incorporated herein by reference for all purposes.Technical Fields of the Invention

[0001] The invention generally relates to novel compounds and therapeutic uses thereof. More particularly, the invention provides novel 5-membered heteroaryl 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

[0002] 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 Reviews Cancer 9:644-654; Brosh, et al. 2013 Nature Reviews Cancer 13 :542-558; Oshima et al. 2017Ageing 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 et al. 2013 PLoS One 8:e59709; Lieb et al. 2019 eLife 8:e43333; Zimmer, etal. 2020 Cancers (Basel) 12(5): 1319.)

[0003] 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

[0004] 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.

[0005] 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.

[0006] 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-membered heteroaryl group;R1is R1A, OR1A, SR1Aor NRR’, wherein R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, orbicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;Z isZ1having the structure of:Z2having the structure of:whereinW is CRR6;U is O or NRN;V is R9or NR9'R9";R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; each of R9, R9and R9is independently C1-C6alkyl, C3-C6carbocyclic or C2-C5heterocyclic group, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted, or R9' and R9together with the N atom they are attached to form an unsubstituted or substituted 4- to 6-membered heterocyclic ring;RNis H or unsubstituted or substituted C1.3 alkyl; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6alkyl, or unsubstituted or substituted 4-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.

[0007] In certain embodiments of (I), the compound has the structural formula:whereinQ is CR3or N;X is CR2, N, S, O or NR2Y is CR4, N, S, O or NR4’, orQ and X together, or Q and Y together, form a 3- to 8-membered carbocyclic, or 4- to 8- membered heterocyclic, aryl or heteroaryl group, wherein said alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted, whereinR2, when bonded to carbon, is H, halogen, Cfo, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted; or when bonded to nitrogen, is H or C1-6alkyl, wherein said alkyl is optionally substituted;R2is H or C.-6 alkyl, wherein said alkyl is optionally substituted;R3is C1-C6alkyl, C1-C6alkenyl, C3-C8carbocyclic, 4- to 6-membered heterocyclic, C6- C10aryl, 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;R4, when bonded to carbon, is H, halogen, CF3, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted; or when bonded to nitrogen, is H or C1-6. alkyl, wherein said alkyl is optionally substituted; andR4, when bonded to nitrogen, is H, C1-6alkyl, wherein said alkyl is optionally substituted.

[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 term consisting essentially of does not exclude pharmacologically inactive or inert agents, e g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0016] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standarddeviations 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, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer. In some embodiments, the amount is that effective for stop the progression or effect reduction of PPD, depression, insomnia, sleep apnea, restless legs syndrome, and narcolepsy, emotional disorders, depression, schizophrenia, bipolar disorder, obsessive- compulsive disorder, and other anxiety disorders, behavioral and pharmacological syndrome of dementia, or neurodegenerative diseases. In some embodiments, the amount is that effective forstop 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-C6alkyl, C1-C6alkyl, -OC1-C6alkenyl, -OC1-C6alkynyl, -C1-C6alkenyl, -C1-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6alkyl, -C(O)C1-C6alkyl, -OC(O)OCi- C6alkyl, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -C(O)NHC1-C6alkyl, - S(O)2-C1-C6alkyl, -S(O)NHC1-C6alkyl, and S(O)N(C1-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, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0027] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropyl amine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0028] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfmic 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 a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term"compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0030] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and / or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0031] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0032] As used herein, the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucoseand sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0033] As used herein, the term “subject” refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.

[0034] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, suchreduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0035] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0036] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0037] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0038] As used herein, the term an “isolated” or “substantially isolated” molecule (such as a polypeptide or polynucleotide) is one that has been manipulated to exist in a higher concentration than in nature or has been removed from its native environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of non-subject-antibody materials with which it is associated in nature have been removed. For example, a polynucleotide or a polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated." Further, recombinant DNA molecules contained in a vector are considered isolated for the purposes of the present invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include synthetically produced molecules.Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

[0039] As used herein, the term “purified” when used in reference to a molecule, it means that the concentration of the molecule being purified has been increased relative to molecules associated with it in its natural environment, or environment in which it was produced, found or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids and sugars but generally do not include water, buffers, and reagents added to maintain the integrity or facilitatethe 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, “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, 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., C1, C2, C3, C4, C5 or C6) 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, 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)2 wherein each Rxis independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-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-C1-C6alkyl, C1-C6alkyl, -C1-C6alkenyl, -OC1-C6alkynyl, -C1-C6alkenyl, -C1-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6alkyl, -C(O)C1-C6alkyl, -OC(O)OCi- C6alkyl, NH2, NH( C1-C6alkyl), N(C1-C6alkyl)2, -S(O)2- C1-C6alkyl, -S(O)NH C1-C6alkyl, and S(O)N(C1-C6alkyl)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, 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 (NZ1Z2)carbonyl. The term "NZ1Z2" as used herein, means two groups, Z1and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Z1and Z2are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2include, 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 be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13cycloalkyl). 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 andincluding 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 (C6), cyclohexenyl (C6), cyclohexadienyl (C6) 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 (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-lH indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3 , -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tN(Ra)2(where t is 1 or 2), - P(=O)(Ra)(Ra), or -O-P(=O)(ORa)2where each Rais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[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-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-lH,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H, 3 'H- spiro[cyclopropane-l,2'-pyrrolizine], hexahydro- IH-pyrrolizinyl, hexahydro- lH-pyrrolo[2,l- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- 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 profiles. The compounds exhibit superior DMPK profiles suitable for development into an orally administered therapeutic agent for treating cancer, e.g., cancers characterized by microsatellite instability and / or defective DNA mismatch repair system.

[0051] In one aspect, the invention generally relates to a compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a substituted 5-membered heteroaryl group;R1is R1A, OR1A, SR1Aor NRR’, wherein R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;Z isZ1having the structure of:Z2having the structure of:whereinW is CRR6;U is O or NRN;V is R9or NR9'R9";R3is H or unsubstituted or substituted C1-C6al kyl ;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; each of R9, R9' and R9is independently C1-C6alkyl, C3-C6carbocyclic or C2-C5heterocyclic group, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted, or R9' and R9together with the N atom they are attached to form an unsubstituted or substituted 4- to 6-membered heterocyclic ring;RNis H or unsubstituted or substituted C1-3alkyl; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6alkyl, or unsubstituted or substituted 4-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), the compound has the structural formula:whereinQ is CR3or N;X is CR2, N, S, O or NR2;Y is CR4, N, S, O or NR4’, orQ and X together, or Q and Y together, form a 3- to 8-membered carbocyclic, or 4- to 8- membered heterocyclic, aryl or heteroaryl group, wherein said alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted, whereinR2, when bonded to carbon, is H, halogen, CF3, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted; or when bonded to nitrogen, is H or C1-6alkyl, wherein said alkyl is optionally substituted;R2is H, C1-6alkyl, wherein said alkyl is optionally substituted;R3is C1-C6alkyl, C1-C6alkenyl, C3-C8carbocyclic, 4- to 6-membered heterocyclic, C6- C10aryl, 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;R4, when bonded to carbon, is H, halogen, CF3, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted; or when bonded to nitrogen, is H or C1 -6alkyl, wherein said alkyl is optionally substituted; andR4is H or C1-6alkyl, wherein said alkyl is optionally substituted.

[0053] In certain embodiments of (IA), Q is CR3, and the compound has the structural formula:wherein X and Y are selected as follows:X is selected from CR2and N, and Y is S, O or NR2’; orX is selected from S, O and NR4’, and Y is CR4or N, whereinR3is C1-C6alkyl, C1-C6alkenyl, C3-C8carbocyclic, 4- to 6-membered heterocyclic, C6- C10aryl, 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.

[0054] In certain embodiments of (IB), X is CR2and Y is S, and the compound has the structural formula:

[0055] In certain embodiments of (IB), X is CR2and Y is O, and the compound has the structural formula:

[0056] In certain embodiments of (IB), X is CR2and Y is NR4, and the compound has the structural formula:

[0057] In certain embodiments of (IB), X is N and Y is S, and the compound has the structural formula.

[0058] In certain embodiments of (IB), X is N and Y is O, and the compound has the structural formula:

[0059] In certain embodiments of (IB), X is N and Y is NR4’, and the compound has the structural formula:

[0060] In certain embodiments of (IB), X is S and Y is CR4, and the compound has the structural formula:

[0061] In certain embodiments of (IB), X is S and Y is N, and the compound has the structural formula:

[0062] In certain embodiments of (IB), X is O and Y is CR4, and the compound has the structural formula:

[0063] In certain embodiments of (IB), X is O and Y is N, and the compound has the structural formula:

[0064] In certain embodiments of (IB), X is NR2and Y is CR4, and the compound has the structural formula:

[0065] In certain embodiments of (IB), X is NR2and Y is N, and the compound has the structural formula:

[0066] In certain embodiments of (IB)-(IN), R3is a substituted or unsubstituted C1-C6alkyl.

[0067] In certain embodiments of (IB)-(IN), R3is a substituted or unsubstituted C1-C4alkyl.

[0068] In certain embodiments of (IB)-(IN), R3is C1-C4alkyl substituted with 1-3 halogen.

[0069] In certain embodiments of (IA), Q is N, X is NR2and Y is CR4, and the compound has the structural formula:whereinR2is H or C1-6alkyl, wherein said alkyl is optionally substituted, andR4is H, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, or C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted.

[0070] In certain embodiments of (I)-(I°), R1is OR,A.

[0071] In certain embodiments, R1Ais substituted or unsubstituted 6-membered aryl or heteroaryl.

[0072] In certain embodiments of (IA)-(I°), R2if present is a substituted or unsubstituted Ci- C6alkyl.

[0073] In certain embodiments of (IA)-(I°), R2is a substituted or unsubstituted C1-C3alkyl.

[0074] In certain embodiments of (IA)-(I°), R2is C1-C2alkyl substituted with 1-3 halogen.

[0075] In certain embodiments of (I)-(I°), Z is Z1.

[0076] In certain embodiments of (I)-(I°), Z is Z2.

[0077] In certain embodiments of (I)-(I°), R5is H.

[0078] In certain embodiments of (I)-(I°), W is CRR6. In certain embodiments, R is H.

[0079] In certain embodiments, R6is a C1-C6alkyl.

[0080] In certain embodiments, R6is a C3-C6carbocyclic.

[0081] In certain embodiments, R6is cyclopropyl.

[0082] In certain embodiments of (I)-(I°), U is O and Z is:Z1having the structure of:Z2having the structure of:

[0083] In certain embodiments of (IIA) / (IIIA), V is R9and Z is:Z1having the structure of:Z2having the structure of:

[0084] In certain embodiments of (I)-(I°), U is NRNand Z is:Z1having the structure of:Z2having the structure of:

[0085] In certain embodiments of (IIC) and (IIIC), the compound is characterized by the chirality of:

[0086] In certain embodiments of (IIC) and (IIIC), the compound is characterized by the chirality of:

[0087] In certain embodiments of (IIC) and (nic), V is R9.

[0088] In certain embodiments of (IIC) and (nic), RNis H and Z is:Z1having the structure of:Z2having the structure of:

[0089] In certain embodiments of (II)-(IIC) and (III)-(IIIC), R7and R8are in a trans configuration:

[0090] In certain embodiments of (II)-(IIC) and (III)-(IIIC), R7and R8are in a cis configuration:

[0091] In certain embodiments of (I)-(I°), (II)-(IIC) and (III)-(IIIC), R7is H.

[0092] In certain embodiments of (I)-(I°), (II)-(IIC) and (III)-(IIIC), R8is H.

[0093] In certain embodiments of (I)-(I°), (II)-(IIC) and (III)-(IIIC), R9is C1-C6alkyl.

[0094] In certain embodiments of (I)-(I°), (II)-(IIC) and (III)-(IIIC), R9is methyl.

[0095] In another aspect, the invention generally relates to a compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4’ is H or optionally substituted ( C1-6alkylR5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0096] 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, whereinY is S, O or NR4;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4’ is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl,R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or Ci-Ce carbocyclic or C2-C5heterocyclic.

[0097] 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 S, O or NR2';R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2’ is H or optionally substituted C: alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[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, whereinX is S, O or NR2;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2’ is H or optionally substituted C1-6alkylR5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.29

[0099] 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, whereinR1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic arid heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0100] 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, whereinR1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H, Ct 6 alkyd, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyd;R8is H, D, or unsubstituted or substituted C1-C6alkyd; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0101] 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, whereinY is S, O or NR4;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4’ is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[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, whereinY is S, O or NR4;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R?is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[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,whereinY is S, O or NR4;RNis H or unsubstituted or substituted C1-3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R?is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0104] 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, whereinY is S, O or NR4;RNis H or unsubstituted or substituted C1-3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0105] 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 S, O or NR2';RNis H or unsubstituted or substituted C1-3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0106] 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 S, O or NR2;RNis H or unsubstituted or substituted C1-3alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0107] 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, whereinRNis H or unsubstituted or substituted C1-3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0108] 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, whereinRNis H or unsubstituted or substituted C1-3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H, C1-6alkyl, CN, OR, NRR’, NRC(0)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0109] 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, whereinY is S, O or NR4;RNis H or unsubstituted or substituted C1-3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0110] In yet another aspect, the invention generally relates to a compound having the structural formula:(IVp) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4;RNis H or unsubstituted or substituted C1-3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, Ce- C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

[0111] In certain embodiments of (IVI)-(IVP) RNis H.

[0112] In certain embodiments of (IVI)-(IVP) RNis CH3.

[0113] In certain embodiments of (IVG)-(IVH) and (IV°)-(IVP), Y is S.

[0114] In certain embodiments of (IVG)-(IVH) and (IV°)-(IVP), Y is O.

[0115] In certain embodiments of (IVA)-(IVP), each of R5is H.

[0116] In certain embodiments of (IVA)-(IVP), each of R7and R8is H.

[0117] In certain embodiments of (IVA)-(IVP), R9is methyl.

[0118] In certain embodiments of (IVA)-(IVP), R6is a substituted or unsubstituted C3-C6carbocyclic.

[0119] In certain embodiments of (IVA)-(IVP), R6is cyclopropyl.

[0120] In certain embodiments of (IVA)-(IVP), R1is substituted or unsubstituted C()aryl.

[0121] In certain embodiments of (IVA)-(IVP), R1is substituted or unsubstituted C2-C5heteroaryl.

[0122] In certain embodiments of (IVA)-(IVP), R2is a substituted or unsubstituted C1-C6alkyl.

[0123] In certain embodiments of (IVA)-(IVP), R2is a halogen.

[0124] In certain embodiments of (IVA)-(IVP), R3is C1-C4 alkyl substituted with 1-5 halogen.

[0125] Non-limiting examples of compounds of the invention include those listed in Table 1.

[0126] In certain embodiments, a compound disclosed herein has one or more deuterium atoms in place of hydrogen.

[0127] In certain embodiments, the compound has one deuterium atom in place of a hydrogen atom.

[0128] 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.

[0129] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0130] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0131] In certain embodiments, is in the form of a tablet. In certain embodiments, is in the form of a capsule.

[0132] 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.

[0133] 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.

[0134] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

[0135] In yet another aspect, the invention generally relates to a method for making a compound disclosed herein.

[0136] Compounds of the invention include deuterated versions of the disclosed compounds, for example, having one or more deuterium atoms in place of hydrogen.

[0137] 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.

[0138] 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.

[0139] 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 atransdermal 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).

[0140] 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.

[0141] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[0142] 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, isopropylalcohol, 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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 powderedcompound 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] Methods of treatment disclosed herein may be employed in combination with or in addition to other therapies. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0161] 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.

[0162] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and 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); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; 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, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), andTAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0163] Examples of the second (or further) agent or therapy may include, but are not limited to, immunotherapies (e.g. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonist, cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab and the like), mitosis inhibitors (e.g., paclitaxel, vincristine, vinblastine and the like), alkylating agents (e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and the like), anti -metabolites (e.g., methotrexate, 5-FU and the like), intercalating anticancer agents, (e.g., actinomycin, anthracycline, bleomycin, mitomycin-C and the like), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide and the like), immunotherapy agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0164] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including c / s- and trans-\ somers, R- and 5-enanti omers, 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.

[0165] 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.

[0166] 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.

[0167] 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,35S,18F, and36C1, respectively.

[0168] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritiated (3H) and carbon- 14 (14C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[0169] Further, substitution of normally abundant hydrogen (1H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. Benefits may also be obtained from replacement of normally abundant12C with13C. (See, WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.)

[0170] Stereoisomers (e.g., cis and trans isomers) and all optical isomers of a presently disclosed compound (c.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] Compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps 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

[0179] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0180] 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.AbbreviationsCDC13 deuterated chloroformHz, MHz, hertz, mega hertzHPLC high-performance liquid chromatographyBOC tert-buty I oxy carbonylEtOAc ethyl acetateJ coupling constantK2CO3 potassium carbonateLCMS liquid chromatography mass spectroscopyMeCN acetonitrileMeOH methanolDAST Diethylaminosulfur trifluorideDMSO-d6 hexadeutero dimethyl sulfoxide brine saturated aqueous sodium chlorideHATU Hexafluorophosphate azabenzotriazole tetramethyl uroniumNMR nuclear magnetic resonanceDCM dichloromethaneDIE A N,N-di isopropyl ethyl aminePd(PPh3)4 palladium-tetrakis(triphenylphosphine), H2O WaterPd2(dba)3tris(dibenzylideneacetone)dipalladiumPd(0Ac)2 palladium di acetatePE petroleum etherPMBC1 / ?-methoxy benzyl chlorideRT room temperatureSFC supercritical fluid chromatographyTEA triethyl amineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin-layer chromatographyTSOH p-Toluenesdfonic acidLC-MS Method

[0181] Shimadzu LCMS2020, Reverse-phase column (Shim-Pack Scepter C18, 33 x 3.0 mm, 3um), elution with A: H2O / MeCN / FA = 90 / 10 / 0.05; B: MeCN; Detection: MS, ELS, UV (100 μL split to MS with in-line UV detector); MS ionization method: Electrospray (positive and negative ion). ES-API = electrospray-atmospheric pressure ionization.HPLC Purification Method

[0182] 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. Detection wavelength = 220, 254 nM. Flow rate = 15ml / min-20ml / min; Run time = 8 min; Column temperature = 25 °C, Modifier, TFA, FA and NH4OH. Spectroscopy

[0183] NMR spectra were run with Bruker Ultrashield TM400 (400 MHz), Bruker UltrashieldTM400 Plus (400 MHz), Bruker UltrashieldTM600 (600 MHz) and Bruker AscendTM400 (400 MHz) 15 spectrometers, all with and without tetramethylsilane as an internal standard. Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (.7) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (single), d (double), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), br (broad).Synthesis of intermediate:(S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine 4-methylbenzenesulfonic acid

[0184] Step A: To a solution of tert-butyl (S)-(l-cyclopropyl-2-hydroxyethyl)carbamate (1.7 g, 8.4 mmol) in DCM (25 mL) was added Dess-Martin periodinane (7.2 g, 16.9 mmol). The reaction was stirred at 25 °C for 2 hours under N2 atmosphere. The reaction was diluted with icewater, extracted with DCM (40 mL x 3), The organic layer was separated, washed with sat. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluted with 0-10% ethyl acetate in petroleum ether to afford tertbutyl (S)-(l-cyclopropyl-2-oxoethyl)carbamate, 1-1 (1.2 g, 71%) as a colorless oil.

[0185] Step B: To a solution of 1-1 (1.2 g, 6.0 mmol) in THF (15 mL) was added diethyl [(methyldioxo-λ6-sulfanyl)methyl]phosphonate (1.25 g, 5.4 mmol) and K2CO3(2.5 g, 18.0 mmol). The reaction was stirred at 60 °C for 3 hours under N2atmosphere. The reaction was diluted with ice-water, extracted with EtOAc (20 mL x 3) The organic layer was separated, washed with brine and concentrated. The residue was purified by flash column chromatography eluted with 0-25% ethyl acetate in petroleum ether to afford tert-butyl (S,E)-(l-cyclopropyl-3- (methylsulfonyl)allyl)carbamate, 1-2 (1.2 g, 72%) as a white solid.LCMS (ESI): m / z 276 [M+H]+. 1H NMR (400 MHz, CDC13) δ 6.93 (dd, J = 15.2, 4.8 Hz, 1H), 6.52 (dd, J = 15.2, 1.6 Hz, 1H), 4.75 (brs, 1H), 3.68 (brs, 1H), 2.95 (s, 3H), 1.45 (s, 9H), 0.95 - 0.82 (m, 1H), 0.70 - 0.55 (m, 2H), 0.49 - 0.29 (m, 2H).

[0186] Step C: To a solution of 1-2 (70 mg, 0.254 mmol) in MeCN (6 mL) was added TsOH (52 mg, 0.305 mmol). The reaction was stirred at 60 °C for 3 hours under N2 atmosphere. The reaction was concentrated to afford (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine 4- methylbenzenesulfonic acid, 1-3 (50 mg, 56%) as a white solid which was used directly for next step without purification. LCMS (ESI): m / z 176 [M+H]+(S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide:

[0187] Step A: To a stirred mixture of 5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxylic acid (200 mg, 0.7 mmol) in DCM (10 mL) was added HATU (401 mg, 1.1 mmol), DIEA (453 mg, 3.5 mmol) and (S)-2-amino-2-cyclopropylethan-l-ol (106 mg, 1.1 mmol). The reaction was stirred at 25°C for 1 hour under nitrogen. The reaction was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford (S)- N-(l-cyclopropyl-2-hydroxyethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (200 mg, 77%). LCMS (ESI): m / z 368 [M+H]+.

[0188] Step B: To a mixture of (S)-N-(l-cyclopropyl-2-hydroxyethyl)-5-(l,l-difluoroethyl)- 3-phenoxythiophene-2-carboxamide (150 mg, 0.41 mmol) in DCM (5 mL) was added Dessmartin periodinane (346 mg, 0.82 mmol) at 0 °C. The result reaction mixture was stirred at 25°C for 1 hour. The reaction was diluted with DCM and water. The organic layer was separated, w washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (100 mg, 67%). LCMS (ESI): m / z 366 [M+H]+.Synthesis of Examples:Example 1: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenoxythiazole-5-carboxamid

[0189] Step A: A mixture of ethyl 4-bromothiazole-5-carboxylate (5 g, 21.2 mmol), CS2CO3 (7.0 g, 21.2 mmol) and Phenol (3.0 g, 31.8 mmol) in NMP (20 mL) was stirred at 120 °C for 2 hours. The cooled mixture was poured into ice-water (50 mL), The mixture was extracted with EtOAc (40 mL x 3). The combined organic phase was washed with brine, dried over , Na2SO4filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography (0 ~ 20% EtOAc in PE) to afford ethyl 4-phenoxythiazole-5-carboxylate (1 g, 19%) as a white solid. LCMS (ESI): m / z 250 [M+H]+

[0190] Step B: To a solution of ethyl 4-phenoxythiazole-5-carboxylate (1 g, 4.01 mmol), FeSO4.7H2O (16.7 g, 60 mmol) and 40% acetaldehyde (13.22 g, 120 mmol) in 4 M H2SO4(10 ml) was added 70% tert-butyl hydroperoxide (12 ml, 120 mmol) at 0°C. The result mixture was stirred at 25 °C for 16 hours. The mixture was poured into ice-water (50 mL), The mixture was extracted with EtOAc (40 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography (0 ~ 20% EtOAc in PE) to afford ethyl 2-acetyl-4-phenoxythiazole-5- carboxylate (100 mg, 9%) as a white solid. LCMS (ESI): m / z 292 [M+H]+

[0191] Step C: To a solution of ethyl 2-acetyl-4-phenoxythiazole-5-carboxylate (100 mg, 0.34 mmol) in DCM (5 mL) was added DAST (553 mg, 3.43 mmol). The mixture was stirred at 25 °C for 16 hours. The mixture was poured into ice-water (10 mL), extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to afford ethyl 2-(l,l-difluoroethyl)-4-phenoxythiazole-5-carboxylate (80 mg, 74%) as a white solid which was used directly for the next step without purification. LCMS (ESI): m / z 314 [M+H]+

[0192] Step D: To a solution of ethyl 2-(l,l-difluoroethyl)-4-phenoxythiazole-5-carboxylate (80 mg, 0.255 mmol) in H2O / THF (3mL / 3mL) was added LiOH (23 mg, 0.55 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice water and adjusted pH = 5~6 with 2N HC1. The mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over Na2SO4.fi Itered and concentrated to concentrated to afford 2-(l, 1- difhioroethyl)-4-phenoxythiazole-5-carboxylic acid (60 mg, 82%) as a white solid which was used directly for next step without purification. LCMS (ESI): m / z 286 [M+H]+

[0193] Step E: To a solution of 2-(l, l-difluoroethyl)-4-phenoxythiazole-5-carboxylic acid (60 mg, 0.21 mmol), (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l -amine (55 mg, 0.32 mmol), HATU (120 mg, 0.31 mmol) in DCM (10 mL) was added DIEA (150 mg, 1.16 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice-water (10 mL), extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4. filtered and concentrated. The residue was purified by reverse phase purification (C18, MeCN / H2O, 0.1% ammonium bicarbonate modifier, 0 to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (S,E)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4-phenoxythiazole-5-carboxamide, (18.9 mg, 20%) as a white solid. LCMS (ESI): m / z 443[M+H]+.1H NMR(400 MHz, DMSO-d6 ) δ 8.33 (d, J = 8.4 Hz, 1H), 7.44 (dd, J= 10.4, 5.6 Hz, 2H), 7.24 (dd, J= 7.6, 5.6 Hz, 3H), 6.90 - 6.78 (m, 2H), 4.04 (td, J= 8.8, 4.4 Hz, 1H), 2.99 (s, 3H), 2.01 (t, J= 19.2 Hz, 3H), 1.26 - 1.16 (m, 1H), 0.60- 0.50 (m, 1H), 0.50 - 0.36 (m, 2H), 0.35 - 0.25 (m, 1H).Example 2: N-[(lS,2E)-l-cyclopropyl-3-(methyldioxo-k6-sulfanyl)prop-2-enyl]-2-(l,l- difluoroethyl)-5-(phenyloxy)-l,3-thiazole-4-carboxamide

[0194] Step A: To a suspension of NaH (190 mg, 4.64 mmol, 60% dispersion in mineral oil) in anhydrous THF (10 mL) was added phenol (395 mg, 4.2 mmol) in THF (3 mL) dropwise under nitrogen at 0 °C. The white suspension was stirred at 25 °C for 0.5 hour, then ethyl 2- amino-5-bromo-l,3-thiazole-4-carboxylate (1 g, 4.2 mmol) in THF (8 mL) was slowly added. The resulting solution was stirred at 25 °C for 2 hours. The reaction was poured into ice-water, extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4, fdtered and concentrated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford ethyl 2- amino-5-(phenyloxy)-l,3-thiazole-4-carboxylate (360 mg, 34%) as a yellow solid. LCMS: 265.1 [M+H]+.

[0195] Step B: To a solution of tert-butyl nitrite (281 mg, 2.7 mmol) in ACN (5 mL) was added CuBr (390 mg, 2.7 mmol). The reaction mixture was stirred at 60 °C for 5 min. Then ethyl 2-amino-5-(phenyloxy)-l,3-thiazole-4-carboxylate (360 mg, 1.36 mmol) in ACN (5 mL) was slowly added and stirred at 60 °C for 0.5 hour. The cooled reaction solution was diluted H2O, extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography to afford ethyl 2-bromo-5-(phenyloxy)-l,3-thiazole-4-carboxylate (360 mg, 80%) as a yellow solid. LCMS: ESI m / z 328.0 [M + H]+.

[0196] Step C: To a mixture of ethyl 2-bromo-5-(phenyloxy)-l,3-thiazole-4- carboxylate (360 mg, 1.1 mmol) and tributyl(l -ethoxy vinyl)-L4-stannane (594 mg, 1.6 mmol) in anhydrous 1,4-dioxane (6 mL) was added Pd(dppf)C12 (80 mg, 0.110 mmol). The reactionmixture was purged with nitrogen for three times, then heated to 100 °C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was quenched with KF solution and extracted with EtOAc three times. The combined extracts were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluted with a gradient of 0-10% EtOAc in petroleum ether to afford ethyl 2-(l-ethoxyvinyl)-5-phenoxythiazole-4-carboxylate (190 mg) as a yellow solid. The yellow solid was dissolved in THF (6 mL), 2N HC1 solution (6 mL) was added into the solution and stirred at room temperature for 1 hour. The mixture was neutralized with NaHCO3solution, extracted with EtOAc twice, the combined extracts were dried over anhydrous Na2SO4, 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 ethyl 2- acetyl-5-(phenyloxy)-l,3-thiazole-4-carboxylate (150 mg, 47%) as a yellow solid LCMS: ESI m / z 292.1 [M + H]+.

[0197] Step D: To a solution of ethyl 2-acetyl-5-(phenyloxy)-l,3-thiazole-4- carboxylate (130 mg, 0.446 mmol) in DCM (4 mL) was added DAST (2 mL). The reaction mixture was stirred at 50 °C under N2 for 16 h. The reaction mixture was poured into ice-water then extracted with DCM, washed with brine, dried over anhydrous Na2SO4, concentrated in vacuum and the residue was purified by flash chromatography to afford ethyl 2-(l , 1 - difluoroethyl)-5-(phenyloxy)-l,3-thiazole-4-carboxylate (130 mg, 93%) as a yellow solid. LCMS: ESI m / z 314.1 [M + H]+.

[0198] Step E: To a solution of ethyl 2-(l,l-difluoroethyl)-5-(phenyloxy)-l,3-thiazole-4- carboxylate (150 mg, 0.48 mmol) in MeOH (3 mL) and (3 mL) aHt22O5 °C was added hydroxylithium hydrate (40 mg, 0.96 mmol). The mixture was stirred at 60 °C for 3 h. Then the MeOH was removed under reduced pressure. The mixture was acidified with 1 N HCI to pH = 4 and extracted with EtOAc. The organic layer was then separated, dried over Na2SO4and concentrated to afford 2-(l,l-difluoroethyl)-5-(phenyloxy)-l,3-thiazole-4-carboxylic acid (130 mg, 0.456 mmol, 95%) as a white solid which was used directly for next step without purification. LCMS: ESI m / z 286.1 [M + H]+.

[0199] Step F: To a solution of 2-(l,l-difluoroethyl)-5-(phenyloxy)-l,3-thiazole-4- carboxylic acid (20 mg, 0.07 mmol) in DCM (2 mL), was added HATU (40 mg, 0.11 mmol), DIEA (27 mg, 0.21 mmol) and (lS,2E)-l-cyclopropyl-3-(methyldioxo-λ6-sulfanyl)prop-2-en-l-amine (15 mg, 0.08 mmol). The reaction mixture was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated to give a residue. The residue was purified by pre-HPLC to give N-[(lS,2E)-l-cyclopropyl-3-(methyldioxo-k6-sulfanyl)prop-2-enyl]-2-(l,l- difluoroethyl)-5-(phenyloxy)-l,3-thiazole-4-carboxamide (22 mg, 71%) as a colorless oil. LCMS: ESI m / z 443.1 [M + H]+. 1H NMR (400 MHz, DMSO-d 6) δ 8.65 (d, J= 8.8 Hz, 1H), 7A7 (dd, J= 9.6, 6.4 Hz, 2H), 7.33-7.22 (m, 3H), 6.94 - 6.70 (m, 2H), 4.04 - 3.89 (m, 1H), 3.02 (s, 3H), 2.17 (t, J= 19.2 Hz, 3H), 1.38-1.22 (m, 1H), 0.64 - 0.45 (m, 2H), 0.43 - 0.25 (m, 2H).Example 3: (S,E)-N-(l-cydopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoro-2- methylpropyl)-4-phenoxythiazole-5-carboxamide

[0200] Step A: To a solution of ethyl 4-phenoxythiazole-5-carboxylate (1.0 g, 4.0 mmol) in H2O (10 mL )and THF (30 mL) was added LiOH (672 mg, 16.0 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice water and adjusted pH = 5~6 by 2 / VHC1. The mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated to afford 4-phenoxythiazole-5- carboxylic acid (800 mg, 90%), which was used directly used for next step. LCMS (ESI): m / z 222 [M+H]+

[0201] Step B: A To a solution of 4-phenoxythiazole-5-carboxylic acid (200 mg, 0.9 mmol), in THFF (10 ml) was added n-BuLi (1 ml, 1.0 mmol, 1.0 m in hexane) dropwise at -70 °C. The mixture was stirred at -50 °C for 1 hours, then isobutyryl chloride (212 mg, 2.0 mmol) was slowly added. The resulting solution was stirred at -40 °C for 1 hours. The reaction mixture was quenched with sat. NH4C1 solution, extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0-40% EtOAc in petroleum ether to afford 2-isobutyiyl-4-phenoxythiazole-5-carboxylic acid (80 mg, 30%). LCMS (ESI): m / z 292 [M+H]+

[0202] Step C: To a solution of 2-isobutyryl-4-phenoxythiazole-5-carboxylic acid (40 mg, 0.137 mmol), (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l -amine (30 mg, 0.171 mmol),HATU (49 mg, 0.130 mmol) in DCM (5 mL) was added DIEA (65 mg, 0.5 mmol). The mixture was stirred at 25 °C for 2 hours. The cooled reaction solution was diluted with , extracted H2O with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by purified by silica gel flash chromatography, eluted with a gradient of 0-40% EtOAc in petroleum ether to afford (S,E)-N- (l-cyclopropyl-3-(methylsulfonyl)allyl)-2-isobutyiyl-4-phenoxythiazole-5-carboxamide (40 mg, 65%). LCMS (ESI): m / z 449 [M+H]+

[0203] Step D: To a solution of (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2- isobutyryl-4-phenoxythiazole-5-carboxamide (40 mg, 0.089 mmol) in DCM (5 mL) was added , DAST (553 mg, 3.4 mmol). The mixture was stirred at 25 °C for 16 hours. The mixture was poured into ice-water, extracted with DCM (10 mL x 3). The organic phase was washed with sat. NaHCO3solution and brine, dried over Na2SO4and filtered. The filtrate was concentrated. The residue was purified by reverse phase purification (C18, MeCN / H2O, 0.1% ammonium bicarbonate modifier, 0 to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoro-2-methylpropyl)-4-phenoxythiazole-5-carboxamide (26 mg, 60%). LCMS (ESI): m / z 471[M+H]+.1HNMR(400 MHz, MeOD-t / 4) 5 7.43 (t, J= 8.0 Hz, 2H), 7.28 - 7.16 (m, 3H), 6.95 (dd, J= 15.2, 5.2 Hz, 1H), 6.74 (dd, J= 15.2, 1.6 Hz, 1H), 4.10-4.04 (m, , 1H), 2.95 (s, 3H), 2.62 - 2.47 (m, 1H), 1.23 - 1.15 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H), 0.72 - 0.64 (m, 1H), 0.61 - 0.54 (m, 1H), 0.48 - 0.38 (m, 2H).Example 4: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-4- phenoxythiazole-5-carboxamideExample 4

[0204] Step A: To a solution of 4-phenoxythiazole-5-carboxylic acid (200 mg, 0.9 mmol) in THF (10 ml) was added n-BuLi (1 ml, 1.0 mmol, 1M in hexane) dropwise at -70 °C. The resulting mixture was stirred at -50 °C for 1 hours, then propionyl chloride (184 mg, 2.0 mmol) was slowly added. The resulting solution was stirred at -50 °C for another 1 hours. The reaction mixture was quenched with sat. NH4C1 solution, extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0-40% EtOAc in petroleum ether to afford 4-phenoxy-2-propionylthiazole-5-carboxylic acid (80 mg, 32%). LCMS (ESI): m / z 278 [M+H]+

[0205] Step B: To a mixture of 4-phenoxy-2-propionylthiazole-5-carboxylic acid (80 mg, 0.29 mmol) and K2CO3(79 mg, 0.57 mmol) in DMF (5 mL) was added CH3I (81 mg, 0.57 mmol). The mixture was stirred at 25 °C for 1 hours. The mixture was poured into water, extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by c silica gel flash chromatography, eluted with a gradient of 0 - 10% EtOAc in petroleum ether to afford methyl 4-phenoxy-2- propionylthiazole-5-carboxylate (40 mg, 48%). LCMS (ESI): m / z 292 [M+H]+

[0206] Step C: To a solution of 4-phenoxy-2-propionylthiazole-5-carboxylate (40 mg, 0.137 mmol) in DCM (5 mL) was added DAST (553 mg, 3.433 mmol). The resulting mixture was stirred at 25 °C for 16 hours. The mixture was poured into ice-water, extracted with DCM (10 mL x 3). The organic phase was washed with sat. NaHCO3solution and brine, dried over Na2SO4and filtered. The filtrate was concentrated to afford methyl 2-(l,l-difluoropropyl)-4-phenoxythiazole-5-carboxylate (30 mg, 70%) which was used directly for next step. LCMS (ESI): m / z 314 [M+H]+

[0207] Step D: To a solution of methyl 2-(l,l-difluoropropyl)-4-phenoxythiazole-5- carboxylate (30 mg, 0.095 mmol) in (3mLH)2aOnd THF (3mL) was added LiOH (16 mg, 0.38 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was was diluted with ice-water and adjusted pH = 5~6 by 2N HC1. The mixture was extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated to afford 2-(l,l-difluoropropyl)-4-phenoxythiazole-5-carboxylic acid (25 mg, 88%). LCMS (ESI): m / z 300 [M+H]+

[0208] Step E: To a mixture of 2-(l,l-difluoropropyl)-4-phenoxythiazole-5-carboxylic acid (25 mg, 0.083 mmol), (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (30 mg, 0.171 mmol), HATU (49 mg, 0.130 mmol) in DCM (5 mL) was added DIEA (65 mg, 0.5 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to give a residue. The residue was purified by The reaction mixture was purified by reverse phase purification (Cl 8, MeCN / H2O, 0.1% ammonium bicarbonate modifier, 0 to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (S,E)-N-(1- cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-4-phenoxythiazole-5-carboxamide (25 mg, 65%). LCMS (ESI): m / z 457[M+H]+’HNMR(400 MHz, MeOD-d4 ) δ 7.47 - 7.39 (m, 2H), 7.29 - 7.16 (m, 3H), 6.95 (dd, J= 15.2, 5.2 Hz, 1H), 6.73 (dd, J= 15.2, 1.6 Hz, 1H), 4.10- 4.04 (m, 1H), 2.95 (s, 3H), 2.35 - 2.19 (m, 2H), 1.24 - 1.14 (m, 1H), 1.00 (t, J= 7.6 Hz, 3H), 0.72 - 0.65 (m, 1H), 0.61 - 0.54 (m, 1H), 0.49 - 0.38 (m, 2H).Example 5: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)- 4-phenoxythiazole-5-carboxamideExample 5

[0209] Step A: To a solution of ethyl 4-phenoxythiazole-5-carboxylate (1 g, 4.0 mmol), FeSO4 7H2O (16.7 g, 60 mmol), Cyclopropanecarboxaldehyde (8.4 g, 120 mmol), in 4 M H2SO4(10 ml) was added 70% tert-butyl hydroperoxide (12 ml, 120 mmol) at 0°C. The mixture was stirred at 25 °C for 16 hours. The mixture was poured into ice-water, extracted with EtOAc (100 mL x 3). The organic phase was washed with brine, dried over Na2SO4and concentrated. The product was purified by column chromatography (silica gel, 20 g, 0 ~ 20% EtOAc in PE) to afford ethyl 2-(cyclopropanecarbonyl)-4-phenoxythiazole-5-carboxylate (100 mg, 9%) as a white solid. LCMS (ESI): m / z 318 [M+H]+

[0210] Step B: A solution of ethyl 2-(cyclopropanecarbonyl)-4-phenoxythiazole-5- carboxylate (100 mg, 0.343 mmol), DAST (553 mg, 3.433 mmol) in DCM (5 mL) was stirred at 25 °C for 16 hours. The mixture was poured into ice-water, extracted with DCM (20 mL x 3). The organic phase washed with Sat. NaHCOs and brine, dried over Na2SO4and concentrated. The crude product was purified by column chromatography (silica gel, 20 g, 0 ~ 20% EtOAc in PE) to afford ethyl 2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5-carboxylate (80 mg, 74%) as a white solid. LCMS (ESI): m / z 340 [M+H]+

[0211] Step C: To a solution of ethyl 2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5- carboxylate (80 mg, 0.26 mmol) in / THFH (23OmL / 3mL) was added LiOH (23 mg, 0.55 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice water and adjusted pH = 5-6 by 2AHC1. The mixture was extracted with EtOAc (50 mL x 3). The organic phase was dried over Na2SO4and concentrated to afford 2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5-carboxylic acid (60 mg, 82%) as a white solid which was used directly for next step without purification. LCMS (ESI): m / z 312 [M+H]+

[0212] Step D: To a solution of 2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5- carboxylic acid (60 mg, 0.210 mmol), (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (55 mg, 0.315 mmol), HATU (49 mg, 0.130 mmol) in DCM (10 mL) was added DIEA (150 mg, 1.163 mmol). The mixture was stirred at 25 °C for 2 hours, extracted with DCM (50 mL x 3). The organic phase was washed with brine, dried over Na2SO4and concentrated. The reaction mixture was purified by reverse phase purification (C18, MeCN / H2O, 0.1% ammonium bicarbonate modifier, 0 to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2- (cyclopropyldifluoromethyl)-4-phenoxythiazole-5-carboxamide, (25 mg, 30%) as a white solid. LCMS (ESI): m / z 469 [M+H]+1H NMR (400 MHz, MeOD-d4 ) δ 7.43 (t, J = 8.0 Hz, 2H), 7.29 - 7.18 (m, 3H), 6.95 (dd, J = 15.2, 5.2 Hz, 1H), 6.73 (dd, J = 15.2, 1.6 Hz, 1H), 4.10-4.02 (m, 1H), 2.95 (s, 3H), 1.77-1.70 (m, 1H), 1.25 - 1.12 (m, 1H), 0.76 - 0.65 (m, 5H), 0.61 - 0.54 (m, 1H), 0.48 - 0.38 (m, 2H).Example 6: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide

[0213] Step A: A mixture of tert-Butyl nitrite (4.36 g, 42.4 mmol) and Cui (8.00 g, 42.36 mmol) in MeCN (20 mL) was stirred at 0 °C for 5 minutes. Then added methyl 3-amino-5- bromothiophene-2-carboxylate (5 g, 21.18 mmol) in MeCN (20 mL) at 0 °C. The result reaction was warmed to 50 °C and stirred at 50 °C overnight. The reaction mixture was poured into water,extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% ethyl acetate in petroleum ether to afford methyl 5-bromo-3-iodothiophene-2-carboxylate (4 g, 11.53 mmol, 54%) as a yellow solid. No Ms.

[0214] Step B: To a mixture of methyl 5-bromo-3-iodothiophene-2-carboxylate (2 g, 5.76 mmol), phenol (650 mg, 6.92 mmol), CS2CO3(2.82 g, 8.65 mmol) in toluene (30 mL) was added CuI (1.10 g, 5.76 mmol). The reaction mixture was purged with nitrogen three times, then heated to 120 °C overnight under nitrogen. The cooled mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 1% EtOAc in petroleum ether. The desired fractions were evaporated to dryness to afford methyl 5-bromo-3- (phenyloxy)thiophene-2-carboxylate (260 mg, 0.83 mmol, 14%) as a colorless solid. LCMS: ESI m / z 313 / 315[M+H]+. 1H NMR (400 MHz, DMSO-d 6) δ 7.44 - 7.39 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.08 (dd, J= 8.8, 0.8 Hz, 2H), 7.02 (s, 1H), 3.73 (s, 3H).

[0215] Step C: To a solution of methyl 5-bromo-3-(phenyloxy)thiophene-2-carboxylate (260 mg, 0.83 mmol) and tributyl(l -ethoxy vinyl)-X4-stannane (389 mg, 1.08 mmol) in DMF (5 mL) was added Pd(PPh3)4(95 mg, 0.08 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 2 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with potassium fluoride solution, and the organic layer was separated. Then added 10 mL 6M HC1. The mixture was stirred at room temperature for 5 minutes and washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to afford methyl 5-acetyl3-(phenyloxy)thiophene-2-carboxylate (105 mg, 0.38 mmol, 45%) as a yellow solid. LCMS (ESI): m / z 277[M + H]+.

[0216] Step D: A solution of methyl 5-acetyl-3-(phenyloxy)thiophene-2-carboxylate (105 mg, 0.38 mmol) in DAST (2 mL, 15.14 mmol) was stirred at 50 °C for 18 hours. The reaction mixture was dissolved in EtOAc, washed with and NaH2CO3, dried over anhydrous Na2SO4and concentrated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0~5% ethyl acetate in petroleum ether to afford methyl 5-(l,l-difluoroethyl)-3- (phenyloxy)thiophene-2-carboxylate (80 mg, 0.27 mmol, 70%) as a yellow solid. LCMS (ESI):m / z 299 [M+H]+. 1H NMR (400 MHz, DMSO-d 6) 5 7.42 (t, J= 8.0 Hz, 2H), 7.20 (d, J = 9.6 Hz, 2H), 7.07 (d, J= 7.6 Hz, 2H), 3.77 (s, 3H), 2.05 (t, J= 18.8 Hz, 3H).

[0217] Step E: To a flask containing methyl 5-(l,l-difluoroethyl)-3-(phenyloxy)thiophene- 2-carboxylate (80 mg, 0.27 mmol) in MeOH (2.00 mL) and (0.70 mLH) w2Oas added LiOH (33.7 mg, 0.80 mmol) at room temperature. The reaction was stirred at 50 °C for 0.5 hour. The reaction was monitored by analysis of LCMS. The mixture was poured into a stirred solution of HC1 solution, extracted with EtOAc twice. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated to afford crude 5-(l,l-difluoroethyl)-3-(phenyloxy)thiophene-2- carboxylic acid (75 mg, 0.26 mmol, 98%) as a yellow solid. LCMS: ESI m / z 285[M+H]+.

[0218] Step F: To a solution of 5-(l,l-difluoroethyl)-3-(phenyloxy)thiophene-2-carboxylic acid (40 mg, 0.14 mmol) in DCM (5 mL) was added (lS,2E)-l-cyclopropyl-3-(methyldioxo-λ6- sulfanyl)prop-2-en-l -amine hydrobromide (36.0 mg, 0.14 mmol), DIEA (54 mg, 0.42 mmol) and HATU (80.2 mg, 0.21 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated and the crude product was purified by reverse phase chromatography (C18, MeCN / H2O, 0.1% formic acid modifier, 5% to 95% gradient, 15 min run) to afford (S,E)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (29 mg, 0.07 mmol, 46%) as a white solid. LCMS (ESI): m / z 442[M + H]+. 1HNMR (400 MHz, DMSO-d 6) δ 8.08 (d, J= 8.4 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.24 (t, J= 7.2 Hz, 1H), 7.20 (d, J= 7.6 Hz, 2H), 7.16 (s, 1H), 6.88 - 6.81 (m, 1H), 6.77 - 6.72 (m, 1H), 4.07 - 4.00 (m, 1H), 2.96 (s, 3H), 2.05 (t, J= 19.2 Hz, 3H), 1.21 - 1.13 (m, 1H), 0.56 - 0.49 (m, 1H), 0.44 - 0.35 (m, 2H), 0.29 - 0.23 (m, 1H).Example 7: (S,E)-4-bromo-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)- 3-phenoxythiophene-2-carboxamide

[0219] Step A: To a mixture of methyl 4,5-dibromo-3-hydroxythiophene-2-carboxylate (1.0 g, 3.2 mmol) in DCE (30 mL) was added phenylboronic acid (1.9 g, 15 mmol), cupric bis(acetate) (860 mg, 4.8 mmol) and pyridine (640 mg, 7.9 mmol). The reaction mixture was purged with oxygen three times, then heated to 20 °C overnight under oxygen. 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 dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluted with a gradient of 0 to 2% EtOAc in petroleum ether. The desired fractions were evaporated to dryness to afford methyl 4,5-dibromo-3- (phenyloxy)thiophene-2-carboxylate (500 mg, 40%) as a yellow solid. LCMS (ESI): m / z 393 [M+H]+.

[0220] Step B: To a mixture of methyl 4,5-dibromo-3-(phenyloxy)thiophene-2-carboxylate (230 mg, 0.59 mmol) in DMF (5 mL) was added tributyl(l -ethoxy vinyl)- λ4stannane (190 mg, 0.53 mmol) and Pd(PPh3)4 (70g, 0.06 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C overnight under nitrogen. After cooling to room temperature, the mixture was removed in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% EtOAc in petroleum ether to afford methyl 4- bromo-5-(l-ethoxyvinyl)-3-(phenyloxy)thiophene-2-carboxylate (200 mg, 88%) as a pale yellow solid. LCMS (ESI): m / z 390 [M+H]+.

[0221] Step C: To a solution of methyl 4-bromo-5-(l -ethoxy vinyl)-3- (phenyloxy)thiophene-2-carboxylate in THF (5 mL) was added HC1 (5 mL, 6 M) at room temperature. The reaction was stirred at room temperature for 1 h. The mixture was poured into a stirred solution of brine solution, extracted with EtOAc twice. The combined extracts were driedover anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient 0% to 5% EtOAc in PE. The desired fractions were evaporated to dryness to afford methyl 5-acetyl-4-bromo-3-(phenyloxy)thiophene-2-carboxylate (100 mg, 43.2%)as a pale yellow solid. LCMS (ESI): m / z 355 [M+H]+.

[0222] Step D: A solution of methyl 4-bromo-5-(l-ethoxyvinyl)-3-(phenyloxy)thiophene- 2-carboxylate (80 mg, 0.23 mmol) in DAST (360 mg, 2.3 mmol) at 0 °C and the mixture was stirred at 50 °C for 1 h. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with NaHCO3, and further washed with brine, and two layers were separated. The aqueous layer was extracted with EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient 2% to 10% EtOAc in PE. The desired fractions were evaporated to dryness to afford methyl 4-bromo- 5-(l,l-difluoroethyl)-3-(phenyloxy)thiophene-2-carboxylate (60 mg, 70%) as a pale yellow solid. LCMS (ESI): m / z 377 [M+H]+.

[0223] Step E: To a solution of methyl 4-bromo-5-(l,l-difluoroethyl)-3- (phenyloxy)thiophene-2-carboxylate (90 mg, 0.24 mmol) in THF (2 mL) and (2 mL) was H2O added LiOH (10 mg, 0.24 mmol) . The reaction was stirred at room temperature for 2 hours. The reaction was monitored by analysis of LC-MS. The mixture was neutralized with 2N HC1 to pH= 3~5, extracted with EtOAc twice. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated to afford 4-bromo-5-(l,l-difluoroethyl)-3- (phenyloxy)thiophene-2-carboxylic acid (80 mg, 92 %) as a yellow solid, which was used directly without further purification. LCMS (ESI): m / z 364 [M+H]+.

[0224] Step F: To a stirred mixture of 4-bromo-5-(l,l-difluoroethyl)-3- (phenyloxy)thiophene-2-carboxylic acid (40 mg, 0.11 mmol) in DCM(3 mL), were added (lS,2E)-l-cy cl opropyl-3-(m ethyldi oxo-λ6-sulfanyl)prop-2-en-l -amine (38 mg, 0.22 mmol), HATU (62 mg, 0.17 mmol) and DIEA (42 mg, 0.33 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed with brine, the combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The reaction mixture was purified by reverse phase purification (Cl 8, MeCN / H2O, ammonium bicarbonate modifier, 0 to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized afford 4-bromo-N-[(lS,2E)-l-cyclopropyl-3-(methyldioxo-λ6-sulfanyl)prop-2-enyl]-5-(l,l-difluoroethyl)-3-(phenyloxy)thiophene-2-carboxamide (11.3 mg, 20 %) as a white solid. LCMS (ESI): m / z 520 [M+H]+. 1H NMR (400 MHz, DMSO-tA) 8 8.28 (d, J= 8.0 Hz, 1H), 7.38 (dd, .7 = 8.8, 7.6 Hz, 2H), 7.12 (t, ,7 = 7.2 Hz, 1H), 6.95 (d, J= 8.0 Hz, 2H), 6.71 (dd, .7 = 15.2, 5.2 Hz, 1H), 6.57 (dd, .7 ~ 15.2, 1.2 Hz, 1H), 3.96-3.88 (m, 1H), 2.92 (s, 3H), 2.15 (t, J= 19.2 Hz, 3H), 1.02-0.93 (m, 1H), 0.51-0.41 (m, 1H), 0.35-0.25 (m, 1H), 0.25- 0.17 (m, 1H), 0.05 - -0.00 (m, 1H).Example 8: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-4-methyl- 3-phenoxythiophene-2-carboxamide

[0225] Step A: To a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (5 g, 29.2 mmol) in DCM (20 mL) was added HOAc (20 mL) and Br2 (9.3 g, 58.4 mmol) under nitrogen with stirring. The mixture was stirred at 50 °C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with sat. NaHCO3and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude was purified by reverse phase chromatography (Cl 8, MeCN / TEO, 0.2% formic acid modifier, 20% to 60% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford the to afford methyl 3-amino-5-bromo-4-methylthiophene-2-carboxylate (1.8 g, 24%) as a yellow solid. LC / MS (ESI) m / z: 250, 252 (M+H)1.

[0226] Step B: To a solution of Cui (2.3 g, 11.99 mmol) in MeCN (5 mL) was added tert- Butyl nitrite (1.2 g, 12.0 mmol) at 0 °C. Methyl 3-amino-5-bromo-4-methylthiophene-2- carboxylate (1.5 g, 6.00 mmol) in MeCN was added to the mixture. The result reaction was stirred at 60 °C for 3 hours under nitrogen. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with further brine and concentrated. The residue was purified by flash column chromatography eluted with 0-10% ethyl acetate in petroleum ether to afford methyl 5-bromo-3-iodo-4-methylthiophene-2-carboxylate (1.1 g, 50%) as a white solid.

[0227] Step C: To a solution of methyl 5-bromo-3-iodo-4-methylthiophene-2-carboxylate (1.1 g, 3.05 mmol), phenol (0.57 g, 6.09 mmol) in toluene (15 mL) was added Cui (60 mg, 0.30 mmol) and CS2CO3(2.9 g, 9.14 mmol) at 25°C. The mixture was stirred at 110 °C for 16 hours under nitrogen. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The crude was purified by reverse phase chromatography (C18, MeCN / H2O, 0.2% formic acid modifier, 20% to 60% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford 5-bromo-4- methyl-3-phenoxythiophene-2-carboxylic acid (100 mg, 10%) as a yellow solid. LC / MS (ESI) m / z: 313, 315 (M+H)+.

[0228] Step D: To a solution of 5-bromo-4-methyl-3-phenoxythiophene-2-carboxylic acid (100 mg, 0.32 mmol), K2CO3 (132 mg, 0.96 mmol) in DMF (6 mL) was added Mel (68 mg, 0.48 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 hours under nitrogen. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with further brine and concentrated. The residue was purified by flash column chromatography eluted with 0-10% ethyl acetate in petroleum ether to afford methyl 5-bromo-4-methyl3-phenoxythiophene-2- carboxylate (90 mg, 86%) as a white solid. LCMS (ESI): m / z 327, 329 [M+H]+.

[0229] Step E: To a solution of tributyl(l -ethoxy vinyl) stannane (100 mg, 0.28 mmol), methyl 5-bromo-4-methyl-3-(phenyloxy)thiophene-2-carboxylate (90 mg, 0.28 mmol) in DMF (6 mL) was added Pd(PPh3)4 (31 mg, 0.03 mmol) at 25 °C. The mixture was stirred at 100 °C for 2 hours under nitrogen. 5N HC1 was added to the cooled mixture and stirred at room temperature for 0.5 hours. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with further brine and concentrated. The residue was purified by flash column chromatography eluted with 0-10% ethyl acetate in petroleum ether to afford methyl 5-acetyl-4-methyl-3-phenoxythiophene-2-carboxylate (70 mg, 87%) as a white solid. LCMS (ESI): m / z 291 [M+H]+.

[0230] Step F: A solution of methyl methyl 5-acetyl-4-methyl-3-phenoxythiophene-2- carboxylate (70 mg, 0.24 mmol) in DAST (5 mL) was stirred at 45 °C for 16 hours under nitrogen. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with Sat. NaHCO3, further washed with brine and concentrated. The residue was purified by flash column chromatography eluted with 0-10% ethyl acetate in petroleum ether to afford methyl 5-(l,l-difluoroethyl)-4-methyl-3-phenoxythiophene-2-carboxylate (40 mg, 53%) as a white solid. LCMS (ESI): m / z 313 [M+H]+.

[0231] Step G: To a solution of methyl 5-(l,l-difluoroethyl)-4-methyl-3-phenoxythiophene- 2-carboxylate (40 mg, 0.13 mmol) in THF / MeOH / H2O 3:3: 1 (7 mL) was added LiOH (16 mg, 0.38 mmol), The reaction mixture was heated at 50 °C for 3 hours under nitrogen. The mixture was poured into ice water and adjusted to pH = 6-7 with 2N HC1. The mixture was extracted with EtOAc (50 mL x 3). The organic phase was dried over Na2SO4and concentrated to afford 5-(1,1-difluoroethyl)-4-methyl-3-phenoxythiophene-2-carboxylic acid (35 mg, 91%) as a yellow solid which was used directly for next step without purification. LCMS (ESI): m / z 299 [M+H]1.

[0232] Step H: To a solution of 5-(1,1-difluoroethyl)-4-methyl-3-phenoxythiophene-2- carboxylic acid (35 mg, 0.12 mmol) in DCM (5 mL) was added (S,E)-l-cyclopropyl-3- (methylsulfonyl)prop-2-en-l -amine (41 mg, 0.23 mmol), HATU (66 mg, 0.18 mmol) and DIEA (75 mg, 0.59 mmol) at 25 °C. The reaction mixture was stirred for 2 hours under nitrogen. The reaction mixture was concentrated and the residue was purified by reverse phase purification (C18, MeCN / H2O, 0.1% FA modifier, 0 to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized afford (S,E)-N-(l-cyclopropyL3- (methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-4-methyl-3-phenoxythiophene-2-carboxamide (31 mg, 58%) as a white solid. LCMS (ESI): m / z 456 [M+H]+. ’H NMR (400 MHz, DMSO-d6 ) δ 8.03 (d, J= 8.0 Hz, 1H), 7.38 (dd, J= 8.4, 7.6 Hz, 2H), 7.11 (t, J= 7.6 Hz, 1H), 6.94 (d, J = 1.6 Hz, 2H), 6.72 (dd, J = 15.2, 5.2 Hz, 1H), 6.54 (dd, J= 15.2, 1.6 Hz, 1H), 3.98-3.90 (m,lH), 2.92 (s, 3H), 2.08 (t, J= 18.6 Hz, 3H), 2.01 (d, J= 1.6 Hz, 3H), 1.05 - 0.93 (m, 1H), 0.5-0.41 (m, 1H), 0.32 - 0.15 (m, 2H), 0.1-0.0 (m, 1H).Example 9: (S,E)-4-cyano-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide

[0233] Step A: To a solution of methyl 4-bromo-5-(1,1-difluoroethyl)-3-phenoxythiophene- 2-carboxylate (180 mg, 0.47 mmol), Potassium vinyltrifluoroborate (126 mg, 0.94 mmol), and K2CO3(198 mg, 1.42 mmol) in 1,4-dioxane (4 mL) and (1 mL) wHa2sO added Pd(dppf)C12 (36 mg, 0.05 mmol) under nitrogen. The resulting mixture was stirred at 100 °C under nitrogen for 3 hours. The cooled reaction mixture was poured into ice-water, extracted with extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0-10% EtOAc in petroleum ether to afford methyl 5 -(l,l-difhioroethyl)-3 -phenoxy - 4-vinylthiophene-2-carboxylate (40 mg, 26%). LCMS (ESI): m / z 325.6 [M+H]+.

[0234] Step B: A solution of methyl 5-(l,l-difluoroethyl)-3-phenoxy-4-vinylthiophene-2- carboxylate (40 mg, 0.15 mmol) in DCM (4 mL) and MeOH (1 mL) was cooled to - 70 °C, O3 was pumped into the solution for 5 mins while stirring. The mixture was quenched with Dimethyl sulfide, diluted with , exHtr2aOcted with extracted with DCM (8 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0-20% EtOAc in petroleum ether to afford a mixture of methyl 5-(l,l-difhioroethyl)-4-fonnyl-3- phenoxythiophene-2-carboxylate and methyl 5-(l,l-difluoroethyl)-4-(dihydroxymethyl)-3- phenoxythiophene-2-carboxylate (- 1 :1, 50 mg, 99%) which was used directly for next step. LCMS (ESI): m / z 345 [M+H]+.

[0235] Step C: A mixture of methyl 5-(l,l-difluoroethyl)-4-formyl-3-phenoxythiophene-2- carboxylate and methyl 5-(l,l-difluoroethyl)-4-(dihydroxymethyl)-3-phenoxythiophene-2- carboxylate (50 mg, 0.15 mmol), Hydroxylamine hydrochloride (16 mg, 0.22 mmol) and K2CO3(41 mg, 0.3 mmol) in MeOH (4 mL) was stirred at reflux for 1 hour. The cooled reaction mixture was poured into ice-water, extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated to afford methyl (E)-5- (l,l-difluoroethyl)-4-((hydroxyimino)methyl)-3-phenoxythiophene-2-carboxylate (50 mg, 95%) which was used directly for next step. LCMS (ESI): m / z 342 [M+H]+.

[0236] Step D: To a solution of methyl (E)-5-(l,l-difluoroethyl)-4-((hydroxyimino)methyl)- 3-phenoxythiophene-2-carboxylate (50 mg, 0.146 mmol) and TEA (30 mg, 0.29 mmol) in DCM (3 mL) was added TFAA (40 mg, 0.19 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hours. The reaction mixture was poured into ice-water, extracted with DCM (5 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0-20% EtOAc in petroleum ether to afford methyl 4-cyano-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxylate (40 mg, 84.4%). No Ms signal.

[0237] Step E: To a solution of methyl 4-cyano-5-(l ,l-difluoroethyl)-3-phenoxythiophene-2-carboxylate (40 mg, 0.12 mmol) in (3mLH)2aOnd THF (3mL) was added LiOH (25 mg, 0.6 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with ice-water and adjusted pH = 5-6 by 2N HC1. The mixture was extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated to afford 4-cyano-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxylic acid (30 mg, 83.6%) which was used directly for next step. LCMS (ESI): m / z 310 [M+H]+.

[0238] Step F: To a mixture of 4-cyano-5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxylic acid (30 mg, 0.097), (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (26 mg, 0.14 mmol), HATU (57 mg, 0.15 mmol) in DCM (5 mL) was added DIEA (65 mg, 0.5 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to give a residue. The residue was purified by The reaction mixture was purified by reverse phase purification (C18, MeCN / H2O, 0.1%TFA modifier, 30 to 90% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (S,E)-4-cyano-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide(23 mg, 50.8%). LCMS (ESI): m / z 467.2[M+H]+ 1HNMR (400 MHz, MeOD) δ 8.17 (d, J= 7.6 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.22 (t, J= 7.6 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.82 (dd, J= 15.2, 5.2 Hz,1H), 6.51 (dd, J= 15.2, 1.6 Hz, 1H), 4.06 - 3.83 (m, 1H), 2.88 (s, 3H), 2.14 (t, J= 18.4 Hz, 3H), 1.09 - 0.95 (m, 1H), 0.65 - 0.56 (m, 1H), 0.44 - 0.31 (m, 2H), 0.24 - 0.20 (m, 1H).Example 10: (S,E)-4-chloro-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)- 3-phenoxythiophene-2-carboxamide

[0239] Step A: To a solution of methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (250 mg, 1.1 mmol) in DCE (5 mL) were added phenylboronic acid (670 mg, 5.49 mmol), cupric bis(acetate) (301 mg, 1.65 mmol) and pyridine (218 mg, 2.75 mmol). The reaction mixture was purged with oxygen three times, then stirred at room temperature overnight under oxygen. The reaction mixture was diluted with water and extracted with DCM. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluted with a gradient of 0 to 5% EtOAc in petroleum ether. The desired fractions were evaporated to dryness to afford methyl 4,5-dichloro-3-phenoxythiophene- 2-carboxylate (160 mg, 48%). LCMS (ESI): m / z 303 [M+H]+.

[0240] Step B: To a solution of methyl 4,5-dichloro-3-phenoxythiophene-2-carboxylate (120 mg, 0.39 mmol) in DMF (2 mL) were added Tributyl(l-ethoxyvinyl)stannane (143 mg, 0.39 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C overnight under nitrogen. After cooling to room temperature, the mixture was removed in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% EtOAc in petroleum ether to afford methyl 4-chloro-5-(l- ethoxyvinyl)-3-phenoxythiophene-2-carboxylate (120 mg, 90 %). LCMS (ESI): m / z 339 [M+H]+.

[0241] Step C: To a solution of methyl 4-chloro-5-(l-ethoxyvinyl)-3-phenoxythiophene-2- carboxylate (120 mg, 0.354 mmol) in THF (5 mL) was added HC1 (5 mL, 6 N) at room temperature. The reaction was stirred at room temperature for 1 h. The mixture was poured into a stirred solution of brine solution, extracted with EtOAc twice. The combined extracts were dried over anhydrous MgSCh, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient 0% to 20% EtOAc in PE. The desired fractions were evaporated to dryness to afford methyl 5-acetyl-4-chloro-3-phenoxythiophene-2-carboxylate (85 mg, 77 %). LCMS (ESI): m / z 311 [M+H]+.

[0242] Step D: A solution of methyl 5-acetyl-4-chloro-3-phenoxythiophene-2-carboxylate (85 mg, 0.274 mmol) in DAST (2 mL) stirred at 60 °C for 2 h. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc and neutralized with saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient 0 to 20 % EtOAc in PE. The desired fractions were evaporated to dryness to afford methyl 4-chloro-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxylate (80 mg, 88%). LCMS (ESI): m / z 333 [M+H]1.

[0243] Step E: To a solution of methyl 4-chloro-5-(l,l-difluoroethyl)-3-phenoxythiophene- 2-carboxylate (50 mg, 0.151 mmol) in THF (4 mL) and (1 mL) wHa2sO added LiOH (12 H2O mg, 0.301 mmol). The reaction was stirred at room temperature for 2 h. The reaction was monitored by analysis of LC-MS. The mixture was neutralized with 2N HC1 to pH=3~5, extracted with EtOAc twice. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated to afford 4-chloro-5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxylic acid (45 mg, 94 %), which was used directly without further purification. LCMS (ESI): m / z 319 [M+H]+.

[0244] Step F: To a stirred mixture of 4-chloro-5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxylic acid (40 mg, 0.126 mmol) in DCM (3 mL) were added (S,E)-l-cyclopropyl-3- (methylsulfonyl)prop-2-en-l -amine (33 mg, 0.188 mmol), HATU (72 mg, 0.188 mmol) and DIEA (49 mg, 0.38 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous MgSCh, filtered and evaporated. The reaction mixture was purified by reverse phase purification (C18, MeCN / H2O, ammonium bicarbonate modifier, 0to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized afford (S,E)-4-chloro-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (32 mg, 53 %). LCMS (ESI): m / z 476 [M+H]+. H NMR (400 MHz, DMSO-t / 6) 5 8.25 (d, J= 8.4 Hz, 1H), 7.34 (dd, J= 8.4, 7.6 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 6.94 (d, J= 8.0 Hz, 2H), 6.68 (dd, J= 15.2, 5.2 Hz, 1H), 6.54 (dd, J= 15.2, 1.2 Hz, 1H), 3.91 - 3.86 (m, 1H), 2.88 (s, 3H), 2.09 (t, J= 19.2 Hz, 3H), 0.99 - 0.93(m, 1H), 0.44 - 0.38 (m, 1H), 0.27 - 0.21 (m, 1H), 0.20 - 0.16 (m, 1H), 0.03 - 0.02 (m, 1H).Example 11: (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoroethyl)-4-fluoro- 3-phenoxythiophene-2-carboxamide

[0245] Step A: To a solution of methyl 3-fluorothiophene-2-carboxylate (3 g, 18.7 mmol) in THF (30 mL) was added TMPMgCl.LiCl (18.3 mL, 18.3 mmol, 1.0 mol / L in THF) dropwise at - 40°C. The reaction was stirred at -45°C for 0.5 hours under nitrogen. The mixture was cooled to -60°C and a solution of I2 (4.9 g, 19.2 mmol) in THF (10 mL) was added into the mixture dropwise at -60°C. The result reaction was stirred at 25°C for 1 hour. The reaction was poured into sat. NH4C1 solution at 0 °C. Extracted with EtOAc. The organic layer was separated, washedwith water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with 0 ~ 4% ethyl acetate in petroleum ether to afford methyl 3-fluoro-5-iodothiophene-2-carboxylate (2.1 g, 39%) as a yellow solid.1H NMR (400 MHz, CDCls) 5 7.00 - 6.92 (m, 1H), 3.79 (s, 3H).

[0246] Step B: To a solution of methyl 3-fluoro-5-iodothiophene-2-carboxylate (500 mg, 1.75 mmol) in THF (15 mL) was added TMPMgCl.LiCl (2.62 mL,, 2.62 mmol, 1.0 mol / L in THF) dropwise at -45°C. The reaction was stirred at -45°C for 0.5 hours under nitrogen. The mixture was cooled to -60°C and a solution of hexachloroethane (413 mg, 1.75 mmol) in THF (3 mb) was added into the mixture dropwise at -60 °C. The result reaction was stirred at 25 °C for 1 hour under nitrogen. The reaction was poured into sat. NH4CI solution at 0 °C. Extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with 0~4 % ethyl acetate in petroleum ether to afford methyl 5-chloro-3-fluoro-4-iodothiophene- 2-carboxylate (170 mg, 30%).1H NMR (400 MHz, CDCI3) 8 3.90 (s, 3H).

[0247] Step C: To a solution of methyl 5-chloro-3-fluoro-4-iodothiophene-2-carboxylate (10 g, 31.2 mmol) in dioxane (75 mL) was added bis(pinacolato)diboron (4.0 g, 15.6 mmol), Pd(dppf)C1 (2.3 g, 3.1 mmol) and KO Ac (6.1 g, 62.4 mmol). The reaction was stirred at 110 °C for 16 hours under nitrogen. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN / H2O, 0.2% formic acid modifier, 5% to 35% gradient, 30 min run) and the fractions containing desired product were concentrated in vacuo to afford (2-chloro-4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid (3.7 g, 34%). LCMS (ESI): m / z 239, 241 [M+H]+.

[0248] Step D: To a stirred solution of (2-chloro-4-fluoro-5-(methoxycarbonyl)thiophen-3- yl)boronic acid (3.7 g, 10.8 mmol) in THF (50 mL) was added 50% H2O2(3.7 g, 54.3 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 hours under nitrogen. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-13% ethyl acetate in petroleum ether to afford methyl 5-chloro-3- fluoro-4-hydroxythiophene-2-carboxylate (1.4 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 3.81 (s, 3H).

[0249] Step E: To a solution of methyl 5-chloro-3-fluoro-4-hydroxythiophene-2-carboxylate (1.4 g, 6.6 mmol) in DCE (25 mL) was added phenylboronic acid (4.0 g, 33.2 mmol), Cu(OAc)2 (1.8 g, 9.9 mmol) and Pyridine (1.3 g, 16.6 mmol) at 25 °C. The reaction was stirred at 25 °C for 16 hours under oxygen. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10 % ethyl acetate in petroleum ether to afford methyl 5-chloro-3-fluoro-4-phenoxythiophene-2-carboxylate (600 mg, 31%). LCMS (ESI): m / z 287, 289 [M+H]+.

[0250] Step F: To a solution of methyl 5-chloro-3-fluoro-4-phenoxythiophene-2-carboxylate (600 mg, 2.09 mmol) in THF / H2O 5:1 (12 mL) was added LiOH (175 mg, 4.2 mmol). The reaction was stirred at 25 °C for 1 hour. The reaction mixture was heated to 50 °C and stirred at 50 °C for 3 hours. The cooled mixture was poured into ice water and adjusted to pH = 3~4 with 2 N HC1. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to afford 5-chloro-3-fluoro-4- phenoxythiophene-2-carboxylic acid (510 mg, 89%). LCMS (ESI): m / z 271, 273 [M-H]‘.

[0251] Step G: To a solution of 5-chloro-3-fluoro-4-phenoxythiophene-2-carboxylic acid (510 mg, 1.9 mmol) in DCM (10 mL) was added N,O-dimethylhydroxylamine (171 mg, 2.8 mmol), EDCI (537 mg, 2.8 mmol), HOBT (378 mg, 2.8 mmol) and TEA (944 mg, 9.4 mmol). The result mixture was stirred at 25 °C for 1 hour. The reaction was diluted with DCM and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10 % ethyl acetate in petroleum ether to afford 5-chloro-3-fluoro-N-methoxy-N-methyl-4- phenoxythiophene-2-carboxamide (410 mg, 69%). LCMS (ESI): m / z 316, 318 [M+H]+.

[0252] Step H: To a stirred solution of 5-chloro-3-fluoro-N-methoxy-N-methyl4- phenoxythiophene-2-carboxamide (410 mg, 1.30 mmol) in THF (15 mL) was added MeMgBr (0.52 mL, 1.55 mmol, 3 mol / L in THF) at -60 °C. The reaction was stirred at 25 °C for 1 hour under nitrogen. The reaction was poured into sat. NH4CI solution at 0 °C. Extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford l-(5-chloro-3-fluoro-4-phenoxythiophen-2- yl)ethan-l-one (245 mg, 69%). LCMS (ESI): m / z 271, 273 [M+H]+.

[0253] Step I: To a solution of l-(5-chloro-3-fluoro-4-phenoxythiophen-2-yl)ethan-l-one (25 mg, 0.09 mmol) in MeOH / DMF 1 :1 (8 mL) was added Pd(dppf)C 12 (7 mg, 0.01 mmol) and TEA (46 mg, 0.46 mmol). The reaction was stirred at 80 °C under carbon monoxide for 16 hours. The cooled reaction was diluted with EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with 0~8% ethyl acetate in petroleum ether to afford methyl 5-acetyl-4-fluoro-3-phenoxythiophene-2-carboxylate (10 mg, 36%). 1HNMR (400 MHz, CDC13 δ 7.28 - 7.25 (m, 2H), 7.06 - 7.02 (m, 1H), 6.91 - 6.89 (m, 2H), 3.75 (s, 3H), 2.53 (d, J = 2.8 Hz, 3H).

[0254] Step J: A solution of methyl 5-acetyl-4-fluoro-3-phenoxythiophene-2-carboxylate (10 mg, 0.03 mmol) in DAST (3 mL) was stirred at 50 °C for 16 hours. The cooled mixture was diluted with EtOAc and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0-10% ethyl acetate in petroleum ether to afford methyl 5-(l,l-difluoroethyl)-4-fluoro-3-phenoxythiophene-2-carboxylate (8 mg, 74%).

[0255] Step K: To a solution of methyl 5-(l,l-difluoroethyl)-4-fluoro-3-phenoxythiophene- 2-carboxylate (8 mg, 0.03 mmol) in THF / H2O 5: 1 (6 mL) was added LiOH (5 mg, 0.08 mmol). The reaction was stirred at 50 °C for 2 hours under nitrogen. The mixture was poured into ice water and adjusted to pH = 3~4 with 2 A HCI. Extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to afford 5-(l , 1 - difluoroethyl)-4-fluoro-3-phenoxythiophene-2-carboxylic acid (5 mg, 65%).

[0256] Step L: To a solution of 5-(l,l-difluoroethyl)-4-fluoro-3-phenoxythiophene-2- carboxylic acid (6 mg, 0.02 mmol) in DCM (2 mL) was added (S, E)-l-cyclopropyL3- (methylsulfonyl)prop-2-en-l -amine (5 mg, 0.03 mmol), HATU (11 mg, 0.03 mmol) and DIEA (12 mg, 0.10 mmol) at 25 °C. The reaction mixture was stirred at 25 °C under nitrogen for 2 hours. The reaction mixture was purified by Prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-5-( 1 , 1 -difluoroethyl)-4-fluoro-3 -phenoxythiophene-2-carboxamide (2 mg, 21%) as a colorless oil. LCMS (ESI): m / z 460 [M+H]+. ’HNMR (400 MHz, DMSO-d6) δ 8.27 (d, J= 8.4 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.19 - 7.16 (m, 1H), 7.11 - 7.09 (m, 2H), 6.77 (dd, J = 15.2, 5.2 Hz, 1H), 6.66 (d, J= 15.2 Hz, 1H), 3.99 - 3.90 (m, 1H), 2.94 (s, 3H), 2.13 - 2.02 (m, 3H), 1.13 - 1.05 (m, 1H), 0.53 - 0.45 (m, 1H), 0.35 - 0.27 (m, 2H), 0.18 - 0.09 (m, 1H).Example 12: (S, E)-4-chloro-N-(l-cyclopropyl-3-(methyIsulfonyl)allyl)-5- (cyclopropyldifluoromethyl)-3-phenoxythiophene-2-carboxamide

[0257] Step A: To a mixture of methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (750 mg, 3.30 mmol), phenylboronic acid (2014 mg, 16.52 mmol), Cu(OAc)2 (900 mg, 4.95 mmol) in DCE (10 mL) was added pyridine (670 mg, 8.26 mmol). The reaction mixture was stirred at room temperature under oxygen (1 atm) overnight. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 10-15% EtOAc in petroleum ether to afford methyl 4,5-dichloro-3- phenoxythiophene-2-carboxylate (200 mg, 20%).

[0258] Step B: To a mixture of methyl 4,5-dichloro-3-phenoxythiophene-2-carboxylate (180 mg, 0.59 mmol), 2-(l-cyclopropylvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (115 mg, 0.59mmol), Pd(dppf)C12 (44 mg, 0.06 mmol) in dioxane (2 mL) and H2O (0.2 mL) was added K3PO4(315 mg, 1.48 mmol). The reaction mixture was purged with nitrogen three times, then stirred at 80 °C for 3 hours under nitrogen. The cooled reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 -5% EtOAc in petroleum ether to afford methyl 4-chloro-5-(l-cyclopropylvinyl)-3-phenoxythiophene-2- carboxylate (110 mg, 55%). LCMS (ESI): m / z 335, 337 [M+H]+.

[0259] Step C: A solution of methyl 4-chloro-5-(l-cyclopropylvinyl)-3-phenoxythiophene- 2-carboxylate (110 mg, 0.33 mmol) in MeOH (3 mL) and DCM (3 mL) was cooled to -65 °C. O3was pumped into the solution for 10 mins while stirring. Then the reaction was quenched with dimethyl sulfide, diluted with H2O , extracted with DCM. The organic phase was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0-5% EtOAc in petroleum ether to afford methyl 4-chloro-5-(cyclopropanecarbonyl)-3-phenoxythiophene-2-carboxylate (60 mg, 54%). LCMS (ESI): m / z 337, 339 [M+H]+.

[0260] Step D: A solution of methyl 4-chloro-5-(cyclopropanecarbonyl)-3- phenoxythiophene-2-carboxylate (60 mg, 0.18 mmol) in DAST (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc, then the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 15-20% EtOAc in petroleum ether to afford methyl 4-chloro-5- (cyclopropyldifluoromethyl)-3-phenoxythiophene-2-carboxylate (40 mg, 63%). LCMS (ESI): m / z: 359, 361 [M+H]+.TH NMR (400 MHz, DMSO-tL) 8 7.38 - 7.32 (m, 2H), 7.13 - 7.06 (m, 1H), 6.97 - 6.90 (m, 2H), 3.72 (s, 3H), 2.02 - 1.87 (m, 1H), 0.88 - 0.77 (m, 4H).

[0261] Step E: To a solution of methyl 4-chloro-5-(cyclopropyldifluoromethyl)-3- phenoxythiophene-2-carboxylate (40 mg, 0.11 mmol) in THF (3 mL) and H2O (0.5 mL), was added LiOH (14 mg, 0.33 mmol). The reaction was stirred at 40 °C for 2 hours. The mixture was neutralized with 2 A HCI solution, extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product waspurified by silica gel flash chromatography, eluted with a gradient of 0-30% EtOAc in petroleum ether to afford 4-chloro-5-(cyclopropyldifluoromethyl)-3-phenoxythiophene-2- carboxylic acid (30 mg, 78%). LCMS (ESI): m / z 345, 347 [M+H]+.

[0262] Step F: To a stirred mixture of 4-chloro-5-(cyclopropyldifluoromethyl)-3- phenoxythiophene-2-carboxylic acid (30 mg, 0.09 mmol) in DCM (3 mb) were added (S, E)-l- cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (17 mg, 0.10 mmol), HATU (66 mg, 0.17 mmol) and DIEA (56 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with brine, and organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified Prep-HPLC to afford (S, E)-4-chloro-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(cyclopropyldifluoromethyl)-3- phenoxythiophene-2-carboxamide (20 mg, 46%). LCMS (ESI): m / z 502, 504 [M+H]+. 1HNMR (400 MHz, CDC13) 8 7.42 - 7.38 (m, 2H), 7.21 - 7.17 (m, 1H), 7.04 - 7.00 (m, 1H), 6.99 - 6.95 (m, 2H), 6.86 (dd, J= 15.2, 4.5 Hz, 1H), 6.18 (dd, J= 15.2, 1.8 Hz, 1H), 4.13 - 4.06 (m, 1H), 2.82 (s, 3H), 1.82 - 1.71 (m, 1H), 0.90 - 0.89 (m, 2H), 0.85 - 0.83 (m, 1H), 0.79 - 0.76 (m, 2H), 0.64 - 0.57 (m, 1H), 0.43 - 0.37 (m, 1H), 0.35 - 0.29 (m, 1H), 0.28 - 0.22 (m, 1H).Example 13: (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- (cyclopropyldifluoromethyl)-4-fluoro-3-phenoxythiophene-2-carboxamide

[0263] Step A: To a solution of methyl 4-bromo-2-formylthiazole-5-carboxylate (100 mg, 0.29 mmol) in THF (3 mL) was added Cyclopropylmagnesium bromide (1.2 mL, 1.2 mmol, 1 M in THF) at -45 °C. The reaction mixture was stirred at -45 °C for 3 hours. The reaction mixture was quenched with NH4CI solution at 0 °C and extracted with EtOAc. The organic extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 15 - 20% EtOAc in petroleum ether to afford methyl 5-(cyclopropanecarbonyl)-4-fluoro-3- phenoxythiophene-2-carboxylate (30 mg, 32%) LCMS (ESI): m / z 321 [M+H]+.

[0264] Step B: A solution of methyl 5-(cyclopropanecarbonyl)-4-fluoro-3- phenoxythiophene-2-carboxylate (60 mg, 0.19 mmol) in DAST (2 mL) was stirred at 65 °C for 72 hours. The cooled reaction mixture was diluted with EtOAc and poured into ice-water. The mixture was extracted with EtOAc. The organic extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Perp-TLC to afford methyl 5-(cyclopropyldifluoromethyl)-4-fluoro-3-phenoxythiophene-2-carboxylate (15 mg, 23%). LCMS (ESI): m / z 343 [M+H]+.

[0265] Step C: To a solution of methyl 5-(cyclopropyldifluoromethyl)-4-fluoro-3- phenoxythiophene-2-carboxylate (15 mg, 0.04 mmol) in THF (2 mL) and H2O (2 mL), was added LiOH (5 mg, 0.11 mmol). The reaction mixture was stirred at 50 °C for 2 hours. The cooled mixture was neutralized with 2 AHC1, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated to afford 5-(cyclopropyldifluoromethyl)-4-fluoro-3-phenoxythiophene-2-carboxylic acid (10 mg, 70%), which was used directly without further purification. LCMS (ESI): m / z 329 [M+H]+.

[0266] Step D: To a stirred mixture of 5-(cyclopropyldifluoromethyl)-4-fluoro-3- phenoxythiophene-2-carboxylic acid (10 mg, 0.03 mmol) in DCM (3 mL) was added (S, E)-l- cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (6 mg, 0.03 mmol), HATU (23 mg, 0.06 mmol) and DIEA (20 mg, 0.15 mmol). The result mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified Prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(cyclopropyldifluoromethyl)-4-fluoro-3- phenoxythiophene-2-carboxamide (2.5 mg, 17%). LCMS (ESI): m / z 486 [M+H]+. 1H NMR (400 MHz, Methanol -d4) 5 7.45 - 7.40 (m, 2H), 7.24 - 7.17 (m, 1H), 7.10 - 7.08 (m, 2H), 6.87 (dd, J= 15.2, 5.0 Hz, 1H), 6.55 (dd, J= 15.2, 1.6 Hz, 1H), 4.04 - 3.96 (m, 1H), 2.90 (s, 3H), 1.85 - 1.68 (m, 1H), 1.10 - 1.02 (m, 1H), 0.83 - 0.79 (m, 4H), 0.67 - 0.59 (m, 1H), 0.47 - 0.35 (m, 2H), 0.31 - 0.24 (m, 1H).Example 14: (S, E)-N-(l-cyclopropyl-3-((2-(dimethylamino)ethyl)sulfonyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0267] Step A: To a suspension of NaH (0.81 g, 33.8 mmol, 60%, dispersion in Paraffin Liquid) in THF (40 mL) was added tert-butyl (2-mercaptoethyl)carbamate (5 g, 28.2 mmol) dropwise under nitrogen at 0 °C. The reaction was stirred at 0 °C for 1 hour, then diethyl (iodomethyl)phosphonate (9.4 g, 33.8 mmol) was added into the mixture at 0 °C. The resulting solution was stirred at 45 °C for 3 hours. The reaction was poured into ice-water, extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 20% ethyl acetate in petroleum ether to afford tert-butyl (2- (((diethoxyphosphoryl)methyl)thio)ethyl)carbamate (5 g, 56%). LCMS (ESI): m / z 328 [M+H]+.

[0268] Step B: A solution of tert-butyl (2- (((diethoxyphosphoryl)methyl)thio)ethyl)carbamate (5 g, 15.3 mmol) in TFA (20 mL). The mixture was stirred at 25 °C for 0.5 hours. The mixture concentrated to afford diethyl (((2- aminoethyl)thio)methyl)phosphonate (3 g, 86%) which was used directly for next step. LCMS (ESI): m / z 228 [M+H]+.

[0269] Step C: To a mixture of diethyl (((2-aminoethyl)thio)methyl)phosphonate (3 g, 13.2 mmol) and (HCHO)n (3.9 g, 132.0 mmol) in MeOH (60 mL) was added HO Ac (0. ImL, cata.).The mixture was stirred at 25 °C for 2 hours. Then NaBH(0Ac).3 (3.9 g, 132.0 mmoL) was added to the mixture by portions and the result mixture was stirred at 25 °C for 3 hours. The reaction was poured into ice-water, extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 80% ethyl acetate in petroleum ether to afford diethyl (((2-(dimethylamino)ethyl)thio)methyl)phosphonate (2 g, 59%). LCMS (ESI): m / z 256 [M+H]+.

[0270] Step D: To a solution of diethyl (((2-(dimethylamino)ethyl)thio)methyl)phosphonate (1 g, 3.9 mmol) in MeOH (8 mL) and H2O (8 mb) was added oxone (5.8 g, 9.8 mmol). The result mixture was stirred at 25 °C for 1 hour. The reaction was diluted with water, extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with 0 - 100% ethyl acetate in petroleum ether to afford diethyl (((2- (dimethylamino)ethyl)sulfonyl)methyl)phosphonate (0.8 g, 80%). LCMS (ESI): m / z 288 [M+H]+.

[0271] Step E: To a suspension of diethyl (((2- (dimethylamino)ethyl)sulfonyl)methyl)phosphonate (102 mg, 0.36 mmol) in THF (10 mL) was added LiHMDS (0.4 mL, 0.4 mmol, 1 Mm THF) dropwise under nitrogen at 0 °C. The reaction was stirred at 0 °C for 1 hour, then the mixture was cooled to -60 °C and a solution of (S)-N-(l- cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (100 mg, 0.27 mmol) in THF (3 mL) was slowly added into the mixture. The resulting solution was stirred at -60°C for another 1 hour. The reaction mixture was poured into ice-water, extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with 0 - 20% ethyl acetate in petroleum ether to afford (S, E)-N-(l-cyclopropyl-3-((2- (dimethylamino)ethyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (60.7 mg, 56%). LCMS (ESI): m / z 499 [M+H]+. ’HNMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.0 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.26 - 7.23 (m, 1H), 7.22 - 7.18 (m, 2H), 7.14 -7.13 (m, 1H), 6.81 (dd, J= 15.2, 5.6 Hz, 1H), 6.68 (dd, J= 15.2, 1.2 Hz, 1H), 4.05 - 3.99 (m, 1H), 3.25 - 3.18 (m, 2H), 2.54 -2.52 (m, 2H), 2.10 (s, 6H), 2.01 (t, J= 18.8 Hz, 3H), 1.23 - 1.13 (m, 1H), 0.53 - 0.47 (m, 1H), 0.45 - 0.34 (m, 2H), 0.29 - 0.23 (m, 1H).Example 15: (S, E)-N-(l-cyclopropyl-3-sulfamoylallyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide

[0272] Step A: To a suspension of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (712 mg, 1.8 mmol) in THF (10 mL) was added LiHMDS (2.2 mL, 1 M in THF) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour, then a solution of benzyl (S)-(l-cyclopropyl-2-oxoethyl)carbamate (350 mg, 1.5 mmol) inTHF (3 mL) was added into the mixture at -20 °C. The resulting solution was stirred at -20°C for another 1 hour. The reaction was poured into NH4CI solution, extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous I Na2SO4and filtered.The filtrate was concentrated and purified by silica gel flash chromatography eluted with 0 - 20% ethyl acetate in petroleum ether to afford benzyl (S, E)-(3-(N-(tert-butoxycarbonyl)sulfamoyl)-l- cyclopropylallyl)carbamate (150 mg, 24%). LCMS (ESI): m / z 411 [M+H]+.

[0273] Step B: A solution of (S, E)-(3-(N-(tert-butoxycarbonyl)sulfamoyl)-l- cyclopropylallyl)carbamate (150 mg, 0.37 mmol) in HBr (3 mL, 33% in HO Ac) was stirred at 25 °C for 0.5 hours. The reaction mixture was diluted with Et2O and the precipitate was filtered and dried to give the desire product (S, E)-3-amino-3-cyclopropylprop-l-ene-l -sulfonamide (60 mg, 93%). LCMS (ESI): m / z 177 [M+H]+.

[0274] Step C: To a stirred mixture of 5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxylic acid (30 mg, 0.11 mmol) in DCM (10 mL) was added HATU (41 mg, 0.11 mmol), DIEA (46 mg, 0.36 mmol) and (S, E)-3-amino-3-cyclopropylprop-l-ene-l -sulfonamide (27 mg,0.16 mmol) at 25°C. The reaction was stirred at 25°C for 1 hour The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated and purified by silica gel flash chromatography, eluted with a gradient of 0-40% ethyl acetate in petroleum ether to afford (S, E)-N-(l-cyclopropyl-3-sulfamoylallyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxamide (26.2 mg, 56%). LCMS (ESI): m / z 443 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J= 8.3 Hz, 1H), 7.46 (dd, J= 8.3, 7.6 Hz, 2H), 7.25 (t, J= 1A Hz, 1H), 7.20 (d, J= 7.8 Hz, 2H), 7.12 (s, 1H), 7.02 (s, 2H), 6.63 (dd, J= 15.2, 5.6 Hz, 1H), 6.52 (dd, J= 15.2, 0.8 Hz, 1H), 4.04 - 3.95 (m, 1H), 2.03 (t, J= 18.8 Hz, 3H), 1.19 - 1.14 (m, 1H), 0.52 - 0.49 (m, 1H), 0.42 - 0.32 (m, 2H), 0.27 - 0.21 (m, 1H).Example 16: (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(perfluoroethyl)-3- phenoxythiophene-2-carboxamide

[0275] Step A: A mixture of methyl 3-phenoxythiophene-2-carboxylate (350 mg, 1.49 mmol), 2,2,3,3,3-pentafluoropropanoic anhydride (1.8 g, 5.98 mmol), Tris(2,2'- bipyridine)ruthenium dichloride (95 mg, 0.15 mmol), 4-Phenylpyridine-N-oxide (1.02 g, 5.98 mmol) in MeCN (5 mb) was purged with nitrogen three times, then the mixture was stirred at room temperature and irradiated with 18W blue LED (460 nm) for 16 hours. T The reaction waspoured into ice- water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluted with 0 - 10% ethyl acetate in petroleum ether to afford methyl 5-(perfluoroethyl)-3-phenoxythiophene-2-carboxylate (50 mg, 10%). LCMS (ESI): m / z 353 [M+H]+.

[0276] Step B: To a solution of methyl 5-(pentafluoroethyl)-3-(phenyloxy)thiophene-2- carboxylate (20 mg, 0.06 mmol) in MeOH / T HF / HO2 (3 mL / 3ml / 3ml) was added lithium hydroxide (10 mg, 0.238 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice water and adjusted pH = 5~6 with 2AHC1. The mixture was extracted with EtOAc (8 mL x 3). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to afford 5-(perfluoroethyl)-3-phenoxythiophene-2-carboxylic acid (18 mg, 93%). LCMS (ESI): m / z 339 [M+H]+.

[0277] Step C: To a mixture of 5-(perfluoroethyl)-3-phenoxythiophene-2-carboxylic acid (15 mg, 0.04 mmol) and (S, E)-l -cyclopropyl-3-(methylsulfonyl)prop-2-en-l -amine (12 mg, 0.07 mmol) in DCM (5 mL) were added DIEA (17 mg, 0.13 mmol) and HATU (25 mg, 0.07 mmol) and the result mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Prep-TLC to afford (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- (perfluoroethyl)-3-phenoxythiophene-2-carboxamide (3 mg, 13%). LCMS (ESI): m / z 496 [M+H]+. 1H NVIR (400 MHz, MeOD-d4) δ 7.52 - 7.48 (m, 2H), 7.32 - 7.29 (m, 1H), 7.24 - 7.22 (m, 2H), 7.13 (s, 1H), 6.96 (dd, J= 15.2, 5.2 Hz, 1H), 6.72 (dd, J= 15.2, 1.6 Hz, 1H), 4.12 - 4.05 (m, 1H), 2.96 (s, 3H), 1.23 - 1.14 (m, 1H), 0.73 - 0.66 (m, 1H), 0.58 - 0.56 (m, 1H),O.46 - 0.40 (m, 2H).Example 17: (S, E)-N-(l-cyclopropyl-3-(ethylsulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide

[0278] Step A: To a solution of diethyl (iodomethyl)phosphonate (1 g, 3.6 mmol) in DMF (10 mL) was added sodium ethanethiolate (0.61 g, 7.2 mmol). The reaction was stirred at 25 °C for 16 hours. The reaction was quenched with ice water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluted with 0 - 40% ethyl acetate in petroleum ether to afford diethyl ((ethylthio)methyl)phosphonate (610 mg, 79%). LCMS (ESI): m / z 213 [M+H]+.

[0279] Step B: To a suspension of diethyl ((ethylthio)methyl)phosphonate (610 mg, 2.8 mmol) in MeOH (3 mL) and (H32mOL) was added Oxone (4.4 g, 7.2 mmol). The reaction was stirred at 25 °C for 16 hours, quenched with ice water, extracted with EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluted with 0 - 20% ethyl acetate in petroleum ether to afford diethyl ((ethyl sulfonyl)methyl)phosphonate (400 mg, 56%). LCMS (ESI): m / z 245 [M+H]+.

[0280] Step C: To a solution of diethyl [(ethyldioxo-X6-sulfanyl)methyl]phosphonate (32.1 mg, 0.13 mmol) in THF (5 mL) was added LiHMDS (0.12 mL, 0.12 mmol, 1 mol / L in Hexane) dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was cooled to - 60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (40 mg, 0.11 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture waspoured into saturated aqueous NH4C1 solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-(ethylsulfonyl)allyl)-5- (l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (10.2 mg, 20%). LCMS (ESI): m / z 456 [M+H]+. 1H NMR (400 MHz, DMSO-^) 5 8.09 (d, J= 8.2 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.28 - 7.23 (m, 1H), 7.22 - 7.18 (m, 2H), 7.16 - 7.14 (m, 1H), 6.84 (dd, J= 15.2, 5.6 Hz, 1H), 6.62 (dd, J= 15.2, 1.4 Hz, 1H), 4.04 (q, J= 8.0 Hz, 1H), 3.04(q, , J= 12 Hz, 2H), 2.05 (t, J= 18.8 Hz, 3H), 1.22 - 1.16 (m, 1H), 1.12 (t, , J = 7.2 Hz, 3H), 0.57 - 0.49 (m, 1H), 0.45 - 0.35 (m, 2H), 0.31 - 0.24 (m, 1H). LCMS (ESI): m / z 428 [M+H]-.Example 18: (S, E)-N-(l-cyclopropyl-3-(N-inethylsulfamoyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide

[0281] Step A: To a mixture of N-methylmethanesulfonamide (2.0 g, 18 mmol) in DCM (20 mL) were add Di-tert-butyl dicarbonate (4.2 g, 19 mmol) and DMAP (110 mg, 0.92 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford tert-butyl methyl(methylsulfonyl)carbamate (3.7 g, 96%).1H NMR (400 MHz, DMSO-d6) 8 3.33 (s, 3H), 3.08 (s, 3H), 1.48 (s, 10H).

[0282] Step B: To a solution of tert-butyl methyl(methylsulfonyl)carbamate (1 g, 4.8 mmol) in anhydrous THF (10 mL) was added n -BuLi (4.8 mL, 4.8 mmol, Imol / L in Hexane) dropwise at -78°C under nitrogen. The resulting mixture stirred at -78°C for 1 hour. The mixture was warmed to 0 °C and a solution of diphenylphosphinyl chloride (1.1 g, 4.8 mmol) in anhydrous THF (5 mL) was added dropwise into the mixture. The result mixture was stirred at room temperature for another 1 hour. The reaction mixture was quenched with saturated NH4CI solution at 0 °C and extracted with EtOAc twice, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 50% ethyl acetate in petroleum ether to afford tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)(methyl)carbamate (800 mg, 40%). LCMS (ESI): m / z 410 [M+H]+.

[0283] Step C: To a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)(methyl)carbamate (84 mg, 0.21 mmol) in anhydrous THF (5 mL) was add LHMDS (0.27 mL, 0.27 mmol, Imol / L in Hexane) at 0 °C. The reaction resulting mixture stirred at 0 °C for 1 hour and cooled to -20 °C. A solution of N-[(S)- cyclopropyl(formyl)methyl]-5-(l,l-difluoroethyl)-3-(phenyloxy)thiophene-2-carboxamide (50 mg, 0.14 mmol) in anhydrous THF (5 mL) added into the above mixture dropwise and stirred at - 20 °C for another 1 hour, The reaction mixture was quenched with saturated NH4CI solution at 0 °C and extracted with EtOAc twice, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford tert-butyl (S, E)-((3-cyclopropyl-3-(5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxamido)prop-l-en-l-yl)sulfonyl)(methyl)carbamate (40 mg, 52%). LCMS (ESI): m / z 555 [M-H]-.

[0284] Step D: To a mixture of tert-butyl (S, E)-((3-cyclopropyl-3-(5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamido)prop-l-en-l-yl)sulfonyl)(methyl)carbamate (20 mg, 0.04 mmol) in DCM (3 mL) were added TFA (1 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and the residue was diluted with H2O, basified with saturated NaHCOi solution, extracted with EtOAc twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-(N-methylsulfamoyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (9.6 mg, 59%). LCMS (ESI): m / z 457 [M+H]+.JH NMR (400 MHz, MeOD-d4) δ 7.48 - 7.44 (t, J= 8.0 Hz, 2H), 7.26 (t, ,7= 7.2 Hz, 1H), 7.18 (d, .7 = 8.0 Hz, 2H), 6.90 (s, 1H), 6.72 (dd, .7= 15.2, 5.6 Hz, 1H), 6.34 (dd, J= 15.2, 1.2 Hz, 1H), 4.08 - 3.96 (m, 1H), 2.54 (s, 3H), 1.96 (t, J = 18.0 Hz, 3H), 1.15 - 1.12 (m, 1H), 0.65 - 0.63(m, 1H), 0.55 - 0.52 (m, 1H), 0.43 - 0.36 (m, 2H).Example 19: tert-butyl (S, E)-((3-cyclopropyl-3-(5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamido)prop-l-en-l-yl)suIfonyI)carbamate

[0285] Step A: To a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (120 mg, 0.3 mmol) in THF (4 mL) was added LiHMDS (0.3 mL, 0.3 mmol, Imol / L in Hexane) at 0 °C. The result mixture was stirred at 0 °C for 1 hour, and cooled to -20 °C. Then a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (81 mg, 0.2 mmol) in THF (2 mL) was added at -20 °C and stirred at 0 °C for another 1 hour. The reaction mixture was quenched with saturated NH4CI solution at 0 °C and extracted with EtOAc twice, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by Prep-HPLC to afford tert-butyl (S, E)-((3-cyclopropyl-3-(5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxamido)prop-l-en-l-yl)sulfonyl)carbamate (2.3 mg, 3%). LCMS (ESI): m / z 543 [M+H]+.1H NMR (400 MHz, CDCI3) δ7.47 - 7.42 (m, 2H), 7.30 - 7.27 (m, 1H), 7.15 (d, J = 7.8 Hz, 2H), 7.00 (dd, .7- 15,2, 4.8 Hz, 1H), 6.72 (s, 1H), 6.61 (dd, J= 15.2, 1.6 Hz, 1H), 4.26 - 4.21 (m, 1H), 1.93 (t, J= 22.8, 12.8 Hz, 3H), 1.45 (s, 9H), 1.03 - 0.94 (m, 1H), 0.70 - 0.62 (m, 1H), 0.58 - 0.52 (m, 1H), 0.45 - 0.36 (m, 2H).Example 20: (S, E)-N-(3-((2-amino-2-oxoethyl)suIfonyI)-l-cyclopropyIaIlyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0286] Step A: To a suspension of diethyl (iodomethyl)phosphonate (2.0 g, 7.2 mmol) and 2-methylpropan-2-yl sulfanylacetate (1.4 g, 9.4 mmol) in DMF (20 mL) was added K2CO3 (1.5 g, 10.8 mmol). The reaction was stirred at 70 °C for 16 hours. The cooled mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford tertbutyl 2-(((diethoxyphosphoryl)methyl)thio)acetate (1.8 g, 82%). LCMS (ESI): m / z 299 [M+H]+.

[0287] Step B: To a suspension of tert-butyl 2-(((diethoxyphosphoryl)methyl)thio)acetate (610 mg, 2.8 mmol) in MeOH (5 mL) and (5 mHL2)Owas added Oxone (9.1 g, 14.9 mmol). The reaction was stirred at 25 °C for 16 hours, poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 40% ethyl acetate in petroleum ether to afford tert-butyl 2- (((diethoxyphosphoryl)methyl)sulfonyl)acetate (400 mg, 56%) as a white oil. LCMS (ESI): m / z 275 [M+H-56]+.

[0288] Step C: To a solution of tert-butyl 2-(((diethoxyphosphoryl)methyl)sulfonyl)acetate (54.2 mg, 0.16 mmol) in THF (5 mL) was added LiHMDS (0.15 mL, 0.15 mmol, 1 mol / L in Hexane) dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (50 mg, 0.14 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford tert-butyl (S, E)-2-((3-cyclopropyl-3-(5-(l,l- difhioroethyl)-3-phenoxythiophene-2-carboxamido)prop-l-en-l-yl)sulfonyl)acetate (10 mg, 13%). LCMS (ESI): m / z 542 [M+H]t

[0289] Step D: To a stirred mixture of tert-butyl (S, E)-2-((3-cyclopropyl-3-(5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamido)prop-l-en-l-yl)sulfonyl)acetate (10 mg, 0.02 mmol) in DCM (2 mL), were added TFA (0.5 mL, 6.53 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to afforded a crude (S, E)-2-((3- cyclopropyl-3 -(5-(l , 1 -difluoroethyl)-3 -phenoxythiophene-2-carboxamido)prop- 1 -en- 1 - yl)sulfonyl)acetic acid (8 mg, 89%) used directly for next step. LCMS (ESI): m / z 486 [M+H]+.

[0290] Step E: To a stirred mixture of (S, E)-2-((3 -cyclopropyl -3 -(5 -(1,1 -difluoroethyl )-3- phenoxythiophene-2-carboxamido)prop-l-en-l-yl)sulfonyl)acetic acid (8 mg, 0.02 mmol) in DCM (1 mL) were added NH4CI (10 mg, 0.2 mmol), HATU (10 mg, 0.02 mmol) and DIEA (11 mg, 0.08 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with brine, and organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified Prep-HPLC to afford (S, E)-N-(3-((2-amino-2- oxoethyl)sulfonyl)- 1 -cy clopropylallyl)-5-( 1 , 1 -difluoroethyl)-3-phenoxythiophene-2- carboxamide (2.5 mg, 31%). LCMS (ESI): m / z 485 [M+H]+. 1H NMR (400 MHz, CDC13) δ 7.48 - 7.41 (m, 2H), 7.32 (d, J= 7.0 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.17 - 7.12 (m, 2H), 7.02 (dd, J = 15.2, 4.8 Hz, 1H), 6.74 - 6.70 (m, 1H), 6.60 (s, 1H), 6.52 (dd, J= 15.2, 1.Example 21: (S, E)-N-(l-cyclopropyl-3-((oxetan-3-ylmethyl)sulfonyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0291] Step A: To a solution of diethyl (mercaptomethyl)phosphonate (200 mg, 1.1 mmol) in anhydrous THF (5 mL) was added sodium hydride (71 .2 mg, 1.1 mmol) at 0 °C under nitrogen. The resulting mixture stirred at 0 °C for 1 hour. A solution of 3-(bromomethyl)oxetane (197 mg, 1.3 mmol) in anhydrous THF (2 mL) was added into the mixture dropwise. The result mixture was stirred at 0 °C for another 1 hour. The reaction mixture was quenched with saturated NH4CI solution at 0 °C and extracted with EtOAc twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 90% ethyl acetate in petroleum ether to afford diethyl (((oxetan-3-ylmethyl)thio)methyl)phosphonate (155 mg, 56%). LCMS (ESI): m / z 255 [M+H]+.

[0292] Step B: To a solution of diethyl (((oxetan-3-ylmethyl)thio)methyl)phosphonate (150 mg, 0.6 mmol) in MeOH (4 mL) and (2 H m2LO) was added Oxone (907 mg, 1.5 mmol). The result mixture was stirred at 25 °C for 2 hours. The mixture poured into ice-water, extracted with EtOAc twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The filtrate was concentrated and the residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 90% ethyl acetate in petroleum ether to afford diethyl (((oxetan-3-ylmethyl)sulfonyl)methyl)phosphonate (100 mg, 59%). LCMS (ESI): m / z 287[M+H]+.

[0293] Step C: To a solution of diethyl (((oxetan-3-ylmethyl)sulfonyl)methyl)phosphonate (50 mg, 0.2 mmol) in THF (5 mL) was added LiHMDS (0.4 mL, 0.4 mmol, 1 mol / L in Hexane) dropwise at 0 °C. The result mixture was stirred at 0 °C for 1 hour, and cooled to -60 °C. A solution of (S)-N-(l-cyclopropy1-2-oxoethyl)-5-(l, l-difluoroethyl)-3-phenoxythiophene-2- carboxamide (40 mg, 0.11 mmol) in THF (2 mL) was added dropwise into the mixture and stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-((oxetan-3-ylmethyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (9.4 mg, 17%). LCMS (ESI): m / z 498 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.48 -7.43(m, 2H), 7.30 - 7.27 (m, 2H), 7.16 - 7.14 (m, 2H), 6.93 (dd, J = 15.2, 4.7 Hz, 1H), 6.75 (s, 1H), 6.35 (dd, J= 15.2, 1.6 Hz, 1H), 4.86 - 4.80 (m, 2H), 4.53 - 4.51 (m, 2H), 4.16 - 4.07 (m, 1H), 3.56 - 3.46 (m, 1H), 3.36 - 3.31 (m, 2H), 1.95 (t, J= 17.8 Hz, 3H), 0.98 - 0.96 (m, 1H), 0.70 - 0.68 (m, 1H), 0.58 - 0.55 (m, 1H), 0.45 - 0.37 (m, 2H).Example 22: (S, E)-N-(l-cyclopropyl-3-(((3-methyloxetan-3-yl)methyl)sulfonyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0294] Step A: To a suspension ofNaH (28.7 mg, 1.2 mmol, 60% dispersion in mineral oil) in THF (2 mL) was added diethyl (mercaptomethyl)phosphonate (200 mg, 1.09 mmol). The reaction was stirred at 0 °C for 30 min, then a solution of 3-(bromomethyl)-3-methyloxetane (197 mg, 1.2 mmol) in THF (2 mL) was slowly added into the mixture. The resulting solution was stirred at 0 °C for another 1 hour. The mixture was poured into ice-water, extracted withEtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 40% ethyl acetate in petroleum ether to afford diethyl ((((3-methyloxetan- 3-yl)methyl)thio)methyl)phosphonate (130 mg, 45%). LCMS (ESI): m / z 269[M+H]+.

[0295] Step B: To a suspension of diethyl ((((3-methyloxetan-3- yl)methyl)thio)methyl)phosphonate (130 mg, 0.48 mmol) in MeOH (2 mL) and (2 mL) was H2O added Oxone (894 mg, 1.45 mmol). The reaction was stirred at 25 °C for 1 hour. The mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 60% ethyl acetate in petroleum ether to afford diethyl ((((3-methyloxetan-3-yl)methyl)sulfonyl)methyl)phosphonate (80 mg, 55%). LCMS (ESI): m / z 301 [M+H]+.

[0296] Step C: To a solution of diethyl ((((3-methyloxetan-3- yl)methyl)sulfonyl)methyl)phosphonate (80 mg, 0.27 mmol) in THF (1 mL) was added LiHMDS (0.27 mL, 0.27 mmol, 1 mol / L in Hexane) dropwise at 0 °C. After stirred at 0 °C for 30 min, the mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide (65 mg, 0.18 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 30 min. The mixture was poured into saturated aqueous NH4CI solution at 0 °C, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-(((3- methyloxetan-3-yl)methyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxamide (11.1 mg, 12%). LCMS (ESI): m / z 512 [M+H]+.1H NMR (400 MHz, DMSOdd6) δ 7.83 (d, J= 8.2 Hz, 1H), 7.22 (t, J= 7.9 Hz, 2H), 7.00 (t, J= 7.4 Hz, 1H), 6.96 (d, J= 7.9 Hz, 2H), 6.89 (s, 1H), 6.59 (dd, J= 15.2, 5.6 Hz, 1H), 6.47 (d, J= 15.2 Hz, 1H), 4.32 - 4.28 (m, 2H), 3.90 (d, .7= 5.6 Hz, 2H), 3.77 - 3.74 (m, 1H), 3.29 (s, 2H), 1.79 (t, J= 18.8 Hz, 3H), 1.23 (s, 3H), 0.96 - 0.88 (m, 1H), 0.29 - 0.01 (m, 4H).Example 23: (S, E)-N-(l-cyclopropyl-3-((trifluoromethyl)sulfonyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamideExample 23

[0297] Step A: To a suspension of 3,3-dimethyl-l-(trifluoromethyl)-l,3-dihydro-113- benzo[d][l,2]iodaoxole (396 mg, 1.19 mmol) in anhydrous DCM (5 mL) was added a solution of diethyl (mercaptomethyl)phosphonate (200 mg, 1.09 mmol) in anhydrous DCM (2 mL) dropwise at -78 °C under nitrogen. The result suspension was stirred at -78 °C for 1 hour and warm to room temperature and stirred at room temperature for another 1 hour. The reaction was poured into ice-water, extracted with DCM. The organic extract was washed with water and brine, dried over anhydrous ISfeSCU, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 40% EtOAc in petroleum ether to afford diethyl (((trifluoromethyl)thio)methyl)phosphonate (210 mg, 76%). LCMS: ESI m / z 253.1[M+H] .1H NMR (400 MHz, DMSO-tZ6) 5 4.09 (dd, J= 8.4, 7.2 Hz, 4H), 3.55 (d, J= 14.8 Hz, 2H), 1.26 (t, J= 7.0 Hz, 6H).

[0298] Step B: To a solution of diethyl (((trifluoromethyl)thio)methyl)phosphonate (130 mg, 0.52 mmol) in anhydrous THF (5 mL) was added LiHMDS (1 mL, 1 mmol, 1.0 mol / L in Hexane) dropwise at -78 °C under nitrogen. The result mixture was stirred at -78 °C for 0.5 hours. Then a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (130 mg, 0.36 mmol) in THF (2 mL) was added into the mixture and stirred at -78 °C for another 1 hour. The reaction mixture was quenched with saturated NH4CI solution at 0 °C and extracted with EtOAc twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crudeproduct was purified by silica gel flash chromatography, eluted with a gradient of 0 - 60% EtOAc in petroleum ether to afford (S, E)-N-(l-cyclopropyl-3-((trifluoromethyl)thio)allyl)-5- (l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (45 mg, 27%). LCMS: ESI m / z 464.4[M+H]~ 1H NMR (400 MHz, CDC13) δ 7.45 - 7.40 (m, 2H), 7.27 - 7.24 (m, 1H), 7.18 (d, .7= 8.0 Hz, 1H), 7.13 - 7.11 (m, 2H), 6.72 (s, 1H), 6.29 (d, J= 15.8 Hz, 1H), 6.19 (dd, J= 15.1, 5.0 Hz, 1H), 4.18 - 4.10(m, 1H), 1.95 (d, J= 17.8 Hz, 3H), 0.96 - 0.86 (m, 1H), 0.61 - 0.48 (m, 2H), 0.41 - 0.31 (m, 2H).

[0299] Step C: To a stirred solution of (S, E)-N-(l-cyclopropyl-3- ((trifluoromethyl)thio)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (40 mg, 0.09 mmol) in DCM (2 mL) were added m-CPBA (44 mg, 0.22 mmol, 87%). The mixture was stirred at 40 °C overnight. The reaction mixture was quenched with saturated Na2S2O3solution at 0 °C, extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by prep-HPLC to give (S, E)-N-(l -cyclopropyl -3-((trifluoromethyl)sulfonyl)allyl)-5-( 1,1 -difluoroethyl)-3- phenoxythiophene-2-carboxamide (2.9 mg, 6%). LCMS (ESI): m / z 496.4 [M+H]+, 1H NMR (400 MHz, CDCI3) 8 7.48 - 7.44 (m, 2H), 7.37 - 7.32 (m, 1H), 7.30 - 7.26 (m, 1H), 7.16 (d, J = 7.8 Hz, 2H), 6.76 (s, 1H), 6.46 (d, J= 15.4 Hz, 1H), 4.29 - 4.22 (m, 1H), 1.99 - 1.90 (m, 3H), 1.04 - 0.96 (m, 1H), 0.76 - 0.60 (m, 2H), 0.49 - 0.42 (m, 2H).Example 24: (S, E)-N-(3-(((lH-pyrazol-4-yl)methyl)sulfonyl)-l-cyclopropylallyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0300] Step A: To a solution of lH-pyrazole-4-carbaldehyde (2 g, 20.8 mmol) in DMF (25 mL) was added NaH (0.75 g, 31.2 mmol, 60% dispersion in mineral oil) at 0 °C under nitrogen. The resulting mixture stirred at 0 °C for 1 hour. A solution of l-chloro-5,5-dimethyl-2-oxa-5- silahexane (3.82 g, 20.9 mmol) in anhydrous DMF (2 mL) was added dropwise into the mixture and stirred at 0 °C for another 1 hour. The reaction mixture was quenched with saturated NH4CI solution at 0 °C and extracted with EtOAc twice, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 10% ethyl acetate in petroleum ether to afford l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-4-carbaldehyde (3 g, 64%). LCMS (ESI): m / z 227 [M+H]+.

[0301] Step B: To a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-4- carbaldehyde (2.0 g, 8.84 mmol) in MeOH (20 mL) was added NaBFL (0.5 g, 13.2 mmol) by portions. The reaction was stirred at 0 °C for 1 hour. The reaction was quenched with saturated NH4CI solution at 0 °C and extracted with EtOAc twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 30% ethyl acetate in petroleumether to afford (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)methanol (2 g, 99%). LCMS (ESI): m / z 229 [M+H]+.

[0302] Step C: To a solution of (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4- yl)methanol (2 g, 8.76 mmol) and PPh.3 (2.53 g, 9.63 mmol) in DMF (30 mL) was added CBr4 (3.19 g, 9.63 mmol). The reaction was stirred at 25 °C for 2 hours. The mixture was poured into water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford 4- (bromomethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (1.4 g, 55%). LCMS (ESI): m / z 291[M+H]+.

[0303] Step D: To a solution of 4-(bromomethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazole (550 mg, 1.89 mmol) in anhydrous DMF (5 mL) was added NaH (45 mg, 1.89 mmol, 60% dispersion in mineral oil) by portions under nitrogen at 0 °C. The suspension was stirred at 0 °C for 1 hour, then a solution of diethyl (mercaptomethyl)phosphonate (348 mg, 1 .89 mmol) in anhydrous DMF (2 mL)was slowly added into the mixture and stirred at 0 °C for another 2 hours. The reaction was quenched with ice-water, extracted with EtOAc. The organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0 - 32% EtOAc in petroleum ether to afford diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4- yl)methyl)thio)methyl)phosphonate (500 mg, 67 %). LCMS (ESI): m / z 395[M+H]+.

[0304] Step E: To a solution of diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol- 4-yl)methyl)thio)methyl)phosphonate (200 mg, 0.51 mmol) in DCM (4 mL) was added m-CPBA (218.68 mg, 1.27 mmol, 85%)by portions at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO3solution, extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, elution with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford diethyl ((((l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)methyl)sulfonyl)methyl)phosphonate (180 mg, 83%). LCMS (ESI): m / z 427[M+H]+.

[0305] Step F To a solution of diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol- 4-yl)methyl)sulfonyl)methyl)phosphonate (100 mg, 0.23 mmol) in THF (4 mL) was addedLiHMDS (0.22 mL, 0.22 mmol, 1 mol / L in Hexane) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2- oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (57.11 mg, 0.16 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by a gradient of 0 - 80% ethyl acetate in petroleum ether to afford (S, E)-N-(l-cyclopropyl-3-(((l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazol-4-yl)methyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (60 mg, 62%) LCMS (ESI): m / z 638[M+H]+.

[0306] Step G: To a solution of (S, E)-N-(l-cyclopropyl-3-(((l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)methyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (60 mg, 0.09 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at 25 °C for 30 minutes. Then the mixture was poured into saturated aqueous NaHCO3solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep- HPLC to afford (S, E)-N-(3-(((lH-pyrazol-4-yl)methyl)sulfonyl)-l-cyclopropylallyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide (16.9 mg, 35%) LCMS (ESI): m / z 508[M+H]+.

[0307] 1H NMR ((400 MHz, MeOD-d4) δ 7.78 - 7.51 (m, 2H), 7.48 - 7.43 (m, 2H), 7.29 -7.23 (m, 1H), 7.20 - 7.15 (m, 2H), 6.91 (t, J= 1.2 Hz, 1H), 6.71 (dd, 15.2, 5.2 Hz, 1H), 6.46 (dd, J= 15.2, 1.4 Hz, 1H), 4.28 - 4.24 (m, 2H), 4.01 - 3.96 (m, 1H), 1.97 (t, J= 18.2 Hz, 3H), 1.09 - 1.00 (m, 1H), 0.64 - 0.49 (m, 2H), 0.37 - 0.30 (m, 2H).Example 25: (S, E)-N-(l-cyclopropyl-3-((oxetan-3-ylidenemethyl)sulfonyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0308] Step A: To a stirred mixture of diethyl (mercaptomethyl)phosphonate (300 mg, 1.63 mmol) and K2CO3 (450 mg, 3.26 mmol) in DMF (3 mL) was added 3-fluoro-3- (iodomethyl)oxetane (351 mg, 1.63 mmol). After stirred at room temperature for 1 hour, the mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, fdtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afford diethyl ((((3-fluorooxetan-3-yl)methyl)thio)methyl)phosphonate (300 mg, 67%). LCMS (ESI): m / z 273.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 4.66 - 4.55 (m, 4H), 4.04 (p, J= 7.2 Hz, 4H), 3.36 (s, 1H), 3.30 (s, 1H), 2.99 (d, J= 13.0 Hz, 2H), 1.25 (t, J= 7.0 Hz, 6H).

[0309] Step B: To a stirred solution of diethyl ((((3-fluorooxetan-3- yl)methyl)thio)methyl)phosphonate (300 mg, 1.10 mmol) in DCM (2 mL) were added m-CPBA (559 mg, 2.75 mmol, 85%) by portions and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and water, quenched with 10% NaS2O3solution, extracted with DCM, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afforddiethyl ((((3-fluorooxetan-3-yl)methyl)sulfonyl)methyl)phosphonate (330 mg, 98%). LCMS (ESI): m / z 305.2 [M+H]+.

[0310] Step C: To a stirred solution of diethyl ((((3-fluorooxetan-3- yl)methyl)sulfonyl)methyl)phosphonate (150 mg, 0.49 mmol) in anhydrous THF (2 mL) was added LiHMDS (1.48 mL, 1.48 mmol, 1 mol / L) dropwise at -78 °C under nitrogen. The result mixture was stirred at -78 °C for 0.5 hours. A solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5- (l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (180 mg, 0.49 mmol) in THF (2 mL) was added into the above solution and stirred for another 1 hour. The mixture was poured into ice-water, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by Prep-HPLC to afford (S, E)- N-(l-cyclopropyl-3-((oxetan-3-ylidenemethyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (23.3 mg, 9%). LCMS (ESI): m / z 496.5[M+H]+. 1H NMR (400 MHz, DMSO-d6 ) δ 8.10 (d, J= 8.4 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.27 - 7.23 (m, 1H), 7.20 (d, J= 7.8 Hz, 2H), 7.14 (s, 1H), 6.86 (dd, J= 15.2, 5.4 Hz, 1H), 6.70 (d, J= 15.2 Hz, 1H), 6.44 (d, J= 2.2 Hz, 1H), 5.39 - 5.33 (m, 2H), 5.26 - 5.18 (m, 2H), 4.08 - 4.00 (m, 1H), 2.08 - 1.99 (m, 3H), 1.20 - 1.13 (m, 1H), 0.55 - 0.49 (m, 1H), 0.44 - 0.37 (m, 2H), 0.29 - 0.22 (m, 1H).Example 26: (S, E)-N-(3-(((lH-pyrazol-3-yl)methyl)sulfonyl)-l-cyclopropylallyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0311] Step A: To a solution of ethyl lH-pyrazole-3-carboxylate (2 g, 14.3 mmol) in DMF (25 mL) was added NaH (1.14 g, 28.5 mmol, 60% dispersion in mineral oil) by portions at 0 °C under nitrogen. The resultmixture stirred at 0 °C for 1 hour. A solution of l-chloro-5,5-dimethyl- 2-oxa-5-silahexane (2.86 g, 17. 1 mmol) in anhydrous DMF (2 mL) was added dropwise into the mixture and stirred at 0°C for 1 hour. The reaction mixture was poured into saturated NH4CI solution at 0 °C and extracted with EtOAc twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 10% ethyl acetate in petroleum ether to afford ethyl l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-3-carboxylate (1.6 g, 42%). LCMS (ESI): m / z 271 [M+H]+.

[0312] Step B: To a solution of ethyl l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-3- carboxylate (1.6 g, 5.9 mmol) in THF (20 mL) was added LiAlFL (8.8 mL,8.8 mmol, 1 mol / L in THF) dropwise at 0 °C. The result mixture was stirred for 1 hour. The reaction was quenched with Na2SO410 H2O 0°C. The mixture was filtered and filter caked was washed with EtOAc. The combined filtrate was concentrated and the crude product was purified by silica gel flash chromatography eluted with 0 - 50% ethyl acetate in petroleum ether to afford (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)methanol (880 mg, 65%). LCMS (ESI): m / z 229 [M+H]+.

[0313] Step C: To a solution of (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3- yl)methanol (880 mg, 3.85 mmol) and PPhs (1212.86 mg, 4.62 mmol) in DMF (10 mL) was added CBr4 (1.5 g, 4.62 mmol). The reaction was stirred at 25 °C for 2 hours. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford 3-(bromomethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazole (700 mg, 62%). LCMS (ESI): m / z 291[M+H]+.

[0314] Step D: To a mixture of 3-(bromomethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazole (700 mg, 2.06 mmol) and K2CO3 (569 mg, 4.12 mmol) in DMF (10 mL) was added diethyl (sulfanylmethyl)phosphonate (417 mg, 2.27 mmol). The reaction was stirred at 40 °C for 2 hours. The cooled mixture was poured into water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 50% ethyl acetate in petroleum ether to afford diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol- 3-yl)methyl)thio)methyl)phosphonate (550 mg, 68%). LCMS (ESI): m / z 395[M+H]+.

[0315] Step E: To a solution of diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazol- 3-yl)methyl)thio)methyl)phosphonate (100 mg, 0.25 mmol) in DCM (4 mL) was added 3- chlorobenzene-l-carboperoxoic acid (131 mg, 0.76 mmol, 85%). The reaction was stirred at 40 °C for 1 hour. The cooled mixture was poured into saturated aqueous NaHCO3solution, extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford diethyl ((((l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)methyl)sulfonyl)methyl)phosphonate (70 mg, 65%). LCMS (ESI): m / z 426[M+H]+.

[0316] Step F: To a solution of diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol- 3-yl)methyl)sulfonyl)methyl)phosphonate (70 mg, 0.16 mmol) in THF (4 mL) was added LiHMDS (0.22 mL, 0.22 mmol, 1 mol / L in Hexane) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (40 mg, 0.11 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by a gradient of 0 - 80% ethyl acetate in petroleum ether to afford (S, E)-N-(l-cyclopropyl-3-(((l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazol-3-yl)methyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (40 mg, 57%) LCMS (ESI): m / z 638[M+H]+.

[0317] Step G: To a solution of (S, E)-N-(l-cyclopropyl-3-(((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)methyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (40 mg, 0.06 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at 25 °C for 30 minutes. The mixture concentrated and the residue was dissolved in saturated aqueous NaHCO3solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (S, E)-N-(3-(((lH-pyrazol-3-yl)methyl)sulfonyl)-l- cyclopropylallyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (2.2 mg, 6.91%) LCMS (ESI): m / z 508[M+H]+. 1H NMR ((400 MHz, MeOD-d4) δ 7.66 - 7.50 (m, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.26 (t, J= 1A Hz, 1H), 7.18 (d, J= 7.8 Hz, 2H), 6.90 (s, 1H), 6.73 (dd, J= 15.2, 5.0 Hz, 1H), 6.49 (dd, J= 15.3, 1.4 Hz, 1H), 6.39 (s, 1H), 4.48 - 4.35 (m, 2H), 4.03 (s, 1H), 1.97 (t, J= 18.2 Hz, 3H), 1.09 - 1.02 (m, 1H), 0.62 - 0.48 (m, 2H), 0.36 - 0.29 (m, 2H).Example 27: (S, E)-N-(3-((azetidin-3-ylmethyl)sulfonyl)-l-cyclopropylallyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide and Example 28: tert-butyl (S, E)-3- (((3-cyclopropyl-3-(5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamido)prop-l-en-l- yl)sulfonyl)methyl)azetidine-l-carboxylate

[0318] Step A: To a suspension of diethyl (mercaptomethyl)phosphonate (500 mg, 2.94 mmol) in anhydrous DMF (10 mL) was added NaH (71 mg, 2.94 mmol, 60% dispersion in mineral oil) by portions. The result mixture was stirred at °Cfor 0.5 hours. A solution of tertbutyl 3-(bromomethyl)azetidine-l-carboxylate (955 mg, 3.82 mmol) in DMF (10 mL) was added dropwise into the above mixture and stirred at 0 °C for another 1 hour. The mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 -30 % ethyl acetate in petroleum ether to afford tertbutyl 3-((((diethoxyphosphoryl)methyl)thio)methyl)azetidine-l-carboxylate (800 mg, 77%). LCMS (ESI): m / z 354.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 4.03 (q, J = 7.2 Hz, 4H), 3.89 (s, 2H), 3.50 (s, 2H), 2.92 - 2.87 (m, 4H), 2.74 (d, J= 9.6 Hz, 1H), 1.37 (s, 9H), 1.24 (t, J = 7.0 Hz, 6H).

[0319] Step B: To a stirred mixture of tertebutyl 3- ((((diethoxyphosphoryl)methyl)thio)methyl)azetidine-l-carboxylate(250 mg, 0.74 mmol) in DCM (5 mL) were added m-CPBA (127 mg, 0.74 mmol, 85%) by portions at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was was poured into saturated aqueous NaHCO3solution, extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, elution with a gradient of 0 - 12% MeOH in DCM ether toafford tert-butyl 3 -((((diethoxyphosphoryl)methyl)sulfonyl)methyl)azetidine-l -carboxylate (250 mg, 91%). LCMS: ESI m / z 372.3 [M+H]+.

[0320] Step C: To a solution of tert-butyl 2-(((diethoxyphosphoryl)methyl)sulfonyl)acetate (205.7 mg, 0.53 mmol) in THF (5 mb) was added LiHMDS (0.55 mL, 0.55 mmol, 1 mol / L in Hexane) dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (100 mg, 0.27 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford tert-butyl (S, E)-3-(((3-cyclopropyl-3-(5-(l,l- difluoroethyl)-3 -phenoxythiophene-2-carboxamido)prop- 1 -en- 1 -yl)sulfonyl)methyl)azetidine- 1 - carboxylate (90 mg, 55%). LCMS (ESI): m / z 597 [M+H]+. 1H NMR (400 MHz, CDCI3) 8 7.49 - 7.42 (m, 2H), 7.29 (d, J= 7.2 Hz, 1H), 7.17 - 7.13 (m, 2H), 6.95 (dd, J= 15.0, 4.7 Hz, 1H), 6.75 (d, J= 1.2 Hz, 1H), 6.36 (dd, J= 15.0, 1.6 Hz, 1H), 4.11 (t, J= 8.6 Hz, 3H), 3.80 - 3.70 (m, 2H), 3.23 (d, J= 7.6 Hz, 2H), 3.07 - 2.94 (m, 1H), 1.95 (t, J= 17.8 Hz, 3H), 1.43 (s, 9H), 1.03 - 0.92 (m, 1H), 0.73 - 0.64 (m, 1H), 0.62 - 0.54 (m, 1H), 0.46 - 0.37 (m, 2H).

[0321] Step D: To a stirred mixture of tert-butyl (S, E)-3-(((3-cyclopropyl-3-(5-(l,l- difluoroethyl)-3 -phenoxythiophene-2-carboxamido)prop- 1 -en- 1 -yl)sulfonyl)methyl)azetidine- 1 - carboxylate (40 mg, 0.07 mmol) in DCM (3 mL), were added TFA (1 mL) at 0 °C. The mixture concentrated and the residue was dissolved in saturated aqueous NaHCO3solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (S, E)-N-(3- ((azetidin-3-ylmethyl)sulfonyl)-l-cyclopropylallyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxamide (15 mg, 45%). LCMS (ESI): m / z 497 [M+H]+. 1H NMR (400 MHz, CDCI3) 8 9.81 (s, 2H), 7.50 - 7.42 (m, 2H), 7.36 (d, J= 6.8 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.19 - 7.12 (m, 2H), 6.96 (dd, J= 15.0, 4.7 Hz, 1H), 6.73 (d, J= 1.2 Hz, 1H), 6.45 - 6.35 (m, 1H), 4.24 (s, 2H), 4.05 (s, 3H), 3.40 (s, 3H), 1.94 (t, J = 17.8 Hz, 3H), 1.06 - 0.94 (m, 1H), 0.73 - 0.65 (m, 1H), 0.62 - 0.54 (m, 1H), 0.47 - 0.36 (m, 2H).Example 29: (S, E)-N-(3-((2-amino-2-oxoethyl)sulfonyl)-l-cydopropylallyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0322] Step A: To a suspension of lH-imidazole-4-carbaldehyde (3.0 g, 31.2 mmol) and K2CO3 (8.6 g, 62.4 mmol) in DMF (20 mL) was added SEM-C1 (7.8 g, 46.8 mmol) dropwise at 0 °C. The reaction was stirred at 60 °C for 1 hours. The cooled mixture was diluted with EtOAc and water, the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 40% ethyl acetate in petroleum ether to afford l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole-4-carbaldehyde (2.4 g, 40%). LCMS (ESI): m / z 227 [M+H]+.

[0323] Step B: To a suspension of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-4- carbaldehyde (2.4 g, 10.6 mmol) in THF (20 mL) was added NaBFL (800 mg, 21.2 mmol) by portions at 0 °C. The reaction was stirred at 25 °C for 1 hours. The mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 25% ethyl acetate inpetroleum ether to afford (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)methanol (870 mg, 36%). LCMS (ESI): m / z 229 [M+H]+.

[0324] Step C: To a solution of (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4- yl)methanol (300 mg, 1.31 mmol) in DCM (3 mL) was added TEA (133mg, 1.31 mmol) and MsCl (302 mg, 2.63 mmol) dropwise at 0 °C, and the mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was diluted with DCM, and organic layer was separated, was washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated to afforded a crude (1- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)methyl methanesulfonate (300 mg, 75%) which was used directly for next step.. LCMS (ESI): m / z 307 [M+H]+.

[0325] Step D: To a suspension of NaH (54 mg, 1.33 mmol, 60% dispersion in mineral oil) in THF (3 mL) was added diethyl (mercaptomethyl)phosphonate (300 mg, 0.98 mmol). The reaction was stirred at 0 °C for 0.5 hours, a solution of (l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazol-4-yl)methyl methanesulfonate (164 mg, 0.89 mmol) in THF (3 mL) was added into the mixture. The result mixture was stirred at 0 °C for another 1 hour. The mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% methanol in di chloromethane to afford diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)methyl)thio)methyl)phosphonate (300 mg, 85%). LCMS (ESI): m / z 395 [M+H]+.

[0326] Step E: To a stirred mixture of diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazol-4-yl)methyl)thio)methyl)phosphonate (100 mg, 0.25 mmol) in DCM (3 mL), were added m-CPBA (131.2 mg, 0.76 mmol, 85%) by portions at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO3solution, extracted with DCM. The organic layer 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 a gradient of 5 - 10% MeOH in DCM to afford diethyl ((((l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)methyl)sulfonyl)methyl)phosphonate (30 mg, 28%). LCMS (ESI): m / z 427 [M+H]+.

[0327] Step F: To a solution of diethyl ((((l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazol-4-yl)methyl)sulfonyl)methyl)phosphonate (30 mg, 0.07 mmol) in THF (5 mL) was added LiHMDS (0.11 mL, 0.11 mmol, 1 mol / L in Hexane) dropwise at 0 °C, and the mixturewas stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l- cyclopropyl-2-oxoethyl)-5-( 1 , 1 -difluoroethyl)-3-phenoxythiophene-2-carboxamide (19.8 mg, 0.05 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-(((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4- yl)methyl)sulfonyl)allyl)-5-(l, l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (10 mg, 29%). LCMS (ESI): m / z 638 [M+H]+.

[0328] Step G: To a stirred mixture of (S, E)-N-(l-cyclopropyl-3-(((l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)methyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (10 mg, 0.02 mmol) in DCM (2 mL), were added TFA (0.5 mL). The mixture was stirred at room temperature for 1 hour. The mixture concentrated and the residue was dissolved in saturated aqueous NaHCO3solution, extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by Prep-HPLC to afforded (S, E)-N-(3-(((lH- imidazol-4-yl)methyl)sulfonyl)-l-cy cl opropylallyl)-5-(l,l-difluoroethyl)-3 -phenoxythiophene-2- carboxamide (2 mg, 25%). LCMS (ESI): m / z 508 [M+H]+. ’H NMR (400 MHz, Methanol-d4) 8 8.91 (d, J= 1.3 Hz, 1H), 7.59 (s, 1H), 7.51 - 7.41 (m, 2H), 7.31 - 7.24 (m, 1H), 7.22 - 7.15 (m, 2H), 6.92 (d, J= 1.4 Hz, 1H), 6.83 (dd, J= 15.2, 5.2 Hz, 1H), 6.60 (dd, J= 15.2, 1.4 Hz, 1H), 4.63 - 4.53 (m, 2H), 3.96 - 3.86 (m, 1H), 1.97 (t, J= 18.2 Hz, 3H), 1.19 - 1.03 (m, 1H), 0.70 - 0.59 (m, 1H), 0.57 - 0.48 (m, 1H), 0.44 - 0.29 (m, 2H).Example 30: (S, E)-N-(1-cyclopropyl-3-((2-hydroxyethyl)sulfonyl)allyl)-5-(1,1- difluoroethyl)-3-phenoxythiophene-2-carboxamideStep C Step D

[0329] Step A: To a suspension of NaH (72 mg, 3.0 mmol, 60% dispersion in mineral oil) in THF (5 mL) was added diethyl (mercaptomethyl)phosphonate (500 mg, 2.71 mmol). The reaction was stirred at 0 °C for 30 min, then (2-bromoethoxy)(tert-butyl)dimethylsilane (714 mg, 3.0 mmol) was slowly added. The resulting solution was stirred at 0 °C for another 1 hour. The cooled mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 40% ethyl acetate in petroleum ether to afford diethyl (((2-((tert- butyldimethylsilyl)oxy)ethyl)thio)methyl)phosphonate (450 mg, 48%). LCMS (ESI): m / z 343 [M+H]+.

[0330] Step B: To a suspension of diethyl (((2-((tert- butyldimethylsilyl)oxy)ethyl)thio)methyl)phosphonate (160 mg, 0.47 mmol) in DCM (2 mL) was added m -chloroperoxybenzoic acid (241 mg, 1.4 mmol, 85%). The reaction was stirred at 25 °C for 1 hours. The reaction mixture was quenched with saturated aqueous Na2S2O3 solution, extracted with DCM twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford diethyl (((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)methyl)phosphonate (150 mg, 86%). LCMS (ESI): m / z 375 [M+H]+.

[0331] Step C: To a suspension of diethyl (((2-((tert- butyldimethylsilyl)oxy)ethyl)sulfonyl)methyl)phosphonate (100 mg, 0.27 mmol) in THF (10 mL) was added LiHMDS (0.4 mL, 1 Min THF) at 0 °C. The reaction was stirred at 0 °C for 1 hour under nitrogen, then a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)- 3-phenoxythiophene-2-carboxamide (100 mg, 0.27 mmol) in THF (3 mL) was slowly added at - 60 °C. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluted with 0 - 40% ethyl acetate in petroleum ether to afford (S, E)-N-(3-((2-((tert- butyldimethylsilyl)oxy)ethyl)sulfonyl)-l-cyclopropylallyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (50 mg, 30%). LCMS (ESI): m / z 586 [M+H]+.

[0332] Step D: A mixture of (S,E)-N-(3-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-l- cyclopropylallyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (50 mg, 0.09 mmol) in THF / HOAc / HCl ( ImL / lmL / lmL) was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-((2- hydroxyethyl)sulfonyl)allyl)-5-(l, l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (3 mg, 7%). LCMS (ESI): m / z 472 [M+H]+. 1H NMR (400 MHz, MeOD-d4) δ 7.47 (t, J= 8.0 Hz, 2H), 7.28 (t, J= 7.2 Hz, 1H), 7.20 (d, J= 8.0 Hz, 2H), 6.94 - 6.9 (m, 2H), 6.65 (d, J= 15.2 Hz, 1H), 4.10 - 4.06 (m, 1H), 3.90 (t, J = 6.0 Hz, 2H), 3.23 (t, J= 6.0 Hz, 2H), 1.97 (t, J = 18.0 Hz, 3H), 1.22 - 1.09 (m, 1H), 0.72 - 0.61 (m, 1H), 0.55 - 0.53 (m, 1H), 0.44 - 0.39 (m, 2H).Example 31: (S, E)-N-(l-cyclopropyl-3-((methoxymethyl)sulfonyl)allyl)-5-(l,l- difluoroethyI)-3-phenoxythiophene-2-carboxamideExample 31

[0333] Step A: To a mixture of diethyl (mercaptomethyl)phosphonate (200 mg, 1 .09 mmol) and K2CO3 (300mg, 2.17 mmol) in DMF (5 mL) was added chloro(methoxy)methane (131mg, 1.63 mmol). The result mixture was stirred at 40 °C for 1 hour. The cooled mixture was poured into ice-water, extracted with EtOAc twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, fdtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 50% ethyl acetate in petroleum ether to afford diethyl (((methoxymethyl)thio)methyl)phosphonate (120 mg, 48%). LCMS (ESI): m / z 229 [M+H]+.

[0334] Step E: To a solution of diethyl (((methoxymethyl)thio)methyl)phosphonate (120 mg, 0.53 mmol) in DCM (4 mL) was added 3-chlorobenzene-l-carboperoxoic acid (272mg, 1.58 mmol, 85%) by portions at 0 °C. The result mixture was reaction was stirred at 30 °C for 1 hour. The mixture was poured into saturated aqueous NaHCO3 solution at 0 °C, extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 30% ethyl acetate in petroleum ether to afford diethyl (((methoxymethyl)sulfonyl)methyl)phosphonate (40 mg, 29%). LCMS (ESI): m / z 261[M+H]+.

[0335] Step F: To a solution of diethyl (((methoxymethyl)sulfonyl)methyl)phosphonate (70 mg, 0.16 mmol) in THF (4 mL) was added LiHMDS (0.31 mL, 0.31 mmol, 1 mol / L in Hexane) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2- carboxamide (84 mg, 0.23 mmol) in THF (2 mL) was added dropwise into the mixture. Theresulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to afford (S, E)-N-(l-cyclopropyl-3-((methoxymethyl)sulfonyl)allyl)-5- (l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (3.5 mg, 5%) LCMS (ESI): m / z 472[M+H]+. 1H NMR ((400 MHz, MeOD-d4) δ 7.48 - 7.44 (m, 2H), 7.26 (t, J= 7.4 Hz, 1H), 7.21 - 7.17 (m, 2H), 6.97 (dd, J= 15.2, 5.0 Hz, 1H), 6.90 (d, J= 1.2 Hz, 1H), 6.57 (dd, J= 15.2, 1.6 Hz, 1H), 4.48 (s, 2H), 4.13 - 4.08 (m, 1H), 3.58 (s, 3H), 1.96 (t, J = 18.2 Hz, 3H), 1.18 - 1.11 (m, 1H), 0.69 - 0.62 (m, 1H), 0.57 - 0.51 (m, 1H), 0.45 - 0.37 (m, 2H).Example 32: (S, E)-N-(3-((2-(azetidin-l-yl)ethyl)sulfonyl)-l-cyclopropylallyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0336] Step A: To a suspension of NaH (324 mg, 8.1 mmol, 60% dispersion in mineral oil) in THF (5 mL) was added diethyl (mercaptomethyl)phosphonate (1.0 g, 5.4 mmol). The reaction was stirred at 0 °C for 30 min, then 2-bromo- 1,1 -di ethoxy ethane (1.6 g, 8.1 mmol) was slowly added. The resulting solution was stirred at 0 °C for 1 hour. The cooled mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried overanhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 40% ethyl acetate in petroleum ether to afford diethyl (((2,2-diethoxyethyl)thio)methyl)phosphonate (1.1 g, 68%). LCMS (ESI): m / z 301 [M+H]+.

[0337] Step B: A solution of diethyl (((2, 2-di ethoxy ethyl)thio)methyl)phosphonate (1000 mg, 3.3 mmol) in anhydrous FA (20 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated and the residue was dissolved in EtOAc and poured into saturated aqueous NaHCO3solution, extracted with EtOAc, The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford diethyl (((2- oxoethyl)thio)methyl)phosphonate (500 mg, 67%). LCMS (ESI): m / z 227 [M+H]+.

[0338] Step C: To a solution of diethyl (((2-oxoethyl)thio)methyl)phosphonate (500 mg, 2.2 mmol) in anhydrous methanol (20 mL) was added azetidine (251mg, 4.4 mmol) and the result mixture was stirred at 25 °C for 1 hour, then NaBH3CN (690 mg, 1 Immol) was slowly added. The resulting solution was stirred at 25°C for 3 hours. The mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 10% MeOH in DCM to afford diethyl (((2-(azetidin-l- yl)ethyl)thio)methyl)phosphonate (200 mg, 34%). LCMS (ESI): m / z 268 [M+H]+.

[0339] Step D: To a solution of diethyl (((2-(azetidin-l-yl)ethyl)thio)methyl)phosphonate (100 mg, 0.37 mmol) in MeOH (lOmL) and (10 mH2LO) was added Oxone (689 mg, 1.12 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 15% MeOH in DCM to afford diethyl (((2-(azetidin-l- yl)ethyl)sulfonyl)methyl)phosphonate (50 mg, 45%). LCMS (ESI): m / z 300 [M+H]+.

[0340] Step E: To a suspension of diethyl (((2-(azetidin-l- yl)ethyl)sulfonyl)methyl)phosphonate (50 mg, 0.16 mmol) in THF (10 mL) was added LiHMDS (0.24 mL, 0.24 mmol, I M in THF) at 0 °C and stirred at 0 °C for 1 hour under nitrogen, then a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l, l-difluoroethyl)-3 -phenoxy thiophene-2 - carboxamide (58 mg, 0.16 mmol) in THF (3 mL) was slowly added at -60 °C. The resulting solution was stirred at -60 °C for another 1 hour. The reaction mixture was poured into ice-water,extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Prep-HPLC to afford (S, E)-N-(3 -((2-(azetidin- 1 -yl)ethyl)sulfonyl)- 1 -cyclopropylallyl)-5-(l , 1 -difluoroethyl)-3 - phenoxythiophene-2-carboxamide (10.3 mg, 12%). LCMS (ESI): m / z 511 [M+H]+. 1HNMR (400 MHz, CDC3) 5 7.47 - 7.43 (m, 2H), 7.33 (d, J= 7.2 Hz, 1H), 7.29 (d, J= 7.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.95 (dd, J= 15.2, 4.8 Hz, 1H), 6.73 (s, 1H), 6.52 (dd, J= 15.2, 1.6 Hz, 1H), 4.16 - 4.10 (m, 1H), 3.50 (t, J= 7.6 Hz, 4H), 3.11 - 3.09 (m, 2H), 3.05 - 2.98 (m, 2H), 2.23 - 2.16 (m, 2H), 1.98 - 1.89(m, 3H), 1.02 - 0.97 (m, 1H), 0.69 - 0.64 (m, 1H), 0.59 - 0.54(m, 1H), 0.43 - 0.39 (m, 2H).Example 33: (S, E)-N-(l-cyclopropyl-3-(((3-hydroxyoxetan-3-yl)methyl)sulfonyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamideExample 33

[0341] Step A: To a solution of 3 -(hydroxy methyl)oxetan-3-ol (250 mg, 2.40 mmol) and TEA (484 mg, 4.80 mmol) in DCM (5 mL) was Tosyl chloride (549 mg, 2.88 mmol). The resulting mixture stirred at 25°C for 1 hour. The reaction mixture was diluted with water, extracted with DCM twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 80% ethyl acetate in petroleum ether to afford (3- hydroxyoxetan-3-yl)methyl 4-methylbenzenesulfonate (170 mg, 27%). LCMS (ESI): m / z 259 [M+H]+.

[0342] Step B: To a solution of diethyl (mercaptomethyl)phosphonate (200 mg, 1.09 mmol) in DMF (5 mL) was added (3-hydroxyoxetan-3-yl)methyl 4-methylbenzenesulfonate (281 mg, 1.63 mmol) and K2CO3 (300 mg, 2.17 mmol) under nitrogen. The resulting mixture stirred at 40 °C for 1 hour. The reaction mixture was quenched with , extracted wHi2tOh EtOAc, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 50% ethyl acetate in petroleum ether to afford diethyl ((((3-hydroxyoxetan-3- yl)methyl)thio)methyl)phosphonate (90 mg, 51%). LCMS (ESI): m / z 271 [M+H]+.

[0343] Step C: To a solution of diethyl ((((3 -hydroxy oxetan-3- yl)methyl)thio)methyl)phosphonate (90 mg, 0.33 mmol) in DCM (4 mL) was added m-CPBA (144 mg, 0.83 mmol, 85%) at 25 °C. The reaction was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated aqueous Na2S2O 3 solution, extracted with DCM twice, the combined extracts were washed with water and brine, dried over anhydrous Na2SO4. filtered and concentrated. The crude product was purified by silica gel flash chromatography eluted with 0 - 100% ethyl acetate in petroleum ether to afford diethyl ((((3 -hydroxy oxetan-3- yl)methyl)sulfonyl)methyl)phosphonate (16 mg, 16%) LCMS (ESI): m / z 303[M+H]1.

[0344] Step D: To a solution of diethyl ((((3 -hydroxy ox etan-3 - yl)methyl)sulfonyl)methyl)phosphonate (16 mg, 0.05 mmol) in THF (5 mL) was added LiHMDS (0.1 mL, 0.08 mmol, 1 mol / L in Hexane) dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2- oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (15 mg, 0.04 mmol) in THF (1 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford (S,E)-N-(1- cy cl opropyl-3 -(((3 -hydroxy oxetan-3-yl)m ethyl)sulfonyl)allyl)-5-(l, 1 -difluoroethyl)-3 - phenoxythiophene-2-carboxamide (2.3 mg, 55%). LCMS (ESI): m / z 514 [M+H]+. 'H NMR (400 MHz, Methanol -d4 ) 5 7.51 - 7.46 (m, 2H), 7.32 - 7.26 (m, 1H), 7.24 - 7.20 (m, 2H), 6.94 - 6.86 (m, 2H), 6.73 (dd, J= 15.2, 1.6 Hz, 1H), 4.76 (t, J= 7.2 Hz, 2H), 4.58 (d, J= 7.2 Hz, 2H), 4.13 - 4.06 (m, 1H), 3.64 (s, 2H), 1.98 (t, J= 18.2 Hz, 3H), 1.19 - 1.09 (m, 1H), 0.71 - 0.62 (m, 1H), 0.58 - 0.51 (m, 1H), 0.45 - 0.36 (m, 2H).Example 34: tert-butyl (S, E)-3-(((3-cyclopropyl-3-(5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamido)prop-l-en-l-yl)sulfonyl)methyl)-3-hydroxyazetidine-l- carboxylate

[0345] Step A: To a stirred solution of diethyl (mercaptomethyl)phosphonate (400 mg, 2.17 mmol) in DMF (10 mL) was added NaH (52 mg, 2.17 mmol, 60% dispersion in mineral oil) by portions at 0 °C. The result mixture was stirred at 0 °C for 1 hour, then a solution of tert-butyl 3- (bromomethyl)-3-hydroxyazetidine-l -carboxylate (578 mg, 2.17 mmol) in DMF (3 mL) was slowly added and the result mixture was stirred at 0 °C for another 1 hour. The mixture was poured into ice-water, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 100% ethyl acetate in petroleum ether to afford tert-butyl 3-((((diethoxyphosphoryl)methyl)thio)methyl)-3-hydroxyazetidine-l- carboxylate (320 mg, 40%). LCMS (ESI): m / z 370 [M+H]+.

[0346] Step B: To a stirred mixture of tert-butyl 3- ((((diethoxyphosphoryl)methyl)thio)methyl)-3-hydroxyazetidine-l-carboxylate (320 mg, 87 mmol) in DCM (5 mL) was added m-CPBA (448 mg, 2.60 mmol, 85%) by portions at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO3 solution, extracted with DCM. The organic layer was washed with water and brine, dried overanhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, eluted with a gradient of 50 - 100% ethyl acetate in petroleum ether to afford tert-butyl 3-((((diethoxyphosphoryl)methyl)sulfonyl)methyl)-3-hydroxyazeti dine- 1 -carboxylate (200 mg, 58%). LCMS (ESI): m / z 402 [M+H]+.

[0347] Step C: To a solution of tert-butyl 3- ((((diethoxyphosphoryl)methyl)sulfonyl)methyl)-3-hydroxyazetidine-l -carboxylate (50 mg, 0.12 mmol) in THF (5 mL) was added LiHMDS (0.36 mL, 0.36 mmol, 1 mol / L in Hexane) dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l, l-difluoroethyl)-3 -phenoxythiophene-2 - carboxamide (35 mg, 0.10 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford tert-butyl (S, E)-3-(((3-cyclopropyl-3-(5-(l,l -difluoroethyl)-3- phenoxythiophene-2-carboxamido)prop-l-en-l-yl)sulfonyl)methyl)-3-hydroxyazetidine-l- carboxylate (7.7 mg, 13%). LCMS (ESI): m / z 613 [M+H]1. 'H NMR (400 MHz, MeOD-d4) 8 7.51 - 7.46 (m, 2H), 7.32 - 7.26 (m, 1H), 7.22 (d, J= 8.2 Hz, 2H), 6.93 - 6.86 (m, 2H), 6.72 (dd, J= 15.2, 1.6 Hz, 1H), 4.20 - 4.06 (m, 3H), 3.84 - 3.82(m, 2H), 3.56 (s, 2H), 1.98 (t, J= 18.2 Hz, 3H), 1.46 (s, 9H), 1.20 - 1.09 (m, 1H), 0.74 - 0.62 (m, 1H), 0.58 - 0.52 (m, 1H), 0.46 - 0.37 (m, 2H).Example 35: N-((1S, E)-l-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide

[0348] Step A: To a solution of diethyl ((methylthio)methyl)phosphonate (1 g, 5.04 mmol) in acetone (4 mL) and water (2 mL) was added NaIC4 (1.62 g, 7.57 mmol). The result mixture stirred at 25 °C for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The crude product was purified by silica gel flash chromatography eluted with 0 - 90% ethyl acetate in petroleum ether to afford diethyl ((methylsulfmyl)methyl)phosphonate (1.0 g, 93%). LCMS (ESI): m / z 215 [M+H]+.

[0349] Step B: To a suspension of diethyl ((methylsulfinyl)methyl)phosphonate (1 g, 4.67 mmol), 2,2,2-trifluoroacetamide (1.06 g, 9.34 mmol), MgO (750 mg, 18.67 mmol) and PhI(OAc)2 (1.51 g, 4.67 mmol) in DCM (40 mL) was added Rh2(OAc)4 (100 mg, 0.23 mmol). The result mixture was stirred at 25 °C for 16 hours. The solid was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 90% ethyl acetate in petroleum ether to afford diethyl ((S-methyl-N-(2,2,2- trifluoroacetyl)sulfonimidoyl)methyl)phosphonate (1.4 g, 92%). LCMS (ESI): m / z 326[M+H]+.

[0350] Step C: To a solution of diethyl ((S-methyl-N-(2,2,2- trifluoroacetyl)sulfonimidoyl)methyl)phosphonate (400 mg, 1.23 mmol) in MeOH (5 mL) was added K2CO3 (170 mg, 1.23 mmol). The reaction was stirred at 25 °C for 1 hour. The solid was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography, eluted with a gradient of 0 - 90% ethyl acetate in petroleum ether to afford diethyl ((S-methylsulfonimidoyl)methyl)phosphonate (160 mg, 57%) LCMS (ESI): m / z 230[M+H]+.

[0351] Step D: To a solution of diethyl ((S-methylsulfonimidoyl)methyl)phosphonate (60 mg, 0.26 mmol) in THF (4 mL) was added LiHMDS (0.79 mL, 0.79 mmol, 1 mol / L in Hexane) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was cooled to -60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (96 mg, 0.26 mmol) in THF (2 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford N-((1S, E)-l-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-5- (l,l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (17.9 mg, 15.5%) LCMS (ESI): m / zExample 36: N-((1S, E)-l-cyclopropyl-3-(N, S-dimethylsulfonimidoyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamideExample 36

[0352] Step A: To a solution of diethyl ((S-methylsulfonimidoyl)methyl)phosphonate (100 mg, 0.4 mmol), formaldehyde (0.03 mL, 0.9 mmol) and EtsSiH (507.3 mg, 4.4 mmol) in MeCN (4 mL) was added TFA (1.6 g, 7.6 mmol). The resulting mixture stirred at 25°C for 18 hours. Then the mixture was poured into saturated aqueous NHCO3 solution, extracted with EtOAc. The organic layer 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 - 20% ethyl acetate in petroleum ether to afford diethyl ((N, S- dimethylsulfonimidoyl)methyl)phosphonate (50 mg, 56 %). LCMS (ESI): m / z 244 [M+H]1.

[0353] Step B: To a solution of diethyl ((N, S-dimethylsulfonimidoyl)methyl)phosphonate (60 mg, 0.3 mmol) in THF (4 mL) was added LiHMDS (0.79 mL, 0.79 mmol, 1 mol / L in Hexane) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was cooled to-60 °C and a solution of (S)-N-(l-cyclopropyl-2-oxoethyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (95.64 mg, 0.26 mmol) in THF (4 mL) was added dropwise into the mixture. The resulting mixture was stirred at -60 °C for another 1 hour. Then the mixture was poured into saturated aqueous NH4CI solution, extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to afford N-((l S, E)-l-cyclopropyl-3-(N, S- dimethylsulfonimidoyl)allyl)-5-(l, l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (9.9 mg, 11%). LCMS (ESI): m / z 455[M+H]+. 1HNMR ((400 MHz, CDCI3) 8 7.47 - 7.42 (m, 2H), 7.28 (d, J= 7.4 Hz, 1H), 7.14 (d, J= 7.8 Hz, 2H), 6.88 (dd, J= 15.0, 4.4 Hz, 1H), 6.74 (s, 1H), 6.27 (dd, J= 15.0, 1.6 Hz, 1H), 4.28 - 4.20 (m, 1H), 2.94 - 2.93 (m, 3H), 2.69 - 2.67 (m, 3H), 1.94 (t, J= 17.8 Hz, 3H), 1.02 - 0.95 (m, 1H), 0.69 - 0.63 (m, 1H), 0.59 - 0.53 (m, 1H), 0.46 - 0.37 (m, 2H).Example 37: N-((S, E)-l-cyclopropyl-3-((S)-N,S-dimethylsulfonimidoyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide and Example 38: N-((S, E)-l- cyclopropyI-3-((R)-N,S-dimethylsulfonimidoyl)alIyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamideExample 37 Example 38

[0354] Step A: N-((1S, E)-l-cyclopropyl-3-(N, S-dimethylsulfonimidoyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide (7 mg, 0.02 mmol) was separated by SFC to give N-((S, E)-l-cyclopropyl-3-((S)-N,S-dimethylsulfonimidoyl)allyl)-5-(l,l-difluoroethyl)-3- phenoxythiophene-2-carboxamide (1.2 mg, 17%). LCMS (ESI): m / z 455 [M+H]+. 1H NMR (400 MHz, CDC13) δ7.45 (t, J = 7.8 Hz, 2H), 7.29 (s, 1H), 7.28 (d, J= 7.2 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.82 (dd, J= 15.2, 5.2 Hz, 1H), 6.74 (s, 1H), 6.28 (d, J= 15.2 Hz, 1H), 4.26 - 4.19 (m,1H), 2.93 (d, .7= 4.4 Hz, 3H), 2.68 (d, J= 6.4 Hz, 3H), 1.97 (d, J= 17.8 Hz, 3H), 1.00 - 0.96 (m, 1H), 0.68 - 0.57 (m, 2H), 0.45 - 0.37 (m, 2H). And N-((S, E)-l-cyclopropyl-3-((R)-N,S- dimethylsulfonimidoyl)allyl)-5-(l, l-difluoroethyl)-3-phenoxythiophene-2-carboxamide (2.4 mg, 34%). LCMS (ESI): m / z 455 [M+H]tJH NMR (400 MHz, CDC13) 87.45 (t, J= 7.8 Hz, 2H), 7.28 (d, J= 7.2 Hz, 1H), 7.14 (d, J= 7.8 Hz, 2H), 6.87 (dd, J= 15.2, 4.4 Hz, 1H), 6.74 (s, 1H), 6.27 (d, J= 15.2 Hz, 1H), 4.28 - 4.20 (m, 1H), 2.94 (s, 3H), 2.67 (s, 3H), 1.94 (t, J= 17.8 Hz, 3H), 1.03 - 0.97 (m, 1H), 0.70 - 0.64 (m, 1H), 0.59 - 0.52 (m, 1H), 0.47 - 0.38 (m, 2H).

[0355] Preparative separation method:Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IC, 250X30mm I.D., 5pm Mobile phase: A for CO2 and B for MEOH Gradient: B 10%Flow rate: 60mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220nm Cycle-time: 10min Eluted time: 2HExample 39: N-((S, E)-l-cyclopropyl-3-((S)-S-methylsulfonimidoyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide and Example 40 N-((S, E)-l- cyclopropyl-3-((R)-S-methylsulfonimidoyl)allyl)-5-(l,l-difluoroethyl)-3-phenoxythiophene- 2-carboxamide

[0356] Step A: N-((1S, E)-l-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide (260 mg, 0.59 mmol) was separated by SFC to give N-((S,E)- 1 -cyclopropyl -3-((S)-S-methylsulfonimidoyl)allyl)-5-(l , 1 -difluoroethyl)-3- phenoxythiophene-2-carboxamide (59.7 mg, 32%). LCMS (ESI): m / z 441 [M+H]+. 1H NMR (400 MHz, CDC13) 87.41 (dd, J= 7.4, 8.0 Hz, 2H), 7.23 (d, J= 7.4 Hz, 1H), 7.12 (d, J= 8.0 Hz, 2H), 6.87 (dd, J= 15.0, 4.6 Hz, 1H), 6.70 (s, 1H), 6.54 (dd, J= 15.0, 1.6 Hz, 1H), 4.19 - 4.11 (m, 1H), 2.94 (s, 3H), 1.91 (t, J= 17.8 Hz, 3H), 0.98 - 0.90 (m, 1H), 0.65 - 0.50 (m, 2H), 0.41 - 0.34 (m, 2H). And N-((S, E)-l-cyclopropyl-3-((R)-S-methylsulfonimidoyl)allyl)-5-(l,l- difluoroethyl)-3-phenoxythiophene-2-carboxamide (20.8 mg, 16%). LCMS (ESI): m / z 441 [M+H]+. 1H NMR (400 MHz, CDCI3) 8 7.45 (dd, J= 7.4, 8.0 Hz, 2H), 7.28 (d, J= 7.4 Hz, 1H), 7.15 (d, J= 8.0 Hz, 2H), 6.89 (dd, J= 15.0, 4.8 Hz, 1H), 6.73 (s, 1H), 6.60 (dd, J= 15.0, 1.6 Hz, 1H), 4.22 - 4.15 (m, 1H), 2.97 (d, J= 5.2 Hz, 3H), 1.94 (t, J = 17.8 Hz, 3H), 1.01 - 0.93 (m, 1H), 0.68 - 0.53 (m, 2H), 0.44 - 0.36 (m, 2H).

[0357] Preparative separation method:Instrument:AUNO LC-2000Column: ChiralCel OJ, 250>X20mm I.D., 5pmMobile phase: A for Hexane and B for EtOH (0.1% FA) Gradient: B 15%Flow rate: 20mL / minColumn temperature: 25°C Wavelength: 220nm Cycle-time: 25min Run time: 25min Injection volume: 1 mL Number of injection needles: 3 Eluted time: 2 HIn vitro WRN (500-1242) unwinding assay

[0358] 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 μL of enzymesolution containing 8 nM WRN (500-1242) and ImM ATP in 1 * Assay buffer (50 mM Tris HC1 (pH 7.5), 2 mM MgC12100 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- 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.

[0359] Compounds having an IC50 less than or equal to 200 nM are represented as “A”; Compounds having an IC50 greater than 200 nM but less than or equal to 1 μM are represented as “B”; Compounds having an IC50 greater than 1 μM but less than 10 μM are represented as “C”; Compounds having an IC50 greater than or equal to 10 μM are represented as “D”. Data of the compounds are disclosed in Table 2.Table 2. WRN DNA Unwinding AssayMethod for detecting effect on cell proliferation

[0360] 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.

[0361] 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# 040021 A, 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.

[0362] 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 (TEC AN). 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.

[0363] 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 comparing 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

[0364] Compounds having an IC50 less than or equal to 1 μM are represented as “AA”; Compounds having an IC50 greater than 1 μM but less than or equal to 2 μM are represented as “BB”; Compounds having an IC50 greater than 2 μM but less than 10 μM are represented as “CC”. The data of the compounds are listed in Table 3.Table 3. CTG HCT116 cell proliferation assay

[0365] 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.

[0366] 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.

[0367] 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.

[0368] 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

[0369] 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

[0370] 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 and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. What is claimed is:CLAIMS1. A compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a substituted 5-membered heteroaryl group;R1is R1A, OR1A, SR1Aor NRR’, wherein R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;Z isZ1having the structure of:Z2having the structure of:whereinW is CRR6;U is O or NRN;V is R9or NR9'R9' ;R is H or unsubstituted or substituted C1-C6alkyl,R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl., carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl ; each of R9, R9and R9is independently C1-C6alkyl, C3-C6carbocyclic or C2-C5heterocyclic group, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted, or R9' and R9" together with the N atom they are attached to form an unsubstituted or substituted 4- to 6-membered heterocyclic ring;RNis H or unsubstituted or substituted C1.3 alkyl; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6alkyl, or unsubstituted or substituted 4-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, having the structural formula:whereinQ is CR3or N;X is CR2, N, S, O or NR2;Y is CR4, N, S, O or NR4, orQ and X together, or Q and Y together, form a 3- to 8-membered carbocyclic, or 4- to 8-membered heterocyclic, aryl or beteroaryl group, wherein said alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, R and R’ are optionally substituted, whereinR2, when bonded to carbon, is H, halogen, CF3, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted; or when bonded to nitrogen, is H or C1-6alkyl, wherein said alkyl is optionally substituted;R2is H, C1-6alkyl, wherein said alkyl is optionally substituted;R3is C1-C6alkyl, C1-C6alkenyl, C3-C8carbocyclic, 4- to 6-membered heterocyclic, C6-C10aryl, 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;R4, when bonded to carbon, is H, halogen, CF.3, C1-6alkyl, CN , OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted; or when bonded to nitrogen, is H or C1-6alkyl, wherein said alkyl is optionally substituted; andR4is H or C1-6alkyl, wherein said alkyl is optionally substituted.

3. The compound of claim 2, wherein Q is CR3, having the structural formula:wherein X and Y are selected as follows:X is selected from CR2and N, and Y is S, O or NR4’; orX is selected from S, O and NR2, and Y is CR4or N, whereinR3is C1-C6alkyl, C1-C6alkenyl, C3-C8carbocyclic, 4- to 6-membered heterocyclic, C6-C10aryl, 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.

4. The compound of claim 3, wherein X is CR2, and Y is S, having the structural formula:

5. The compound of claim 3, wherein X is CR2, and Y is O, having the structural formula:

6. The compound of claim 3, wherein X is CR2, and Y is NR4’, having the structural formula:

7. The compound of claim 3, wherein having the structural formula:

8. The compound of claim 3, wherein X is N, and Y is O, having the structural formula:

9. The compound of claim 3, wherein X is N, and Y is NR4’, having the structural formula:

10. The compound of claim 3, wherein X is S, and Y is CR4, having the structural formula:

11. The compound of claim 3, wherein X is S, and Y is N, having the structural formula:

12. The compound of claim 3, wherein X is O, and Y is CR4, having the structural formula:

13. The compound of claim 3, wherein X is O, and Y is N, having the structural formula:

14. The compound of claim 3, wherein X is NR2’, and Y is CR4, having the structural formula:

15. The compound of claim 3, wherein X is NR2’, and Y is N, having the structural formula:

16. The compound of any one of claims 3-15, wherein R3is a substituted or unsubstituted C1- C6alkyl.

17. The compound of claim 16, wherein R3is a substituted or unsubstituted C1-C4alkyl.

18. The compound of claim 17, wherein R3is a substituted or unsubstituted C2-C4alkyl.

19. The compound of claim 16, wherein R3is C1-C4 alkyl substituted with 1-5 halogen.

20. The compound of claim 19, wherein R3is C2-C4alkyl substituted with 1-3 halogen.

21. The compound of claim 2, wherein Q is N, X is NR2and Y is CR4, having the structural formula:whereinR2is H or C1-6alkyl, wherein said alkyl is optionally substituted; andR4is H, C1-6alkyd, CN, OR, NRR’, NRC(O)R’, or C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted.

22. The compound of any one of claims 1-21, wherein R1is OR1A.

23. The compound of claim 22, wherein R1Ais substituted or unsubstituted 6-membered aryl or heteroaryl.

24. The compound of any one of claims 2-23, wherein R2if present is a substituted or unsubstituted C1-C6alkyl.

25. The compound of any one of claims 2-23, wherein R2if present is a halogen.

26. The compound of any one of claims 2-23, wherein R2if present is CN.

27. The compound of claim 26, wherein R2is a substituted or unsubstituted C1-C3alkyl.

28. The compound of claim 26, wherein R2is C1-C2alkyl substituted with 1-3 halogen.

29. The compound of any one of claims 1-28, wherein Z is Z1.

30. The compound of any one of claims 1-28, wherein Z is Z2.

31. The compound of any one of claims 1-30, wherein R5is H.

32. The compound of any one of claims 1-31, wherein W is CRR6.

33. The compound of claim 32, wherein R is H.

34. The compound of claim 32 or 33, wherein R6is a C1-C6alkyl.

35. The compound of claim 32 or 33, wherein R6is a C3-C6carbocyclic.

36. The compound of claim 35, wherein R6is cyclopropyl.

37. The compound of any one of claims 1-36, wherein U is O and Z is:Z1having the structure of:Z2having the structure of:

38. The compound of claim 37, wherein V is R9and Z is:Z1having the structure of:Z2having the structure of:

39. The compound of claim 1, wherein U is NRNand Z is:Z1having the structure of:Z2having the structure of:

40. The compound of claim 39, having the chirality of:

41. The compound of claim 39, having the chirality of:

42. The compound of any one of claims 39-41, wherein V is R9.

43. The compound of any one of claims 39-42, wherein RNis H and Z is:Z1having the structure of:Z2having the structure of:

44. The compound of any one of claims 1-43, wherein R7and R8are in a trans configuration:

45. The compound of any one of claims 1-43, wherein R7and R8are in a cis configuration:

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

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

48. The compound of any one of claims 1-47, wherein V is R9and R9is C1-C6alkyl.

49. The compound of claim 48, wherein R9is methyl.

50. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof,whereinY is S, O or NR4;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

51. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4’;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4’ is H or optionally substituted Cus alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3,-C6carbocyclic or C2-C5heterocyclic.

52. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinX is S, O or NR2;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2’ is H or optionally substituted C1-6alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

53. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinX is S, O or NR2;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is II or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

54. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H, C1.6 alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4’ is H or optionally substituted C1-6, alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

55. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H , C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4is H or optionally substituted C1-6, alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

56. A compound having the structural formula:(IV°) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4’ is H or optionally substituted CM alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

57. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4’;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4' is H or optionally substituted C 1 alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

58. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4;RNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

59. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4’;RNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

60. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinX is S, O or NR2';RNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

61. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinX is S, O or NR2;RNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

62. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4is H or optionally substituted C1-6alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

63. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof,whereinRNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R2is H, C1-6alkyl, CN, OR, NRR’, NRC(O)R’, C(O)NRR’, wherein said alkyl, R and R’ are optionally substituted;R4is H or optionally substituted C1-6alkyl;R3is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

64. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4;RNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R5is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

65. A compound having the structural formula:or a pharmaceutically acceptable form or an isotope derivative thereof, whereinY is S, O or NR4’;RNis H or unsubstituted or substituted C1.3 alkyl;R1Ais selected from C1-C6alkyl, C3-C8carbocyclic, 5- to 6-membered heterocyclic, C6-C10aryl, 5- to 6-membered heteroaryl, or bicyclic heteroaryl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl are optionally substituted;R4is H or optionally substituted C1-6alkyl;R is H or unsubstituted or substituted C1-C6alkyl;R6is H, D, halogen, C1-C6alkyl, C3-C6carbocyclic, C2-C5heterocyclic, wherein said alkyl, carbocyclic and heterocyclic are optionally substituted;R7is H, D, or unsubstituted or substituted C1-C6alkyl;R8is H, D, or unsubstituted or substituted C1-C6alkyl; andR9is unsubstituted or substituted C1-C6alkyl or C3-C6carbocyclic or C2-C5heterocyclic.

66. The compound of any one of claims 58-65, wherein RNis H.

67. The compound of any one of claims 58-65, wherein RNis CH3.

68. The compound of any one of claims 56, 57 and 64-67, wherein Y is S.

69. The compound of any one of claims 56, 57 and 64-67, wherein Y is O.

70. The compound of any one of claims 50-69, wherein each of R5is H.

71. The compound of any one of claims 50-70, wherein each of R7and R8is H.

72. The compound of any one of claims 50-71, wherein R9is methyl.

73. The compound of any one of claims 50-72, wherein R6is a substituted or unsubstitutedC3-C6carbocyclic.

74. The compound of claim 73, wherein R6is cyclopropyl.

75. The compound of any one of claims 50-74, wherein R1is substituted or unsubstituted C6aryl.

76. The compound of any one of claims 50-74, wherein R1is substituted or unsubstituted C2- C5heteroaryl.

77. The compound of any one of claims 50-76, wherein R2is a substituted or unsubstituted C1-C6alkyl.

78. The compound of any one of claims 50-76, wherein R2is a halogen.

79. The compound of any one of claims 50-78, wherein R3is C1-C4alkyl substituted with 1-5 halogen.

80. The compound of any of claims 1-79, having one or more deuterium atoms in place of hydrogen.

81. A pharmaceutical composition comprising a compound according to any one of claims 1- 80 and a pharmaceutically acceptable excipient, carrier, or diluent.

82. The pharmaceutical composition of claim 81, being suitable for oral administration.

83. A unit dosage form comprising a pharmaceutical composition according to claim 81 or 82.

84. The unit dosage form of claim 83, being in the form of a tablet or capsule.

85. 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 1-80.

86. The method of claim 85, 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.87 The method of claim 85, 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.

88. The method of any one of claims 85-87, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

89. Use of a compound according to any one of claims 1-80, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

90. The use of claim 89, wherein the disease or disorder is cancer.

91. The use of claim 90, 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.

92. The use of claim 91, 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.

93. A method for making a compound of any one claims 1-80.