Novel derivatives of quinolinones, and compositions and methods thereof

Abstract

The invention provides novel cyclic sulfonyl and sulfoximinyl 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

NOVEL DERIVATIVES OF QUINOLINONES, AND COMPOSITIONS ANDMETHODS THEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 545,146, filed October 20, 2023, and 63 / 569,337, filed March 25, 2024, the entire content of each of which is incorporated herein by reference for all purposes.Technical Fields of the Invention

[0002] The invention generally relates to novel compounds and therapeutic uses thereof More particularly, the invention provides novel cyclic sulfonyl and sulfoximinyl derivatives of quinolinones that inhibit Wemer Syndrome ATP dependent helicase enzyme (WRN) activity. The invention also provides pharmaceutical compositions comprising compounds of the invention and methods thereof for treating various diseases and disorders associated with or related to WRN activity, such as various types of cancer.Background of the Invention

[0003] Wemer 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 Wemer 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 RN 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, etal. 2013 Nature Reviews Cancer 13:542-558; Oshima etal. 2017 Ageing Research Reviews 33: 105 114; Goto et al. 2013 BioScience Trends 7: 13- -22; Hickson, et al.2003 Nature Reviews Cancer 3: 169-178; Lauper et al. 2013 PLoS One 8:e59709; Lieb et al. 2019 eLife 8:e43333; Zimmer, et al. 2020 Cancers (Basel) 12(5): 1 19.)

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

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

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

[0007] In one aspect, the invention generally relates to a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinwhereinX is O or NRX, wherein Rxis H or unsubstituted or substituted C1-6 alkyl and, 5-6 membered heteroaryl, each of Rlaand Rlbis independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’ and NRC(O)NRR’ and NRC(O)OR’, wherein the C1-C6alkyl, C3-C6 cycloalkyl, R and R’ is optionally substituted with 0-2 RA; or Rlaand Rlb, together with the carbon atom they are bound to, form a 3 - or 4-membered carbocyclic ring, optionally substituted with 0-2 RA; each of Rlcand Rldis independently H, halo or unsubstituted or substituted C1-6 alkyl; andRleis H, halogen, NRR’, OR, C(O)NRR’, C(O)OR, or unsubstituted or substituted C1-6 alkyl; each of R2, R3, R4and R6is independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, CN, OR, SR, S(O)2NRR”, C(CF3)NR”, NRR’, NRC(O)R”, C(O)NRR”, OC(O)NRR”, NRC(O)OR’ and NRC(O)NRR’, wherein each of the C1-C6alkyl, C3-C6cycloalkyl, R, R’ and R” is optionally substituted with 0-2 RB; wherein R6is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;R5isH, halogen, C1-6alkyl, CN, OR, SR, NRR’, S(O)2R, SF5, C2-3 alkene or C2alkyne; C3-C8saturated carbocyclic or saturated heterocyclic ring;5-membered unsaturated heterocyclic ring or heteroaryl; or6- to 10-membered aryl or heteroaryl, wherein each of C1-C6alkyl, C3-C8carbocyclic ring, 5-membered heterocyclic ring, 6- to 10- membered heteroaryl, R and R’ is optionally substituted with 0-8 Rc;RAIS selected from halo, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’;RBIS selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR, NRR’, C(O)NRR’, OC(O)NRR’, NRC(O)R’, NRC(O)OR’ and NHC(O)NRR’; and each of R, R’ and R” is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 4-to 6-membered carbocyclic ring, or where R and R’, or R and R”, are attached to the same N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; wherein R” is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB; and the heteroatoms are selected from N, O and S.

[0001] In another aspect, the invention generally relates to a compound having the structural formula (III):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRlais selected from the group consisting of H, halogen, C1-C6alkyl and C3-C6 cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’, wherein the C1-C6alkyl, C3-C6cycloalkyl, R and R’ is optionally substituted with 0-2 RA;Rldis independently H, halo or unsubstituted or substituted C1-6 alkyl;Rleis H, halogen, NRR’, OR, C(O)NRR’, C(O)OR, or unsubstituted or substituted C1-6 alkyl; each of R2, R3, R4and R6is independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, CN, OR, SR, S(O)2NRR”, C(CF3)NRR”, NRR”, NRC(O)R”, C(O)NRR”, OC(O)NRR”, NRC(O)OR’ and NRC(O)NRR’, wherein each of the C1-C6alkyl, C3-C6cycloalkyl, R, R’ and R” is optionally substituted with 0-2 RB; wherein R6is additionally selectedfrom 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;Ring A isC3-C8saturated carbocyclic or saturated heterocyclic ring;5-membered unsaturated heterocyclic ring or heteroaryl; or6- to 10-membered aryl or heteroaryl, wherein each of the C3-C8carbocyclic ring, 5- or 6-membered heterocyclic ring and 5-membered heteroaryl group is optionally substituted with 0-8 Rc;RAis selected from halo, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’;RBIS selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR, NRR’, C(O)NRR’, OC(O)NRR’, NRC(O)R’, NRC(O)OR’ and NHC(O)NRR’; each of R, R’ and R” is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’, or R and R”, are attached to the same N atom, together form an unsubstituted or substituted 4-to 6-membered heterocyclic ring; wherein R” is additionally selected from 5 or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB; the heteroatoms are selected from N, O and S; and7 is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0002] In yet another aspect, the invention generally relates to a compound having the structural Formula (V):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR5is C1-6 alkyl, C3-8 branched alkyl or C3-6 carbocyclic or heterocyclic ring, optionally substituted with 0-4 Rc;R6Ais selected from C1-6 alkyl, C3-6 cycloalkyl, 5- or 6-membered heterocyclic comprising 0- 3 heteroatoms, or 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl groups comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;RBis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR and NRR’ ; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, 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.

[0003] In yet another aspect, the invention generally relates to a compound having the structural Formula (VI):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR5is C4-C5 carbocyclic or heterocyclic ring, optionally substituted with 0-4 Rc;R6Bis selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, or 8- to 10- membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;RBis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR and NRR’ ; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, 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.

[0004] 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.

[0005] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0006] 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.

[0007] 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.

[0008] In yet another aspect, the invention generally relates to a method for making a compound disclosed herein.Definitions

[0009] 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.

[0010] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0011] 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.

[0012] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.

[0013] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0014] 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 otherpharmaceutically acceptable form thereof, using any suitable formulation or route of administration, as discussed herein.

[0015] 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.

[0016] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0017] 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.

[0018] 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 for stop the progression or effect reduction of Parkinson's disease (PD). In some embodiments, the amount is that effective for stop the progression or effect reduction of Alzheimer's disease (AD).

[0019] 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 speciesof 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.

[0020] 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)OC1-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.

[0021] 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.

[0022] 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 hereininclude 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.

[0023] 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+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0024] 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 ethyl succinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0025] 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.

[0026] 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.

[0027] 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., "Prodrugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriersin 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.

[0028] As used herein, the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com 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.

[0029] 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.

[0030] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to,therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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 vivoor 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.”

[0035] As used herein, the term “purified” when used in reference to a molecule, it means that the concentration of the molecule being purified has been increased relative to molecules associated with it in its natural environment, or environment in which it was produced, found or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids and sugars but generally do not include water, buffers, and reagents added to maintain the integrity or facilitate the purification of the molecule being purified. According to this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

[0036] 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 sub-range within the range. By way of example, “C1-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-4, C1- 3, C1-2, C2-5, C2-4, C3-6, C3.5 and C4-6 alkyl groups.

[0037] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C1-6 (e.g., Ci, C2, C3, C4, C5 or Ce) alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, - n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3 -methylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3 -methylhexyl, 4-methylhexyl, 5- methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate,carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -SI(RX)3, -ORX, -SRX, -OC(O)-RX, -N(RX)2, -C(O)RX, -C(O)ORX, -OC(O)N(RX)2, -C(O)N(RX)2, - N(RX)C(O)ORX, -N(RX)C(O)RX, -N(RX)C(O)N(RX)2, -N(RX)C(NRX)N(RX)2, -N(Rx)S(O)tN(Rx)2(where t is 1 or 2), -P(=O)(RX)(RX), or -O-P(=O)(ORX)2wherein each Rxis independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2 -hydroxy ethyl, 3- hydroxypropyl, benzyl, and phenethyl.

[0038] 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)OC1-C6alkyl, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, -S(O)2-C1-C6alkyl, -S(O)NHC1-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, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

[0039] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0040] 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, IH-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-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thi enothiazolyl, 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.

[0041] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZiZ2)carbonyl. The term "NZ1Z2" as used herein, means two groups, Zi and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Zi and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0042] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0043] 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 13ring atoms (i.e., C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (Ce), cyclohexadienyl (C6) and the like. Examples of C3-7 carbocyclyl groups include norbomyl (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- 1H 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.

[0044] 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-morpholm-4-yl, l-cyclopropyl-4-methyl-piperazin-2-yl. 2-pyrrolinyl, 3-pyrrolinyl, dihydro- 2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[l,4]oxazine, etc.

[0045] 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 quatemized. 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- TH, 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 -dioxi de.Detailed Description of the Invention

[0046] The invention is based in part on the discovery of novel WRN inhibitors that selectively bind to (e.g., covalently) and inhibit the activity of WRN. The novel compounds have been shown to exhibit favorable potency and selectivity profdes. The compounds exhibit superior DMPK profilessuitable 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.

[0047] In one aspect, the invention generally relates to a compound having the structuralFormula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR1iswhereinX is O or NRX, wherein Rxis H or unsubstituted or substituted C1-6 alkyl and, 5-6 membered heteroaryl, each of Rlaand Rlbis independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6 cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’ and NRC(O)NRR’ and NRC(O)OR’, wherein the C1-C6alkyl, C3-C6 cycloalkyl, R and R’ is optionally substituted with 0-2 RA; or Rlaand Rlb, together with the carbon atom they are bound to, form a 3 - or 4-membered carbocyclic ring, optionally substituted with 0-2 RA; each of Rlcand Rldis independently H, halo or unsubstituted or substituted C1-6 alkyl; andRleis H, halogen, NRR’, OR, C(O)NRR’, C(O)OR, or unsubstituted or substituted C1-6 alkyl; each of R2, R\ R4and R6is independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, CN, OR, SR, S(O)2NRR”, C(CF3)NR”, NRR’, NRC(O)R”,C(O)NRR”, OC(O)NRR”, NRC(O)OR’ and NRC(O)NRR’, wherein each of the C1-C6alkyl, C3-C6cycloalkyl, R, R’ and R” is optionally substituted with 0-2 RB; wherein R6is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;R5isH, halogen, C1-6 alkyl, CN, OR, SR, NRR’, S(O)2R, SF5, C2-3alkene or C2alkyne;C3-C8saturated carbocyclic or saturated heterocyclic ring;5-membered unsaturated heterocyclic ring or heteroaryl; or6- to 10-membered aryl or heteroaryl, wherein each of C1-C6alkyl, C3-C8carbocyclic ring, 5-membered heterocyclic ring, 6- to 10- membered heteroaryl, R and R’ is optionally substituted with 0-8 Rc;RAIS selected from halo, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’;RBis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR, NRR’, C(O)NRR’, OC(O)NRR’, NRC(O)R’, NRC(O)OR’ and NHC(O)NRR’; and each of R, R’ and R” is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 4-to 6-membered carbocyclic ring, or where R and R’, or R and R”, are attached to the same N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; wherein R” is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB; and the heteroatoms are selected from N, O and S.

[0048] In certain embodiments of (I) and (II), X is O and R1is

[0049] In certain embodiments

[0050] In certain embodiments racterized by the following chirality:

[0051] In certain embodiments of (I) and (II), R1is characterized by the following chirality:

[0052] In certain embodiments of (I) and (II), each of Rlband Rlcis H and R1is selected from:

[0053] In certain embodiments of (I)-(IIh), Rldis H.

[0054] In certain embodiments of (I)-(IIh), Rldis not H.

[0055] In certain embodiments of (I)-(IIh), Rldis methyl.

[0056] In certain embodiments of (I)-(IIh), Rlais H.

[0057] In certain embodiments of (I)-(IIh), Rlais not H.

[0058] In certain embodiments of (I)-(IIh), Rlais F or Cl.

[0059] In certain embodiments of (I)-(IIh), Rlais C1-3 alkyl, optionally substituted with OH, halogen, CN or NHR.

[0060] In certain embodiments of (I)-(IIh), Rlais methyl.

[0061] In certain embodiments of (I)-(IIh), Rleis H.

[0062] In certain embodiments of (I)-(IIh), Rleis not H.

[0063] In certain embodiments of (I)-(IIh), Rleis methyl.

[0064] In certain embodiments of (I)-(IIh), each of R3and R4is H.

[0065] In certain embodiments of (l)-(llh), at least one of R' and R4is not H.

[0066] In certain embodiments of (I)-(IIh), R5is C3-C8carbocyclic ring, optionally substituted with 0-4 Rc. In certain embodiments, the carbocyclic ring is a monocyclic ring. In certain embodiments, the carbocyclic ring is a fused bicyclic ring. In certain embodiments, the carbocyclic ring is a bridged bicyclic ring.

[0067] In certain embodiments of (I)-(IIh), R5is a 5 -membered unsaturated heterocyclic ring or heteroaryl group, optionally substituted with 0-3 Rc.

[0068] In certain embodiments of (I)-(IIh), R3is a 6- to 10-membered aryl or heteroaryl group, optionally substituted with 0-5 Rc.

[0069] In certain embodiments of (I)-(IIh), R3is a 6-membered aryl or heteroaryl, optionally substituted with 0-5 Rc.

[0070] In certain embodiments of (I)-(IIh), R3is a 10-membered aryl or heteroaryl, optionally substituted with 0-5 Rc.

[0071] In certain embodiments of (I)-(IIh), R3is a 5-membered unsaturated heterocyclic ring, optionally substituted with 0-3 Rc.

[0072] In certain embodiments of (I)-(IIh), R3is C3-C8branched alkyl, optionally substituted with 0-4 Rc.

[0073] In certain embodiments of (l)-(llh), R2is H.

[0074] In certain embodiments of (I)-(IIh), R2is not H.

[0075] In certain embodiments of (I)-(IIh), R2is NH2.

[0076] In certain embodiments of (I)-(IIh), R6is NRC(O)R”.

[0077] In certain embodiments of (I)-(IIh), R6is C(O)NRR”.

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

[0079] In certain embodiments of (I)-(IIh), R” is a C1-6 alkyl substituted with 0-2 RB.

[0080] In certain embodiments of (I)-(IIh), R” is a 3 - to 6-membered carbocyclic or heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0081] In certain embodiments of (I)-(IIh), R” is an 8- to 10-membered heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0082] In certain embodiments of (I)-(IIh), R” is an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RD.

[0083] In certain embodiments of (I)-(IIh), R6is a 5 -or 6-membered heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0084] In certain embodiments of (I)-(IIh), R6is an 8- to 10-membered bicyclic carbocyclic or heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0085] In certain embodiments of (I)-(IIh), R6is a 5- or 6-membered aryl or heteroaryl group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0086] In certain embodiments of (I)-(IIh), R6is an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0087] In another aspect, the invention generally relates to a compound having the structural formula (III):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRlais selected from the group consisting of H, halogen, C1-C6alkyl and C3-C6 cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’, wherein the C1-C6alkyl, C3-C6cycloalkyl, R and R’ is optionally substituted with 0-2 RA;Rldis independently H, halo or unsubstituted or substituted C1-6 alkyl;Rleis H, halogen, NRR’, OR, C(O)NRR’, C(O)OR, or unsubstituted or substituted C1-6 alkyl; each ofR2, R3, R4and R6is independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, CN, OR, SR, S(O)2NRR”, C(CF3)NRR”, NRR”, NRC(O)R”,C(O)NRR”, OC(O)NRR”, NRC(O)OR’ and NRC(O)NRR’, wherein each of the C1-C6alkyl, C3-C6cycloalkyl, R, R’ and R” is optionally substituted with 0-2 RB; wherein R6is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;Ring A is C3-C8saturated carbocyclic or saturated heterocyclic ring;5-membered unsaturated heterocyclic ring or heteroaryl; or6- to 10-membered aryl or heteroaryl, wherein each of the C3-C8carbocyclic ring, 5- or 6-membered heterocyclic ring and 5-membered heteroaryl group is optionally substituted with 0-8 Rc;RAIS selected from halo, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’;RBis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR, NRR’, C(O)NRR’, OC(O)NRR’, NRC(O)R’, NRC(O)OR’ and NHC(O)NRR’; each of R, R’ and R” is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’, or R and R”, are attached to the same N atom, together form an unsubstituted or substituted 4-to 6-membered heterocyclic ring; wherein R” is additionally selected from 5 or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB; the heteroatoms are selected from N, O and S; and z is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0088] In certain embodiments of (III), Rleis H.

[0089] In certain embodiments of (III), Rleis not H.

[0090] In certain embodiments of (III), Rleis methyl.

[0091] In certain embodiments of (III), Rldis H.

[0092] In certain embodiments of (III), Rldis not H.

[0093] In certain embodiments of (III), Rldis methyl.

[0094] In certain embodiments of (III), each of R2and R’ is H.

[0095] In certain embodiments of (III), one of R2and R3is not H.

[0096] In certain embodiments of (III), R4is H.

[0097] In certain embodiments of (III), R4is not H.

[0098] In certain embodiments of (III), each of R2, R3and R4is H.

[0099] In certain embodiments of (III), R6is NRC(O)R”.

[0100] In certain embodiments of (III), R6is C(O)NRR”.

[0101] In certain embodiments of (III), R is H.

[0102] In certain embodiments of (III), R” is a C1-6 alkyl substituted with 0-2 RB.

[0103] In certain embodiments of (III), R” is a 3- to 6-membered carbocyclic or-heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0104] In certain embodiments of (III), R” is an 8- to 10-membered heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0105] In certain embodiments of (III), R” is an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0106] In certain embodiments of (III), R6is a 5- or 6-membered heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0107] In certain embodiments of (III), R6is an 8- to 10-membered heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0108] In certain embodiments of (III), R6is a 5- or 6-membered heteroaryl group comprising 0- 3 heteroatoms, substituted with 0-2 RB.

[0109] In certain embodiments of (III), R6is an 8- to 10-membered-heteroaryl group comprising0-5 heteroatoms, substituted with 0-2 RB.

[0110] In certain embodiments of (III), Ring A is a saturated -C8carbocycliCc3ring optionally substituted with 0-8 Rc.

[0111] In certain embodiments of (III), Ring A is a saturated C4-C8heterocyclic ring optionally substituted with 0-8 Rc.

[0112] In certain embodiments, the carbocyclic or heterocyclic ring is a monocyclic ring.

[0113] In certain embodiments, the carbocyclic or heterocyclic ring is a fused bicyclic ring.

[0114] In certain embodiments, the carbocyclic or heterocyclic ring is a bridged bicyclic ring.

[0115] In certain embodiments of (III), Ring A is:whereinR5ais selected from H, halo, CN, R, OR, NRR’, C(O)NRR’, NRC(O)R’, NRC(O)OR’, NHC(O)NRR’ and OC(O)NRR’; each of R5b, R5c, R5d, R5e, R5fand R5gis independently selected from H, halogen, R and OR; or any two of R5a, R5b, R5c, R5d, R5e, R5fand R5gmay optionally join together to form a (CH2)m bridge, wherein m is 1 or 2; and n is 0, 1, 2 or 3.

[0116] In certain embodiments of (III)-(I V), each of R5a, R5b, R5c, R5d, R5e, R5fand R5gis H.

[0117] In certain embodiments of (III)-(IV), at least of one of R3a, R5b, R5c, R5d, R5e, R5fand R5gis not H.

[0118] In certain embodiments of (III)-(I V), n is h

[0119] In certain embodiments of (III)-(IV), R5aand R5djoin together to form a (CItjm bridge, wherein m is 1.

[0120] In certain embodiments of (III), Ring A is selected from:

[0121] In certain embodiments of (III), Ring A is a 5-membered unsaturated heterocyclic or heteroaryl ring.

[0122] In certain embodiments of (III), Ring A is selected from:

[0123] In certain embodiments of (III), Ring A is a 6- to 10-membered aryl or heteroaryl optionally substituted with 0-2 Rc.

[0124] In certain embodiments of (III), Ring A is selected from:

[0125] In certain embodiments of (I) and (III), the compound comprises a moiety selected from:

[0126] In certain embodiments of (I), the compound comprises a moiety selected from:

[0127] In yet another aspect, the invention generally relates to a compound having the structural Formula (V):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR5is C1-6 alkyl, C3-8 branched alkyl or C3-6 carbocyclic or heterocyclic ring, optionally substituted with 0-4 Rc;R6Ais selected from C1-6 alkyl, C3-6 cycloalkyl, 5- or 6-membered heterocyclic comprising 0- 3 heteroatoms, or 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl groups comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;RBIS selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR and NRR’ ; andeach of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, 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.

[0128] In certain embodiments of (V), R5is C1-5 alkyl.

[0129] In certain embodiments of (V), R5is C4 carbocyclic ring, optionally substituted with 0-4Rc.

[0130] In certain embodiments of (V), R5is Cs carbocyclic ring, optionally substituted with 0-4Rc.

[0131] In certain embodiments of (V), R5is selected from:

[0132] In certain embodiments of (V), R6is selected from:

[0133] In certain embodiments of (V), R6Ais a C1-6 alkyl substituted with 0-2 RB.

[0134] In certain embodiments of (V), R6Ais a 3- to 6-membered carbocyclic or heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0135] In certain embodiments of (V), R6Ais an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0136] In certain embodiments of (V), R6Ais a 5- or 6-membered heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0137] In certain embodiments of (V), R6Ais a 5- or 6-membered aryl or heteroaryl group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0138] In certain embodiments of (V), R6Ais a 5 : 6-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0139] In certain embodiments of (V), R6Ais a 6 : 5-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0140] In yet another aspect, the invention generally relates to a compound having the structural Formula (VI):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR5is C4-C5 carbocyclic or heterocyclic ring, optionally substituted with 0-4 Rc;R6Bis selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, or 8- to 10- membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;RBIS selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR and NRR’; andeach of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, 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.

[0141] In certain embodiments of (VI), R5is C1-5 alkyl.

[0142] In certain embodiments of (VI), R5is C4 carbocyclic ring, optionally substituted with 0-4Rc.

[0143] In certain embodiments of (VI), R5is C5 carbocyclic ring, optionally substituted with 0-4 Rc.

[0144] In certain embodiments of (VI), R5is selected from:

[0145] In certain embodiments of (VI), R6Bis a 3- to 6-membered carbocyclic or heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0146] In certain embodiments of (VI), R6Bis an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0147] In certain embodiments of (VI), R6Bis a 5- or 6-membered aryl or heteroaryl group comprising 0-3 heteroatoms, substituted with 0-2 RB.

[0148] In certain embodiments of (VI), R6Bis an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0149] In certain embodiments of (VI), R6Bis a 5 : 6-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0150] In certain embodiments of (VI), R6Bis a 6 : 5-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

[0151] In certain embodiments, a compound disclosed herein has one or more deuterium atoms in place of hydrogen.

[0152] In certain embodiments, the compound has one deuterium atom in place of a hydrogen atom.

[0153] 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.

[0154] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0155] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0156] In certain embodiments, is in the form of a tablet. In certain embodiments, is in the form of a capsule.

[0157] 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.

[0158] 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.

[0159] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

[0160] In yet another aspect, the invention generally relates to a method for making a compound disclosed herein.

[0161] Compounds of the invention include deuterated versions of the disclosed compounds, for example, having one or more deuterium atoms in place of hydrogen.

[0162] 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.

[0163] 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 carboxymethyl cellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0164] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch). Other formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[0165] 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.

[0166] 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.

[0167] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3 -butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com 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.

[0168] 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.

[0169] 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.

[0170] 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 nonaqueous 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.

[0171] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[0172] In the case of tablets for oral use, carriers that are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0173] 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.

[0174] 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 nonaqueous 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.

[0175] 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 anon-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.

[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] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0186] 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 tothe subject. In certain embodiments, the method further comprises administering hormonal therapy to the subject.

[0187] 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), Lonafamib (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 methylamel amines 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 cryptophy cin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1- TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and rammnustine; 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, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin,streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, di deoxy uridine, 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; emluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK* polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel; Rhone- Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; temposide; 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.

[0188] 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, pazopamb, trastuzumab, bevacizumab, cetuximab, rambizumab, pegaptanib, panitumumab and the like), mitosis inhibitors (e.g., paclitaxel, vincristine, vinblastine and the like), alkylating agents (e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and thelike), anti -metabolites (e.g., methotrexate, 5-FU and the like), intercalating anticancer agents, e.g., actinomycin, anthracy cline, 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).

[0189] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and tra -isomers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0190] 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.

[0191] 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.

[0192] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively.

[0193] 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) labeledcompounds 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.

[0194] 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.)

[0195] Stereoisomers (e.g., cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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 appliesto 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

[0204] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0205] 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.AbbreviationsLC-MS Method.

[0206] 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 pL 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.

[0207] 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.2H NMR Spectroscopy:

[0208] 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 (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (single), d (double), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), br (broad).SFC Purification Method

[0209] Instrument: SHIMADZU PREP Solution SFC, Column: ChiralPak C-IG, 250x30mm I.D., 5pm, Mobile phase: A for CO2 and B for MeOH+MeCN (0.1% 2mol / L NH3in MeOH), Gradient: B 50%, Flow rate: 60 mL / min, Back pressure: 100 bar, Column temperature: 35°C, Wavelength: 220 nm, Cycle-time: 14 min.Preparation of common intermediatesEthyl 7-bromo-2-oxo-l,2-dihydroquinoline-3-carboxylate (Int 1)

[0210] Step A: A mixture of 2-amino-4-bromobenzaldehyde (50 g, 250 mmol), diethyl malonate (80 g, 500 mmol), piperidine (63.75 g, 750 mmol) and HOAc (2.1 mL, 25 mmol) were refluxed in EtOH (500 mL, 687 mmol) overnight. The reaction was cooled to RT and filtered. The solid was washed with cold EtOH to afford ethyl 7-bromo-2-oxo-lH- quinoline-3 -carboxylate, Int 1 (63 g, 85%) LCMS (ESI): m / z 296, 298 [M+H]+.Ethyl 7-bromo-2-methoxyquinoline-3-carboxyIate (Int 2)

[0211] Step A: To a solution of ethyl 7-bromo-2-oxo-l,2-dihydroquinoline-3 -carboxylate, Int 1 (50 g, 169.5 mmol) in DCM (800 mL) was added trimethyloxonium tetrafluoroborate (37.6 g, 254.2 mmol) and the mixture was stirred at RT for 24 h. The solution was filtered and washed with DCM. The filter cake was purified by flash column chromatography using (0-8% DCM in PE) to afford ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (30 g, 57 %) as a white solid. LCMS (ESI): m / z 310, 312 [M+H]'.(( / ?)-3-Amino-2,3-dihydrothiophene 1,1-dioxide (Int 3)

[0212] Step A: A solution of 2-methylpropan-2-yl (4A)-4-formyl-2,2-dimethyl-l,3-oxazolidine- 3-carboxylate (3 g, 13.1 mmol) in methanol (60 mL) was added the Bestmann-Ohira reagent (1Z)-1- (diazyn-l-iumyl)-l- [dimethoxy (oxo)- 5-phosphanyl]prop-l-en-2-olate) (3.02 g, 15.7 mmol) and cooled to 0 °C. K2CO3(3.44 g, 24.8 mmol) was added in a single portion and the resulting bright yellow suspension was stirred for 14 h. The reaction mixture was diluted with saturated aqueous NH4CI and extracted EtOAc (20 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc) in PE to afford 2-methylpropan-2-yl (4R) -4-ethynyl-2,2-dimethyl-l,3-oxazolidine-3- carboxylate, Int 3-1 (2.5 g, 85%) as a colorless oil. LCMS (ESI): m / z 226 [M+H]+;1H NMR (400 MHz, DMSO) δ 4.53 (s, 1H), 4.03 - 3.97 (m, 1H), 3.88 (dd, J = 9.0, 2.0 Hz, 1H), 3.20 (d, J= 15 Hz, 1H), 1.51 (s, 3H), 1.43 (s, 9H), 1.41 (s, 3H).

[0213] Step B: A solution of Int 3-1 (3 g, 13.3 mmol) in 3N HC1 in dioxane (30mL was stirred at RT overnight and the solution was concentrated. The residue was dissolved in THF (30 mL) andH2O (30 mL) and the solution was cooled to 0 °C. K2CO3(3.68 g, 26.6 mmol) was added and followed by benzyl chloroformate (2.7 g, 15.9 mmol). The resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted withH2O, extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc in PE) to afford benzyl {[(2R)-l-hydroxybut-3-yn-2-yl]amino}methanoate, Int 3-2 (2.1 g, 72%) as a colorless oil. LCMS (ESI): m / z [M+H]+;1H NMR (400 MHz, DMSO) δ 7.64 (d, J= 8.0 Hz, 1H), 7.44 - 7.27 (m, 5H), 5.11 - 4.96 (m, 3H), 4.27 (td, J= 8.0, 2.0 Hz, 1H), 3.57 - 3.39 (m, 2H), 3.17 (s, 1H).

[0214] Step C: To a solution of Int 3-2 (200 mg, 0.91 mmol), thiobenzoic O-acid (151 mg, 1.1 mmol) and PPh; (359 mg, 1.4 mmol) in THF (10 mL) was added DIAD (277mg, 1.37 mmol) at 0 °C and the reaction was stirred at RT for 18 h under N2 atmosphere. The reaction was concentrated andthe residue was purified by silica gel chromatography (0-20% EtOAc in PE) to afford benzyl {[(2R)- l-(benzoylsulfanyl)but-3-yn-2-yl]amino}methanoate Int 3-3 (300 mg) as an off-white solid. LCMS (ESI): m / z 340 [M+H]+.

[0215] Step D: To a solution of Int 3-3 (200 mg, 0.59 mmol) in MeOH (10 mL) was added CH3OK (46 mg, 0.65 mmol) and the reaction mixture was stirred at RT for 1 h (open to air). The reaction was quenched with ice-water and was diluted with EtOAc (25 mL). The organic layer was separated, washed with brine and concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc in PE) to afford benzyl {[(3R)-2,3-dihydrothiophen-3- yl] amino }methanoate, Int 3-4 (100 mg, 72%) as a white solid.JH NMR (400 MHz, DMSO-t / 6) δ 7.71 (d, .7= 7.0 Hz, 1H), 7.49 - 7.33 (m, 5H), 6.55 (dd, J= 6.0, 2.0 Hz, 1H), 5.64 (dd, J= 6.0, 3.0 Hz, 1H), 5.09 (s, 2H), 5.01 - 4.91 (m, 1H), 3.49 (dd, J= 12.0, 6.0 Hz, 1H), 3.03 (dd, J= 12.0, 6.0 Hz, 1H). LCMS (ESI): m / z 236 [M+H]+.

[0216] Step E: To a solution of Int 3-4 (100 mg, 0.425 mmol) in DCM (5 mL) were added 3- chloroperoxybenzoic acid (215 mg, 1.06 mmol) in small portions and the reaction was stirred at RT for 3 h. The reaction was quenched with cold saturated aqueous NaHCCL and 10% Na2S2O?. The organic layer was separated and the aqueous layer extracted with DCM (10 mL x 2). The combined organic layers were washed with brine and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc in PE) to afford benzyl [[(3 / / )- 1 , 1 -dioxo-2,3-dihydrothiophen-3- yl]amino}methanoate, Int 3-5 (60 mg, 53%, ee -87%) as a white solid.The crude compound was further purified by SFC to afford Int 3-5 with ee~99%. LCMS (ESI): m / z 268 [M+H]~;JH NMR (400 MHz, DMSO-d6) δ 8.02 (d, J= 8.0 Hz, 1H), 7.42 - 7.28 (m, 5H), 7.18 (dd, J= 7.0, 2.0 Hz, 1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 5.05 (d, J= 12.0 Hz, 2H), 4.99 - 4.93 (m, 1H), 3.74 (dd, J= 14.0, 8.0 Hz, 1H), 3.06 (dd, J= 14.0, 5.2 Hz, 1H).

[0217] Step F: A solution of Int 3-5 (80 mg, 0.3 mmol) in 33% HBr in HOAc (2 mL) was stirred at RT for 2 h and the reaction was diluted with Et2O (5 mL). The reaction mixture was filtered and the filter cake was dried in vacuo to afford (A)-3-amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (40 mg, 100%) as an off-white solid. LCMS (ESI): m / z 134 [M+H]+;1H NMR (400 MHz, DMSO- t / 6) δ 8.02 (d, J= 7.6 Hz, 1H), 7.42 - 7.28 (m, 5H), 7.18 (dd, J= 7.0, 2.0 Hz, 1H), 6.83 (dd, J= 7.0, 2.0 Hz, 1H), 5.05 (d, J= 12.0 Hz, 2H), 4.99 - 4.93 (m, 1H), 3.74 (dd, J= 14.0, 8.0 Hz, 1H), 3.06 (dd, J= 14.0, 5.0 Hz, 1H).(2S,3R)-3-Amino-2-methyl-2,3-dihydrothiophene1,1-dioxide (Int 4)

[0218] Step A: To a solution of N-{ [(2-methylprop-2-yl)oxy ] carbonyl }-L- threonine (1 g, 4.5 mmol) and 2,2-dimethoxypropane (1.43 g, 13.7 mmol) in THF (20 mL) was added PPTS (230 mg, 0.9 mmol) and the solution was stirred at 80 °C for 18 h. The reaction was diluted with water and extracted with EtOAc (20 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in PE) to afford (4S, 5 )-2,2,5-trimethyl-3-{[(2-methylprop-2-yl)oxy]carbonyl}-l,3- oxazolidine-4-carboxylic acid, Int 4-1 (1.0 g, 84%) as a colorless oil. LCMS (ESI): m / z 260 [M+H]+;1HNMR (400 MHz, DMSO) δ 12.88 (s, 1H), 4.17 - 4.05 (m, 1H), 3.76 (t, J= 8.0 Hz, 1H), 1.64 - 1.24 (m, 18H).

[0219] Step B: To a solution of Int 4-1 (900 mg, 3.5 mmol), N,O-Dimethylhydroxylamine hydrochloride (440 mg, 4.5 mmol) and HATU (1.7 g, 4.5 mmol) in DMF (35 mL) was added DIEA (1.4 g, 10.4 mmol) at 0 °C and the reaction mixture was stirred at RT for 18 h. The mixture was diluted with water, extracted with EtOAc (15 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in PE) to afford 2-methylpropan-2-yl (45',5R) -2,2,5- trimethyl-4-(3-methyl-4-oxo-3-aza-2-oxabut-4-yl)-l, 3 -oxazolidine-3 -carboxylate, Int 4-2 (900 mg, 86%) as a colorless oil. LCMS (ESI): m / z 303 [M+H]+;1H NMR (400 MHz, DMSO) δ 4.38 (dd, J = 22.0, 6.0 Hz, 1H), 4.01 (dd, J= 11.0, 4.0 Hz, 1H), 3.71 (d, J= 10.0 Hz, 3H), 3.14 (d, J= 8.1 Hz, 3H), 1.53 (d, .7= 3.0 Hz, 3H), 1.48 (s, 3H), 1.40 (s, 3H), 1.32 (d, J= 8.0 Hz, 9H).

[0220] Step C: To a solution of Int 4-2 (2 g, 6.6 mmol) in THF (100 mL) were added DIBAL-H (10 mL, 1.0 M in hexane) at -78 °C and the reaction mixture was allowed to warm to RT and stirredfor 18 h. The reaction cooled to 0 °C and quenched with saturated NH4CI solution, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to afford 2-methylpropan-2-yl (4.S',5R) -4-formyl-2,2,5-trimethyl-l,3- oxazolidine-3 -carboxylate, Int 4-3 (300 mg, 18.6%) as a colorless oi. LCMS (ESI): m / z 244 [M+H]+.

[0221] Step D: A solution of Int 4-3 (300 mg, 1.2 mmol) in MeOH (10 mL) was treated with the dimethyl (diazomethyl)phosphonate (355 mg, 1.8 mmol), cooled to 0 °C and K2CO3 (255 mg, 1.8 mmol) was added in a single portion. The resulting bright yellow suspension was allowed to stirr at RT for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc in PE) to afford 2-methylpropan-2-yl (4R,5R) -4-ethynyl-2,2,5-trimethyl-l,3-oxazolidine-3-carboxylate, Int 4-4 (200 mg, 68%) as a colorless oil. LCMS (ESI): m / z 240 [M+H]+; NMR (400 MHz, DMSO-d 6) δ 4.14 (dq, J= 12.0, 6.0 Hz, 1H), 4.03 - 3.94 (m, 1H), 3.37 (t, J= 11.0 Hz, 1H), 1.49 (s, 3H), 1.47 - 1.39 (m, 12H), 1.27 (d, J = 6.0 Hz, 3H).

[0222] Step E: A solution of Int 4-4 (400 mg, 1.7 mmol) in HC1 (10 mL, 3M in 1,4- dioxane) was stirred at RT for 2 h and the reaction mixture was concentrated. The crude product was dissolved in THF (5 mL) and H2O (5 mL) and cooled to 0 °C, K2CO3(462 mg, 3.4 mmol) was added followed by CbzCl (427 mg, 2.5 mmol). The reaction mixture was stirred at RT overnight. The reaction was diluted with water, extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc in PE) to afford benzyl {[(3R,4R)-4- hydroxypent-l-yn-3-yl]amino]methanoate, Int 4-5 (300 mg, 77%) as a colorless oil. LCMS (ESI): m / z 234 [M+H]+;1H NMR (400 MHz, DMSO) δ 7.61 (d, J= 8.0 Hz, 1H), 7.44 - 7.23 (m, 5H), 5.04 (s, 2H), 4.92 (d, J= 4.9 Hz, 1H), 4.20 (t, J= 6,0 Hz, 1H), 3.62 (dd, J= 12.0, 6.0 Hz, 1H), 3.15 (s, 1H), 1.13 (d, J = 6,0 Hz, 3H).

[0223] Step F: To a stirred solution of PPh3 (674 mg, 2.6 mmol) in THF (10 mL) was added DIAD (520 mg, 2.6 mmol) drop wise at 0 °C and the reaction mixture was stirred at 0 °C for 20 min. Int 4-5 (300 mg, 1.3 mmol) in THF (5 mL) was added into the mixture and stirred for another 20 min. Thiobenzoic-O-acid (178 mg, 1.3 mmol) was added into the mixture and stirred at RT for 2 h. The reaction was diluted with water and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with saturated Nal ICO3 solution, brine, dried overanhydrous Na2S,O f4iltered and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to afford benzyl [[(3 / ?,4.S')-4-(benzoylsulfanyl)pent-l -yn-3- yl] amino }methanoate, Int 4-6 (300 mg, 66%) as a gray solid. LCMS (ESI): m / z 354 [M+H]+.

[0224] Step G: To a solution of Int 4-6 (300 mg, 0.8 mmol) in MeOH (10 mL) was added potassium methoxide (119 mg, 1.7 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction was poured into ice-water, extracted with EtOAc (20 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0- 20% EtOAc in PE) to afford benzyl { [(2R,3S)-2- methyl-2,3-dihydrothiophen-3-yl]amino}methanoate Int 4-7 (130 mg, 60%) as a white solid. LCMS (ESI): m / z 251 [M+H]+; NMR (400 MHz, DMSO) 6 7.58 (d, J= 7.0 Hz, 1H), 7.42 - 7.27 (m, 5H), 6.46 (d, J= 5.0 Hz, 1H), 5.50 (td, J= 6.0, 3.0 Hz, 1H), 5.03 (s, 2H), 4.80 (t, J= 8.0 Hz, 1H), 4.48 (s, 1H), 3.86 (t, J= 7.0 Hz, 1H), 3.56 - 3.45 (m, 1H), 1.32 (d, J = 7.0 Hz, 2H), 1.18 (d,J= 7.0 Hz, 1H).

[0225] Step H: To a solution of Int 4-7 (300 mg, 1.20 mmol) in DCM (15 mL) were added 3- chloroperoxybenzoic acid (724 mg, 3.6 mmol, wt. 86%) in small portions at 0 °C and the solution was stirred at RT for 2 h. The reaction mixture was poured into ice-water, quenched with NaiSiO?,, extracted with DCM (20 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO an4d concentrated. The residue was purified by silica gel chromatography (20- 100% EtOAc in PE) to afford the title compound benzyl ((2A, 37?)-2-methyl- 1,1 -dioxi do-2, 3- dihydrothiophen-3-yl)carbamate Int 4-8 (280 mg, 82.72%, ee~ 80%) as an off-white solid. LCMS (ESI): m / z 282 [M+H]+; 'll NMR (400 MHz, DMSO) 6 7.97 (d, J= 8.1 Hz, 1H), 7.43 - 7.28 (m, 5H), 7.20 (dd, J= 7.0, 2.0 Hz, 1H), 6.84 (dd, J= 7.0, 2.0 Hz, 1H), 4.40 (ddd, J= 9.0, 5.0, 2.0 Hz, 1H), 3.12 (p, .7= 7.0 Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.07 (d, J= 7.2 Hz, 1H). Int 4-8 was further purified by SFC (ChiralPak C-IG, 250x30mm I.D.5pm, A for CO2 and B for MeOH / ACN, 0.1% NH3 / MeOH, 0% to 50% gradient, flow rate 60 mL / min, 14 min run) to afford benzyl [ [(2 / ?,3.S')-2- methyl-l,l-dioxo-2,3-dihydrothiophen-3-yl]amino}methanoate, Int 4-8 (200 mg, 83%, ee~ 99%) as an off-white solid.

[0226] Step I: A solution of Int 4-8 (200 mg, 0.71 mmol) in HBr (2 mL, 33% wt. in HOAc) was stirred at RT for Ih and the reaction mixture was diluted with Et2O. The precipitate was filtered and dried under reduced pressure to afford (2R, 3 S)-3-amino-2-methyl-2, 3 -dihydrothiophene- 1,1 -dioxide, Int 4 (100 mg, 0.68 mmol, 96%) as an off- white solid. LCMS (ESI): m / z 148 [M+H]+.(1S,3R)- 3-Amino-l-imino-2,3-dihydrothiophene 1-oxide (Int 5)

[0227] Step A: To a solution of Int 3-4 (500 mg, 2.12 mmol) and ammonium carbamate (249 mg, 3.2 mmol) in MeOH (10 mL) were added diacetoxyiodobenzene (1.03 g, 3.2 mmol) and the reaction was stirred at RT for 2 h. The reaction was diluted with water (5 mL), the solvent was removed by reduce pressure and the reaction mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na^SO i, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc in PE) to afford the benzyl {[(3R)- 1-azanylidene-l -oxo-2, 3 -dihydrothiophen-3-yl] amino (methanoate, Int 5-1 (400 mg, 71% yield).

[0228] Step B: The crude Int 5-1 (400 mg) was further purified by SFC to afford benzyl {[(lS,3R)-l-azanylidene-l-oxo-2,3-dihydrothiophen-3-yl]amino}methanoate, Int 5-2A (230 mg, 41 %) as an off white solid. LCMS (ESI): m / z 266 [M+H]+;’H NMR (400 MHz, DMSO-d6) 5 7.92 (d, J= 7.5 Hz, 1H), 7.40 - 7.31 (m, 5H), 6.93 (dd, J= 7.0, 2.3 Hz, 1H), 6.52 (dd, J= 7.0, 3.0 Hz, 1H), 5.05 (s, 2H), 4.96 - 4.80 (m, 1H), 4.29 (s. 1H), 3.62 (dd, J = 13.0, 7.9 Hz, 1H), 2.98 (dd, J = 13.4, 5.5 Hz, 1H). and benzyl {[(1R, 3R)- 1 -azanylidene- 1 -oxo-2,3-dihydrothiophen-3- yl] amino }methanoate Int 5-2B (80 mg, 14%) as a white solid, LCMS (ESI): m / z 266 [M+H]+.

[0229] Step C: A solution of Int 5-2A (100 mg, 0.38 mmol) in 33% HBr (2 mL in HO Ac) was stirred at RT for 1 h and the reaction mixture was diluted with Et2O. The precipitate was filtered and dried in vacuo to afford (1S,3R) -3-amino-l-imino-2,3-dihydrothiophene-l-oxide, Int-5 (50 mg, 99%) as an off- white solid. LCMS (ESI): m / z 133 [M+H]+.Ethyl 7-bromo-2-((4-methoxybenzyl)oxy)quinoline-3-carboxylate (Int 6)

[0230] Step A: A solution of ethyl 7-bromo-2-oxo-l,2-dihydroquinoline-3 -carboxylate, Int 1 (2 g, 6.75 mmol), l-(chloromethyl)-4-methoxybenzene (1.38 g, 8.78 mmol), CS2CO3 (4.4 g, 13.51 mmol) in DMF (15 mL) was stirred at 50 °C overnight. The mixture was extracted with EtOAc (50 mL x 3) and the organic phase was dried over Na2SO4and concentrated. The residue was purified bysilica gel chromatography (0-10% EtOAc in PE) to afford ethyl 7-bromo-2-((4- methoxybenzyl)oxy)quinoline-3 -carboxylate, Int-6 (630 mg, 22 %) as a white solid.1HNMR (400 MHz, DMSO- ) δ 8.78 (s, 1H), 8.08 - 7.96 (m, 2H), 7.67 (d, J= 8.8 Hz, 1H), 7.49 (d, J= 8.0 Hz, 2H), 6.96 (d, J= 8.0 Hz, 2H), 5.49 (s, 2H), 4.32 (q, J= 7.2 Hz, 2H), 3.76 (s, 3H), 1.30 (t, J= 7.2 Hz, 3H).Ethyl 8-bromo-7-cyclobutyl-2-methoxyquinoline-3-carboxylate (Int 7)

[0231] Step A: To a suspension of Int 2 (10 g, 32.2 mmol), 2-[(cy cl obutylcarbonyl)oxy]isoindole- 1,3 -dione (11.9 g, 48 mmol), [(bipy)2Ni2(p-Cl)2C12(H2O)2] (2.07 g, 3.22 mmol) and Zn dust (16.8 g, 258 mmol) in DMA (40 mL) was added a solution of TMSC1 (10.5 g, 96.7 mmol) in DMA (60 mL) at 0 °C under N2 atmosphere and the solution was stirred at 0 °C for 1.5 h. The reaction mixture was poured into ice-cooled sat. NH4CI (200 mL), extracted with EtOAc (80 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in PE) to afford ethyl 7-cyclobutyl-2-methoxyquinoline-3-carboxylate, Int 7-1 (3.7 g, 40 %) as a colorless oil. LCMS (ESI): m / z 286 [M+H]+.

[0232] Step B: To a solution of Int 7-1 (11.8 g, 41.35 mmol) in H2SO4(70 mL) was added NBS (8.83 g, 49.62 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. The cooled reaction mixture was diluted with ice-water (200 mL), extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-6% EtOAc in PE) to afford ethyl 8-bromo-7- cyclobutyl-2-methoxyquinoline-3-carboxylate, Int 7 (13 g, 86%) as a white solid. LCMS (ESI): m / z 364 [M+H]+7-Cyclobutyl-3-(ethoxycarbonyl)-2-methoxyquinoline-8-carboxylic acid (Int-8)

[0233] Step A: A mixture of Int 7 (9 g, 24.7 mmol), Pd(PPh3)4 (2.85 g, 2.47 mmol) and tributyl(vinyl)-4-stannane (11.75 g, 37 mmol) in dioxane (100 mL) was stirred at 120 °C under N2 for 16 h. The cooled mixture was diluted with and extracHte2Od with EtOAc (100 mLx3). The organic phase was dried over anhydrous , conceNnat2raStOe4d and the residue was purified by silica gel chromatography (0 -10% EtOAc in PE) to afford ethyl 7-cyclobutyl-2-methoxy-8-vinylquinoline- 3 -carboxylate, Int 8-1 (6.8 g, 88 %) as a light yellow oil. LCMS: 312[M+H]+.

[0234] Step B: To a mixture of Int 8-1 (6.8 g, 21.8 mmol), K2OsO4 (480 mg, 1.3 mmol) in THF / H2O (200 mL / 40mL) was added NaIO4 (28 g, 131 mmol) at 0 °C under N2 and the reaction was stirred at 25 °C for 8 h. The reaction mixture was diluted with water and extracted with EtOAc (500 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc in PE) to afford ethyl 7- cyclobutyl-8-formyl-2-methoxyquinoline-3-carboxylate, Int 8-2 (5.3 g, 77%) as a white solid.LCMS: 314 [M+H]+.

[0235] Step C: To a solution of Int 8-2 (5.3 g, 16.9 mmol), NaH2P4 (12.18 g, 101.5 mmol) and 2-methylbut-2-ene (9.47 g, 135.3 mmol) in t-BuOH / H2O / THF (30 mL / 30mL / 10mL) was added NaClO2 (4.57 g, 50.7 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with EtOAc (300 mL x 3), the organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford 7-cyclobutyl-3 -(ethoxy carbonyl)-2-methoxy quinoline-8-carboxylic acid, Int 8 (5.3 g, 95%) as a white solid which was used directly for next step. LCMS: 330 [M+H]+. (R)-7-CycIobutyl-3-((l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamoyI)-2-oxo-l,2- dihydroquinoline-8-carboxylic acid (Int-9)

[0236] Step A: A solution of 7-cyclobutyl-3 -(ethoxy carbonyl)-2-methoxyquinoline-8-carboxylic acid, Int 8 (200 mg, 0.61 mmol) in SOCI2 (5 mL) was stirred at 80 °C for 1 h and the reaction mixture was concentrated to afford ethyl 8-(chlorocarbonyl)-7-cyclobutyl-2-methoxyquinoline-3- carboxylate, Int 9-1 (70 mg, 33%) as a yellow solid.

[0237] Step B: To a solution of Int 9-1 (70 mg, 0.201 mmol) in THF (5 mL) was added t-BuOH (4 mL, 43.7 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction was diluted with EtOAc (10 mL) and water. The organic layer was separated, washed with brine and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc in PE) to afford the title compound 8-( / erZ-butyl) 3-ethyl 7-cyclobutyl-2-methoxyquinoline-3,8-dicarboxylate, Int 9-2 (70 mg, 90%) as a white solid. LCMS (ESI): m / z 386 [M+H]1.

[0238] Step C: A solution of Int 9-2 (70 mg, 0.18 mmol) and LiOH (30 mg, 0.73 mmol) in THF / MeOH / H2O 3:3: 1 (14 mL) was stirred at 25 °C for 3 h and 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 anhydrous Na2SO4and concentrated to afford 8-(tert-butoxy carbonyl)-7-cyclobutyl-2-methoxyquinoline-3 -carboxylic acid, Int 9-3 (60 mg, 92%) as a white solid. LCMS (ESI): m / z 358 [M+H]+.

[0239] Step D: To a solution of Int 9-3 (70 mg, 0.20 mmol) in MeCN (5 mL) was added (R)-3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (34 mg, 0.26 mmol), TCFH (58 mg, 0.29 mmol) and NMI (48 mg, 0.59 mmol) and the mixture was stirred at 25 °C for 3 h. The mixture was extracted with EtOAc (50 mL x 3), the organic phase was dried over Na2SO4and concentrated to afford tertbutyl (R)-7-cyclobutyl-3-((l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamoyl)-2-methoxyquinoline-8- carboxylate, Int 9-4 (80 mg, 86%) as a white solid. LCMS (ESI): m / z 473 [M+H]+.

[0240] Step E: To a solution of Int 9-4 (80 mg, 0.169 mmol) in MeCN (10 mL) was added TMSI (169 mg, 0.845 mmol) and the mixture was stirred at 25 °C for 3 h. The mixture was extracted with EtOAc (50 mL x 3) and the organic phase was dried over anhydrous Na2SO4and concentrated to afford (R)-7-cyclobutyl-3-((l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamoyl)-2-oxo-l,2- dihydroquinoline-8-carboxylic acid, Int 9 (50 mg, 73%) as a yellow solid. LCMS (ESI): m / z 403 [M+H]+.Methyl 7-bromo-2-methoxy-8-(thiophen-3-ylcarbamoyl)quinoline-3-carboxylate, (Int 10)

[0241] Step A: To a solution of 2-amino-4-bromo-3 -methylbenzene- 1-carbaldehy de (9 g, 42.0 mmol) in MeOH (200 mL) was added methyl 3-methoxy-3-oxopropanoate (15 g, 117.7 mmol), HOAc (0.3 mL) and piperidine (12 mL, 126.1 mmol) and the solution was stirred at 60 °C for 16 h. The solution was filtered and the filter cake washed with PE to get methyl 7-bromo-8-methyl-2-oxo- lH-quinoline-3-carboxylate, Int 10-1 (11 g, 86%) as a yellow solid. LCMS (ESI):m / z 296, 298 [M+l]+.

[0242] Step B: To a mixture of Int 10-1 (10.7 g, 36.1 mmol) in DMF (500 mL) was added Ag2CO3(29.8 g, 108.4 mmol) and iodomethane (5.7 g, 39.8 mmol) and the solution was stirred at 40 °C for 16 h. The solution was filtered and the filtrate was concentrated, diluted with water and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (0-5 % of EtOAc in PE) to afford methyl 7-bromo-2-methoxy-8-methylquinoline-3- carboxylate, Int 10-2 (5.4 g, 48 %) as a yellow solid. LCMS(ESI):m / z 310, 312 [M+l]+.

[0243] Step C: To a mixture solution of Int 10-2 (5.4 g, 17.41 mmol) in CCL (100 mL) was added NBS (3.4 g, 19.15 mmol) and benzoic peroxyanhydride (0.4 g, 1.74 mmol), then the solution was stirred at 80 °C for 16 h. The solution was diluted with water and extracted with DCM (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (0-5 % of EtOAc in PE) to afford methyl 7-bromo-8-(bromomethyl)-2-methoxyquinoline-3 -carboxylate, Int 10-3 (3.5 g, 51 %) as a yellow solid. LCMS (ESI):m / z 389 [M+l]+.

[0244] Step D: To a mixture solution of Int 10-3 (3.5 g, 9.0 mmol) in MeCN (100 mL) was added NMO (2.1 g, 18.0 mmol) and the solution was stirred at 60 °C for 1 h. The cooled mixture was diluted with water and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine, dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated, the crude product was triturated in 50% EtOAc in PE (50 mL) and the mixture was filtered. The filter cake was dried in vacuo to afford methyl 7-bromo-8-formyl-2-methoxyquinoline-3-carboxylate, Int 10-4 (1.7 g, 58 %) as a yellow solid. LCMS (ESI):m / z 324, 326 [M+l]+.1HNMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.92 (s, 1H), 8.20 (d, J= 8.8 Hz, 1H), 7.84 (d, J= 8.4 Hz, 1H), 4.08 (s, 3H), 3.90 (s, 3H).

[0245] Step E: To a mixture solution of Int 10-4 (1.7 g, 5.2 mmol) was added NaH2PO4 (615 mg, 5.2 mmol), NaClO2(233 mg, 2.6 mmol) and 2-methylbut-2-ene (2.9 g, 42.0 mmol) in THF (60 mL), Z-BuOH (60 mL) and H2O (20 mL) and the solution was stirred at 25 °C for 16 h. The cooled solution was acidified with IN HC1 (pH = 4~5) and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine, dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to afford 7-bromo-2-methoxy-3 -(methoxy carbonyl)quinoline-8-carboxylic acid, Int 10-5 (1.7 g, crude) as a yellow solid which was used for the next step directly without further purification. LCMS (ESI): m / z 340, 342 [M+H]+.

[0246] Step F: To a solution of Int 10-5 (1.7 g, 5.0 mmol) in DMF (60 mL) was added thi ophen-3 -amine (0.7 g, 7.5 mmol), HATU (2.8 g, 7.5mmol) and DIEA (2.5 g, 20.0 mmol) and thesolution was stirred at 60 °C for 16 h. The reaction mixture diluted with water (50 mL) and extracted with EtOAc (50 mL x 3), The organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (5 % DCM in EtOAc) to afford methyl 7-bromo-2-methoxy-8-(thiophen-3- ylcarbamoyl)quinoline-3-carboxylate, Int 10 (1 g, 47 %) as a yellow solid. LCMS (ESI): m / z 420,422 [M+H]+.Preparation of Final CompoundsExample 1 (R)-N- (l,l-Dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxamide (1)

[0247] Step A: To a solution of 2-nitro-4-(trifluoromethyl)benzene- 1 -carbaldehyde (1 g, 4.56 mmol) in H2O (10 mL), HOAc (17 mL) and EtOH (20 mL) was added Fe powder (0.76 g, 13.70 mmol) and the solution stirred at 90 °C for 16 h. The mixture was filtered and the filtrate was concentrated to afford amino-4-(trifluoromethyl)benzene-l -carbaldehyde, 1-1 (1 g) as ayellow oil. LCMS (ESI): m / z 190 [M+H]+.

[0248] Step B: To a solution of 1-1 (500 mg, 2.64 mmol) in EtOH (20 mL) was added ethyl 3- ethoxy-3-oxopropanoate (4.0 mL, 26.43 mmol) and piperidine (0.3 mL, 2.64 mmol) and the solution was stirred for at 70 °C for 16 h. The solution diluted with water and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated. The crude product was purified by silica gel chromatography (40 % EtOAc in PE) to afford ethyl 2-oxo-7-(trifluoromethyl)-lH-quinoline-3 -carboxylate, 1-2 (50 mg, 6%) as a white solid. LCMS (ESI): m / z 286 [M+H]’

[0249] Step C: To a solution of 1-2 (55 mg, 0.19 mmol) in THF (3 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH (8 mg, 0.19 mmol) and the solution was stirred for at 25 °C for 16 h. The solution diluted with water and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated to afford 2-oxo-7-(trifluoromethyl)-lH- quinoline-3 -carboxylic acid, 1-3 (50 mg, 99%) as a white solid. LCMS (ESI): m / z 258 [M+H]+.

[0250] Step D: To a mixture solution of 1-3 (50 mg, 0.19 mmol) in DMF (10 mL) was added (R)-3-amino-2, 3 -dihydrothiophene- 1,1 -di oxide, Int 3 (31 mg, 0.23 mmol), DIEA (75 mg, 0.58 mmol) and HATU (88 mg, 0.23 mmol) and the solution was stirred at RT for 16 h. The solution diluted with water and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-A-(l, 1 -dioxi do-2, 3- dihydrothiophen-3-yl)-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinolme-3-carboxamide, 1 (15 mg, 20%) as a white solid. LCMS (ESI): m / z 373 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (s, 1H), 10.08 (d, J= 8.0 Hz, 1H), 8.95 (s, 1H), 8.22 (d, J= 8.0 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.29 (dd, J= 6.0, 2.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.2 Hz, 1H), 5.47 - 5.36 (m, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.36 - 3.33 (m, 1H).Example 2(R (T rifluoromethyl)phenyl)- l,2-dihydroquinoline-3-carboxamide (2)

[0251] Step A: A solution of 1-2 (1 g, 3.54 mmol), Pd(dppf)C12 (0.26 g, 0.35 mmol), and K2CO3(1.5 g, 10.64 mmol) in dioxane (15 mL) was stirred at 90 °C under N2 for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel cchromatography (0 - 10% MeOH in DCM) to afford methyl 2-oxo-7-[4-(trifluoromethyl)phenyl]- lH-quinoline-3 -carboxylate, 2-1 (220 mg, 17%) as a red solid. LCMS (ESI): m / z 348 [M+H]+.

[0252] Step B: To a solution of 2-1 (180 mg, 0.52 mmol) in THF / MeOH LO (14 mL, 3:3: 1) was added NaOH (20 mg, 0.52 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice water and adjusted the pH = 5 ~ 6 by 1 / V HCI. The mixture was extracted with EtOAc (50 mL x 3) and the organic phase was washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford 2-oxo-7-[4- (trifluoromethyl)phenyl]-lH-quinoline-3-carboxylic acid, 2-2 (160 mg, 92%) as a white solid. LCMS (ESI): m / z 334 [M+H]+.

[0253] Step C: To a solution of 2-2 (60 mg, 0.18 mmol) in DCE (6 mL) was added SOCI2 (214 mg, 1.8 mmol) and the reaction mixture was stirred at 80 °C for 30 min. The mixture was concentrated under reduced pressure to afford 2-oxo-7-[4-(trifluoromethyl)phenyl]-lH-quinoline-3- carbonyl chloride, 2-3 (50 mg, 78%) as a red solid.

[0254] Step D: To a solution of (R) -3 -ami no-2, 3 -dihydrothiophene 1,1 -dioxide, Int 3 (22 mg, 0.17 mmol) in THF (5 mL) and MeCN (2 mL) was added TEA (0.02 mL, 0.14 mmol). The mixture was stirred at RT for 15 min and 2-oxo-7-[4-(trifluoromethyl)phenyl]-lH-quinoline-3-carbonyl chloride, 2-3 (50 mg, 0.14 mmol) in THF was added. The reaction mixture was concentrated and the crude product was purified by reverse phase chromatography (Cl 8, MeCNTbO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford A-[(3A)-l,l-dioxo-2,3-dihydrothiophen-3-yl]-2-oxo-7-[4- (trifluoromethyl)phenyl]-lH-quinoline-3-carboxamide, 2 (10 mg, 15%) as a yellow solid. LCMS (ESI): m / z 449 [M+H]+;1H NMR (400 MHz, DMSO- 6) 5 12.64 (s, 1H), 10.17 (d, J= 8.0 Hz, 1H), 8.93 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.92 (q, J = 8.4 Hz, 4H), 7.73 - 7.63 (m, 2H), 7.29 (dd, J = 6.0, 2.0 Hz, 1H), 7.02 (dd, J= 6.0, 3.0 Hz, 1H), 5.42 (s, 1H), 3.77 (dd, J= 14.0, 8.0 Hz, 1H), 3.35 (d, J = 4.0 Hz, 1H).Example 3 (R) -7V-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3-carboxamide (3)

[0255] Step A: To a solution of 2-oxo-l,2-dihydroquinoline-3 -carboxylic acid (40 mg, 0.21 mmol) in DMF (3 mL) was added (R) -3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (33 mg, 0.25 mmol), DIEA (81 mg, 0.63 mmol) and HATU (120 mg, 0.32 mmol). The mixture was stirred at RT for 2 h and the crude product was purified by reverse phase chromatography (C18, MeCN / H2O 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford(R) -A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3 -carboxamide, 3 (20 mg, 31%) as a white solid. LCMS (ESI): m / z 305 [M+H]+;JH NMR (400 MHz, DMSO-d6) 5 12.54 (s, 1H), 10.20 (d, J= 8.0 Hz, 1H), 8.87 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68 (t, J= 8.0 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.37 - 7.23 (m, 2H), 7.01 (dd, J= 6.0, 3.0 Hz, 1H), 5.41 (s, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 (d, J= 4.0 Hz, 1H).Example 4(R) - / V-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-7-ethyl-2-oxo-l,2-dihydroquinoline-3- carboxamide (4)

[0256] Step A: To a solution of 1-2 (200 mg, 0.71 mmol) in dioxane (4 mL) and (1 H2O mL) was added trifluoro(vinyl)borane, potassium salt (189 mg, 1.42 mmol), K2CO3(293 mg, 2.13 mmol) and Pd(dppf)C12.DCM (58 mg, 0.07 mmol). The mixture was stirred at 100 °C under N2 for 5 h. The reaction mixture was diluted with water 50 mL, extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (15 g column, 0-50% EtOAc in hexanes) to afford methyl 2-oxo-7-vinyl-lH-quinoline-3 -carboxylate 4-1 (70 mg, 43 %) as a yellow solid. LCMS (ESI): m / z 230 [M+H]-.

[0257] Step B: To a solution of 4-1 (200 mg, 0.87 mmol) in MeOH (5 mL) was added Pd / C 10% (20 mg, 0.19 mmol). The mixture was stirred at RT under EE balloon for 2 h and the reaction mixture was concentrated to afford methyl 7-ethyl-2-oxo-lH-quinoline-3-carboxylate 4-2 (70 mg, 89%) as a white solid. LCMS (ESI): m / z 232[M+H]+.

[0258] Step C: To a solution of 4-2 (200 mg, 0.87 mmol) in MeOH (5 mL) and (5 mL) was H2O added LiOH (18 mg, 4.4 mmol). The mixture was stirred at 50 °C for 2 h. and the reaction mixture was diluted with water 50 mL, extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (15 g column, 0-5% EtOAc in hexanes) to afford 2-oxo-7-vinyl-lH-quinoline-3- carboxylic acid, 4-3 (180 mg, 95%) as a yellow solid. LCMS (ESI): m / z 216[M+H]+.

[0259] Step D: To a solution of 4-3 (50 mg, 0.23 mmol) in DMF (5 mL) was added (l?)-3- amino-2,3-dihydrothiophene-l,l-dioxide, Int 3 (30.7 mg, 0.23 mmol), HATU (131 mg, 0.35 mmol) and DIEA (148 mg, 1.15 mmol). The mixture was stirred at RT for 2h and the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / ELO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-7-ethyl-2-oxo-l,2- dihydroquinoline-3 -carboxamide 4 (5 mg, 06 %) as a white solid. LCMS (ESI): m / z 333 [M+H]+;!H NMR (400 MHz, DMSO-d6) 6 12.46 (s, 1H), 10.21 (d, J= 8.0 Hz, 1H), 8.83 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 6.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 2H), 2.75 - 2.69 (m, 2H), 1.22 (d, J= 8.0 Hz, 3H).Example 5 (R) -A-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-7-fluoro-2-oxo-l,2-dihydroquinoline-3- carboxamide (5)

[0260] Step A: To a mixture of 2-amino-4-fluorobenzene-l-carbaldehyde (325 mg, 2.33 mmol) in methyl 3-methoxy-3-oxopropanoate (10 mL, 2.34 mmol) was heated to 140 °C for 4 h. The reaction mixture was allowed to RT and the resulting precipitate was filtered, washed with tert-butyl methyl ether and dried under vacuo to afford methyl 7-fluoro-2-oxo-lH-quinolme-3 -carboxylate, 5-1 (330 mg, 63%) as a white solid. LCMS (ESI): m / z 222 [M+H]+.

[0261] Step B: To a solution of 5-1 in THF:MeOH:H2O (7 mL, 3:3:1,) was added LiOH (313 mg, 7.46 mmol) at room temperature and the reaction mixture was stirred at RT for 4 h. The reaction mixture was adjusted to pH = 3 with 2N HC1 and the precipitate was filtered, washed with H2O and dried under reduced presure to afford 7-fluoro-2-oxo-lH-quinoline-3-carboxylic acid 5-2 (290 mg, 93%) as a yellow solid. LCMS (ESI): m / z 208[M+H]+.

[0262] Step C: To a solution of 5-2 (30 mg, 0.15 mmol) in DMF (3 mL) were added ( / ?)-3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (23 mg, 0.17 mmol), HATU (82 mg, 0.22 mmol) and DIEA (56 mg, 0.43 mmol) and the reaction was stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic extracts were washed with brine, dried over anhydrous Na2S,O f4iltered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford R)-A-( 1,1 -dioxi do-2, 3- dihydrothiophen-3-yl)-7-fluoro-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 5 (12.4 mg, 26%) as a white solid. LCMS (ESI): m / z 323 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.06 (d, J =8.0 Hz, 1H), 8.89 (s, 1H), 8.08 (dd, J= 9.0, 6.0 Hz, 1H), 7.28 (dd, J=7.0, 2.0 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.00 (dd, J= 7.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 (d, J = 4.0 Hz, 1H).Example 6 (R) -iV-(l,l-Dioxido-2,3-dihydrothiophen-3-yI)-7-(methyIthio)-2-oxo-l,2-dihydroquinoline-3- carboxamide (6)

[0263] Step A: To a solution of 2-amino-4-fluorobenzene-l-carbaldehyde (1 g, 7.19 mmol) in DMSO (20 mL) was added sodium methanethiolate (0.50 g, 7.2 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 30 min and at RT for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to afford 2-amino-4-(methylsulfanyl)benzene-l-carbaldehyde, 6-1 (450 mg, 37%) as a yellow solid. LCMS (ESI): m / z 168 [M+H]+.

[0264] Step B: To a solution of 6-1 (450 mg, 2.69 mmol) in EtOH (20 mL) was added ethyl 3- ethoxy-3-oxopropanoate (1.2 g, 7.53 mmol), piperidine (687 mg, 8.07 mmol) and HOAc (1 drop). The mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford ethyl 7-(methylsulfanyl)-2- oxo- lH-quinoline-3 -carboxylate 6-2 (400 mg, 56%) as a white solid. LCMS (ESI): m / z 264 [M+H]+.

[0265] Step C: To a solution of 6-2 (200 mg, 0.76 mmol) in MeOH (5 mL) and (5 mL) was H2O added LiOH (159 mg, 3.80 mmol) and the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated, diluted with water (5 mL) and adjusted the pH = 5. The solution was extracted with EtOAc and the organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 7-(methylsulfanyl)-2-oxo-lH-quinoline-3- carboxylic acid, 6-3 (200 mg, 92%) as a yellow solid. LCMS (ESI): m / z 236 [M+H]+.

[0266] Step D: To a solution of 6-3 (50 mg, 0.21 mmol) in DMF (5 mL) was added (3R)-3- amino-2,3-dihydrothiophene-l, 1-dione, Int 3 (28 mg, 0.21 mmol), HATU (121 mg, 0.32 mmol) and DIEA (137 mg, 1.06 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The crude product was purified by reverse phase chromatography (C18, MeCN / H O, 0.1% formic acid modifier, 0% to 70% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R) -V-( 1 , 1 -Dioxido-2,3- dihydrothi ophen-3 -yl)-7-(methylthio)-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 6 (21.3 mg, 29 %) as a white solid. LCMS (ESI): m / z 233[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.21 (d, J= 8.0 Hz, 1H), 8.83 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.20 (d, J= 8.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 2H), 2.75 - 2.69 (m, 2H), 1.22 (d, J = 8.0 Hz, 3H).Example 7 (R) - / V-(l,l-Dioxido-2,3-dihydrothiophen-3-yI)-7-(methylamino)-2-oxo-l,2-dihydroquinoline-3- carboxamide (7)

[0267] Step A: To a solution of methyl 7-bromo-2-oxo-lH-quinoline-3-carboxylate, 2-1 (300 mg, 1.06 mmol) in dioxane (5 mL) was added 2-methylpropan-2-yl (methylamino)methanoate (139 mg, 1.0 mmol), Pd2(dba)3 (97 mg, 0.1 mmol), Xantphos (123 mg, 0.21 mmol) and CS2CO3 (1030 mg, 3.2 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by a silica gel chromatography (0-5% MeOH in DCM) to afford 2-methylpropan-2-yl {[3-(methoxycarbonyl)-2-oxo-lH-quinolin-7- yl](methyl)amino}methanoate, 7-1 (150 mg, 42%) as a light yellow solid. LCMS (ESI): m / z 333 [M+H]+.

[0268] Step B: To a solution of 7-1 (150 mg, 0.45 mmol) in THE (5 mL) was added LiOH (94.7 mg, 2.2 mmol) in H (22O mL) and the reaction mixture was stirred at RT for 2 h. The pH was adjusted to 3-4 by adding 2M HC1 and the aqueous layer was extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous and concentrNatae2dSO u4nder reduced pressure to afford 7-(2,2-dimethyl-4-oxo-5-aza-3-oxahex-5-yl)-2-oxo-lH-quinoline-3-carboxylic acid, 7-2 (100 mg, 69%) as a white solid. LCMS (ESI): m / z 319 [M+H]+.

[0269] Step C To a solution of 7-2 (50 mg, 0. 16 mmol) in DMF (3 mL) were added (R)-3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (21 mg, 0.15 mmol), DIEA (61 mg, 0.47 mmol) and T3P, 50% in EtOAc (100 mg, 0.31 mmol) and the reaction mixture was stirred at RT for 2 h, poured into water and extracted with EtOAc (5 mL x 3), the organic layer was washed with brine, dried overanhydrous Na2SO4and concentrated. The residue was purified by prep-TLC (70% EtOAc in PE) to afford 2-methylpropan-2-yl { [ 3 - ( { [ (3 R) - 1 , 1 -dioxo-2, 3 -dihydro- 1 λ6-thi ophen-3 -yl]amino } carbonyl)- 2-oxo-lH-quinolin-7-yl](methyl)amino]methanoate, 7-3 (20 mg, 29%) as a white solid. LCMS (ESI): m / z 434 [M+H]+.

[0270] Step D To a solution of 7-3 (20 mg, 0.05 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred RT for 1 h. The reaction mixture concentrated in vacuo and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford A-[(37?)-l,l-dioxo-2,3-dihydrothiophen-3-yl]-7-(methylamino)-2-oxo-lH- quinoline-3 -carboxamide, 7 (4.5 mg, 29%) as a white solid. LCMS (ESI): m / z 334 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 6 11.96 (s, 1H), 10.17 (d, J= 8.0 Hz, 1H), 8.55 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.25 (dd, J= 6.7, 2.0 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.60 (dd, J= 9.0, 2.0 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 5.37 (s, 1H), 3.73 (dd, J= 14, 8.0 Hz, 1H), 3.23 (dd, J= 14.0, 4.0 Hz, 1H), 2.75 (d, J = 4.8 Hz, 3H).Example 8 (R) -A-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-2-oxo-7-(trifluoromethyl)-l,2- dihydroquinoline-3-carboxamide (8)

[0271] Step A: To a solution of 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.55 g, 10.08 mmol), [4-(trifluoromethyl)phenyl]boranediol (358 mg, 1.88 mmol) and Na2SO4(2.46 g, 23.25 mmol) in dioxane (10 mL) and (2 mHL2)O was added Pd(dppf)C12 (0.57 g, 0.78 mmol) and themixture was stirred at 90 °C for 16 h. The resulting solution was diluted with brine (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0- 50% EtOAc in PE) to afford 4-fluoro-5-(trifluoromethyl)-2-vinylaniline, 8-1 (1 g, 63%) as a yellow solid. LCMS (ESI): m / z 206 [M+H]+.

[0272] Step B: To a solution of 8-1 (1 g, 4.87 mmol) and potassium citrate (0.04 g, 0.10 mmol) in THF (10 mL) and H2O (2 mL) was added NaIO4 (4.17 g, 19.50 mmol) and the solution was stirred at RT for 16 h. The resulting solution was diluted with of brine (10 mL), extracted with EtOAc (20 mL x 3) and washed with brine (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to afford 2-amino-5-fluoro-4-(trifluoromethyl)benzene-l- carbaldehyde 8-2 (200 mg, 20%) as a white solid. LCMS (ESI): m / z 208 [M+H]+.

[0273] Step C: To a solution of 8-2 (200 mg, 0.97 mmol), methyl 3-methoxy-3-oxopropanoate (127 mg, 0.97 mmol) and piperidine (246 mg, 2.90 mmol) in MeOH (5 mL) was added HOAc (0.006 mL) and the solution was stirred at 60 °C for 2 h. The resulting solution was diluted with brine (10 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% EtOAc in PE) to afford methyl 6-fluoro-2-oxo-7-(trifluoromethyl)-lH- quinoline-3 -carboxylate, 8-3 (200 mg, 72%) as a white solid. LCMS (ESI): m / z 290 [M+H]+.

[0274] Step D: To a solution of 8-3 (200 mg, 0.69 mmol) in THF (3 mL), MeOH (3 mL) and H2O (1 mL) was added LiOH (145 mg, 3.46 mmol) and the solution was stirred at RT for 2 h. The residue was diluted with water, pH was adjusted 4 ~ 5 with IN HC1, extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 5-oxo-3-[4-(trifluoromethyl)phenyl]-4H-l,2,4-triazine-6-carboxylic acid 8-4 (100 mg, 55%) as a yellow solid. LCMS (ESI): m / z 276 [M+H]+.

[0275] Step E: To a solution of 8-4 (100 mg, 0.36 mmol) in pyridine (5 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (102 mg, 0.36 mmol) and the solution was stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 2,3,4,5,6- pentafluorophenyl 6-fluoro-2-oxo-7-(trifluoromethyl)-lH-quinoline-3-carboxylate, 8-5 (80 mg, 50%) as a yellow solid. The residue was used without purification in the next step. LCMS (ESI): m / z 442 [M+H]+.

[0276] Step F: To a solution of 8-5 (60 mg, 0.14 mmol) and DIEA (52.73 mg) in DMF (5 mL) was added (R) -3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (18 mg, 0.14 mmol) and the solution was stirred at RT for 16 h. The resulting solution was diluted with brine, and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / ELO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (A)-Af-( I , I -dioxido-2,3- dihydrothiophen-3-yl)-6-fluoro-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinohne-3 -carboxamide, 8 (21.0 mg, 40%) as a white solid. LCMS (ESI): m / z 391 [M+H]+;1H NMR(400 MHz, DMSO-d6) 5 12.82 (s, 1H), 10.11 (d, J= 8.0 Hz, 1H), 8.90 (s, 1H), 8.20 (d, J= 11.0 Hz, 1H), 7.76 (d, J= 6.0 Hz, 1H), 7.29 (dd, J= 7.0, 1.9 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.47 - 5.36 (m, 1H), 3.76 (dd, J = 14.0, 8.0 Hz, 1H), 3.30 (s, 1H).Example 9 (R) -7-Bromo-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3- carboxamide (9)

[0277] Step A: To a solution of methyl 7-bromo-2-oxo-l,2-dihydroquinoline-3 -carboxylate, 1- 2 (200 mg, 0.71 mmol) in THF / MeOH / H2O (9 mL, 3:3:3) was added NaOH (142 mg, 3.54 mmol) and the solution was stirred at RT for 4 h. The solution was poured into ice water and adjusted the pH = 3 with 2A HCI. The mixture was extracted with EtOAc (50 mL x 3), the organic phase was dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to afford 7-bromo-2-oxo-l,2- dihydroquinoline-3 -carboxylic acid, 9-1 (155 mg, 81%) as a white solid. LCMS (ESI): m / z 268,270 [M+H]+.

[0278] Step B: To a solution of 9-1 (30 mg, 0.11 mmol) in DMF (5 mL) were added -3- (R) amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (22 mg, 0.17 mmol), DIEA (43 mg, 0.34 mmol) and HATH (63 mg, 0.17 mmol) and the mixture was stirred at RT for 2 h. The crude product was purifiedby reverse phase chromatography (C 18, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R) -7- bromo-A-( 1 , 1 -dioxi do-2, 3 -dihy drothiophen-3 -y l)-2-oxo- 1 ,2-dihy droquinoline-3 -carboxamide, 9 (6 mg, 14%) as a white solid. LCMS (ESI): m / z 383, 385 [M+H]+; H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.07 (d,J= 8.0 Hz, 1H), 8.86 (s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.48 (dd, J = 8.0, 2.0Hz, 1H), 7.28 (dd, J= 6.0, 2.0Hz, 1H), 6.99 (dd, J= 6.Q, 3.0 Hz, 1H), 5.39 (s, 1H), 3.74 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 (dd, J= 4.0 Hz, 1H).Example 10 (R) -7-CycIopropyl-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3- carboxamide (10)

[0279] Step A: To a solution of 1-2 (1.06 g, 3.76 mmol) and 4-cyclopropylboranediol (0.96 g, 11.18 mmol) in dioxane (20 mL) and water (2 mL) was added K2CO3(2.12 g, 15.34 mmol) followed by Pd(dppf)C12.DCM (0.3 g, 0.41 mmol) under N2 with stirring and the solution was refluxed for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The organic layer was dried over anhydrous Na2S,O fi4ltered and concentrated to afford the crude product which was purified by silicagel chromatography (0-100% EtOAc in PE) to afford methyl 7-cyclopropyl-2-oxo-lH-quinoline-3- carboxylate, 10-1 (450 mg, 49%) as a light brown solid. LCMS (ESI): m / z 244 [M+H]+.

[0280] Step B: To a solution of 10-1 (450 mg, 1.85 mmol) in THF (3 mL), MeOH (5 mL) and water (1 mL) at 0 °C was added NaOH (222 mg), the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (20 mL), and adjusted the pH to 4 ~ 5 with HC1 (2 N). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to afford 7-cyclopropyl- 2-oxo- lH-quinoline-3 -carboxylic acid, 10-2 (180 mg, 43%) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z 230 [M+H]+.

[0281] Step C: To a solution of 10-2 (50 mg, 0.22 mmol) in pyridine (4 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (611 mg, 2.18 mmol) at 0 °C and the reaction mixture was stirred at 40 °C for 30 min. The reaction mixture was concentrated under reduced pressure to afford 2,3,4,5,6-pentafluorophenyl 7-cyclopropyl-2-oxo-lH-quinoline-3-carboxylate, 10- 3 (86 mg, 100%) as a light yellow solid. LCMS (ESI): m / z 396 [M+H]+.

[0282] Step D: To a solution of 10-3 (86 mg, 0.19 mmol) and (R)-3-amino-2,3- dihydrothiophene 1,1-dioxide, Int 3 (38 mg, 0.28 mmol) in DMF (3 mL) was added DIEA (84 mg, 0.65 mmol) at 0 °C and the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with ice-water (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse phase purification (C 18, MeCNELO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford ( / / )-7-cyclopropyl-A-( 1, 1 -dioxi do-2, 3 -dihydrothiophen-3-yl)-2-oxo-l ,2- dihydroquinoline-3 -carboxamide, 10 (11 mg, 14%) as a light white solid. LCMS (ESI): m / z 345 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 10.18 (d, J= 8.0 Hz, 1H), 8.80 (s, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.28 (d, J= 6.0 Hz, 1H), 7.13 (s, 1H), 7.00 (d.. / - 7.0 Hz, 2H), 5.39 (s, 1H), 3.74 (dd, J= 14.0, 8.0 Hz, 1H), 3.28 (s, 1H), 2.05 (m, 1H), 1.09 (d, J= 8.0 Hz, 2H), 0.78 (d, J= 4.0 Hz, 2H).Example 11 (R) -7-(terf-Butyl)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3- carboxamide (11)

[0283] Step A: To a mixture solution of 2-amino-4-(2-methylprop-2-yl)benzoic acid (5 g, 25.87 mmol) in THF (50 mL) was added LiAlTU (2.95 g, 77.62 mmol) and the solution was stirred at RT for 16 h. The solution diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried with anhydrous MeCN / H a2nOd concentrated. The crude product was purified by silica gel chromatography (0-10% of EtOAc in PE) to afford [2-amino-4-(2-methylprop-2-yl) phenyl]methanol, 11-1 (3.8 g, 81%) as a white solid. LCMS (ESI): m / z 180 [MTH]+; 'HNMR (400 MHz, CDCh-d) δ 8.31 (d, J= 9.0 Hz, 1H), 7.76 (dd, J= 6.0, 1.0 Hz, 2H), 7.67 (ddd, J= 8.0, 6.0, 2.0 Hz, 1H), 4.02 (s, 3H)

[0284] Step B: To a mixture solution of 11-1 in DCM (200 mL) was added Mn02 (9.70 g, 111.57 mmol) and the solution was stirred at 25 °C for 2 h. The solution was filtered and the filtrate was concentrated. The residue was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc in PE) to afford 2-amino-4-(2-methylprop-2-yl) benzene- 1-carbaldehy de, 11-2 (1.7 g, 85%) as a white solid. LCMS (ESI): m / z 178 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 6 9.75 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.04 (s, 2H), 6.76 (d, J= 1.0 Hz, 1H), 6.71 (dd, J= 8.0, 1.0 Hz, 1H), 1.24 (s, 9H).

[0285] Step C: To a mixture solution of 11-2 (800 mg, 4.513 mmol) in MeOH (20 mL) was added methyl 3-methoxy-3-oxopropanoate (1.7 g, 12.64 mmol), piperidine (1.34 mL, 13.54 mmol) and HOAc (0.03 mL) and the solution was stirred at 60 °C for 16 h. The solution was fdtered, thefilter cake was dried to afford methyl 7-(2-methylprop-2-yl)-2-oxo-lH-quinoline-3 -carboxylate, 11-3 (1 g, 3.85 mmol, 85%) as a white solid. LCMS (ESI): m / z 260 [M+H]+

[0286] Step D: To a mixture solution of 11-3 (900 mg, 3.47 mmol) in THF (6 mL), MeOH (6 mL) and H2O (2 mL) was added LiOH (730 mg, 17.35 mmol) and the solution was stirred at RT for 15 min. The solution diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous NazSO-i, filtered and concentrated to afford 7-(2- methylprop-2-yl)-2-oxo-lH-quinoline-3 -carboxylic acid, 11-4 (756 mg, 88 %) as a white solid. LCMS (ESI): m / z 246 [M+H]+

[0287] Step E: To a mixture solution of 11-4 (50 mg, 0.20 mmol) in DMF (2 mL) was added (R)-3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (41 mg, 0.31 mmol), HATU (93 mg, 0.24 mmol) and DIEA (79 mg) and the solution was stirred at RT for 16 h. The solution was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R) -7-( / er / -butyl)-A-(l,l-dioxido-2,3- dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3 -carboxamide 11 (41 mg, 55%) as a white solid. LCMS (ESI): m / z 361 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.22 (d, J= 7.6 Hz, 1H), 8.82 (s, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.49 -7.39 (m, 2H), 7.28 (dd, J= 6.4, 1.9 Hz, 1H), 7.00 (dd, J= 6.4, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 7.9 Hz, 1H), 3.28 (d, J= 4.0 Hz, 1H), 1.32 (s, 9H).Example 12 (R) -iV-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-vinyl-l,2-dihydroquinoline-3- carboxamide (12)

[0288] Step A: To a solution of methyl 2-oxo-7-vinyl-l,2-dihydroquinoline-3 -carboxylate, 4-1(200 mg, 0.87 mmol) in THF / MeOH / H2O (9 mL, 3:3:3) was added NaOH (70 mg, 1.75 mmol) andthe mixture was stirred at RT for 18 h. The solution was poured into ice water and adjusted pH =2~3 with 2N HC1. The solution was extracted with EtOAc (50 mL x 3), the organic phase was dried over anhydrous Na2SO an4d filtered. The filtrate was concentrated to afford 2-oxo-7-vinyl-l,2- dihydroquinoline-3 -carboxylic acid, 12-1 (160 mg, 85%) as a white solid. LCMS (ESI): m / z 216 [M+H]+.

[0289] Step B: To a solution of 12-1 (30 mg, 0.14 mmol) in DMF (6 mL) were added (R)-3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (28 mg, 0.21 mmol), DIEA (54 mg, 0.42 mmol) and HATH (79 mg, 0.21 mmol). The solution was stirred at RT for 2 h and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / IfiO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford -A(-R()l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-vinyl-l,2- dihydroquinoline-3 -carboxamide, 12 (20 mg, 43%) as a white solid. LCMS (ESI): m / z 331 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.17 (d, J= 8.0 Hz, 1H), 8.83 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.50 (dd, J= 8.0, 1.1 Hz, 1H), 7.40 (s, 1H), 7.28 (dd, J= 7.0, 2.0 Hz, 1H), 7.00 (dd, J = 7.0, 3.0 Hz, 1H), 6.85 (dd, J= 18.0, 11.0 Hz, 1H), 6.01 (d, J= 17.6 Hz, 1H), 5.49 (d, J= 11.0 Hz, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 (dd, J = 4.0 Hz, 1H).Example 13 (R) -7-Cyclobutyl-N -(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3- carboxamide (13)

[0290] Step A: To a solution of methyl 7-bromo-2-oxo-l ,2-dihydroquinoline-3-carboxylate (1g, 3.5 mmol) in DCM (15 mL) was added trimethyloxonium tetrafluoroborate (0.79 g, 5.3 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was filtered and washed with DCM. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (0-8% EtOAc in hexanes) to afford to afford methyl 7-bromo-2-methoxyquinoline- 3 -carboxylate, 13-1 (250 mg, 23%) as a white solid. LCMS (ESI): m / z 296,298 [M+H]+.

[0291] Step B: A solution of 13-1 (100 mg, 0.34 mmol), potassium cyclobutyltrifluoroborate (109 mg, 0.68 mmol), NiBr2(dtbbpy) (16 mg, 0.03 mmol) and 2,6-dimethylpyridine (54 mg, 0.51 mmol) in dioxane (20 mL) and DMA (4 mL) was stirred at 2x24 W blue LED (450 nm) under N2 for 1 h and the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford methyl 7-cyclobutyl-2-methoxyquinoline-3-carboxylate, 13-2 (40 mg, 43%) as a yellow solid. LCMS (ESI): m / z 272 [M+H]+.

[0292] Step C: A mixture of 13-2 (70 mg, 0.26 mmol) in cone. HC1 (4 mL) was stirred at 100 °C under N2 for 5 h and the reaction mixture was concentrated to afford 7-cyclobutyl-2-oxo-l,2-dihydroquinoline-3 -carboxylic acid, 13-3 (50 mg, 79%) as a yellow solid. LCMS (ESI): m / z 244 [M+H]+.

[0293] Step D: To a solution of 13-3 (30 mg, 0.12 mmol) in DMF (3 mL) was added DIEA (47 mg) and HATU (46 mg, 0.12 mmol) and the reaction mixture was stirred at RT for 2 h. (R)-3 -amino- 2,3 -dihydrothiophene 1,1-dioxide, Int 3 (21 mg, 0.16 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture concentrated under reduced pressure and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R) -7-cyclobutyl-A-( I , l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3- carboxamide, 13 (10 mg, 22%) as a yellow solid. LCMS (ESI): m / z 359 [M+H]+;rH NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.20 (d, J= 8.0 Hz, 1H), 8.82 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.34 - 7.22 (m, 2H), 7.19 (d, J= 8.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.49 - 5.30 (m, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.32 - 3.27 (m, 1H), 2.40 - 2.29 (m, 2H), 2.17 - 1.99 (m, 3H), 1.91 - 1.78 (m, 1H).Example 14

[0294] Step A: To a solution of ethyl 7-bromo-2-oxo-lH-quinoline-3-carboxylate, Int 1 (500 mg, 1.68 mmol) in dioxane (5 mL) and (1 mL)H w2Oere added potassium trifluoro(vinyl)borate (452 mg, 3.37 mmol), K2CO3(700 mg, 5.06 mmol) and bis[5-(diphenylphosphanyl)cyclopenta-l,3- dienyl]iron(II) palladium chloride (123 mg, 0.17 mmol) and the reaction mixture was stirred at 100 °C under N2 for 18 h. The solution was filtered through a celite pad and the resulting solution was diluted with water and extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried over anhydrous , filterNeda2aSnOd4concentrated. The crude product was purified by silica gel chromatography (0-50% EtOAc in PE) to afford ethyl 2-oxo-7-(prop-2-enyl)- lH-quinoline-3-carboxylate, 14-1 (190 mg, 43%) as a white solid. LCMS (ESI): m / z 258 [M+H]+.

[0295] Step B: To a solution of 14-1 (190 mg, 0.74 mmol) in MeOH (4 mL) was added Pd / C 10%> (31 mg, 0.30 mmol) and the reaction mixture was stirred at RT with H2 balloon for 18 h. After filtration through a celite pad, the filtrate was concentrated to afford ethyl 2-oxo-7-propyl-lH- quinoline-3 -carboxylate 14-2 (110 mg, 57%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.45 (s, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.16 - 7.06 (m, 2H), 4.26 (q, J= 7.0 Hz, 2H), 2.63 (t, J= 8.0 Hz, 2H), 1.62 (dd, J= 15.0, 7.0 Hz, 2H), 1.30 (t, 7 = 8.0 Hz, 3H), 0.91 (t, 7 = 7.0 Hz, 3H).

[0296] Step C: To a solution of 14-2 (80 mg, 0.31 mmol) in MeOH (5 mL) and (5 mL) was H2O added LiOH (65 mg, 1.54 mmol) and the mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 2- oxo-7-propyl-lH-quinoline-3-carboxylic acid 14-3 (70 mg, 98%) as a white solid. LCMS (ESI): m / z 232 [M+H]-.

[0297] Step D: To a solution of 14-3 in pyridine (1 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (181 mg, 0.65 mmol) at 40 °C and the mixture was stirred at 40 °C for 30 min. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0 - 50%> in EtOAc / hexane) to afford 2,3,4,5,6-pentafluorophenyl 2-oxo-7-propyl-lH-quinoline-3- carboxylate, 14-4 (50 mg, 97%) as a white solid. LCMS (ESI): m / z 398 [M+H]+.

[0298] Step E: To a solution of 14-4 (50 mg, 0.13 mmol) in DMF (2 mL) was added (R) -3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (16.8 mg, 0.13 mmol) and DIEA (81.4 mg, 0.63 mmol), the mixture was stirred at 25 °C for 10 min and concentered. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / HzO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-propyl-l,2-dihydroquinoline-3-carboxamide, 14 (9.7 mg, 22%) as a white solid. LCMS (ESI): m / z 346 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.20 (d, .7= 8.0 Hz, 1H), 8.82 (s, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 7.23 (s, 1H), 7.17 (dd, J= 8.0, 1.0 Hz, 1H), 7.00 (dd, J = 6.4, 3.2 Hz, 1H), 5.46 - 5.35 (m, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.28 (d, J= 4.0 Hz, 1H), 2.73 - 2.62 (m, 2H), 1.63 (d, J= 8.0 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H).Example 157-Cyclopentyl-A-[(3 R)-l,l-dioxo-2,3-dihydrothiophen-3-yl]-2-oxo-lH-quinoline-3-carboxamide(15)

[0299] Step A: A mixture of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (500 mg, 1.6 mmol), 2-(cyclopent-l-enyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (625 mg, 3.2 mmol), K2CO3(668 mg, 4.8 / mmol) and Pd(dppf)C12 CH2CI2 (132 mg, 0.16 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 100 °C under N2 atmosphere for 4 h. The reaction mixture was cooled and concentrated. The residue was dissolved in EtOAc (5 mL) and washed with H2O, and brine. The combined organic phase was dried over anhydrous , filtered and N coan2cSeOn4trated. The crude product was purified using silica gel chromatography (0-60% in EtOAc / PE) to afford 7- (cyclopent-l-enyl)-2-methoxyquinoline-3 -carboxylate, 15-1 (400 mg, 83%) as yellow solid. LCMS (ESI): m / z 298 [M+H]+.

[0300] Step B: A suspension of 15-1 (400 mg, 1.3 mmol) and 10% Pd / C (32 mg) in EtOH (8 mL) was stirred under EE atmosphere using a balloon at RT for 2 h,. The reaction mixture was fdtered through a celite pad and the fdtrate was concentrated afford ethyl 7-cyclopentyl-2- methoxyquinoline-3 -carboxylate, 15-2 (400 mg, 99%) as a gray solid. LCMS (ESI): m / z 300 [M+H]+

[0301] Step C: A solution of 15-2 (400 mg, 1.3 mmol) in cone. HC1 (5 mL) was stirred at 100 °C for 2 h and the reaction was cooled to RT. The reaction mixture was fdtered and the solid cake was dried in vacuo to afford 7-cyclopentyl-2-oxo-lH-quinoline-3-carboxylic acid, 15-3 (330 mg, 96%) as a white solid which was used directly for next step. LCMS (ESI): m / z 258 [M+H]+.

[0302] Step D: To a solution of 15-3 (330 mg, 1.2 mmol) in pyridine (8 mL) was added perfluorophenyl 2,2,2-trifluoroacetate (1.0 g, 3.6 mmol) dropwise and the resulting solution was stirred at 40 °C for 2 h. The solution was concentrated and the residue was suspended in 10% EtOAc in PE (5 mL). The solution was fdtered and the solid was dried to afford 2, 3, 4,5,6- pentafluorophenyl 7-cyclopentyl-2-oxo-lH-quinoline-3-carboxylate, 15-4 (400 mg, 78%) as a gray solid which was used directly for next step. LCMS (ESI): m / z 424 [M+H]+.

[0303] Step E: To a solution of 15-4 (200 mg, 0.47 mmol) and (3R) -3-amino-2,3- dihydrothiophene- 1,1 -dioxide, Int 3 (63 mg, 0.47 mmol) in DMF (3 mL) was added DIEA (184 mg, 1.4 mmol) and the resulting solution was stirred at RT for 20 min. Water (2 mL) was added to the reaction mixture and the resulting solution was purified by reverse phase chromatography (Cl 8, MeCN / PEO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford 7-cyclopentyl-N -[(3 / ?)- 1 , 1 -dioxo-2,3- dihydrothiophen-3-yl]-2-oxo-lH-quinoline-3-carboxamide 15, (15 mg, 8%) as a white solid. LCMS (ESI): m / z 373 [M+H] ;1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.22 (s, 1H), 8.81 (s, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.33 - 7.19 (m, 3H), 7.00 (dd, J= 7.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.01- 3.06 (m, 1H), 2.46-2.44 (m, 1H), 2.09-2.02 (m, 2H), 1.83 - 1.74 (m, 2H), 1.71-1.65 (m, 2H), 1.60-1.52 (m, 2H).Example 16 (R) -7-Cyclopr opyl- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-8-fluoro-2-oxo-1,2- dihydroquinoline-3-carboxamide (16)

[0304] Step A: To a solution of 2-amino-4-bromo-3 -fluorobenzoic acid (2 g, 8.55 mmol) and cyclopropylboranediol (2.2 g, 25.64 mmol) in dioxane (20 mL) and water (2 mL) was added K2CO3 (3.54 g, 25.64 mmol) followed by Pd(dppf)C12 (0.63 g, 0.86 mmol) under N2. The mixture was refluxed for 16 h and the reaction mixture was cooled to RT. The reaction mixture was concentrated, the residue was poured into water (10 mL) and the aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous and Na2SO4filtered. The solvent was removed under reduced pressure and the crude product which was purified by silica gel chromatography (0-20% EtOAc in PE) to afford product 2-amino-4-cyclopropyl-3- fluorobenzoic acid, 16-1 (1.3 g, 78 %) as a white solid. LCMS (ESI): m / z 196 [M+H] ,

[0305] Step B: To a solution of 16-1 (350 mg, 1.80 mmol) in THF (15 mL) at 0 °C was added LiAlEL (204 mg, 5.38 mmol) and the resulting mixture was stirred at RT for 2 h under N2. The residue was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate wasconcentrated under reduced pressure and the crude product was purified by silica gel chromatography (0-10% EtOAc in PE) to afford (2-amino-4-cyclopropyl-3-fluorophenyl)methanol, 16-2 (180 mg, 55 %) as a white solid. LCMS (ESI): m / z 182 [M+H]+.

[0306] Step C: To a solution of 16-2 (700 mg, 0.95 mmol) in DCM (10 mL) at 0 °C was added MnO2(864 mg, 9.93 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (20 mL), filtered and concentrated. The crude product was purified by silica gel chromatography (0-30% EtOAc in PE) to afford the 2-amino-4-cyclopropyl-3- fluorobenzaldehyde, 16-3 (140 mg, 0.64 mmol, 67 %) as a white solid. LCMS (ESI): m / z 180 [M+H]+.

[0307] Step D: To a solution of 16-3 (165 mg, 0.92 mmol), methyl 3-methoxy-3-oxopropanoate (243 mg, 1.84 mmol) and HOAc (0.005 mL) in MeOH (150 mL) was added piperidine (157 mg, 1.84 mmol) at 0 °C and the resulting mixture was stirred at 60 °C for 2 h under N2. The reaction mixture was filtered, concentrated and the crude product was purified by silica gel chromatography (0-10% EtOAc in PE) to afford methyl 7-cyclopropyl-8-fluoro-2-oxo-l,2-dihydroquinoline-3 -carboxylate, 16-4 (185 mg, 77 %) as a light yellow solid. LCMS (ESI): m / z 262 [M+H]+.

[0308] Step E: To a solution of 16-4 (185 mg, 0.71 mmol) in THF (3 mL), MeOH (5 mL) and water (1 mL) at 0 °C was added LiOH (59 mg, 1.42 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and adjusted the pH to 4 ~ 5 with 2N HC1. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7-cyclopropyl-8-fluoro-2-oxo-l,2-dihydroquinoline-3 -carboxylic acid 16-5 (97 mg, 55 %) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z 248 [M+H]~.

[0309] Step F: To a solution of 16-5 (55 mg, 0.22 mmol) in pyridine (4 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (623 mg, 2.23 mmol) at 0 °C and the resulting solution was stirred at 40 °C for 30 min. The reaction mixture was concentrated to afford 7- cyclopropyl-8-fluoro-3-(perfluorobenzoyl)quinolin-2(lH)-one 16-6 (85 mg, 92%) as a light yellow oil. LCMS (ESI): m / z 414 [M+H]+.

[0310] Step G: To a solution of 16-6 (85 mg, 0.21 mmol) and (R) -3-amino-2,3- dihydrothiophene 1,1-dioxide, Int 3 (36 mg, 0.27 mmol) in DMF (3 mL) was added DIEA (80 mg,) at 0 °C and the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with icewater (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4and filtered. The solvent was removed under reduced pressureand the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-7-cyclopropyl-N-(l,l -dioxi do-2, 3-dihydrothiophen-3-yl)-8-fluoro-2-oxo- 1 ,2-dihydroquinoline-3 -carboxamide (13.5 mg, 18 %) as a light white solid. LCMS (ESI): m / z 363 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.12 (d, J= 8.0 Hz, 1H), 8.82 (s, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.29 (d, J= 6.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.30 (d, J= 4.0 Hz, 1H), 2.30 - 2.16 (m, 1H), 1.11 (d, J = 6.4 Hz, 2H), 0.88 (d, J = 4.0 Hz, 2H).Example 17 (R) -iV-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-6,8-difluoro-2-oxo-7-(trifluoromethyI)-l,2- dihydroquinoline-3-carboxamide (17)

[0311] Step A: The H2SO4 (5.1 mL) was added drop wise to HNO3 (2.7 mL,) at 0 °C and 5- bromo-l,3-difluoro-2-(trifluoromethyl)benzene (5.0 g, 19.16 mmol) was added. The reaction mixture stirred at 0 °C for 5 min and diluted with water. The aqueous layer was extracted with EtOAc (50 mL x 3) and the organic phase was washed with brine. The organic phase was dried over anhydrousNa2SO4. filtered and concentrated. The crude product was purified by silica gel chromatography (0- 20% EtOAc in PE) to afford l-bromo-3,5-difluoro-2-nitro-4-(trifluoromethyl)benzene, 17-1 (4.8 g, 75%) as a yellow solid.1H NMR (400 MHz, DMSO) δ 8.27 (dd, J= 10.5, 1.4 Hz, 1H).

[0312] Step B: To a mixture of 17-1 (1.5 g, 4.90 mmol) in dioxane (40 mL) was added potassium vinyltrifluoroborate (790 mg, 5.88 mmol), ISfeCCh (1.8 g, 17.16 mmol) and Pd(dppf)C12 (3.5 g, 4.90 mmol) at RT and the reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (25 mL x3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc in PE) to afford l,3-difluoro-4-nitro-2-(trifluoromethyl)-5- vinylbenzene, 17-2 (600 mg, 54%) as a yellow oil. 'll NMR(400 MHZ, DMSO) δ 8.02 (d, J = 12.0 Hz, 1H), 6.72 (dd, J= 17.0, 11.0 Hz, 1H), 6.35 (d, J= 17.0 Hz, 1H), 5.85 (d, J= 11.0 Hz, 1H).

[0313] Step C: To a mixture of 17-2 (400 mg, 1.580 mmol) in MeOH (30 mL) was added Zn powder (206 mg, 3.16 mmol) and NH4CI (422 mg) at RT under N2 and reaction was stirred at 90 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (10 mL x3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc in PE) to afford 2,4- difluoro-3-(trifluoromethyl)-6-vinylaniline, 17-3 (180 mg, 51%) as a yellow oil. LCMS (ESI): m / z 224 [M+H]-;1HNMR (400 MHz, DMSO) δ 7.33 (d, J= 13.0 Hz, 1H), 7.03 - 6.94 (m, 1H), 5.91 (d, J= 17.0 Hz, 1H), 5.51 (s, 2H), 5.44 (d, J= 11.0 Hz, 1H).

[0314] Step D: To a mixture of 17-3 (180 mg, 0.81 mmol) in THF (15 mL) and (5 mL) was H2O added KOsO4 (15 mg, 0.04 mmol) and the reaction mixture was cooled to 0 °C. NaIO4 (345 mg, 1.61 mmol) was added and the reaction was stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc in PE) to afford 2-amino-3,5-difluoro-4- (trifluoromethyl)benzaldehyde, 17-4 (120 mg, 66%) as a yellow solid. LCMS (ESI): m / z 226 [M+H]+

[0315] Step E: To a mixture of 17-4 (120 mg, 0.53 mmol) in MeOH (10 mL) was added methyl dimethyl malonate (197 mg, 1.49 mmol), HO Ac (9 mg) and piperidine (0.1 mL) and the reaction was stirred at 60 °C for 16 h. The resulting precipitate was collected by filtration, washed with MeOH, and dried to afford methyl 6,8-difluoro-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3- carboxylate, 17-5 (110 mg, 67%) as a yellow solid. LCMS (ESI): m / z 308 [M+H]

[0316] Step F: To a mixture of 17-5 (100 mg, 0.33 mmol) in THF (3 mL), MeOH (3 mL) and H2O (1 mL) was added LiOH (68 mg, 1.63 mmol) at RT under N2 and the reaction mixture was stirred at RT for 2 h. The reaction mixture was adjusted the pH to ~3 with 2AHC1 and diluted with water. The aqueous layer was extracted with EtOAc (10 mL x3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 6,8-difluoro-2-oxo-7-(trifluoromethyl)-l,2- dihydroquinoline-3 -carboxylic acid, 17-6 (70 mg, 73%) as a white solid. LCMS (ESI): m / z 294 [M+H]+.

[0317] Step G: To a mixture of 17-6 (60 mg, 0.21 mmol) in DMF (3 mL) was added (R)-3- ) amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (35 mg, 0.27 mmol), HATU (77 mg, 0.21 mmol) and DIEA (79 mg) and reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (5 mL x3). The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-A-(l,l-dioxido-2,3- dihydrothiophen-3-yl)-6,8-difluoro-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxamide, 17 (11 mg, 13%) as a yellow solid. LCMS (ESI): m / z 409 [M+H]+;1H NMR (400MHz, DMSO-d6) δ 12.97 (s, 1H), 9.99 (d, J= 8.0 Hz, 1H), 8.88 (s, 1H), 8.05 (d, J= 11.0 Hz, 1H), 7.30 (d, J = 5.0 Hz, 1H), 7.00 (dd, J= 7.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.36 (d, J= 4.0 Hz, 1H).Example 18 (R) -7-(Difluoromethyl)-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3- carboxamide (18)

[0318] Step A: To a solution of methyl 7-bromo-2-oxo-l,2-dihydroquinoline-3 -carboxylate 1-2 (4.1g, 14.5 mmol) in DCM (50mL) at 0 °C was added trimethyloxomum tetrafluoroborate (3.22 g, 21.8 mmol) and the resulting mixture was stirred at RT for 48 h under N2. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4and filtered. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (0-100% EtOAc in PE) to afford methyl 7-bromo-2-methoxyquinoline-3-carboxylate 18-1 (1.13 g, 26%) as a white solid. LCMS (ESI): m / z 296 [M+H]+.

[0319] Step B: To a solution of 18-1 (300 mg, 1.01 mmol) and triethylsilane (157 mg, 1.35 mmol) in DMF (5 mL) was added TEA (0.24 mL), followed by Pd(dppf)C12 (37 mg, 0.05 mmol) under CO balloon with stirring. The mixture was stirred at 100 °C for 16 h and the reaction mixture was cooled to RT and poured into water (10 mL). The aqueous layer extracted with EtOAc (10 mL x 3) and the organic layers were washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc in PE) to afford methyl 7-formyl-2-methoxyquinoline-3 -carboxylate, 18-2 (160 mg, 65 %) as a light brown solid. LCMS (ESI): m / z 246 [M+H]+.

[0320] Step C: To a solution of 18-2 (150 mg, 0.61 mmol) in DCM (10 mL) at 0 °C was added DAST (296 mg, 1.84 mmol) and the resulting mixture was stirred at RT for 16 h.. The reactionmixture was diluted with EtOAc (20 mL) and the organic phase was separated, dried over anhydrous Na2SO4. The organic layer was filtered, and concentrated to afford methyl 7-(difluoromethyl)-2- methoxyquinoline-3 -carboxylate 18-3 (140 mg, 86%) as a white solid. LCMS (ESI): m / z 268 [M+H]+.

[0321] Step D: To a solution of 18-3 (140 mg, 0.58 mmol) in THF (3 mL), MeOH (3 mL) and water (1 mL) at 0 °C was added LiOH (42 mg, 1.0 mmol) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was diluted with EtOAc (10 mL) and adjusted the pH to 4-5 with 2AHC1. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7-(difluoromethyl)-2-methoxyquinoline-3-carboxylic acid 18-4 (130 mg, 93%) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z 254 [M+H]+.

[0322] Step E: To a solution of 18-4 (60 mg, 0.24 mmol), (R) -3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (41 mg, 0.31 mmol) and HATU (90 mg, 0.24 mmol) in DMF (3 mL) was added DIEA (92 mg) at 0 °C and the resulting mixture was stirred at RT overnight. The reaction mixture was diluted with ice-water (2 mL), extracted with EtOAc (5 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford (R)-7-(difluoromethyl)-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxyquinoline-3- carboxamide, 18-5 (130 mg, 75%) as a light yellow solid. LCMS (ESI): m / z 369 [M+H]+.

[0323] Step F: To a solution of 18-5 (120 mg, 0.33 mmol) in MeCN (2 mL) was added TMSI (92 mg, 0.65 mmol) at 0 °C and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with ice-water (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-7-(difluoromethyl)- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)- 2-oxo- l,2-dihydroquinoline-3 -carboxamide, 18 (24 mg, 21%) as a light yellow solid. LCMS (ESI): m / z 355 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.11 (d, J= 8.0 Hz, 1H), 8.92 (s, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.60 (s, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.33 - 7.05 (m, 2H), 7.00 (dd, J = 6.0, 3.0 Hz, 1H), 5.47 - 5.36 (m, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.34 (d, J= 4.0 Hz, 1H).Example 19 (R) - / V-(l,l-Dioxido-2,3-dihydi’othiophen-3-yl)-2-oxo-7-(tetrahydro-2 / / -pyran-4-yl)-1,2- dihydroquinoline-3-carboxamide (19)

[0324] Step A: To a solution of 1-2 (800 mg, 2.84 mmol) in dioxane (8 mL) and H2O (2 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (595 mg, 2.84 mmol), Pd(dppf)CE.DCM (232 mg, 0.28 mmol) and K2CO3(1.17 g, 8.51 mmol) and the mixture was stirred at 100 °C for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexane) to afford methyl 2-oxo-7-(tetrahydro-2ELpyran-4-yl)-l,2-dihydroquinoline-3 -carboxylate, 19-1 (170 mg, 21%) as a white solid. LCMS (ESI): m / z 286 [M+H]+.

[0325] Step B: To a solution of methyl 19-1 (170 mg, 0.6 mmol) in EtOH (5 mL) was added 10%Pd / C (20 mg) and the reaction was stirred at RT under H2atmosphere using a H2balloon for 2 h. The reaction was filtered and concentrated to afford ethyl 7-cyclopentyl-2-oxo-lH-quinoline- 3 -carboxylate, 19-2 (150 mg, 87%) as a gray solid. LCMS (ESI): m / z 288. [M+H]+

[0326] Step C: A solution of 19-3 (150 mg, 0.5 mmol) and LiOH (103 mg, 2.5 mmol) in MeOH (3 mL) and H2(O3 mL) was stirred at 50 °C for 2 h and the reaction mixture was concentrated. The residue dissolved in ice-EEO and the pH was adjusted to 4~5 with 2N HCL The solution was extracted with EtOAc (10 mL x 3) and the organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0 -80% EtOAc in hexanes) to afford 2-oxo-7-(tetrahydro-2H-pyran-4-yl)-l,2-dihydroquinolme-3 -carboxylic acid, 19-4 (100 mg, 70%) as a gray solid. LCMS (ESI): m / z 274 [M+H]+.

[0327] Step D: To a solution of 19-4 (40 mg, 0.15 mmol) in DMF (2 mL) were added (R) -3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (19.5 mg, 0.15 mmol), HATU (83.5 mg, 0.22 mmol) and DIEA (95 mg) and the reaction mixture was stirred at RT for 2 h. Water (1 mL) was added and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford N- [(3 R )- 1 , 1 -dioxo-2,3 -dihy drothiophen-3 -y 1] -2-oxo-7-(3 ,4, 5 ,6-tetrahy dro-2H- pyran-4-yl)-lH-quinoline-3-carboxamide, 19 (6.3 mg, 11%) as a white solid. LCMS (ESI): m / z 389 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.20 (d, J= 8.0 Hz, 1H), 8.83 (s, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.34 - 7.18 (m, 3H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.97 (dd, J = 11.0, 3.0 Hz, 2H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.46 (d, J= 2.0 Hz, 1H), 3.29 (d, J= 4.0 Hz, 1H), 2.97 - 2.85 (m, 1H), 1.79 - 1.59 (m, 4H).Example 20 (R) -7-Cyclohexyl-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydi’oquinoline-3- carboxamide (20)

[0328] Step A: To a solution of Int 1(1 g, 3.38 mmol) in dioxane / H2O (15 mL / 1.5mL) were added Pd(dppf)C12 (0.25 g, 0.34 mmol), K2CO3(1.40 g, 10.13 mmol), 2-(cyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.84 g, 4.05 mmol) and the mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to RT and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous and concentratedNa2SO4under reduced pressure. The residue was precipitated with PE / EtOAc (4:1) to afford ethyl 7- (cy cl ohex-l-en-l-yl)-2-oxo-l,2-dihydroquinoline-3 -carboxylate, 20-1 (500 mg, 50%) as a white solid. LCMS (ESI): m / z 298 [M+H]+.

[0329] Step B: To a solution of 20-1 (300 mg, 1.01 mmol) in 1 , 1 -dideuterio- 1 - (deuteriooxidanyl)-2,2,2-trifluoroethane (10 mL) was added 10% Pd / C (32 mg) and the mixture was stirred at RT with H2balloon for 16 h. The solution was filtered and the filtrate was diluted with water. The mixture was extracted with EtOAc (50 mL x 3), the organic phase was dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to afford ethyl 7-cyclohexyl-2-oxo- 1 ,2-dihydroquinoline-3 -carboxylate, 20-2 (250 mg, 82%)) as a white solid. LCMS (ESI): m / z 300 [M+H]+.

[0330] Step C: To a solution of 20-2 (250 mg, 0.84 mmol) in THF / MeOH / H2O ( 9 mL, 1: 1:1) was added NaOH (167 mg, 4.18 mmol) and the reaction mixture was stirred at RT for 2 h. The mixture was poured into ice water and adjusted to pH = 3 with 2AHC1. The reaction mixture was extracted with EtOAc (50 mL x 3), the organic phase was dried over anhydrous Na2SO4. and filtered. The solvent was removed under reduced pressure to afford 7-cyclohexyl-2-oxo-l,2- dihydroquinoline-3 -carboxylic acid, 20-3 (210 mg, 92%) as a white solid. LCMS (ESI): m / z 272 [M+H]+.

[0331] Step D: To a solution of 20-3 (70 mg, 0.26 mmol) in pyridine (5 mL) was added perfluorophenyl 2,2,2-trifluoroacetate (361 mg, 1.29 mmol) and the mixture was stirred at 40 °C for 2 h and the organic phase concentrated to afford perfluorophenyl 7-cyclohexyl-2-oxo-l,2- dihydroquinoline-3 -carboxyl ate, 20-4 (110 mg, 97%) as a yellow solid. LCMS (ESI): m / z 438 [M+H]+.

[0332] Step E: To a solution 20-4 (110 mg, 0.25 mmol) in DMF (3 mL) was added -3- (R) amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (43 mg, 0.33 mmol), DIEA (97 mg) and the reaction mixture was stirred at RT for 2 h. The solvent was removed under reduced pressure and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 mm run) and the fractions containing desired product were lyophilized to afford -7-(cRy)clohexyl- / V-(I,I-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3 -carboxamide, 20 (50 mg, 51%) as a white solid. LCMS (ESI): m / z 387 [M+H]+;1H NMR (400 MHz, DMSO-d6) 6 12.45 (s, 1H), 10.20 (d, J= 8.0 Hz, 1H), 8.82 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.29 - 7.20 (m, 3H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 - 3.27 (m, 1H), 2.71 - 2.57 (m, 1H), 1.84 - 1.77 (m, 4H), 1.46 - 1.22 (m, 6H).Example 21 (R) -7-(Bicyclo[l.l.l]pentan-l-yl)-2V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (21)

[0333] Step A: To a solution of bicyclof 1.1.1 ]pentane-l -carboxylic acid (100 mg, 0.89 mmol) in DCM (3 mL) were added 2 -hydroxyisoindoline- 1,3 -dione (160 mg, 0.98 mmol), DCC (202 mg, 0.98 mmol), DMAP (10 mg, 0.09 mmol) and the reaction mixture was stirred at 25 °C for 16 h. The rection mixture was diluted with water and DCM, the organic layer was separated and concentrated to afford l,3-dioxoisoindolin-2-ylbicyclo[l. l.l]pentane-l-carboxylate, 21-1 (210 mg, 92%) as a white solid.1H NMR (400 MHz, CDC13) δ 7.88 (dt, J= 7.0, 4.0 Hz, 2H), 7.82 - 7.76 (m, 2H), 2.56 (s, 1H), 2.33 (s, 6H).

[0334] Step B: To a vial containing 21-1 (124 mg, 0.48 mmol), ethyl 7-bromo-2- methoxyquinoline-3 -carboxylate, Int 2 (100 mg, 0.32 mmol), ethyl 5-(ethoxycarbonyl)-2,6-dimethyl- l,4-dihydropyridine-3 -carboxy late (163 mg, 0.65 mmol) was added NiBr2, (dtbbpy) (31 mg, 0.06 mmol), and NaHCO3 (54 mg, 0.65 mmol). The vial was purged with N2 and capped. The reactionmixture was irradiated with 18 W Photosyn-10 purple LED (390 nm) lamp (1 cm away with cooling fan) under N2 for 3 h. The reaction mixture was filtrated and concentrated under reduced pressure. The crude product was purified by reverse phase purification (C18, MeCN / H2O, 0.1% formic acid modifier, 0% to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford ethyl 7-(bicyclo[l.l.l]pentan-l-yl)-2-methoxyquinoline-3-carboxylate, 21-2 (30 mg, 31%) as a white solid. LCMS (ESI): m / z 298 [M+H]+.

[0335] Step C: A mixture of 21-2 (45 mg, 0.15 mmol) in con. HC1 (4 mL) was stirred at 100 °C under N2 for 2 h and the mixture was concentrated to afford 7-(bicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2- dihydroquinoline-3 -carboxylic acid, 21-3 (35 mg, 90%) as a white solid. LCMS (ESI): m / z 256 [M+H]+.

[0336] Step D: A mixture of 21-3 (35 mg, 0.14 mmol) and perfluorophenyl 2,2,2- trifluoroacetate (192 mg, 0.69 mmol) in pyridine (5 mL) was stirred at 40 °C under N2 for 2 h and the mixture was concentrated to afford perfluorophenyl 7-(bicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2- dihydroquinoline-3 -carboxyl ate, 21-4 (45 mg, 0.107 mmol, 77%) as a yellow solid. LCMS (ESI): m / z 422 [M+H]+.

[0337] Step E: To a solution of 21-4 (40 mg, 0.1 mmol) in DMF (3 mL) were added (R) -3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (16 mg, 0.12 mmol) and DIEA (36 mg, 0.285 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture concentrated and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / ELO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford(R) - 7- (bi cy clo [1.1.1 ]pentan- 1 -yl)-N-( 1 , 1 -dioxi do-2, 3 -dihydrothi ophen-3 -y l)-2-oxo- 1,2- dihydroquinoline-3 -carboxamide, 21 (20 mg, 56%).1H NMR %) as a white solid. LCMS (ESI): m / z 371 [M+Hf; (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.18 (d, J = 8.0Hz, 1H), 8.82 (s, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.07 - 6.93 (m, 1H), 5.54 - 5.25 (m, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.31 - 3.27 (m, 1H), 2.60 (s, 1H), 2.10 (s, 6H).Compounds 22 to 35

[0338] Compounds 22 to 35 (Table 1) were prepared from the appropriate carboxylic acid reagents as described for compound 21. The carboxylic acids were obtained from commercial sources.Table 1. IUPAC name, structure, and physicochemical data for Compounds 22-35bEnantiomerically pure 34a and 34 b were separated in step E using SFC but absolute configurations are arbitrary assigned.Example 36(R) -.V-( l.l-Dioxido-2.3-diliydrothio|)hen-3-yl)-7-( l-(liydroxyinethyl)cyclobutyl)-2-oxo-1.2- dihydroquinoline-3-carboxamide (36)

[0339] Step A: To a solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (770 mg, 2.48 mmol), potassium 1 -cyanocyclobutane- 1 -carboxylate (466 mg, 3.72 mmol) and S-Phos (61 mg, 0.15 mmol) in mesitylene (10 mL) was added allyl Pd2(allyl)2C12 (90 mg, 0.25 mmol) under N2 with stirring and the mixture was stirred at 140 °C for 3 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with water and brine, dried over anhydrous Na2SCU, filtered and concentrated. The crude product was purified by silica gel chromatography (0-20% EtOAc in PE) to afford the desired product ethyl 7-(l-cyanocyclobutyl)-2-methoxyquinoline-3-carboxylate, 36-1 (380 mg, 49%) as a brown oil. LCMS (ESI): m / z 311 [M+H]+.

[0340] Step B: To a solution of 36-1 (380 mg, 1.22 mmol) in THF (3 mL) was added bis(cyclopentadienyl)zircomum chloride hydride (631 mg, 2.45 mmol) at 0 °C and the mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with ice-water (5 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with water and brine, the combined organic phase was dried over anhydrous and filtered . The filtrate was concentrated and thecrude product which was purified by silica gel chromatography (0-10% EtOAc in PE) to afford ethyl 7-(l-formylcyclobutyl)-2-methoxyquinoline-3-carboxylate, 36-2 (60 mg, 16%) as a brown solid. LCMS (ESI): m / z 314 [M+H]+.

[0341] Step C: To a stirred solution of 36-2 (60 mg, 0.19 mmol) in THF (3 mL), NaBFL (14 mg, 0.38 mmol) was added and the resulting mixture was stirred at RT for 30 min. The mixture was concentrated to afford the ethyl 7-( 1 -(hy droxymethyl)cy cl obutyl)-2-methoxyquinoline-3 -carboxylate, 36-3 (50 mg, 83%) as a white solid. LCMS (ESI): m / z 316 [M+H]+.

[0342] Step D: To a solution of 36-3 (50 mg, 0.16 mmol) in THF (1 mL), MeOH (1 mL) and water (0.5 mL) at 0 °C was added LiOH (13.31 mg, 0.32 mmol) and the resulting solution was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and adjusted the pH to 4-5 with 2N HC1. The organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated to afford crude product 7-(l-(hydroxymethyl)cyclobutyl)-2-methoxyquinoline-3-carboxylic acid, 36-4 (45 mg, 99%) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z 288 [M+H]+.

[0343] Step E: To a solution of 36-4 (45 mg, 0.16 mmol) in pyridine (4 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (439 mg, 1.57 mmol) at 0 °C and the resulting mixture was stirred at 40 °C for 30 min. The reaction mixture was concentrated in vacuo to afford 2,3,4,5,6-pentafluorophenyl 7-[(hydroxymethyl)cyclobutyl]-2-methoxyquinoline-3-carboxylate, 36-5 (80 mg, 79 %) as a light yellow oil. LCMS (ESI): m / z 454 [M+H]+.

[0344] Step F: To a solution of 36-5 (80 mg, 0.12 mmol) and (A)-3-amino-2, 3 -dihydrothiophene 1,1 -dioxi de, Int 3 (21 mg, 0.16 mmol) in DMF (3 mL) was added DIEA (48 mg) at 0 °C and the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with ice-water (2 mL), extracted with EtOAc (5 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford (R)-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-7-(l-(hydroxymethyl)cyclobutyl)-2-methoxyquinoline-3-carboxamide 36-6 (50 mg, 0.09 mmol, 70%) as a brown oil. LCMS (ESI): m / z 403 [M+H]+.

[0345] Step G: To a solution of 36-6 (50 mg, 0. 12 mmol) in MeCN (5 m ) was added TMSI (49 mg, 0.25 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with ice-water (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous , filtered anNd a c2oSnOc4entrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 mm run) and the fractions containing desired product were lyophilized to afford -jV(-R()l,l-dioxido-2,3-dihydrothiophen-3-yl)-7-(l-(hydroxymethyl)cy cl obutyl)-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 36 (19 mg, 39%) as a white solid. LCMS (ESI): m / z 389 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.22 (d, J = 8.0 Hz, 1H), 8.82 (s, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.28 (dd, J= 1.0, 2.0 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J= 8.0 Hz, 1H), 7.01 (dd, J = 1.0, 3.0 Hz, 1H), 5.40 (s, 1H), 4.85 (t, J = 5.0 Hz, 1H), 3.75 (dd, J = 14.0, 8.0 Hz, 1H), 3.58 (d, J= 5.0 Hz, 2H), 3.28 (d, J= 4.0 Hz, 1H), 2.20 (dd, J= 18.0, 9.0 Hz, 4H), 2.02 (dd, J=19. 0, 10.0 Hz, 1H), 1.80 (s, 1H).Example 37 R)-N -(l,l-Dioxido-2,3-dihydrothiophen-3-yI)-7-(l-hydroxycyclobutyl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (37)

[0346] Step A: To a solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (500 mg, 1.61 mmol) in THF (3 mL), MeOH (5 mL) and water (1 mL) at 0 °C was added Li OH (13 mg, 3.22 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and adjusted the pH to 4 ~ 5 with 2N HC1. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7-bromo-2-methoxyquinoline-3- carboxylic acid, 37-1 (454 mg, 99%) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z 282 [M+H]+.

[0347] Step B: To a solution of 37-1 (454 mg, 1.61 mmol) and cyclobutanone (90 mg, 1.29 mmol) in THF (5 mL) was added 2.5M n-BuLi (0.6 mL, 1.45 mmol) at -78 °C and the resulting solution was stirred at -78 °C for 30 min. The reaction mixture was diluted with ice-water (5 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product which was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford 7-(l -hydroxy cyclobutyl)-2- methoxyquinoline-3 -carboxylic acid, 37-2 (60 mg, 14%) as a white solid. LCMS (ESI): m / z 274 [M+H]+.

[0348] Step C: To a solution 37-2 (60 mg, 0.22 mmol) in pyridine (4 mL) was added 2, 3, 4,5,6- pentafluorophenyl 2,2,2-trifluoroacetate (615 mg, 2.19 mmol) at 0 °C and the reaction mixture was stirred at 40 °C for 30 min. The reaction mixture was concentrated in vacuo to afford perfluorophenyl 7-(l -hydroxy cyclobutyl)-2-methoxyquinoline-3 -carboxylate, 37-3 (80 mg, 83%) as a light-yellow oil. LCMS (ESI): m / z 440 [M+H]+.

[0349] Step D: To a solution of 37-3 (80 mg, 0.18 mmol) and -3-amino-2,3-(R) dihydrothiophene 1,1-dioxide, Int 3 (32 mg, 0.24 mmol) in DMF (3 mL) was added DIEA (71 mg) at 0 °C and the solution was stirred at RT for 2 h. The reaction mixture was diluted with ice-water (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous N,a f2ilSteOr4ed and concentrated to afford (R)-A-(l,l-dioxido-2,3- dihydrothiophen-3-yl)-7-(l-hydroxycyclobutyl)-2-methoxyquinoline-3-carboxamide, 37-4 (210 mg) as a brown oil. LCMS (ESI): m / z 389 [M+H]+.

[0350] Step E: To a solution of 37-4 (210 mg, 0.16 mmol) in MeCN (5 mL) was added TMSI (65 mg, 0.32 mmol) at 0 °C and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with ice-water (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-N-( 1,1 -dioxi do-2, 3 -dihy drothiophen-3-yl)- 7-(l-hydroxycyclobutyl)-2-oxo-l,2-dihydroquinoline-3-carboxamide, 37 (40 mg, 66%) as a yellow solid. LCMS (ESI): m / z 375 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.22 (d, J = 8.0 Hz, 1H), 8.84 (s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.59 (s, 1H), 7.45 (dd, J= 8.0, 2.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.78 (s, 1H), 5.40 (s, 1H), 3.75 (dd,J= 14.0, 8.0 Hz, 1H), 3.29 (d, J= 4.0 Hz, 1H), 2.42 - 2.28 (m, 4H), 1.98 (ddd, . / 15.0, 10.0, 6.0 Hz, 1H), 1.73 (dd, J= 19.0, 8.0 Hz, 1H).Example 38 (R) - / V-(l,l-Dioxido-2,3-dihydrothiophen-3-yI)-7-(l-fluorocyclobutyl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (38)

[0351] Step A: To a mixture solution of 37 (20 mg, 0.053 mmol) in DCM (10 mL) was added DAST (17 mg, 0.12 mmol) at 0 °C and the solution stirred at RT for 4 h. The mixture was concentrated and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-N-( 1,1 -dioxi do-2, 3 -dihy drothiophen-3-yl)- 7-(l-fluorocyclobutyl)-2-oxo-l,2-dihydroquinoline-3-carboxamide, 38 (12 mg, 58%) as a white solid. LCMS (ESI): m / z 377 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.18 (d, J = 8.0 Hz, 1H), 8.87 (s, 1H), 8.02 (d, J= 8.0 Hz, 1H), 7.53 (s, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.27 (dd, J = 6.0, 2.0 Hz, 1H), 7.00 (dd, J = 6.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J = 14.0, 8.0 Hz, 1H), 3.29 (d, J= 4.0 Hz, 1H), 2.69 - 2.54 (m, 4H), 2.13 - 2.02 (m, 1H), 1.79 (dt, J = 17.0, 8.0 Hz, 1H).Example 39 (R) - / V-(l,l-Dioxido-2,3-dihydi’othiophen-3-yl)-2-oxo-7-(thiophen-2-yl)-l,2-dihydroquinoline-3- carboxamide (39)

[0352] Step A: To a solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (500 mg, 1.61 mmol) and thiophen-2-ylboranediol (412 mg, 3.22 mmol) in dioxane (10 mL) and water (1 mL) was added K2CO3(668 mg, 4.84 mmol), followed by Pd(dppf)C12 (118 mg, 0.16 mmol) under N2 and the mixture was refluxed 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product which was purified by silica gel chromatography on silica gel (0-20% EtOAc in PE) to afford ethyl 2-methoxy-7-(thiophen-2-yl)quinoline-0-20% -carboxylate, 39- 1 (500 mg, 99 %) as a white solid. LCMS (ESI): m / z 314 [M+H]+.

[0353] Step B: To a solution of 39-1 (200 mg, 0.64 mmol) in HC1 (5 mL) at 100 °C and the resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (5 mL) and organic phase collected. The organic phase, dried over anhydrous Na2SO4, filtered, and concentrated to afford 2-oxo-7-(thiophen-2-yl)-l,2-dihydroquinoline-3-carboxylic acid, 39-2 (180 mg, 99%) as a yellow solid. LCMS (ESI): m / z 272 [M+H]+.

[0354] Step C: To a solution of 39-2 (80 mg, 0.30 mmol) in pyridine (4 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (826 mg, 2.95 mmol) at 0 °C and the reaction mixture was stirred at 40 °C for 30 min. The reaction mixture was concentrated in vacuo to affordperfluorophenyl 2-oxo-7-(thiophen-2-yl)-l,2-dihydroquinoline-3 -carboxylate, 39-3 (130 mg, 91%) as a light-yellow oil. LCMS (ESI): m / z 438 [M+H]+.

[0355] Step D: To a solution of 39-3(130 mg, 0.30 mmol) and (R)-3-amino-2,3- dihydrothiophene 1,1-dioxide, Int 3 (51 mg, 0.39 mmol) in DMF (3 mL) was added DIEA (115 mg) at 0 °C and the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with icewater (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / HzO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford -7V-(l,l- (R) dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-(thiophen-2-yl)-l,2-dihydroquinoline-3-carboxamide, 39 (21 mg, 19%) as a white solid. LCMS (ESI): m / z 387 [M+H]+;1H NMR (400 MHz, DMSO-d6) 8 12.49 (s, 1H), 10.16 (d, J= 8.0 Hz, 1H), 8.85 (s, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.73 - 7.65 (m, 4H), 7.29 (dd, J= 6.0, 2.0 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.41 (s, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 (d, J= 4.0 Hz, 1H).Compounds 40 to 43

[0356] Compounds 40 to 43 (Table 2) were prepared from the appropriate boronic acid / boronate reagents as described for compound 39. Boronic acids / boronates were obtained from commercial sources.Table 2. IUPAC name, structure, and physicochemical data for Compounds 40-43Example 44 (R) -2V-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-(l,3,4-thiadiazol-2-yl)-l,2- dihydroquinoline-3-carboxamide (44)

[0357] Step A: To a solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (900 mg, 2.90 mmol) 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (736 mg, 2.90 mmol), KO Ac (284 mg, 2.90 mmol) in dioxane (10 mL) was added bis[5-(diphenylphosphanyl)cyclopenta-l,3-dienyl]-iron(II)palladium chloride (2.12 g, 2.9 mmol) and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford ethyl 2-methoxy-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline-3 -carboxylate 44-1 (600 mg, 57 %) as a white solid. LCMS (ESI): m / z 358 [M+H]+.

[0358] Step B: To a solution of 44-1 (400 mg, 1.12 mmol) 2-bromo-l,3,4-thiadiazole (184 mg, 1.12 mmol), K2CO3(463 mg, 3.36 mmol) in DME (4 mL) and (1 mL) was aHd2dOed bis[5- (diphenylphosphanyl)cyclopenta-l,3-dienyl]iron(II)palladium chloride (818 mg, 1.12 mmol) and the reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried overanhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford ethyl 2-methoxy-7-(l,3,4-thiadiazol-2-yl)quinoline-3- carboxylate 44-2 (40 mg, 11%) as a white solid. LCMS (ESI): m / z 316 [M+H]+.

[0359] Step C: To a solution of 44-2 (40 mg, 0.13 mmol) in MeOH (5 mL) and EEO (5 mL) was added LiOH (26.6 mg, 0.63 mmol), the mixture was stirred at 20 °C for 2 h and the pH was adjusted to 7~8. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated to afford 2- methoxy-7-(l,3,4-thiadiazol-2-yl)quinoline-3-carboxylic acid 44-3 (35 mg, 96%) as a white solid. LCMS (ESI): m / z 288 [M+H]+.

[0360] Step D: To a solution of 44-3 (40 mg, 0.14 mmol) in DMF (3 mL) was added (37?)- amino-2,3-dihydrothiophenel,l-dioxide, Int 3 (18.5 mg, 0.14 mmol), HATU (79.4 mg, 0.21 mmol) and DIEA (90 mg, 0.7 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes to afford (R) -.V-( l,l-dioxido-2.3-dihydrothiophen-3-yl)- 2-methoxy-7-(l,3,4-thiadiazol-2-yl)quinoline-3-carboxamide 44-4 (50 mg, 89 %) as a white solid. LCMS (ESI): m / z 403 [M+H]+.

[0361] Step E: To a solution of 44-4 (50 mg 0.12 mmol) in ACN (10 mL) was added TMSI (17.4 mg, 0.09 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 0% to 70% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford to afford (R)-N-( 1 , 1 -dioxi do-2, 3 -dihydrothi ophen-3 -yl)-2-oxo-7-(l ,3 ,4-thiadiazol-2-yl)- 1,2- dihydroquinoline-3 -carboxamide, 44 (2.4 mg, 4 %) as a white solid. LCMS (ESI): m / z 389 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.13 (d, J= 8.0 Hz, 1H), 9.74 (s, 1H), 8.92 (s, 1H), 8.20 - 8.04 (m, 2H), 7.89 (dd, J= 8.0, 1.0 Hz, 1H), 7.29 (dd, J= 6.0, 2.0 Hz, 1H), 7.01 (dd, J= 6.0, 3.0 Hz, 1H), 5.42 (s, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.31 (s, 1H).Example 45Synthesis of (-R7)-(l,l-Difluoroethyl)- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- hydroxyquinoline-3-carboxamide (45)

[0362] Step A: To a solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (1 g, 3.22 mmol) and tributyl(l -ethoxy vinyl)stannane (1.40 g, 3.87 mmol) in DMF (10 mL) was added Pd(PPli3)4 (0.37 g, 0.32 mmol) under N2 and the reaction mixture was stirred at 100 °C for 16 h. The solution was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with 2N HC1, brine and dried over anhydrous Na2SO4. The solution was filtered and concentrated. The crude product which was purified by silica gel chromatography (0-20% EtOAc in PE) to afford ethyl 7-acetyl-2-methoxyquinoline-3-carboxylate, 45-1 (650 mg, 71%) as a white solid. LCMS (ESI): m / z 274 [M+H]+.

[0363] Step B: To a solution of 45-1 (475 mg, 1.74 mmol) in DCM (3 mL) at 0 °C was added DAST (737 mg, 4.57 mmol) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (20 mL), the organic phase was separated, dried over anhydrous Na2SO4. The solution was filtered and concentrated to afford ethyl 7-(l,l-difluoroethyl)-2- methoxyquinoline-3 -carboxylate, 45-2 (450 mg, 26 %) as a white solid. LCMS (ESI): m / z 296 [M+H]+.

[0364] Step C: To a solution of 45-2 (80 mg, 0.27 mmol) in THF (3 mL), MeOH (3 mL) and water (1 mL) at 0 °C was added LiOH (12 mg, 0.27 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (10 mL) and adjusted to pH 4 ~ 5 with 2N HC1. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7-(l,l-difluoroethyl)-2-methoxyquinoline-3 -carboxylic acid, 45-3 (80 mg, 99%) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z 268 [M+H]+.

[0365] Step D: To a solution of 45-3 (80 mg, 0.30 mmol) in pyridine (4 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (838 mg, 2.99 mmol) at 0 °C and the resulting mixture was stirred at 40 °C for 30 min. The reaction mixture was concentrated in vacuo to afford perfluorophenyl 7-(l,l-difluoroethyl)-2-methoxyquinoline-3-carboxylate, 45-4 (120 mg, 92 %) as a light-yellow oil. LCMS (ESI): m / z 434 [M+H]+.

[0366] Step E: To a solution of 45-4 (120 mg, 0.28 mmol) and (3R )-amino-2,3- dihydrothiophenel,! -dioxide, Int 3 (48 mg, 0.36 mmol) in DMF (3 mL) was added DIEA (107 mg, 0.83 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with ice water (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na^SOi, filtered and concentrated to afford (R) -7-(l,l-difluoroethyl)-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxyquinoline-3- carboxamide, 45-5 (200 mg, 94 %) as a brown oil. LCMS (ESI): m / z 383 [M+H]+.

[0367] Step F: To a solution of 45-5 (200 mg, 0.52 mmol) in MeCN (2 mL) was added TMSI (147 mg, 1.05 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with ice-water (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / FLO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R) -7-(l,l-difluoroethyl)-A-(l,l-dioxido-2,3-dihydrothiophen-3- yl)-2-hydroxyquinoline-3 -carboxamide, 45 (53 mg, 27 %) as a light yellow solid. LCMS (ESI): m / z 369 [M+H]’;1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.12 (d, J= 8.0 Hz, 1H), 8.91 (s, 1H), 8.11 (d, J= 8.0 Hz, 1H), 7.59 (s, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.29 (dd, J= 6.8, 2.0 Hz, 1H), 7.00 (dd, J= 7.0, 3.0 Hz, 1H), 5.41 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.30 (d, J= 4.0 Hz, 1H), 2.00 (t, J= 19.0 Hz, 3H).Example 46 7-(2,2-Difluorocyclopropyl)- / V-(R) -l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (46)

[0368] Step A: A mixture of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (1 g, 3.2 mmol), potassium vinyltrifluoroborate (0.52 g, 3.8 mmol), Pd(dppf)C12.DCM (0.24 g, 0.322 mmol) and Na2SO4(0.68 g, 6.4 mmol) in dioxane (15 mL) was stirred at 100 °C under N2 for 16 h, the reaction mixture was filtrated and concentrated. The residue was purified by silica gel chromatography (0-20% DCM in hexanes) to afford ethyl 2-methoxy-7-vinylquinoline-3 -carboxylate 46-1 (0.4 g, 48%) as a colorless oil. LCMS (ESI): m / z 258 [M+H]+.

[0369] Step B: To a solution of 46-1 (370 mg, 1.5 mmol) in toluene (5 mL) was added (bromodifluoromethyl)trimethylsilane (473 mg, 2.3 mmol) and TBAB (50 mg, 0.15 mmol) and the reaction mixture was stirred at 110 °C for 16 h. The cooled reaction mixture was diluted with water 50 mL, extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO an4d concentrated. The residue was purified by silica gel chromatography (0-8% EtOAc in hexane) to afford ethyl 7-(2,2-difluorocyclopropyl)-2-methoxyquinoline-3 -carboxylate, 46- 2 (240 mg, 53%) as a white solid. LCMS (ESI): m / z 3O8[M+H]+.

[0370] Step C: To a solution of 46-2 (220 mg, 0.75 mmol) in MeCN (10 mL) was added TMSI (219 mg, 1.56 mmol) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford ethyl 7-(2,2-difluorocyclopropyl)-2-oxo-l,2- dihydroquinoline-3 -carboxyl ate, 46-3 (170 mg, 81%) as a white solid. LCMS (ESI): m / z 294[M+H]+.

[0371] Step D: To a solution of 46-3 (50 mg, 0.17 mmol) in THF / MeOH / H2O (1: 1:1, 9 mL) was added LiOH (7 mg, 0.17 mmol) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into ice water and adjusted pH=5 ~ 6 by 2N HC1. The reaction mixture was extracted with EtOAc (50 mL x 3) and the organic phase was dried over anhydrous and Na2SO4concentrated to afford 7-(2,2-difluorocyclopropyl)-2-oxo-l,2-dihydroquinoline-3-carboxylic acid, 46-4 (40 mg, 88%) as a white solid. LCMS (ESI): m / z 266 [M+H]+.

[0372] Step E: A mixture of 46-4 (40 mg, 0.15 mmol) and perfluorophenyl 2,2,2- trifluoroacetate (211 mg, 0.76 mmol) in pyridine (5 mL) was stirred at 40 °C under N2 for 2 h and the mixture was concentrated to afford perfluorophenyl 7-(2,2-difluorocyclopropyl)-2-oxo-l,2- dihydroquinoline-3 -carboxyl ate, 46-5 (50 mg, 76%) as a yellow solid. LCMS: 432 [M+H]+

[0373] Step F: To a solution of perfluorophenyl 7-(2,2-difluorocyclopropyl)-2-oxo-l,2- dihydroquinoline-3 -carboxyl ate 46-5 (50 mg, 0.12 mmol) in DMF (3 mL) was added (R)-3-amino- 2,3 -dihydrothiophene 1,1-dioxide, Int 3 (18 mg, 0.14 mmol) and DIEA (74 mg) and the reaction mixture was stirred at RT for 2 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford 7-(2,2-difluorocyclopropyl)-A-((R)-l,l- dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3-carboxamide, 46 (30 mg, 68%) as a white solid. LCMS (ESI): m / z 381[M+H]+;1HNMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.16 (d, J= 8.0 Hz, 1H), 8.85 (s, 1H), 7.94 (d, J= 8.0 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.22 (d, J= 8.0 Hz, 1H), 7.00 (dd, 7= 6.0, 3.0 Hz, 1H), 5.41 (d, 7 = 4.4 Hz, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 (d, .7 = 4,0 Hz, 1H), 3.20 (td, 7= 12.0, 8.0 Hz, 1H), 2.17 - 2.07 (m, 1H), 1.97 (m, 1H).Example 47 (R) -7-Cyclopropyl-7V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-6-fhioro-2-oxo-l,2- dihydroquinoline-3-carboxamide (47)

[0374] Step A: To a stirred mixture of 4-bromo-5-fluoro-2-nitrobenzene-l-carbaldehyde (1 g, 4.03 mmol) in H (21O.5 mL), HOAc (3 mL) and EtOH (10 mL) was added Fe powder (2.25 g, 40.3 mmol) and the reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc:PE / 1: 3) to afford 2-amino-4- bromo-5-fluorobenzene-l-carbaldehyde, 47-1 (800 mg, 91%) as a yellow solid. LCMS (ESI): m / z 218[M+H]+.

[0375] Step B: To a stirred mixture of 47-1 (800 mg, 3.67 mmol) and ethyl 3-ethoxy-3- oxopropanoate (1.67 mL, 11.0 mmol) in EtOH (1 mL) was added piperidine (1.1 mL, 11.0 mmol) and HOAc (0.023 mL) and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (EtOAc:PE / I: 3) to afford ethyl 7-bromo-6-fluoro-2-oxo-lH-quinoline-3-carboxylate, 47-2 (1 g, 87%) as a yellow solid. LCMS (ESI): m / z 314[M+H]+.

[0376] Step C: To a stirred mixture of 47-2 (200 mg, 0.64 mmol) and cyclopropylboranediol (65.6 mg, 0.76 mmol) in dioxane (6 mL) and (2 mL) wHa2sO added Pd(dppf)C12 (93 mg, 0.13 mmol) and K2CO3(264 mg, 1.91 mmol) and the reaction mixture was stirred at 110 °C under nitrogen for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (5 mL x3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered andconcentrated. The residue was purified by silica gel column chromatography eluting with EtOAc: PE (1: 2) to afford ethyl 7-cyclopropyl-6-fluoro-2-oxo-lH-quinoline-3-carboxylate, 47-3 (80 mg, 46%) as a yellow solid. LCMS (ESI): m / z 276[M+H]+.

[0377] Step D: To a stirred mixture of ethyl 7-cyclopropyl-6-fluoro-2-oxo-lH-quinoline-3- carboxylate 47-3 (80 mg, 0.29 mmol) in EtOH (2 rnL) and (1 rnL) was aHd2dOed LiOH (61.0 mg, 1.46 mmol) and the reaction mixture was stirred at RT for 2 h. The mixture was acidified to pH = 5 with IN HC1 and extracted with EtOAc (5 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc: PE / 1: 2) to afford 7-cyclopropyl-6-fluoro-2-oxo-lH-quinoline-3-carboxylic acid, 47-4 (40 mg, 56%) as a yellow solid. LCMS (ESI): m / z 248 [M+H]+.

[0378] Step E: To a stirred mixture of 47-4 (35 mg, 0.14 mmol) and (K)-3-amino-2,3- dihydrothiophene 1,1-dioxide, Int 3 (19 mg, 0.14 mmol) and DIEA (37 mg) was added HATH (108 mg, 0.28 mmol) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (5 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc:PE / 1:2) to afford (R) -7-cyclopropyl-N-( l , l -dioxido-2,3-dihydrothiophen-3- yl)-6-fluoro-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 47 (20 mg, 38%) as a yellow solid. LCMS (ESI): m / z 363 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.18 (d, J= 8.0 Hz, 1H), 8.81 (s, 1H), 7.81 (d, J= 10.0 Hz, 1H), 7.28 (dd, J=7.0, 2.0 Hz, 1H), 6.99 (dd, J= 7.0, 3.0 Hz, 2H), 5.39 (s, 1H), 3.74 (dd, J= 14.0, 8.0 Hz, 1H), 3.27 (d, J= 4.0 Hz, 1H), 2.22 - 2.11 (m, 1H), 1.16 - 1.10 (m, 2H), 0.81 - 0.74 (m, 2H).Example 48 (R) -N-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-8-methyl-2-oxo-7-(trifluoromethyl)-l,2- dihydroquinoline-3-carboxamide (48)

[0379] Step A: To a solution of 2-methyl-3-(trifluoromethyl)aniline (4 g, 22.8 mmol) in MeCN (20 mL) was added NBS (4.07 g, 22.8 mmol) at 0 °C and the reaction mixture was stirred at stirred at RT for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous NazSCL, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford 6-bromo-2-methyl-3-(trifluoromethyl)aniline, 48-1 (1.4 g, 24 %) as a white solid. LCMS (ESI): m / z 255 [M+H]+.

[0380] Step B: To a solution of 48-1 (200 mg, 0.79 mmol) in dioxane (4 mL) and (1 mL) H2O was added trifluoro(vinyl)borane potassium salt (210 mg, 1.57 mmol), K2CO3(326 mg, 2.36 mmol) and Pd(dppf)C12.DCM (65 mg, 0.08 mmol) and the reaction mixture was stirred at 100 °C under N2 for 6 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford 2-methyl-3- (trifluoromethyl)-6-vinylaniline, 48-2 (100 mg, 63%) as a white solid. LCMS (ESI): m / z 202 [M+H]+.

[0381] Step C: To a solution of 48-2 (600 mg, 3.0 mmol) in (10 mL) anHd2TOHF (10 mL) was added NaIO4 (638 mg, 2.98 mmol) and K2OSO4. (1.1 mg, 3 H m2mOol) at 0 °C. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase waswashed with brine, dried over Na2SO4. filtered and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford 2-amino-3-methyl-4- (trifluoromethyl)benzene-l-carbaldehyde, 48-3 (90 mg, 17%) as a white solid. LCMS (ESI): m / z 204 [M+H]+.

[0382] Step D: To a solution of 48-3 (120 mg, 0.59 mmol) in EtOH (10 mL) was added ethyl 3- ethoxy-3-oxopropanoate (0.09 mL, 0.59 mmol), piperidine (50.3 mg, 0.59 mmol) and HOAc (1 drop) and the reaction mixture was stirred at 80 °C for 16 h. The suspension was filtered and the filter cake was dried in a vacuum to afford ethyl 8-methyl-2-oxo-7-(trifluoromethyl)-lH-quinolme-3- carboxylate, 48-4 (100 mg, 56%) as a yellow solid which was used for the next step directly without further purification. LCMS (ESI): m / z 300 [M+H]+.

[0383] Step E: To a solution of 48-4 (120 mg, 0.40 mmol) in MeOH (5 mL) and H2O (5 mL) was added LiOH (17 mg, 0.40 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The suspension was filtered and the filter cake was dried in vacuum to afford 8-methyl-2-oxo-7- (trifluoromethyl)-lH-quinoline-3 -carboxylic acid, 48-5 (100 mg, 91%) as a yellow solid which was used for the next step directly without further purification. LCMS (ESI): m / z 272 [M+H]+.

[0384] Step F: To a solution of 48-5 (40 mg, 0.15 mmol) in DMF (2 mL) was added (R)-3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (19.6 mg, 0.15 mmol), HATU (84 mg, 0.22 mmol) and DIEA (95 mg) and the mixture was stirred at RT for 2 h. Water (1 mL) was added and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford ( )-A-( 1,1 -dioxi do-2, 3 -dihydrothiophen-3-yl)-8-methyl-2-oxo-7- (trifluoromethyl)-l,2-dihydroquinoline-3-carboxamide, 48 (15 mg, 26%) as a white solid. LCMS (ESI): m / z 387 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.05 (d, J= 8.0 Hz, 1H), 8.91 (s, 1H), 8.03 (d, .7 - 8.0 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.29 (dd, J= 6.Q, 2.0 Hz, 1H), 7.01 (dd, J= 6.Q, 3.0 Hz, 1H), 5.47 - 5.35 (m, 1H), 3.77 (dd, J= 14.0, 8.0 Hz, 1H), 3.33 (s, 1H), 2.58 (s, 3H).Example 49 (R) -7-Cyclobutyl-N -(l,l-dioxido-2,3-dihydrothiophen-3-yl)-6-fhioro-2-oxo-l,2- dihydroquinoline-3-carboxamide (49)

[0385] Step A: To a stirred mixture of 47-2 (700 mg, 2.23 mmol) in DCM (10 mL) were added trimethyloxonium tetrafluoroborate (660 mg, 4.46 mmol) and the mixture was stirred at RT for two days. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM to afford ethyl 7-bromo-6-fluoro-2- methoxyquinoline-3 -carboxylate, 49-1 (180 mg, 54%) as a white solid. LCMS (ESI): m / z 328 [M+H]+.

[0386] Step B: To a stirred mixture of 49-1 (180 mg, 0.55 mmol) and potassium cyclobutyltrifluoroborate (89 mg, 0.55 mmol) in DMA (1 mL) and dioxane (4 mL) was added [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (12 mg, 0.01 mmol), NiBr2(dtbbpy) (32 mg, 0.07 mmol) and 2,6-dimethylpyridine (88 mg, 0.82 mmol) and the reaction vial was irradiated with blue LED light (450 nm) at RT for 7 h and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc / 2:l) to afford ethyl 7- cyclobutyl-6-fluoro-2-methoxyquinoline-3-carboxylate, 49-2 (120 mg, 72%) as a yellow solid. LCMS (ESI): m / z 304 [M+H] ' .

[0387] Step C: To a stirred solution of 49-2 (100 mg, 0.33 mmol) in MeCN (1 mL) was added TMSI (93 mg, 0.66 mmol) dropwise at 0 °C and the resulting mixture was stirred at RT for 2 h. The reaction was quenched by the addition of water and extracted with EtOAc (5 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered andconcentrated to afford 7-cyclobutyl-6-fluoro-2-oxo-lH-quinoline-3-carboxylate, 49-3 (80 mg, 84%) as a yellow solid. LCMS (ESI): m / z 290 [M+H]+. LCMS: m / z 290 [M+H]+.

[0388] Step D: To a stirred mixture of 49-3 (90 mg, 0.31 mmol) in THF (3 mL) and (1 H2O mL) was added LiOH (39 mg, 0.93 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was acidified to pH~5 with IN HC1 and extracted with EtOAc (5 mL x 3). The organic phase was dried over anhydrous , filNteare2SdO a4nd concentered to afford 7-cyclobutyl-6-fluoro-2- oxo- lH-quinoline-3 -carboxylic acid, 49-4 (70 mg, 86%) as a yellow solid. LCMS (ESI): m / z 262 [M+H]+.

[0389] Step E: To a stirred solution of 49-4 (35 mg, 0.13 mmol) and -3-amino-2,3- (R) dihydrothiophene 1,1-dioxide, Int 3 (18 mg, 0.13 mmol) in DMF (1 mL) was added HATU (102 mg, 0.27 mmol) and DIEA (35 mg, 0.27 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (5 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (A)-7-cyclobutyl-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-2-oxo-l,2- dihydroquinoline-3 -carboxamide, 49 (36 mg, 71%) as a white solid. LCMS (ESI): m / z 377 [M+H]+;1H NMR (400 MHz, DMSO-d6) 6 12.52 (s, 1H), 10.21 (d, J= 8.0 Hz, 1H), 8.83 (s, 1H), 7.79 (d, 7 = 10.0 Hz, 1H), 7.36 (d, J= 6.0 Hz, 1H), 7.29 (dd, J= 6.0, 1.9 Hz, 1H), 7.00 (dd, J= l.Q, 3.0 Hz, 1H), 5.40 (d, J= 5.0 Hz, 1H), 3.85 - 3.70 (m, 2H), 3.31 - 3.28 (m, 1H), 2.37 (dt, J= 13.0, 6.0 Hz, 2H), 2.19 - 2.04 (m, 3H), 1.87 (t, J= 7.0 Hz, 1H).Example 50 (R) -7-Cyclobutyl- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-8-fhioro-2-oxo-l,2- dihydroquinoline-3-carboxamide (50)

[0390] Step A: A solution of 2-amino-4-bromo-3 -fluorobenzoic acid (2 g, 8.5 mmol) in 1 M BH3-THF (42 mL) was stirred at 40 °C for 10 h and the cooled reaction mixture was diluted with water (50 mL). The solution was extracted with EtOAc (80 mL x 3), the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc in hexane) to afford (2-amino-4-bromo-3- fluorophenyl)methanol, 50-1 (1.6 g, 85%) as a white solid. LCMS (ESI): m / z 220, 222 [M+H]+.

[0391] Step B: To a mixture solution of 50-1 (1.6 g, 7.3 mmol) in DCM (100 mL) was added Mn02 (5.1 g, 58 mmol) and the solution was stirred for at RT for 3 h. The mixture solution was filtered and the filtrate was concentrated to afford 2-amino-4-bromo-3-fluorobenzaldehyde, 50-2 (1.5 g, 94%) as a yellow solid. LCMS (ESI): m / z 218 [M+H]+.

[0392] Step C: To a solution of 50-2 (1.5 g, 6.8 mmol) in EtOH (25 mL) was added diethyl malonate (3.1 g, 19.3 mmol), HOAc (50 mg, 0.76 mmol) and piperidine (1.76 g, 20.6 mmol) and themixture was stirred at 60 °C for 8 h. The mixture was filtered and the solid was washed with EtOH to afford ethyl 7-bromo-8-fluoro-2-oxo-l,2-dihydroquinoline-3 -carboxylate, 50-3 (2 g, 83%) as a white solid. LCMS (ESI): m / z 314, 316 [M+H]+.

[0393] Step D: To a solution of 50-3 (900 mg, 2.8 mmol) in THF (10 mL) was added NaH (172 mg, 4.3 mmol) and SEMC1 (713 mg, 4.3 mmol) and the mixture was stirred at RT for 2 h. The cooled reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / FLO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford ethyl 7-bromo-8-fluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)quinoline-3 -carboxylate, 50-4 (700 mg, 55%) as a colorless oil.1H NMR (400 MHz, CDCh) δ 8.57 (s, 1H), 7.51 (dd, J= 9.0, 6.0 Hz, 1H), 7.44 (d, J= 9.0 Hz, 1H), 5.84 (s, 2H), 4.42 (q, J= 7.0 Hz, 2H), 3.96 - 3.85 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H), 1.05 - 0.99 (m, 2H), -0.00 (s, 9H).

[0394] Step E: A solution of 50-4 (100 mg, 0.23 mmol), cyclobutyltrifluoroborane, potassium salt (72 mg, 0.45 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (25 mg, 0.023 mmol), NiBr2.(dtbbpy) (10 mg, 0.023 mmol) and 2,6-dimethylpyridine (36 mg, 0.34 mmol) in dioxane (16 mL) and DMA (4 mL) was irradiated with 24 W blue LED (450 nm) under N2 for 3 h. The mixture was filtrated and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Cl 8, 0-70% MeOH / FLO, 0.1% FA) to afford ethyl 7-cyclobutyl-8-fluoro-2-oxo- 1 ,2-dihydroquinoline-3 -carboxylate, 50-5 (25 mg, 38%) as a yellow solid. LCMS (ESI): m / z 290 [M+H]+.

[0395] Step F: To a solution of 50-5 (40 mg, 0.14 mmol) in THF / MeOIWLO (7 mL, 3 :3 ; 1) was added LiOH (11 mg, 0.28 mmol) and the mixture was stirred at RT for 2 h. The mixture was poured into ice water and adjusted the pH= 5 with 2N HC1. The reaction mixture was extracted with EtOAc (50 mL x 3), the organic phase was dried over anhydrous NaiSOi, filtered and concentrated to afford 7-cy cl obutyl-8-fluoro-2-oxo-l,2-dihydroquinoline-3 -carboxylic acid, 50-6 (32 mg, 88%) as a white solid. LCMS (ESI): m / z 262 [M+H]+.

[0396] Step G: A mixture of 50-6 (35 mg, 0.13 mmol) and perfluorophenyl 2,2,2- trifluoroacetate (187 mg, 0.67 mmol) in pyridine (5 mL) was stirred at 40 °C under N2 for 2 h and the mixture was concentrated to afford perfluorophenyl 7-cyclobutyl-8-fluoro-2-oxo-l,2- dihydroquinoline-3 -carboxyl ate, 50-7 (35 mg, 61%) as a yellow solid. LCMS (ESI): m / z 428 [M+H]+.

[0397] Step H: To a solution of 50-7 (35 mg, 0.08 mmol) in DMF (5 mL) was added (R) -3 - amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (10 mg, 0.08 mmol) and DIEA (10 mg, 0.08 mmol) and the reaction mixture was stirred at RT for 2 h. The solvent was removed under reduced pressure and the crude product was purified by reverse phase chromatography (C 18, MeCN / EbO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-7-cyclobutyl-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-8-fluoro-2-oxo-l,2- dihydroquinoline-3 -carboxamide, 50 (22 mg, 71%) as a white solid. LCMS (ESI): m / z 377 [M+H]+;NMR(400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.11 (d, J= 8.0 Hz, 1H), 8.85 (d, J= 1.0 Hz, 1H), 7.77 (d, J= 8.0 Hz, 1H), 7.34 -7.22 (m, 2H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.50 - 5.29 (m, 1H), 3.83 (dd, J= 16.0, 7.0 Hz, 1H), 3.81 - 3.72 (m, 1H), 3.32 - 3.29 (m, 1H), 2.38 - 2.31 (m, 2H), 2.26 - 2.17 (m, 2H), 2.11 - 2.02 (m, 1H), 1.90 - 1.81 (m, 1H).Example 51 (R) -iV-(l,l-Dioxido-2,3-dihydrothiophen-3-yI)-2-oxo-7-(trifluoromethoxy)-l,2- dihydroquinoline-3-carboxamide (51)

[0398] Step A: To a solution of 2-bromo-5-[(trifluoromethyl)oxy]aniline (2 g, 7.81 mmol) in H2O (10 mL) and dioxane (10 mL) was added trifluoro(vinyl)-14-borane, potassium salt (2.1 g, 15.6 mmol), K2CO3(3.23 g, 23.4 mmol) and Pd(dppf)C12.DCM (0.06 g, 0.08 mmol) and the mixture was stirred at 100 °C under N2 for 16 h. The reaction mixture was diluted with water (50 mL) andextracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford 5-[(trifluoromethyl)oxy]-2-vinylaniline, 51-1 (1.4 g, 88%) as a white solid. LCMS (ESI): m / z 204 [M+H]+.

[0399] Step B: To a solution of 51-1 (800 mg, 3.94 mmol) in THF (10 mL) and (10 mL) H2O was added sodium periodate (4.21 g, 19.6 mmol) and K2OSO4 (145 mg, 0.39 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 30 min and stirred at RT for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford 2-amino-4- [(trifl uoromethyl)oxy ]benzene-l- carbaldehyde, 51-2 (100 mg, 12%) as a white solid. LCMS (ESI): m / z 206 [M+H]+.

[0400] Step C: To a solution of 51-2 (160 mg, 0.78 mmol) in EtOH (10 mL) was added piperidine (200 mg), ethyl 3 -ethoxy-3 -oxopropanoate (0.33 mL, 2.18 mmol) and HOAc ( 1 drop) and the mixture was stirred at 80 °C for 16 h. The precipitate was filtered and the filter cake was dried under vacuum to afford ethyl 2-oxo-7-[(trifluoromethyl)oxy]-lH-quinoline-3-carboxylate, 50-3 (70 mg, 29%) as a yellow solid which was used for the next step directly without further purification. LCMS (ESI): m / z 301 [M+H]+.

[0401] Step D: To a solution of 51-3 (140 mg, 0.46 mmol) in MeOH (10 mL) and EEO (10 mL) was added LiOH (20 mg, 0.46 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford 2-oxo- 7-[(trifluoromethyl)oxy]-lH-quinoline-3-carboxylic acid, 51-4 (100 mg, 65%) acid as a white solid. LCMS (ESI): m / z 274 [M+H]+.

[0402] Step E: To a solution of 51-4 (50 mg, 0.18 mmol) in pyridine (1 mL) was added 2,3 ,4,5 ,6-penlafluorophenyl 2,2,2-trifluoroacetate (1 mL, 0.18 mmol) at 40 °C and the mixture was stirred at 40 °C for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford 2,3,4,5,6-pentafluorophenyl 2-oxo-7- [(trifluoromethyl)oxy]-lH-quinoline-3-carboxylate, 51-5 (27 mg, 33%) as a white solid. LCMS (ESI): m / z 440 [M+H]+.

[0403] Step F: To a solution of 51-5 (27 mg, 0.06 mmol) in DMF (2 mL) was added -3- (R) amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (13 mg, 0.06 mmol), DIEA (39 mg) and the mixturewas stirred at RT for 1 h. Water (1 mL) was added and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / I^O, 0.1% formic acid modifier, 0% to 70% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R) -A-( I , I -Dioxido-2,3- dihydrothiophen-3-yl)-2-oxo-7-(trifluoromethoxy)-l,2-dihydroquinoline-3-carboxamide, 51 (5.0 mg, 19%) as a white solid. LCMS (ESI): m / z 389 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.05 (d, J = 8.0 Hz, 1H), 8.91 (s, 1H), 8.14 (d, . / - 9.0 Hz, 1H), 7.36 (s, 1H), 7.29 (dd, J= 10.0, 5.0 Hz, 2H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.30 (d, J = 4.0 Hz, 1H).Example 52 (R) -iV-(l,l-Dioxido-2,3-dihydrothiophen-3-yI)-7-(oxazol-2-yl)-2-oxo-l,2-dihydroquinoline-3- carboxamide (52)

[0404] Step A: A solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (800 mg, 2.58 mmol)), oxazole (356 mg, 5.16 mmol), Pd(OAc)2 (64 mg, 0.28 mmol), RuPhos (241 mg, 0.51 mmol), K2CO3(1.1 g), pivalic acid (51 mg, 0.50 mmol) in toluene (16 mL) was stirred at 110 °C for 16 h and cooled to RT. The combined organic layers were washed with EtOAc (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was precipitated with PE:EtOAc (4:1) to afford ethyl 2-methoxy-7-(oxazol-2-yl)quinoline-3-carboxylate, 52-1 (144 mg, 19%) as a green solid.LCMS (ESI): m / z 299 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.57 (s, 1H), 8.16 - 8.06 (m, 2H), 8.02 (s, 1H), 7.87 (dd, J= 8.0, 2.0 Hz, 1H), 4.35 (q, J= 7.0 Hz, 2H), 4.05 (d, J= l.Q Hz, 3H), 1.35 (t, J = 7.0 Hz, 3H).

[0405] Step B: A mixture of 52-1 (120 mg, 0.40 mmol) in HC1 (6 mL) was stirred at 100 °C under N2 for 2 h and the reaction mixture was concentrated to afford 7-(oxazol-2-yl)-2-oxo-l,2- dihydroquinoline-3 -carboxylic acid, 52-2 (100 mg, 97%) as a green solid. LCMS (ESI): m / z 257 [M+H]+.

[0406] Step C: A mixture of 52-2 (50 mg, 0.2 mmol) and perfluorophenyl 2,2,2-trifluoroacetate (55 mg, 0.2 mmol) in pyridine (3 mL) was stirred at 40 °C under N2 for 2 h and the mixture was concentrated to afford perfluorophenyl 7-(oxazol-2-yl)-2-oxo-l,2-dihydroquinoline-3 -carboxylate, 52-3 (80 mg, 97%) as a yellow solid. LCMS (ESI): m / z 423 [M+H]+.

[0407] Step D: To a solution of 52-3 (80 mg, 0.19 mmol) in DMF (2 mL) was added (R)-3- amino-2,3-dihydrothiophene 1,1 -dioxide, Int 3 (28 mg, 0.21 mmol), DIEA (73 mg) and the reaction mixture was stirred at RT for 4 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford to afford (R) - / V-(l , 1 -dioxido-2,3- dihydrothiophen-3-yl)-7-(oxazol-2-yl)-2-oxo-l,2-dihydroquinolme-3-carboxamide, 52 (30 mg, 43%) as a white solid. LCMS (ESI): m / z 372 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.14 (d, J = 8.0 Hz, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.08 - 8.04 (m, 1H), 7.91 (s, 1H), 7.70 (dd, J = 4.0, 3.0 Hz, 2H), 7.29 (dd, J= l.Q, 2.0 Hz, 1H), 7.01 (dd, J= 7.0, 3.0 Hz, 1H), 5.40 (d, J= 5.0 Hz, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.30 (d, J= 4.0 Hz, 1H).Example 53 (R) -7-Cyclobutyl-N -(l,l-dioxido-2,3-dihydrothiophen-3-yl)-5-hydroxy-2-oxo-l,2- dihydroquinoline-3-carboxamide (53)

[0408] Step A: To a solution of 5-bromo-3-methoxy-2-methyl-l-nitrobenzene (1 g, 4.06 mmol) in CCI4 (10 mL) was added NBS (0.72 g, 4.06 mmol) and benzoyl peroxide(0.13 g, 0.41 mmol) and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford 5 -bromo-2-(bromomethyl)-3 -methoxy- 1 -nitrobenzene, 53-1 (1 g, 75%) as a white solid. 'HNMR (400 MHz, DMSO-d6) δ 7.82 (d, J= 2.0 Hz, 1H), 7.68 (d, J= 2.0 Hz, 1H), 4.66 (s, 2H), 4.00 (s, 4H).

[0409] Step B: To a solution of 53-1 (1 g, 3.08 mmol) in MeCN (10 mL) was added NMO (0.72 g, 6.16 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h and the reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to afford 4-bromo-6-methoxy-2-nitrobenzene-l-carbaldehyde, 53-2 (570 mg, 71%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.83 (dd, .7= 11.0, 2.0 Hz, 2H), 3.99 (s, 4H).

[0410] Step C: To a solution of 53-2 (570 mg, 2. 19 mmol) in EtOH (10 mL) and H2O (2 mL) were added Fe powder (612 mg, 11 mmol) and NH4CI (586 mg, 11.0 mmol) and the reaction mixture was stirred at 80 °C for 3 h. The fdtrate was concentrated under reduced pressure to afford the 2- amino-4-bromo-6-methoxybenzene- 1 -carbaldehyde, 53-3 (500 mg, 95%) as a yellow solid which was used for the next step directly without further purification.JH NMR (400 MHz, DMSO-d6) 5 10.21 (s, 1H), 6.58 (d, J= 1.2 Hz, 1H), 6.33 (d, J= 1.2 Hz, 1H), 5.75 (s, 1H), 3.83 (s, 3H).

[0411] Step D: To a solution of 53-3 (500 mg, 2.17 mmol) in EtOH (10 mL) was added piperidine (518 mg, 6.1 mmol), ethyl 3 -ethoxy-3 -oxopropanoate (1 mL, 6.52 mmol) and HOAc (1 drop) and the reaction mixture was stirred at RT for 1 h. The precipitate was filtered and the filtrate was concentrated to afford ethyl 7-bromo-5-methoxy-2-oxo-lH-quinoline-3-carboxylate, 53-4 (200 mg, 28%) as a white solid. LCMS (ESI): m / z 257 [M+H]+.

[0412] Step E: To a solution of 53-4 (200 mg, 0.61 mmol) in DCM (5 mL) was added trimethyloxonium tetrafluoroborate (56 mg, 0.92 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (5 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO , filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford ethyl 7-bromo-2,5- dimethoxyquinoline-3-carboxylate 53-5 (100 mg, 47%) as a white solid. LCMS: m / z 340 [M+H]+

[0413] Step F: A vial equipped with a stirring bar, were added 53-5 (20 mg, 0.06 mmol) and potassium cyclobutyltrifluoroborate (19 mg, 0.12 mmol) in DMA (1 mL) and dioxane (4 mL) was added Ir[dF(CF3)ppy]2(dtbpy))PF6 (7 mg, 0.006 mmol), NiBr2(dtbbpy) (4 mg, 0.007 mmol) and 2,6-dimethylpyridine (0.01 mL). The vial was capped and placed in pennPHD photoreactor M2 (Blue LED) for 16 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc:PE / 1 : 1) to afford ethyl 7-cyclobutyl-2,5-dimethoxyquinoline-3-carboxylate, 53-6 (2 mg, 11%) as a yellow solid. LCMS (ESI): m / z 316 [M+H]+.

[0414] Step G: To a stirred mixture of 53-6 (55 mg, 0.17 mmol) in THF (2 mL) and H2O (1 mL) was added LiOH (22 mg, 0.52 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was acidified to pH 5 with IN HC1 and extracted with EtOAc (5 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 7- cyclobutyl-2,5-dimethoxyquinoline-3-carboxylic acid, 53-7 (45 mg, 90%) as a yellow solid. LCMS (ESI): m / z 288 [M+H]+.

[0415] Step H: To a stirred mixture of 53-7 (45 mg, 0.16 mmol) and (R) -3-amino-2,3- dihydrothiophene 1,1-dioxide, Int 3 (21 mg, 0.16 mmol), DIEA (40.5 mg) in DMF (2 mL) was added HATU (119 mg, 0.31 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was quenched by the addition of water and extracted with EtOAc (5 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, (EtOAc:PE / 1: 1) to afford 7-cyclobutyl-A-[(3 / )- 1 , 1 -dioxo- 2,3-dihydrothiophen-3-yl]-2,5-dimethoxyquinoline-3-carboxamide, 53-8 (50 mg, 79%) as a yellow solid. LCMS (ESI): m / z 403 [M+H]+.

[0416] Step I: To a stirred mixture of 53-8 (50 mg, 0.13 mmol) in DCM (2 mL) was added TMSI (35 mg, 0.25 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction was quenched by the addition of water and extracted with EtOAc (5 mL x 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford 7- cyclobutyl- V-[(3R)-l,l-dioxo-2,3-dihydrothiophen-3-yl]-5-methoxy-2-oxo-lH-quinoline-3- carboxamide, 53 (29 mg, 59%) as a yellow solid. LCMS (ESI): m / z 389 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.15 (d, J= 8.0 Hz, 1H), 8.93 (s, 1H), 7.27 (dd, J= 6.0, 2.0 Hz, 1H), 6.99 (dd, J= 6.0, 3.0 Hz, 1H), 6.85 (s, 1H), 6.69 (s, 1H), 5.39 (s, 1H), 3.97 (s, 3H), 3.74 (dd, J = 14.0, 8.0 Hz, 1H), 3.65 - 3.55 (m, 1H), 3.27 (d, J = 4.0 Hz, 1H), 2.40 - 2.28 (m, 2H), 2.20 - 2.09 (m, 2H), 2.02 (s, 1H), 1.84 (d, J= 10.0 Hz, 1H).Example 54 l,l-Dioxido-2,3-dihydrothiophen-3-yI)-7-iodo-2-oxo-l,2-dihydroquinoline-3- carboxamide (54)

[0417] Step A: To a solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (500 mg, 1.61 mmol), methyl[(lR,2R)-2-(methylamino)cyclohexyl]amine (92 mg, 0.65 mmol) and Nal(483 mg, 3.22 mmol) in dioxane (10 mL) was added Cui (61 mg, 0.32 mmol) and the reaction mixture was stirred at 120 °C for 36 h. The solution was diluted with brine (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-7% EtOAc in PE) to afford ethyl 7-iodo-2-methoxyquinoline-3- carboxylate, 54-1 (360 mg, 62%) as a white solid. LCMS (ESI): m / z 258 [M+H]+.

[0418] Step B: A solution of 54-1 (360 mg, 1.0 mmol) in HC1 (5 mL) was stirred at 100 °C for 5 h, the reaction was mixture cooled and filtered. The solid was dried under vacuum to afford 7-iodo-2- oxo- lH-quinoline-3 -carboxylic acid, 54-2 (250 mg, 79%) as a white solid. LCMS (ESI): m / z 316 [M+H]+.

[0419] Step C: To a solution of 54-2 (50 mg, 0.16 mmol) and -3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (27 mg, 0.21 mmol) in DMF (5 mL) was added HATU (72 mg, 0.19 mmol) and DIEA. (61 mg) and the solution was stirred at RT for 2 h. The resulting solution was diluted with brine (10 mL), extracted with EtOAc (20 mL x 3) and washed with brine (20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-N-( 1,1 -dioxi do-2, 3 -dihydrothiophen-3-yl)-7-iodo-2-oxo- 1,2- dihydroquinoline-3 -carboxamide, 54 (40 mg, 0.09 mmol, 58%) as a yellow solid. LCMS (ESI): m / z 431 [M+H]’; NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.08 (d, J= 8.0 Hz, 1H), 8.83 (s, 1H), 7.80 (s, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.63 (dd, J= 9.0, 2.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 6.99 (dd, J= 6.0, 3.0 Hz, 1H), 5.45 - 5.35 (m, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.29 (d, J = 4.0 Hz, 1H).Example 55 (R) -7-Chloro- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yI)-2-oxo-l,2-dihydroquinoline-3- carboxamide (55)

[0420] Step A: To a solution of 7-chloro-2-oxo-l,2-dihydroquinoline-3 -carboxylic acid (35 mg, 0.16 mmol) in DMF (5 mL) was added -3-amino(-R2), 3 -dihydrothiophene 1,1 -dioxi de, Int 3 (25 mg, 0.19 mmol), DIEA (60 mg) and HATU (89 mg, 0.24 mmol) and the mixture was stirred at RT for 2 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford -7-ch(Rlo)ro-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3 -carboxamide, 55 (6 mg, 10%) as a white solid. LCMS (ESI): m / z 339 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.09 (d, J= 8.0 Hz, 1H), 8.88 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.44 (d, 7= 2.0 Hz, 1H), 7.36 (dd, J= 8.0, 2.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 6.99 (dd, .7= 6.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.32 (dd, 1H).Example 56 (R) -7-(Dimethylamino)-A,-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline- 3-carboxamide, (56).

[0421] Step A To a solution of 7-3 (20 mg, 0.04 mmol) in DCM (2 mL) was added TFA (2 mL) and paraformaldehyde (5 mg) and the reaction mixture was stirred RT for 1 h. Sodiumcyanoborohydride (5.7 mg, 0.1 mmol) was added and the reaction mixture was stirred RT for 10 min. The reaction mixture concentrated and the crude product was purified by reverse phase purification (Cl 8, MeCN / H?O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R) -7-(dimethylamino)-A-(l,l-dioxido-2,3- dihydrothiophen-3-yl)-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 56 (1.7 mg, 10%) as a white solid. LCMS (ESI): m / z 348 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.17 (d, J = 8.0 Hz, 1H), 8.61 (s, 1H), 7.69 (d, 7= 9.0 Hz, 1H), 7.25 (dt, J= 10.0, 5.0 Hz, 1H), 6.98 (dd, 7= 7.0, 3.0 Hz, 1H), 6.81 (dd, 7 = 9.0, 3.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 5.38 (s, 1H), 3.73 (dd, 7 = 14.0, 8.0 Hz, 1H), 3.24 (dd, J= 14.0, 4.0 Hz, 1H), 3.05 (s, 6H).Example 57 (R) - / V-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-7-methoxy-2-oxo-l,2-dihydroquinoline-3- carboxamide (57)

[0422] Step A: To a solution of 2-amino-4-fluorobenzene-l-carbaldehyde (1 g, 7.2 mmol) in MeOH (10 mL) was added sodium methanolate (1.94 g, 36 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over ; and conceNntar2aSteOd4. The crudeproduct was purified by silica gel chromatography (0-5% EtOAc in hexanes) to afford 2-amino-4- methoxybenzene-l-carbaldehyde, 57-1 (340 mg, 31%) as a white solid. LCMS (ESI): m / z 152 [M+H]+.

[0423] Step B: To a solution of 57-1 (340 mg, 2.25 mmol) in EtOH (10 mL) was added ethyl 3- ethoxy-3-oxopropanoate (0.96 mL, 6.30 mmol), piperidine (0.67 mL, 6.75 mmol) and HOAc (1 drop) and the reaction mixture was stirred at 80 °C for 16 h. The suspension was filtered and the filter cake was dried in vacuo to afford ethyl 7-methoxy-2-oxo-lH-quinoline-3-carboxylate, 57-2 (300 mg, 53%) as a yellow solid which was used for the next step directly without further purification. LCMS (ESI): m / z 248 [M+H]+.

[0424] Step C: To a solution of ethyl 57-2 (300 mg, 1.21 mmol) in MeOH (10 mL) and H2O (10 mL) was added LiOH (254 mg, 6.07 mmol) and the reaction mixture was stirred at 70 °C for 3 h. The cooled reaction mixture was concentrated, diluted with water and adjusted to pH=5 with IN HC1. The suspension was filtered and the cake was dried to afford 7-methoxy-2-oxo-lH-quinoline-3- carboxylic acid, 57-3 (200 mg, 75%) which was used for the next step directly without further purification. LCMS (ESI): m / z 248 [M+H]+.

[0425] Step D: To a solution of 57-3 (50 mg, 0.23 mmol) in DMF (5 mL) was added (R) -3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (30 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol) and DIEA (147 mg, 1.14 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / EbO, 0.1% formic acid modifier, 0% to 70% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford to afford (R)-N 1(l,l-dioxido-2,3-dihydrothiophen-3-yl)-7-methoxy-2-oxo-l,2-dihydroquinoline-3- carboxamide, 57 (11 mg, 14%) as a white solid. LCMS (ESI): m / z 335 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.15 (d, J = 8.0 Hz, 1H), 8.79 (s, 1H), 7.89 (d, 9.0 Hz, 1H), 7.27(dd, J= 6.0, 2.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 6.97 - 6.88 (m, 2H), 5.39 (s, 1H), 3.86 (s, 3H), 3.75 (dd, J= 8.0, 14.0 Hz, 1H), 3.28 (dd, J= 14.0, 4.0 Hz, 1H).Example 58 l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-(piperidin-l-yl)-l,2-dihydroquinoline-3- carboxamide (58)

[0426] Step A: To a mixture of 2-amino-4-fluorobenzene-l-carbaldehyde (500 mg, 3.59 mmol) in MeOH (10 mL) was added methyl 3-methoxy-3-oxopropanoate (1.33 g, 10.06 mmol), HOAc(0.02 mL) and piperidine (916 mg) and the reaction mixture was stirred at 60 °C for 16 h. The resulting precipitate was collected by filtration, washed with MeOH, and dried in vacuo to afford methyl 7- (hexahydropyri din- l-yl)-2-oxo-lH-quinoline-3 -carboxylate, 58-1 (530 mg, 51%) as a yellow solid. LCMS (ESI): m / z 287 [M+H]+.

[0427] Step B: To a mixture of 58-1 (530 mg, 1.85 mmol) in THF:MeOH:H2O (3:3: 1, 13 mL) was added LiOH (388 mg, 9.26 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was adjusted to pH ~3 with 2N HC1, the precipitate was filtered, washed with H2O and dried in vacuo to afford 7-(hexahydropyri din- l-yl)-2-oxo-lH-quinoline-3 -carboxylic acid, 58-2 (430 mg, 85%) as a yellow solid. LCMS (ESI): m / z 273 [M+H]+.

[0428] Step C: To a mixture of 58-2 (30 mg, 0.11 mmol) in DMF (3 mL) was added (R)-3- amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (22 mg, 0.17 mmol), HATU (62 mg, 0.17 mmol) and DIEA (42 mg, 0.33 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (5 mLx 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography (C18, MeCN / H2O, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford (R)-7V-(1,1- dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-(piperidin-l-yl)-l,2-dihydroquinoline-3-carboxamide, 58 (26 mg, 59%) as a yellow solid. LCMS (ESI): m / z 388 [M+H]+;1H NMR (400 MHz, DMSO-d6) 5 11.96 (s, 1H), 10.17 (d, J =8.0 Hz, 1H), 8.61 (s, 1H), 7.68 (d, J= 9.0 Hz, 1H), 7.26 (dd, J= 7.0, 2.0 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.69 (d, J = 1.0 Hz, 1H), 5.38 (s, 1H), 3.73 (dd, J= 14.0, 8.0 Hz, 1H), 3.39 (s, 4H), 3.27 - 3.23 (m, 1H), 1.61 (s, 6H).Example 59(R) - / V-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-(thiazol-2-yl)-l,2-dihydroquinoline-3- carboxamide (59)

[0429] Step A: To a mixture solution of ethyl 7-bromo-2-methoxyquinoline-3 -carboxylate, Int 2 (300 mg, 0.97 mmol) in THF (3 mL), MeOH (3 mb) and (1 mL) waHs2aOdded LiOH (121 mg, 2.90 mmol) and the solution was stirred at RT for 1 h. The mixture solution diluted with water, adjusted the pH = 2 and extracted with EtOAc (10 mL x 2). The organic layers were, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 7-bromo-2- methoxyquinoline-3 -carboxylic acid, 59-1 (270 mg, 98%) as a white solid. LCMS (ESI): m / z 282[M+H]+.

[0430] Step B: To a mixture solution of 59-1 (270 mg, 0.96 mmol) in pyridine (10 mL) was added 2, 3, 4, 5, 6-pentafluorophenyl 2, 2, 2-trifluoroacetate (1.65 mL, 9.57 mmol) and the solution was stirred at 40 °C for 2 h. The solution was concentrated to afford perfluorophenyl 7-bromo-2- methoxyquinoline-3 -carboxylate, 59-2 (400 mg, 99 %) as a yellow oil. LCMS (ESI): m / z 448,450 [M+H]+.

[0431] Step C: To a mixture solution of 59-2 (400 mg, 0.955 mmol) in DMF (10 mL) was added DIEA (493 mg, 3.82 mmol) and (R)-3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (152 mg, 1.15 mmol) and the solution was stirred at RT for 16 h. The solution diluted with water and extracted with EtOAc (10 mL x 2). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (45 % of EtOAc in PE) to afford (R)-7-bromo-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- methoxyquinoline-3 -carboxamide, 59-3 (370 mg, 97%) as a white solid. LCMS (ESI): m / z 397,399 [M+H]+.

[0432] Step D: To a solution of 59-3 (100 mg, 0.25 mmol) and 2-(tributylstannyl)thiazole (113 mg, 0.30 mmol) in dioxane (5 mL) was added Pd(PPhs)4 (29 mg, 0.023 mmol) and the solution was stirred at 120 °C for 2 h. The reaction mixture was diluted with water, extracted with EtOAc (20 mL x 3) and washed with brine (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-70% EtOAc in PE) to afford (R)-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- methoxy-7-(thiazol-2-yl)quinoline-3-carboxamide, 59-4 (90 mg, 89%) as a yellow solid. LCMS (ESI): m / z 402 [M+H]+.

[0433] Step E: To a solution of 59-4 (50 mg, 0.13 mmol) in CH3CN (5 mL) was added TMSI (87 mg, 0.62 mmol) at 0 °C and the solution was stirred at RT for 2 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / FLO, 0.1% formic acid modifier, 10% to 95% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (R)-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-(thiazol-2-yl)-l,2-dihydroquinoline-3- carboxamide, 59 (29 mg, 60%) as a white solid. LCMS (ESI): m / z 388[M+H]+;NMR (400 MHz, DMSO-1 ) δ 12.58 (s, 1H), 10.15 (d, J= 8.0 Hz, 1H), 8.89 (s, 1H), 8.13 - 8.01 (m, 3H), 7.94 (d, J = 3.0 Hz, 1H), 7.86 (dd, J= 8.0, 2.0 Hz, 1H), 7.29 (dd, J= 6.0, 2.0 Hz, 1H), 7.01 (dd, J= 6.0, 3.0 Hz, 1H), 5.42 (d, J= 4.0 Hz, 1H), 3.76 (dd, J= 14.0, 8.0 Hz, 1H), 3.30 (d, J= 4.0 Hz, 1H).Example 60 (R) -A-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-l,2-dihydroquinoline-3- carboxamide (60)

[0434] Step A: To a solution of ethyl 7-bromo-2-methoxyquinoline-3-carboxylate, Int 2 (500 mg, 1.61 mmol) in dioxane (5 mL) and (2 mL)H w2Oas added potassium trifluoro(prop-l-en-2- yl)boroate (238 mg, 1.61 mmol), Pd(dppf)C12 (118 mg, 0.16 mmol) and K2CO3(446 mg, 3.22 mmol) at RT under N2 and the solution was stirred at 90 °C for 16 h. The reaction mixture was concentrated, the residue was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-10 % EtOAc in PE) to afford ethyl 2-methoxy-7-(prop-l-en-2-yl)quinoline-3-carboxylte, 60-1 (350 mg, 80%) as ayellow oil. LCMS: ESI m / z 272 [M + H]+.

[0435] Step B: A suspension of 60-1 (300 mg, 1.10 mmol) and 10% Pd / C (30 mg) in THF (5 mL) was stirred at RT under H2 atmosphere using a balloon for 3 h. The mixture was filtered and the filtrate was concentrated to afford ethyl 2-methoxy-7-(prop-2-yl)quinoline-3-carboxylate, 60-2 (260 mg, 86%) as a light yellow oil. LCMS: (ESI) m / z 274 [M + H]+.

[0436] Step C: A solution of 60-2 (290 mg, 1.06 mmol) in cone. HC1 (5 mL) was stirred at 100 °C for 3 h, the mixture was cooled to RT and diluted with water (10 mL). The precipitate was filtered and lyophilized to afford 2-hydroxy-7-(prop-2-yl)quinoline-3 -carboxylic acid, 60-3 (200 mg, 82%) as a white solid. LCMS: (ESI) m / z 232 [M + H]+.

[0437] Step D: To a solution of 60-3 (120 mg, 0.52 mmol) in pyridine (3 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (1 mL) at RT and the reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford 2,3,4,5,6-pentafluorophenyl 2-hydroxy-7-(prop-2-yl)quinoline-3-carboxylate, 60-4 (200 mg, 97%) as a yellow oil which was used directly for next step. LCMS: (ESI) m / z 398 [M + H]+.

[0438] Step E: To a solution of 60-4 (200 mg, 0.50 mmol) in DMF (3 mL) was added TEA (0.35 mL) and ( )-3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (67 mg, 0.50 mmol) and the mixture was stirred at RT for 3 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / EbO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford1,1 -dioxi do-2, 3 -dihy drothi ophen-3 -yl)-7-isopropyl-2-oxo-l,2-dihydroquinoline-3-carboxamide 60 (21 mg, 12%) as a white solid. LCMS: (ESI) m / z 247 [M + H]+.JH NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 10.21 (d, J= 8.0 Hz, 1H), 8.82 (s, 1H), 7.88 (d, 7= 8.0 Hz, 1H), 7.41 - 7.17 (m, 3H), 7.00 (dd, 7= 7.0, 3.0 Hz, 1H), 5.40 (s, 1H), 3.75 (dd, 7= 14.0, 8.0 Hz, 1H), 3.28 (d, 7= 4.0 Hz, 1H), 3.00 (dt, 7= 14.0, 8.0 Hz, 1H), 1.24 (d, 7= 7.0 Hz, 6H).Example 61 7-Cyclobutyl-A-((25,3 ?)-2-methyl-l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (61)

[0439] Step A: To a solution of 7-cyclobutyl-2-oxo-lH-quinoline-3-carboxyhc acid, 13-3 (250 mg, 1.02 mmol) in pyridine (4 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (864 mg, 3.08 mmol) and the reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated and the residue was suspended in EtOAc / PE (10 mL, 10:1). The precipitate was filteredand dried under reduce pressure to afford 2,3,4,5,6-pentafluorophenyl 7-cyclobutyl-2-oxo-lH- quinoline-3 -carboxylate, 61-1 (400 mg, 95%) as a light yellow solid which was used directly for next step without further purification. LCMS (ESI): m / z 410 [M+H]+.

[0440] Step B: To a solution of 61-1 (124 mg, 0.30 mmol) and (2 ',3R)-3-amino-2-methyl-2,3- dihydrothiophene 1,1 -dioxide, Int-4 in DMF (3 mL) was added DIEA (132 mg) and the reaction was stirred at RT for 20 min. The reaction was quenched with (1 mL) and thHe2cOrude product was purified by reverse phase chromatography (C 18, MeCN / EbO, 0.1% NH4HCO3 modifier, 25% to 95% gradient, 30 mm run) and the fractions containing desired product were lyophilized to afford 7- cyclobutyl-A-((21S',37?)-2-methyl- 1 , 1 -dioxido-2,3-dihydrothiophen-3-yl)-2-oxo- 1 ,2-dihydroquinoline- 3-carboxamide 61 (4.5 mg, 4%) as a white solid. LCMS (ESI): m / z 373 [M+H]+; 'll NMR (400 MHz, DMSO-d6) 5 12.40 (s, 1H), 10.21 (d, 7= 8.0 Hz, 1H), 8.82 (s, 1H), 7.88 (d, 7= 8.0 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.20 (d, 7= 8.0 Hz, 1H), 6.97 (dd, 7=7.0, 2.0 Hz, 1H), 4.90 (dd, 7= 8.0, 6.0 Hz, 1H), 3.69 - 3.59 (m, 1H), 3.43 (dd, 7= 13.0, 7.0 Hz, 2H), 2.35 (td, 7= 8.0, 6.0 Hz, 2H), 2.15 - 1.98 (m, 3H), 1.91 - 1.79 (m, 1H), 1.37 (d, 7= 7.0 Hz, 3H).Example 62 (R) -7-CycIobutyl-JV-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-4-methyl-2-oxo-l,2- dihydroquinoline-3-carboxamide (62)

[0441] Step A: To a solution of l-(2-amino-4-bromophenyl)ethan-l-one (4.0 g, 18.7 mmol) in diethyl malonate (20 mL) was added piperidine (3.7 mL, 37.4 mmol) and HOAc (0.1 mL) and the resulting mixture was stirred at 130 °C for 16 h. The mixture was concentrated under vacuum and the residue was diluted with water and extracted with EtOAc (15 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-20% in EtOAc in PE) to afford ethyl 7-bromo-4-methyl-2- oxo-1 H-quinoline-3 -carboxylate, 62-1 (2.0 g, 34%) as a gray solid. LCMS (ESI): m / z 310 / 312 [M + H]+.

[0442] Step B: To a solution of 62-1 (2.0 g, 6.45 mmol) in DCM (20 mL) was added trimethyloxonium tetrafluoroborate (1.15 g, 7.74 mmol). The mixture was stirred at 25 °C overnight and the mixture was poured into saturated NaHCOs solution (10 mL) and extracted with DCM (10 mL x 3). The organic layer was separated, washed with brin, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-5% in EtOAc in PE) to afford ethyl 7-bromo-2-methoxy-4-methylquinoline-3-carboxylate, 62-2 (800 mg, 38%) as a yellow oil. LCMS (ESI): m / z 324 [M + H]+.

[0443] Step C: To a solution of 62-2 (454 mg, 1.85 mmol) in DMA (4 mL) were added ethyl 7- bromo-2-methoxy-4-methylquinolme-3-carboxylate (400 mg, 1.23 mmol), NiBr2(dtbbpy) (120 mg, 0.25 mmol), ethyl 5-(ethoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate (625 mg, 2.47 mmol) and NaHCCL (207 mg, 2.47 mmol) at RT under N2 and the reaction mixture was irradiated with 18 W Photosyn-10 purple LED lamp (390 nm) (1 cm away with cooling fan) for 4 h. The mixture was diluted with water and extracted with EtOAc (10 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous JSfeSCL and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-10% in EtOAc in PE) to afford ethyl 7-cyclobutyl-2-methoxy-4-methylquinoline-3-carboxylate 62-3 (150 mg, 40%) as a yellow solid. LCMS: (ESI) m / z 300 [M + H]+.

[0444] Step D: A solution of 62-3 (150 mg, 0.50 mmol) in cone. HC1 was stirred at 100 °C for 4 h and the reaction mixture was cooled to RT. The reaction mixture was filtered and the filter cake was dried in vacuo to afford 7-cyclobutyl-2-hydroxy-4-methylquinoline-3-carboxylic acid, 62-4 (100 mg, 74%) as a white solid. LCMS (ESI): m / z 258 [M + H]+.

[0445] Step E: To a solution of 62-4 (120 mg, 0.47 mmol) in pyridine (3 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (653 mg, 2.33 mmol) and the solution was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to afford 2,3,4,5,6-pentafluorophenyl 7-cyclobutyl-2-hydroxy-4-methylquinoline-3-carboxylate 62-5 (150 mg, 53%) as a crude yellow oil. LCMS (ESI): m / z 424 [M + H]+.

[0446] Step F: To a solution of 62-5 (150 mg, 0.25 mmol) in DMF (3 mL) was added TEA (0.25 mL, 1.77 mmol) and (R)-3-amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (47 mg, 0.35 mmol) and the mixture was stirred at RT for 2 h and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / ELO, 0.1% formic acid modifier, 0% to 70% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (A’)-7-cyclobutyl- / V-( 1 , 1 -dioxi do- 2,3 -dihydrothiophen-3-yl)-4-methyl-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 62 (24 mg, 18%) as a white solid. LCMS (ESI): m / z 373 [M + H]+; H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.03 (d, J= 7.0 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.24 (dd, J= 7.0, 2.0 Hz, 1H), 7.18 - 7.04 (m, 2H), 6.88 (dd, J= 7.0, 3.0 Hz, 1H), 5.50 - 5.13 (m, 1H), 3.84 (dd, J= 14.0, 8.0 Hz, 1H), 3.71 - 3.53 (m, 1H), 3.11 (dd, J= 14.0, 5.0 Hz, 1H), 2.37 (s, 3H), 2.33 (ddd, J= 11.0, 7.0, 4.0 Hz, 2H), 2.19 - 1.94 (m, 3H), 1.91 - 1.78 (m, 1H).Example 63(R) -5-Acetamido-7-cyclobutyl-7V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (63)

[0447] Step A: To a solution of 4-bromo-l-methyl-2-nitrobenzene (25 g, 115 mmol) in H2SO4 (300 mL) was added NTS (26 g, 115 mmol) by portions at 0 °C. and solution was stirred at 0 °C for 1 h. The reaction mixture was poured into ice water and the solution was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous , filtered Na2SO4and concentrated. The crude product was purified by silica gel chromatography (0-5% EtOAc in PE)to afford 5 -bromo-3-iodo-2-methyl-l -nitrobenzene, 63-1 (30 g, 76%) as a light yellow solid. 'H NMR (400 MHz, CDC13) δ 8.20 (d, J= 2.0 Hz, 1H), 7.87 (d, J= 2.0 Hz, 1H), 2.54 (s, 3H).

[0448] Step B: To a solution of 63-1 (15 g, 43.8 mmol) and NBS (11 g, 65.8 mmol) in CCI4 (150 mL) was added and benzoyl peroxide (1.06 g, 4.3 mmol) and the reaction mixture was stirred for 16 h at 90 °C. The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in PE) to afford 5-bromo-2-(bromomethyl)- 3 -iodo- 1 -nitrobenzene, 63-2 (7 g, 38%) as a light-yellow oil.1H NMR (400 MHz, CDCh) 5 8.29 (d, 7= 2.0 Hz, 1H), 8.02 (d, 7= 2.0 Hz, 1H), 4.82 (s, 2H).

[0449] Step C: To a solution of 63-2 (7 g, 16.6 mmol) in MeCN (50 mL) was added NMO (1.9 g, 16.6 mmol) and the reaction mixture was stirred 0 °C for 2 h. The reaction mixture was poured into water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NazSO^ filtered and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in PE) to afford 4-bromo-6-iodo-2-nitrobenzene-l-carbaldehyde, 63-3 (4 g, 67.5%) as a light yellow solid.1H NMR (400 MHz, CDCh) 6 10.04 (d, J = 0.5 Hz, 1H), 7.38 (d, J= 2.0 Hz, 1H), 6.82 (dd, J= 7.0, 6.0 Hz, 1H).

[0450] Step D: To a solution of 63-3 (5 g, 14 mmol) and cone. HC1 (2.8 mL) in EtOH (50 mL) and H2O (15 mL) was added iron powder (2.3 g, 42 mmol) and the reaction mixture was stirred at 85 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in PE) to afford 2- amino-4-bromo-6-iodobenzene-l-carbaldehyde, 63-4 (3 g, 66%) as a light yellow solid. LCMS (ESI): m / z 326 [M+H]+

[0451] Step E: To a solution of 63-4 (4 g, 12.2 mmol) in EtOH (20 mL) was added diethyl malonate (3.7 mL, 24.5 mmol), piperidine (2.1 g, 24.5 mmol) and HOAc (1 drop) and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered and the filter cake was dried in vacuo to afford ethyl 7-bromo-2-hydroxy-5-iodoquinoline-3-carboxylate, 63-5 (3.9 g, 75%) as a light yellow solid. LCMS (ESI): m / z 422 [M+H]+

[0452] Step F: To a solution of 63-5 (4.5 g, 10.6 mmol) in DCM (100 mL) was added trimethyloxonium tetrafluoroborate (2.4 g, 15.9 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-10% EtOAc in PE) to afford ethyl 7-bromo-5-iodo-2- methoxyquinoline-3 -carboxylate, 63-6 (1.1 g, 24%) as a white solid. LCMS (ESI): m / z 436 [M+H]+.

[0453] Step G: To a solution of 63-6 (300 mg, 0.7 mmol) in dioxane (10 mL) was added acetamide (53 mg, 0.89 mmol), Pd2(dba)s (63.0 mg, 0.07 mmol), Xantphos (80 mg, 0.14 mmol), CS2CO3 (673 mg, 2.06 mmol) and the reaction mixture was stirred at 70 °C under N2 for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-50% EtOAc in PE) to afford ethyl 5-(acetylamino)-7-bromo-2-methoxyquinoline-3-carboxylate, 63-7 (110 mg, 44%) as a white solid. LCMS (ESI): m / z 367 [M+H]+.

[0454] Step H: To a vial containing 63-7 (160 mg, 0.44 mmol) in DMA (5 mL) were added 2- [(cy cl obutylcarbonyl)oxy]isoindole- 1,3 -dione (160 mg, 0.7 mmol), diethyl l,4-dihydro-2,6-dimethyl- 3,5-pyridinedicarboxylate (220 mg, 0.9 mmol), (dtbbpy)NiC12 (80 mg, 0.16 mmol) and NaHCCL (73 mg, 0.87 mmol) and the reaction mixture was irradiated with 18 W Photosyn-10 purple LED (390 nm) lamp (1 cm away with cooling fan) under N2 for 3 h. The mixture diluted with water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-50% EtOAc in PE) to afford ethyl 5-(acetylamino)-7-cyclobutyl-2- methoxyquinoline-3 -carboxylate, 63-8 (80 mg, 54%) as a white solid. LCMS (ESI): m / z 343 [M+H]+.

[0455] Step I: To a solution of 63-8 in (5 mHL2)O and THF (5 mL) was added LiOH (49 mg, 1.2 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into water, the pH of the mixture was adjusted to 3~4 with 2N HC1 and he solution was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 5-(acetylamino)-7-cyclobutyl-2-methoxyquinoline-3- carboxylic acid, 63-9 (60 mg, 82%) as a white solid used directly for next step. LCMS (ESI): m / z 315 [M+H]’.

[0456] Step J: To a solution of 63-9 (60 mg, 0.19 mmol) in DMF (5 mL) was added -3- (R) amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (28 mg, 0.2 mmol), DIEA (74 mg, 0.57 mmol) and T?P (242 mg, 0.38 mmol, 50% wt. in EtOAc) and the reaction mixture was stirred RT for 2h. The reaction mixture was poured into water and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-70%> EtOAc in PE) to afford 5-(acetylamino)-7- cyclobutyl-Ar-[(37?)-l,l-dioxo-2,3-dihydrothiophen-3-yl]-2-methoxy-l,2-dihydroquinoline-3- carboxamide, 63-10 (50 mg, 60.6%) as a white solid. LCMS (ESI): m / z 430 [M+H]+.

[0457] Step K: To a solution of 63-10 (50 mg, 0. 12 mmol) in MeCN (3 mL) was added TMST (50.6 mg, 0.36 mmol) and the reaction mixture was stirred RT for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S,O f4iltered and concentrated. The residue was purified by silica gel chromatography DCM (0-5% MeOH in DCM) to afford -5-ac(eRt)amido-7-cyclobutyl-JV-(l,l-dioxido-2,3- dihydrothi ophen-3 -yl)-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 63 (35 mg, 70%) as a white solid. LCMS (ESI): m / z 416 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.19 (d, J= 8.0 Hz, 2H), 8.93 (s, 1H), 7.37 (s, 1H), 7.27 (dd, J= 7.0, 2.0 Hz, 1H), 7.07 (s, 1H), 7.00 (dd, J= 1.0, 3.0 Hz, 1H), 5.36 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.60 (dd, J= 17.0, 9.0 Hz, 2H), 3.29 (d, J = 4.0 Hz, 2H), 2.34 (ddd, J= 13.0, 10.0, 6.0 Hz, 2H), 2.16 (s, 3H), 2.04 (tdd, J= 10, 8.0, 2.0 Hz, 3H), 1.83 (dd, J= 17.0, 9.0 Hz, 1H).Example 64 (R) -5-Amino-7-cyclobutyl-JV-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (64).

[0458] Step A: To a solution of 63 (20 mg, 0.05 mmol) in EtOH (2 mL) was added 4N HC1 (2 mL) and the reaction mixture was stirred at 80 °C for 4 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (0-6% MeOH in DCM) to afford (R)-5-amino-7-cyclobutyl-iV-(l , 1 -dioxi do-2, 3 -dihydro thiophen-3 -yl)-2-oxo- 1 ,2-dihydroquinoline-3- carboxamide -oxo- lH-quinoline-3 -carboxamide, 64 (7 mg, 39%) as a light yellow solid. LCMS (ESI): m / z 374 [M+H]+;1H NMR (400 MHz, DMSO-t / 6) δ 12.00 (s, 1H), 10.23 (d, J= 8.0 Hz, 1H), 9.03 (s, 1H), 7.26 (d, J= 6.0 Hz, 1H), 7.07 - 6.89 (m, 1H), 6.38 (s, 1H), 6.31 (s, 1H), 5.37 (s, 1H), 3.74 (dd, J= 14.0, 8.0 Hz, 1H), 3.46 (s, 2H), 3.26 - 3.20 (m, 3H), 2.26 (d, J= 8.0 Hz, 2H), 2.09 - 1.93 (m, 3H), 1.80 (s, 1H).Example 65 (R) -7-Cyclobutyl- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-5-hydroxy-2-oxo-l,2- dihydroquinoline-3-carboxamide (65).

[0459] Step A: To a stirred solution of 53-5 (150 mg, 0.44 mmol) and 2- [(cyclobutylcarbonyl)oxy] isoindole- 1,3 -dione (162 mg, 0.66 mmol) in DMA (3 mL) was added ethyl 5-(ethoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate (223 mg, 0.88 mmol), NiBr2(dtbbpy) (43 mg, 0.09 mmol) and NaHCCL (74 mg, 0.88 mmol) under N2 atmosphere. The reaction vial was irradiated with 18 W Photosyn-10 purple LED (390 nm) lamp (1 cm away with cooling fan) under N2 for 16 h. The reaction was diluted with water and extracted with EtOAc (8 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4. filtered and concentrated. The crude product was purified by silica gel chromatography (0- 60% EtOAc in PE) to afford ethyl 7-cyclobutyl-2,5-dimethoxyquinoline-3-carboxylate, 65-1 (100 mg, 72%) as a yellow solid. LCMS (ESI): m / z 316 [M+H]+.

[0460] Step B: A solution of 65-1 (100 mg, 0.32 mmol) in HBr (3 mL, 48% wt. in water) was stirred at 120 °C for 16 h and the resulting mixture was concentrated under reduced pressure to afford 7-cyclobutyl-2,5-dihydroxyquinoline-3-carboxylic acid, 65-2 (60 mg, 73%) as a yellow solid used directly for next step. LCMS (ESI): m / z 260 [M+H]+.

[0461] Step C: To a stirred mixture of 65-2 (50 mg, 0.19 mmol) and -3-amino-2, 3- (R) dihydrothiophene 1,1 -dioxide, Int 3 (25 mg, 0.19 mmol) in DMF (2 mL) was added HATU (73 mg, 0.19 mmol) and DIEA (25 mg, 0.19 mmol) and the solution was stirred at RT for 2 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / ELO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford 7-cyclobutyl-A-[(3R)-l,l-dioxo-2,3-dihydro-thiophen-3-yl]-5-hydroxy-2-oxo- lH-quinoline-3-carboxamide, 65 (3.2 mg, 4%) as a white solid. LCMS (ESI): m / z 375 [M+H]+; 'H NMR (400 MHz, DMSO-r / 6) δ 12.23 (s, 1H), 10.17 (d, J = 8.0 Hz, 1H), 8.94 (s, 1H), 7.27 (dd, J =6.0, 2.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 6.68 (s, 1H), 6.53 (s, 1H), 5.39 (s, 1H), 3.74 (dd, J = 14.0, 8.0 Hz, 1H), 3.54 (d, J= 9.0 Hz, 1H), 3.27 (d, J= 4.0 Hz, 1H), 2.35 - 2.26 (m, 2H), 2.15 - 1.91 (m, 4H), 1.83 (t, J= 8.0 Hz, 1H).Example 66 (R) -8-Chloro-7-cyclobutyl- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3- (66)

[0462] Step A: To a solution of 13-2 (100 mg, 0.35 mmol) in DMF (3 mL) was added NCS (84 mg, 0.63 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SCU and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc in PE) to afford ethyl 8-chloro-7-cyclobutyl-2-methoxyquinoline-3- carboxylate 66-1 (90 mg, 80 %) as a white solid. LCMS (ESI): m / z 320 [M+H]+.

[0463] Step B: A solution of 66-1 (70 mg, 0.22 mmol) in cone. HC1 (3 mL) was stirred at 100 °C for 2 h and the mixture was cooled to RT. The suspension was filtered and the filter cake was dried in vacuo to afford the 8-chloro-7-cyclobutyl-2-hydroxyquinoline-3-carboxylic acid 66-2 (50 mg, 82 %) as a white solid. LCMS (ESI): m / z 278 [M+H]+.

[0464] Step C: To a solution of 66-2 (70 mg, 0.25 mmol) in DMF (2 mL) was added (R) -3- amino-2, 3 -dihydrothiophene 1,1-dioxide, Int 3 (33 mg, 0.25 mmol), HATU (143 mg, 0.38 mmol) and DIE A (162 mg) and the reaction mixture was stirred at RT for 2 h. The mixture was diluted with H2O (1 mL) and the resulting solution was purified by reverse phase chromatography (C18, MeCN / FLO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford 8-chloro-7-cyclobutyl-A-[(3 / ?)-l,l-dioxo-2,3- dihy drothi ophen-3 -yl] -2-oxo- lH-quinoline-3 -carboxamide, 66 (5 mg, 04 %) as a white solid. LCMS (ESI): m / z 393 [M+H]+;1H NMR (400 MHz, DMSO- 6) δ 11.57 (s, 1H), 10.03 (d, J= 8.0 Hz, 1H), 8.86 (s, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 7.01(dd, J= 6.0, 3.0 Hz, 1H), 5.40 (dd, J= 6.0, 4.0 Hz, 1H), 3.88 (t, J= 9.0 Hz, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.31 (s, 1H), 2.47 - 2.35 (m, 2H), 2.25 - 2.11 (m, 2H), 2.08 - 2.01 (m, 1H), 1.84 (t, J = 9.2 Hz, 1H).Example 67 (R) -7-(l-Cyanocyclobutyl)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (67)

[0465] Step A: To a solution of 36-1 (100 mg, 0.32 mmol) in MeOH / H2O / THF (9 mL, 3:3:3) was added Li OH (40 mg, 0.97 mmol) and the reaction mixture was stirred at RT for 2 h. The mixture was poured into ice water and adjusted pH = 5 ~ 6 with 2N HC1. The mixture was extracted with EtOAc (50 mL x 3), the organic phase was dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to afford 7-(l-cyanocyclobutyl)-2-methoxyquinoline-3 -carboxylic acid 67-1 (80 mg, 88%) as a white solid. LCMS (ESI): m / z 283 [M+H]+.

[0466] Step B: A mixture of 67-1 (76 mg, 0.27 mmol) and perfluorophenyl 2,2,2- trifluoroacetate (377 mg, 1.35 mmol) in pyridine (3 mL) was stirred at 40 °C under N2 for 2 h and thereaction mixture was concentrated to afford perfluorophenyl 7-(l-cyanocyclobutyl)-2- methoxyquinoline-3 -carboxylate 67-2 (70 mg, 58%) as a white solid. LCMS (ESI): m / z 449 [M+H]+.

[0467] Step C: A solution of perfluorophenyl 7-(l-cyanocyclobutyl)-2-methoxyquinoline-3- carboxylate, 67-2 (70 mg, 0.16 mmol), (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (23 mg, 0.172 mmol), DIEA (60 mg) in DMF (3 mL) was stirred at RT for 2 h and the reaction mixture was extracted with EtOAc (50 mL x 3). The organic phase was dried over anhydrous , filtered and Na2SO4concentrated to afford (R)-7-(l-cyanocyclobutyl)-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- methoxyquinoline-3 -carboxamide, 67-3 (60 mg, 97%) as a white solid. LCMS (ESI): m / z 398[M+H]+.

[0468] Step D: To a solution of 67-3 (45 mg, 0.11 mmol) in MeCN (4 mL) was added TMSI (113 mg, 0.57 mmol) and the mixture was stirred at RT for 4 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 5% to 95% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (R)-7-(l- cyanocyclobutyl)-A-(l,l -dioxi do-2, 3-dihy drothiophen-3-yl)-2-oxo-l, 2-dihydroquinoline-3- carboxamide, 67 (17 mg, 39%) as a white solid. LCMS (ESI): m / z 384 [M+H]+;JH NMR (400 MHz, DMSO-t / 6) S 12.56 (s, 1H), 10.15 (d, J = 8.0 Hz, 1H), 8.88 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.44 (dd, J= 8.0, 2.0 Hz, 1H), 7.29 (dd, J= 7.0, 2.0 Hz, 1H), 7.00 (dd, J= 7.0, 3.2 Hz, 1H), 5.46 - 5.36 (m, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.30 (d, J= 4.0 Hz, 1H), 2.83 - 2.76 (m, 2H), 2.66 (ddd, J= 11.0, 10.0, 6.0 Hz, 2H), 2.37 - 2.28 (m, 1H), 2.11 - 2.01 (m, 1H).Example 68 (R) -4-Amino-7-cyclobutyl- / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (68)

[0469] Step A: To a solution of 2-amino-4-bromobenzonitrile (2 g, 10.2 mmol) in DCM (40 mL) was added TEA (1.5 mb) and ethyl 3-chloro-3-oxopropanoate (1.68 g, 11.2 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc in hexanes) to afford ethyl 3-((5-bromo-2-cyanophenyl)amino)-3-oxopropanoate, 68-1 (700 mg, 22%) as a white solid. LCMS (ESI): m / z 311, 313 [M+H]+.

[0470] Step B: A vial containing mixture of 68-1 (300 mg, 0.96 mmol), l,3-dioxoisoindolin-2- yl cyclobutanecarboxylate (354 mg, 1.4 mmol), ethyl 5 -(ethoxy carbonyl)-2,6-dimethyl- 1,4- dihydropyridine-3 -carboxylate (487 mg, 1.9 mmol), NiBr2(dtbbpy) (94 mg, 0.19 mmol) and NaHCCL (161 mg, 1.9 mmol) in DMA (9 mL) was irradiated with 18 W photosyn-10 purple LED (390 nm) lamp (1 cm away with cooling fan) under N2 for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to afford ethyl 3-((2-cyano-5-cyclobutylphenyl)amino)-3-oxopropanoate, 68-2 (250 mg, 90%) as a yellow oil. LCMS (ESI): m / z 287 [M+H]+.

[0471] Step C: To a solution of 68-2 (250 mg, 0.87 mmol) in EtOH (10 mL) was added 20% NaOEt (593 mg, 1.75 mmol) in EtOH and the mixture was stirred at 80 °C under N2 for 1.5 h. Thereaction mixture was poured into ice water and adjusted the pH = 5 ~ 6 with 2N HC1. The mixture was extracted with EtOAc (50 mL x 3) and the organic phase was dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to afford ethyl 4-amino-7-cyclobutyl-2-oxo-l,2- dihydroquinoline-3 -carboxyl ate, 68-3 (60 mg, 24%) as a white solid. LCMS (ESI): m / z 287 [M+H]+.

[0472] Step D: To a solution of 68-3 (50 mg, 0.18 mmol) in THF / MeOHTLO (7 mL, 3:3:1) was added NaOH (14 mg, 0.35 mmol) and the mixture was stirred at 50 °C for 6 h. The mixture was poured into ice water and adjusted the pH = 5 ~ 6 with 2N HC1. The mixture was extracted with EtOAc (50 mL x 3) and the organic phase was dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to afford 4-amino-7-cyclobutyl-2-oxo-l,2-dihydroquinoline-3 -carboxylic acid, 68- 4 (40 mg, 88%) as a white solid. LCMS (ESI): m / z 259 [M+H]+.

[0473] Step E: To a solution of 68-4 (35 mg, 0.14 mmol) in DMF (4 mL) was added -3- (R) amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (23 mg, 0.18 mmol), DIEA (105 mg, 0.813 mmol) and HATU (66 mg, 0.18 mmol) and the mixture was stirred at RT for 2 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCbWLO, 0.1% formic acid modifier, 20% to 95% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (R) -4-amino-7-cyclobutyl-A-( 1 , 1 -dioxi do-2, 3 -dihydrothiophen-3 -yl)-2-oxo- 1 ,2-dihydroquinoline-3- carboxamide, 68 (8 mg, 16%) as a white solid. LCMS (ESI): m / z 374 [M+H]+;1H NMR (400 MHz, DMSO-C / 6) δ 11.15 (S, 1H), 11.04 (d, J= 8.0 Hz, 1H), 10.47 (s, 1H), 8.21 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 6.0, 2.0 Hz, 1H), 7.15 - 7.04 (m, 2H), 6.98 (dd, J = 6.0, 3.0 Hz, 1H), 5.31 (s, 1H), 3.72 (dd, J= 14.0, 8.0 Hz, 1H), 3.64 - 3.50 (m, 1H), 3.19 (dd, J= 14.0, 4.0 Hz, 1H), 2.33 (ddd, J = 14.0, 8.0, 4.0 Hz, 2H), 2.15 - 2.05 (m, 2H), 1.99 (dd, J= 13.2, 5.7 Hz, 1H), 1.88 - 1.78 (m, 1H).Example 69 (R) -7-Cyclobutyl-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-5-methyl-2-oxo-l,2- dihydroquinoline-3-carboxamide (69)

[0474] Step A: To a mixture of 5 -bromo- 1 ,2-dimethyl-3 -nitrobenzene (9.0 g, 39.12 mmol) in DMF (36 mL) was added (dimethylamino)dimethoxymethane (13.9 g, 117.36 mmol) and the solution stirred at 100 °C under N2 for 12 h. The reaction mixture was then cooled to RT and (E)-2-(4-bromo- 2-methyl-6-nitrophenyl)-A,A-dimethylethen-l -amine, 69-1 was used for next step directly.

[0475] Step B: To a mixture of (E)-2-(4-bromo-2-methyl-6-nitrophenyl)-N,N-dimethylethen-l- amine, 69-1 (10.0 g, 35.07 mmol) was added to rapidly stirred solution of NalCh (30.0 g, 140.3 mmol) in DMF (50 mL) and (5H02mOL) at 0 °C and the reaction mixture was stirred at RT for 5 h. The reaction mixture was diluted with water and extracted with EtOAc (100 mLx 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0 ~ 5% EtOAc in PE) to afford 4-bromo-2- methyl-6-nitrobenzaldehyde, 69-2 (3.4 g, 39 %) as a yellow solid.1H NMR (400 MHz, DMSO-t >) 5 10.22 (s, 1H), 8.19 (d, J= 1.2 Hz, 1H), 8.02 (s, 1H), 2.49 (s, 3H).

[0476] Step C: A solution of 69-2 (1 .7 g, 6.97 mmol) and NH4CI (370 mg, 6.97 mmol) in EtOH (60 mL) and H2(O20 mL) was heated to 60 °C and Fe powder (390 mg, 6.97 mmol) was added in small portions. The reaction mixture was stirred at 60 °C for 3 h and the mixture was fdtered through a Cehte pad. The filtrate was extracted with EtOAc (10 mL x 3) and the organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to afford 2- amino-4-bromo-6-methylbenzaldehyde, 69-3 (1.40 g, 93%) as a yellow solid. LCMS (ESI): m / z 214, 216 [M+H]~;1H NMR(400 MHz, DMSO-i / e) δ 10.18 (s, 1H), 7.51 (s, 2H), 6.86 (d, J= 2.0 Hz, 1H), 6.54 (d, J= 1.0 Hz, 1H), 2.48 (s, 3H).

[0477] Step D: To a mixture of 69-3 (1.4 g, 6.54 mmol) in EtOH (30 mL) was added diethyl malonate (2.7 mL, 18.31 mmol), HOAc (0.1 mL, 0.65 mmol) and piperidine (1.9 mL, 19.62 mmol) and the reaction was stirred at 60 °C for 16 h. The resulting precipitate was collected by filtration, washed with EtOH, and dried in vacuo to afford ethyl 7-bromo-5-methyl-2-oxo-l,2- dihydroquinoline-3 -carboxylate, 69-4 (1.2 g, 59%) as a yellow solid. LCMS (ESI): m / z 310, 312 [M+H]+.

[0478] Step E: To a mixture of 69-4 (1.2 g, 3.87 mmol) and trimethyloxonium tetrafluoroborate (1.1 g, 7.74 mmol) in DCM (20 mL) was stirred at RT under N2 for 16 h and the reaction mixture was extracted with DCM (50 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0 -10 % EtOAc in PE) to afford ethyl 7-bromo-2-methoxy-5-methylquinoline-3- carboxylate, 69-5 (640 mg, 51%) as a white solid. LCMS (ESI): m / z 324, 326 [M+H]+.

[0479] Step F: A vial containing 69-5 (300 mg, 0.93 mmol), l,3-dioxoisoindolin-2-yl cyclobutanecarboxylate (340 mg, 1.39 mmol), NaHCOs (155 mg, 1.85 mmol), ethyl 5- (ethoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate (468 mg, 1.85 mmol) and NiBr2(dtbbpy) (90 mg, 0.19 mmol) in DMA (9 mL) was irradiated with 18 W photosyn-10 purple LED (390 nm) lamp (1 cm away with cooling fan) under N2 for 4 h. The reaction mixture was extracted with EtOAc (10 mL x3) and the organic layer was washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% formic acid modifier, 20% to 80% gradient, 20 min run) and the fractions containing desired product were lyophilized to afford ethyl 7-cyclobutyl-2- methoxy-5-methylquinoline-3-carboxylate 69-6 (170 mg, 61%) as a yellow oil. LCMS (ESI): m / z 300 [M+H]7

[0480] Step G: To a mixture of 69-6 (140 mg, 0.47 mmol) in HC1 (10 mL) was stirred at 100 °C under N2 for 3 h and the reaction mixture was concentrated to afford 7-cyclobutyl-5-methyl-2-oxo- l,2-dihydroquinoline-3-carboxylic acid, 69-7 (110 mg, 91%) as a yellow solid. LCMS (ESI): m / z 258 [M+H]7

[0481] Step H: To a mixture of 69-7 (40 mg, 0.16 mmol) in pyridine (7 mL) was added perfluorophenyl 2,2,2-trifluoroacetate (435 mg, 1.55 mmol) and stirred at 40 °C under N2 for 2 h and the reaction mixture was cooled to RT. The reaction mixture was concentrated under reduced pressure to afford perfluorophenyl 7-cyclobutyl-5-methyl-2-oxo-l,2-dihydroquinoline-3-carboxylate, 69-8 (50 mg, 75%) as a yellow solid. LCMS (ESI): m / z 424 [M+H]+

[0482] Step I: To a mixture of 69-8 (50 mg, 0.12 mmol) and (R)-3-amino-2,3-dihydrothiophene1.1 -dioxi de, Int 3 (20 mg, 0.15 mmol) in DMF (5 mL) was added DIEA (45 mg) and the reaction was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (10 mL x 2). The organic layer was washed with brine, dried over , filtered andN coan2cSeOn4trated. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / tLO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford -7-(cRy)clobutyl-A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-5-methyl-2-oxo-1.2-dihydroquinoline-3 -carboxamide, 69 (34 mg, 77%) as a white solid. LCMS (ESI): m / z 373 [M+H]+;1H NMR(400 MHz, DMSO-< / 6) δ 12.28 (s, 1H), 10.22 (d, J= 8.0 Hz, 1H), 8.85 (s, 1H), 7.27 (dd, J= 7.0, 2.0 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 7.00 (dd, J = 7.0, 3.0 Hz, 1H), 5.38 (dd, J= 6.0, 4.0 Hz, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.59 (t, J= 9.0 Hz, 1H), 3.29 (d, J= 4.0 Hz, 1H), 2.57 (s, 3H), 2.36 - 2.30 (m, 2H), 2.13 - 2.00 (m, 3H), 1.82 (dd, J= 10.0, 9.0 Hz, 1H).Example 70 (R) -7-( Bicycl 0 [ 1.1.1] pentan- 1-yl) - / V-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-8-fluoro-2-oxo-l,2- dihydroquinoline-3-carboxamide (70)

[0483] Step A: To a solution of 2-amino-4-bromo-3 -fluorobenzoic acid (2 g, 8.5 mmol) was added IM BH3-THF (42 mL) and the solution was stirred at 40 °C for 10 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL x 3). The organic phase was washed with brine, dried over anhydrous ISfeSO-i, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in PE) to afford (2-amino-4-bromo-3- fluorophenyl)methanol, 70-1 (1.6 g, 85%) as a white solid. LCMS (ESI): m / z 220, 222 [M+H]+.

[0484] Step B: To a solution of (2-amino-4-bromo-3-fluorophenyl)methanol, 70-1 (1.6 g, 7.3 mmol) in DCM (100 mL) was added Mn02 (5.1 g, 58 mmol) and the solution was stirred for at RT for 3 h. The mixture solution was filtered and the filtrate was concentrated to afford 2-amino-4- bromo-3 -fluorobenzaldehyde, 70-2 (1.5 g, 94%) as ayellow solid. LCMS (ESI): m / z 218 [M+H]+.

[0485] Step C: To a solution of 70-2 (1.5 g, 6.8 mmol) in EtOH (25 mL) was added diethyl malonate (3.1 g, 19 mmol), HOAc (50 mg) and piperidine (1.76 g) and the mixture was stirred at 60 °C for 8 h. The reaction mixture was filtered and washed with EtOH to afford ethyl 7-bromo-8- fluoro-2-oxo- 1 ,2-dihydroquinoline-3 -carboxylate, 70-3 (1.8 g, 83%) as a white solid. LCMS (ESI): m / z 314, 316 [M+H]+.

[0486] Step D: To a solution of 70-3 (1 g, 3.2 mmol) in DMF (7 mL) was added CS2CO3 (2.1 g, 6.4 mmol) and PMBC1 (0.65 g, 4.1 mmol) and the mixture was stirred at 50 °C for 5 h. The cooled reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SOr and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0 -20% EtOAc in hexanes) to afford methyl 7-bromo-8-fluoro-2-((4-methoxybenzyl)oxy)quinoline-3 -carboxylate, 70-4 (580 mg, 42%) as a white solid. LCMS (ESI): m / z 434, 436 [M+H]+.

[0487] Step E: A vial containing 70-4 (300 mg, 0.69 mmol),l,3-dioxoisoindolin-2-yl bicyclo [l.l.l]pentane-l -carboxy late (266 mg, 1.0 mmol), ethyl 5-(ethoxycarbonyl)-2,6-dimethyl-l,4- dihydropyridine-3 -carboxylate (349 mg, 1.38 mmol), NiBr2(dtbbpy) (67 mg, 0.14 mmol) and NaHCOs (118 mg, 1.382 mmol) in DMA (9 mL) was irradiated with 18 W Photosyn-10 purple LED lamp (390 nm) (1 cm away with cooling fan) under N2 for 5 h. The mixture was filtrated and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (Cl 8, MeCbWLO, 0.1% formic acid modifier, 20% to 80% gradient, 20 min run) and the fractions containing desired product were lyophilized to afford ethyl 7-(bicyclo[l.1. l]pentan- l-yl)-8-fluoro-2-((4-methoxybenzyl)oxy)quinoline-3-carboxylate, 70-5 (60 mg, 20%) as a yellow oil. LCMS (ESI): m / z 422 [M+H]+.

[0488] Step F: To a solution of 70-5 (60 mg, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL) and the mixture was stirred at RT for 1.5 h. The reaction mixture was adjusted the pH = 6 ~ 7 with aqueous NaHCCE and the mixture was extracted with DCM (50 mL x 3). The organic phase was dried over anhydrous N,a fi2lSteOr4ed and concentrated to afford ethyl 7-(bicyclo[l.1. l]pentan-l-yl)- 8-fluoro-2-oxo-l,2-dihydroquinoline-3-carboxylate, 70-6 (40 mg, 93%) as a yellow solid. LCMS (ESI): m / z 302 [M+H]+.

[0489] Step G: To a solution of 70-6 (40 mg, 0.133 mmol) in THF / MeOH / H2O (7 mL, 3:3:1) was added Li OH (6 mg, 0.13 mmol) and the reaction mixture was stirred at RT for 8 h. The reaction mixture was poured into ice water and adjusted the pH = 5 ~ 6 with 2 / VHC1 and the mixture was extracted with EtOAc (50 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered andconcentrated to afford 7-(bicyclo[l.l.l]pentan-l-yl)-8-fluoro-2-oxo-l,2-dihydroquinoline-3- carboxylic acid, 70-7 (35 mg, 96%) as a white solid. LCMS (ESI): m / z 274 [M+H]+.Step H: A mixture of 70-7 (35 mg, 0.13 mmol) and perfluorophenyl 2,2,2-trifluoroacetate (179 mg, 0.64 mmol) in pyridine (5 mL) was stirred at 40 °C under N2 for 2 h and the mixture was concentrated to afford perfluorophenyl 7-(bicyclo[l.l.l]pentan-l-yl)-8-fluoro-2-oxo-l,2- dihydroquinoline-3 -carboxylate, 70-8 (45 mg, 79%) as a yellow solid. LCMS (ESI): m / z 440 [M+H]+.

[0490] Step I: To a solution of 70-8 (45 mg, 0.10 mmol) in DMF (5 mL) was added (R)-3- amino-2,3-dihydrothiophene 1,1 -dioxide, Int 3 (17 mg, 0.13 mmol) and DIEA (65 mg) and the mixture was stirred at RT for 2 h. The crude product was purified by reverse phase chromatography (C 18, MeCN / TEO, 0.1% formic acid modifier, 20% to 95% gradient, 21 min run) and the fractions containing desired product were lyophilized to afford -7-(bicyclo[l.l(R.)l]pentan-l-yl)-jV-(l,l- dioxido-2,3-dihydrothiophen-3-yl)-8-fluoro-2-oxo-l,2-dihydroquinoline-3-carboxamide, 70 (20 mg, 50%) as a white solid. LCMS (ESI): m / z 389 [M+H]+;1H NMR (400 MHz, DMSO-c / g) δ 12.34 (s, 1H), 10.11 (d, J= 8.0 Hz, 1H), 8.84 (d, J= 1.0 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 7.10 (dd, J= 8.0, 7.0 Hz, 1H), 7.00 (dd, J= 6.0, 3.0 Hz, 1H), 5.47 - 5.29 (m, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.31 - 3.29 (m, 1H), 2.63 (s, 1H), 2.21 (s, 6H).Example 71 (R) -A-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-8-fluoro-7-(l-methylcyclobutyl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (71)

[0491] Step A: To a mixture solution of 70-4 (300 mg, 0.69 mmol) were added 2- {[(methylcyclobutyl)carbonyl]oxy} isoindole- 1,3 -dione (268 mg, 1.04 mmol), NaHCCL (116 mg, 1.38 mmol), ethyl 5-(ethoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate (349 mg, 1.38 mmol) and NiBr2(dtbbpy) (67 mg, 0.138 mmol) in DMA (9 rnL) and the reaction vial was irradiated with 18 W photosyn-10 purple LED (390 nm) lamp (1 cm away with cooling fan) under N2 for 4 h. The reaction mixture was filtrated and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (Cl 8, MeOH / HO, 0.1% formic acid modifier, 0 to 80% gradient, 40 min run) and the fractions containing desired product were concentrated to afford ethyl 8-fluoro-2-((4-methoxybenzyl)oxy)-7-(l-methylcyclobutyl)quinoline-3-carboxylate, 71-1 (48 mg, 16 %) as a white solid. LCMS (ESI): m / z 424 [M+H]+;

[0492] H NMR (400 MHz, DMSO-tA,) δ 8.85 (d, J= 1.2 Hz, 1H), 7.89 (dd, .7= 13.0, 8.0 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.34 (dd, J = 8.0, 7.0 Hz, 1H), 7.09 - 7.00 (m, 2H), 5.59 (s, 2H), 4.41 (q, J = 8.0 Hz, 2H), 3.85 (s, 3H), 2.27 (d, J= 5.0 Hz, 2H), 2.18 - 1.99 (m, 2H), 1.88 (ddd, J= 22.0, 15.0, 8.0 Hz, 2H), 1.40 (d, J= 7.0 Hz, 3H), 1.32 (s, 3H).

[0493] Step B: To a mixture of 71-1 (48 mg, 0.11 mmol) in DCM (5 mL) was added TFA (1 mL, 13.06 mmol) at 0 °C and the solution was stirred for 30 min. The residue was concentrated toafford ethyl 8-fluoro-7-(l-methylcyclobutyl)-2-oxo-l,2-dihydroquinoline-3-carboxylate, 71-2 (34 mg, 98 %) as a yellow solid. LCMS (ESI): m / z 304 [M+H]+.

[0494] Step C: To a mixture solution of 71-2 (34 mg, 0.11 mmol) in THF (3 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH (23 mg) and the solution was stirred at RT for 16 h. The solution diluted with water, adjusted the pH = 1 with IN HC1 and aqueous layer extracted with EtOAc (10 mL x3). The organic layer was washed with brine, dried over anhydrous Na2SO4, fdtered and concentrated to afford 8-fluoro-7-(l-methylcyclobutyl)-2-oxo-l,2-dihydroquinoline-3-carboxylic acid, 71-3 (30 mg, 97 %) as a yellow solid. LCMS (ESI): m / z 276 [M+H]+.

[0495] Step D: To a solution of 71-3 (34 mg, 0.124 mmol) in pyridine (10 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (345 mg, 1.24 mmol)) and the solution was stirred for at 40 °C for 2 h. The solution was concentrated to afford perfluorophenyl 8-fluoro-7-(l- methylcyclobutyl)-2-oxo-l,2-dihydroquinoline-3 -carboxylate, 71-4 (50 mg, 91%) as a yellow oil. LCMS (ESI): m / z 442 [M+H]+.

[0496] Step E: To a solution of 71-4 (50 mg, 0.113 mmol) in DMF (3 mL), DIEA (58 mg, 0.45 mmol) was added -3-(Ra)mino-2,3-dihydrothiophene-l,l-dioxide, Int 3 (18 mg, 0.14 mmol) and the solution was stirred at RT for 16 h. The crude product was purified by reverse phase chromatography (Cl 8, MeCN / ELO, 0.1% ammonium bicarbonate modifier, 20% to 85% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford ( / / )-A-(l , I -dioxido-2,3- dihydrothiophen-3-yl)-8-fluoro-7-(l -methyl cy cl obutyl)-2-oxo-l,2-dihydroquinoline-3 -carboxamide, 71 (21.2 mg, 47 %) as a white solid. LCMS (ESI): m / z 391 [M+H]+;1H NMR (400 MHz, DMSO-iL) § 12.48 (s, 1H), 10.12 (d, J= 8.0 Hz, 1H), 8.84 (d, J= 1.0 Hz, 1H), 7.73 (dd, J= 12.0, 8.0 Hz, 1H), 7.28 (dd, J= 6.0, 2.0 Hz, 1H), 7.09 - 6.97 (m, 2H), 5.40 (s, 1H), 3.75 (dd, J= 14.0, 8.0 Hz, 1H), 3.30 (d, J= 4.0 Hz, 1H), 2.89 - 2.56 (m, 1H), 2.49 - 2.29 (m, 2H), 2.12 (dd, J= 18.0, 9.0 Hz, 2H), 1.87 - 1.73 (m, 1H), 1.72 - 1.42 (m, 3H).Example 72 (R) - / V-(l,l-Dioxido-2,3-dihydrothiophen-3-yl)-2-hydroxy-7-(lH-tetrazol-5-yl)quinoline-3- carboxamide (72)

[0497] Step A: To a mixture solution of ethyl 7-bromo-2-methoxyquinoline-3 -carboxylate, Int 2 (780 mg, 2.52 mmol) in DMF (10 mL) was added bis (cyclopentyldiphenylphosphane) iron (0) (283 mg, 0.503 mmol), Pd2(dba)s (203 mg, 0.25 mmol) and Zn(CN)2 (472 mg, 4.024 mmol) and the reaction mixture was stirred at 100 °C for 16 h. The solution diluted with water, extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0 -7% EtOAc in PE) to afford ethyl 7-cyano-2-methoxyquinoline-3-carboxylate, 72-1 (620 mg, 96%) as a white solid. LCMS (ESI): m / z 257 [M+H]+.

[0498] Step B: To a solution of 72-1 (300 mg, 1.17 mmol) in toluene (10 mL) was added azidotrimethylsilane (202 mg, 1.76 mmol) and dibutyltin oxide (19 mg, 0.12 mmol) and the solution was stirred at 110 °C for 16 h. The solution was concentrated and the crude product was purified by silica gel chromatography (0-10% MeOH in DCM) to afford ethyl 2-methoxy-7-(lH-tetrazol-5-yl) quinoline-3 -carboxylate, 72-2 (190 mg, 54 %) as a yellow solid. LCMS (ESI): m / z 300 [M+H]+;NMR (400 MHz, DMSO-iL) δ 8.81 (s, 1H), 8.49 (s, 1H), 8.24 (d, J= 8.0 Hz, 1H), 8.13 (dd, J= 8.0, 2.0 Hz, 1H), 4.35 (t, J = 7.0 Hz, 2H), 4.08 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H).

[0499] Step C: To a mixture solution of 72-2 (120 mg, 0.40 mmol) in HC1 (1 mL) was stirred at 100 °C for 1 h and the solution was filtered. The filter cake was concentrated, dried to afford 2-oxo- 7-(lH-tetrazol-5-yl)-l,2-dihydroquinoline-3-carboxylic acid, 72-3 (100 mg, 96%) as a yellow solid. LCMS (ESI): m / z 257 [M+H]+.

[0500] Step D: To a solution of 72-3 (100 mg, 0.39 mmol) in pyridine (10 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (1088 mg, 3.90 mmol) and the solution was stirred for at 40 °C for 2 h. The solution was concentrated to afford perfluorophenyl 2-oxo-7-(lH-tetrazol-5- yl)-l, 2-dihydroquinoline-3-carboxylate, 72-4 (100 mg, 60%) as a yellow solid. LCMS (ESI): m / z 424 [M+Hf.

[0501] Step E: To a solution of 72-4 (100 mg, 0.24 mmol), DIEA (122 mg) in DMF (5 mL) was added (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide, Int 3 (37 mg, 0.28 mmol) and the solution was stirred at RT for 16 h. The reaction mixture was concentrated and the crude product was purified by reverse phase chromatography (Cl 8, MeCN / H2O, 0.1% ammonium bicarbonate modifier, 20% to 95% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford (R) -A-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-hydroxy-7-(lH-tetrazol-5-yl)quinoline-3- carboxamide, 72 (17 mg, 19 %) as a yellow solid. LCMS (ESI): m / z 373 [M+H]+;1H NMR(400 MHz, DMSO-c / >) δ 12.78 (s, 1H), 10.13 (d, J = 8.0 Hz, 1H), 8.90 (s, 1H), 8.21 - 8.12 (m, 2H), 7.89 (dd, J= 8.0, 2.0 Hz, 1H), 7.28 (dd, J = 6.0, 2.0 Hz, 1H), 7.01 (dd, J = 6.0, 4.0 Hz, 1H), 5.46 - 5.36 (m, 1H), 3.76 (s, 1H), 3.32 (s, 1H).Example 73 7-Cyclobutyl-A-((lS,37?)-l-imino-l-oxido-2,3-dihydro-lJf-thiophen-3-yl)-2-oxo-l,2- dihydroquinoline-3-carboxamide (73)

[0502] Step A: To a solution of Int 5 (50 mg, 0.38 mmol) and 60-1 (155 mg, 0.38 mmol) in DMF (3 mL) was added DIE A (132 mg, 1.0 mmol) and the reaction was stirred at RT for 20 min. The reaction was quenched with (1 mL) anHd2tOhe resulting solution was purified by reverse phase chromatography (Cl 8, MeCN / FLO, 0.1% TFA modifier, 25 to 95% gradient, 30 min run) and the fractions containing desired product were lyophilized to afford desire product 7- cy cl obuty I - / V-(( I S,3R)- 1 -imino- 1 -oxi do-2, 3 -dihydro- 1 H-thi ophen-3 -yl)-2-oxo- 1 ,2-dihy droquinoline- 3 -carboxamide, 73 (3.5 mg, 4%) as a white solid. LCMS (ESI): m / z 358 [M+H] ,1H NMR (400 MHz, DMSO-r / 6) δ 12.39 (s, 1H), 10.16 (d, J = 8.0 Hz,...

Claims

What is claimed is:CLAIMS1. A compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR1iswhereinX is O or NRX, wherein Rxis H or unsubstituted or substituted C1-6 alkyl and, 5-6 membered heteroaryl, each of Rlaand Rlbis independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’ and NRC(O)NRR’ and NRC(O)OR’, wherein the C1-C6alkyl, C3-C6cycloalkyl, R and R’ is optionally substituted with 0-2 RA; or Rlaand Rlb, together with the carbon atom they are bound to, form a 3 - or 4-membered carbocyclic ring, optionally substituted with 0-2 RA; each of Rlcand Rldis independently H, halo or unsubstituted or substituted C1-6 alkyl; andRleis H, halogen, NRR’, OR, C(O)NRR’, C(O)OR, or unsubstituted or substituted C1-6 alkyl; each of R2, R3, R4and R6is independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, CN, OR, SR, S(O)2NRR”, C(CF3)NR”, NRR’,NRC(O)R”, C(O)NRR”, OC(O)NRR”, NRC(O)OR’ and NRC(O)NRR’, wherein each of the C1-C6alkyl, C3-C6 cycloalkyl, R, R’ and R” is optionally substituted with 0-2 RB; wherein R6is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;R5isH, halogen, C1-6 alkyl, CN, OR, SR, NRR’, S(O)2R, SF5, C2-3 alkene or C2 alkyne; C3-C8saturated carbocyclic or saturated heterocyclic ring;5-membered unsaturated heterocyclic ring or heteroaryl; or6- to 10-membered aryl or heteroaryl, wherein each of C1-C6alkyl, C3-C8carbocyclic ring, 5-membered heterocyclic ring, 6- to 10- membered heteroaryl, R and R’ is optionally substituted with 0-8 Rc;RAIS selected from halo, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’;RBis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR, NRR’, C(O)NRR’, OC(O)NRR’, NRC(O)R’, NRC(O)OR’ and NHC(O)NRR’; and each of R, R’ and R” is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 4-to 6-membered carbocyclic ring, or where R and R’, or R and R”, are attached to the same N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; wherein R” is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB; and the heteroatoms are selected from N, O and S.

2. The compound of claim 1 , wherein X is O and R1is3. The compound of claim 1 , wherein X is NRXand R1is4. The compound of any one of claims 1-3, wherein R1is characterized by the following chirality:

5. The compound of any one of claims 1-3, wherein R1is characterized by the following chirality:

6. The compound of any one of claims 1-5, wherein each of Rlband Rlcis H and R1is selected from:

7. The compound of any one of claims 1-6, wherein Rldis H.

8. The compound of any one of claims 1-6, wherein Rldis not H.

9. The compound of claim 8, wherein Rldis methyl.

10. The compound of any one of claims 1-9, wherein Rlais H.

11. The compound of any one of claims 1-9, wherein Rlais not H.

12. The compound of claim 11, wherein Rlais F or Cl.

13. The compound of claim 11, wherein Rlais C1-3 alkyl, optionally substituted with OH, halogen, CN or NHR.

14. The compound of claim 13, wherein Rlais methyl.

15. The compound of any one of claims 1-14, wherein Rleis H.

16. The compound of any one of claims 1-14, wherein Rleis not H.

17. The compound of claim 16, wherein Rleis methyl.

18. The compound of any one of claims 1-17, wherein each of R ’ and R4is H.

19. The compound of any one of claims 1-17, wherein at least one of R3and R4is not H.

20. The compound of any one of claims 1-19, wherein R5is C3-C8carbocyclic ring, optionally substituted with 0-4 Rc.

21. The compound of any one of claims 1-19, wherein R5is C3-C8branched alkyl, optionally substituted with 0-4 Rc.

22. The compound of claim 20, wherein the carbocyclic ring is a monocyclic ring.

23. The compound of claim 20, wherein the carbocyclic ring is a fused bicyclic ring.

24. The compound of claim 20, wherein the carbocyclic ring is a bridged bicyclic ring.

25. The compound of any one of claims 1-19, wherein R5is a 5 -membered unsaturated heterocyclic ring or heteroaryl group, optionally substituted with 0-3 Rc.

26. The compound of any one of claims 1-1 , wherein R5is a 6- to 10-membered aryl or heteroaryl group, optionally substituted with 0-5 Rc.

27. The compound of any one of claims 1 -26, wherein R2is H.

28. The compound of any one of claims 1-26, wherein R2is not H.

29. The compound of any one of claims 1-26, wherein R2is NH2.

30. The compound of any one of claims 1-29, wherein R6is NRC(O)R”.

31. The compound of any one of claims 1-29, wherein R6is C(O)NRR”.

32. The compound of claim 30 or 31, wherein R is H.

33. The compound of claim 32, wherein R” is a C1-6 alkyl substituted with 0-2 RB.

34. The compound of claim 32, wherein R” is a 3- to 6-membered carbocyclic or heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

35. The compound of claim 32, wherein R” is an 8- to 10-membered heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

36. The compound of claim 32, wherein R” is an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

37. The compound of any one of claims 1-29, wherein R6is a 5 -or 6-membered heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

38. The compound of any one of claims 1-29, wherein R6is an 8- to 10-membered bicyclic carbocyclic or heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

39. The compound of any one of claims 1 -29, wherein R6is a 5- or 6-membered aryl or heteroaryl group comprising 0-3 heteroatoms, substituted with 0-2 RB.

40. The compound of any one of claims 1-29, wherein R6is an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

41. A compound having the structural formula (III):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRlais selected from the group consisting of H, halogen, C1-C6alkyl and Q-Ce cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’, wherein the C1- C6alkyl, C3-C6 cycloalkyl, R and R’ is optionally substituted with 0-2 RA;Rldis independently H, halo or unsubstituted or substituted C1-6 alkyl;Rleis H, halogen, NRR’, OR, C(O)NRR’, C(O)OR, or unsubstituted or substituted C1-6 alkyl; each of R2, R3, R4and R6is independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, CN, OR, SR, S(O)2NRR”, C(CF3)NRR”, NRR”, NRC(O)R”, C(O)NRR”, OC(O)NRR”, NRC(O)OR’ and NRC(O)NRR’, wherein each of the C1-C6alkyl, C3-C6cycloalkyl, R, R’ and R” is optionally substituted with 0-2 RB; wherein R6is additionally selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;Ring A isC3-C8saturated carbocyclic or saturated heterocyclic ring;5-membered unsaturated heterocyclic ring or heteroaryl; or6- to 10-membered aryl or heteroaryl, wherein each of the C3-C8carbocyclic ring, 5- or 6-membered heterocyclic ring and 5- membered heteroaryl group is optionally substituted with 0-8 Rc;RAis selected from halo, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’;RBis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR, NRR’, C(O)NRR’, OC(O)NRR’, NRC(O)R’, NRC(O)OR’ and NHC(O)NRR’; each of R, R’ and R” is independently selected from H, unsubstituted or substituted C1-6 alkyl, or unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’, or R and R”, are attached to the same N atom, together form an unsubstituted or substituted 4-to 6-membered heterocyclic ring; wherein R” is additionally selected from 5 or 6-membered heterocyclic comprising 0-3 heteroatoms, 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB; the heteroatoms are selected from N, O and S; and i is 0, 1 , 2, 3, 4, 5, 6, 7 or 8.

42. The compound of claim 41, wherein Rleis H.

43. The compound of claim 41, wherein Rleis not H.

44. The compound of claim 41, wherein Rleis methyl.

45. The compound of any one of claims 41-44, wherein Rldis H.

46. The compound of any one of claims 41-44, wherein Rldis not H.

47. The compound of claim 46, wherein Rldis methyl.

48. The compound of any one of claims 41-46, wherein each of R2and R3is H.

49. The compound of any one of claims 41-46, wherein one of R2and R3is not H.

50. The compound of any one of claims 41-49, wherein R4is H.

51. The compound of any one of claims 41 -49, wherein R4is not H.

52. The compound of claim 41, wherein each of R2, R3and R4is H.

53. The compound of any one of claims 41-52, wherein R6is NRC(O)R”.

54. The compound of any one of claims 41-52, wherein R6is C(O)NRR”.

55. The compound of claim 53 or 54, wherein R is H.

56. The compound of claim 55, wherein R” is a C1-6 alkyl substituted with 0-2 RB.

57. The compound of claim 55, wherein R” is a 3- to 6-membered carbocyclic or-heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

58. The compound of claim 55, wherein R” is an 8- to 10-membered heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

59. The compound of claim 55, wherein R” is an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

60. The compound of any one of claims 41-52, wherein R6is a 5- or 6-membered heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

61. The compound of any one of claims 41-52, wherein R6is an 8- to 10-membered heterocyclic group comprising 0-5 heteroatoms, substituted with 0-2 RB.

62. The compound of any one of claims 41-52, wherein R6is a 5- or 6-membered heteroaryl group comprising 0-3 heteroatoms, substituted with 0-2 RB.

63. The compound of any one of claims 41-52, wherein R6is an 8- to 10-membered-heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

64. The compound of any one of claims 41-52, wherein Ring A is a saturated -Cg carbocyclic C3ring optionally substituted with 0-8 Rc.

65. The compound of any one of claims 41-63, wherein Ring A is a saturated C4-C8heterocyclic ring optionally substituted with 0-8 Rc.

66. The compound of claim 64 or 65, wherein the carbocyclic or heterocyclic ring is a monocyclic ring.

67. The compound of claim 64 or 65, wherein the carbocyclic or heterocyclic ring is a fused bicyclic ring.

68. The compound of claim 64 or 65, wherein the carbocyclic or heterocyclic ring is a bridged bicyclic ring.

69. The compound of claim 64, wherein Ring A is:whereinR5ais selected from H, halo, CN, R, OR, NRR’, C(O)NRR’, NRC(O)R’, NRC(O)OR’, NHC(O)NRR’ and OC(O)NRR’; each of R5b, R5c, R5d, R5e, R5fand R5gis independently selected from H, halogen, R and OR; or any two of R5a, R5b, R5c, R3d, R5e, R5fand R5gmay optionally join together to form a (CH2)mbridge, wherein m is 1 or 2; and n is 0, 1, 2 or 3.

70. The compound of claim 69, wherein each of R5a, R5b, R5c, R5d, R5e, R5fand R5gis H.

71. The compound of claim 69, wherein at least of one of R5a, R5b, R5c, R5d, R5e, R5fand R5gis not H.

72. The compound of any one of claims 69-71, wherein n is 1.

73. The compound of any one of claims 69-72, wherein R5aand R5djoin together to form a (CJfcjm bridge, wherein m is 1.

74. The compound of any one of claims 41-73, wherein Ring A is selected from:

75. The compound of any one of claims 41-63, wherein Ring A is a 5 -membered unsaturated heterocyclic or heteroaryl ring.

76. The compound of claim 75, wherein Ring A is selected from:

77. The compound of any one of claims 41-63, wherein Ring A is a 6- to 10-membered aryl or heteroaryl optionally substituted with 0-2 Rc.

78. The compound of claim 77, wherein Ring A is selected from:

79. The compound of claim 1 or 41, comprising a moiety selected from:

80. The compound of claim 1, comprising a moiety selected from:

81. A compound having the structural Formula (V):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR5is C1-6 alkyl, C3-8 branched alkyl or C3-6 carbocyclic or heterocyclic ring, optionally substituted with 0-4 Rc;R6Ais selected from C1-6 alkyl, C3-6 cycloalkyl, 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, or 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl groups comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;RRis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR and NRR’ ; andeach of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, 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.

82. The compound of claim 81, wherein R5is C1-5 alkyl.

83. The compound of claim 81, wherein R5is C4 carbocyclic ring, optionally substituted with 0-4 Rc.

84. The compound of claim 81, wherein R5is C5 carbocyclic ring, optionally substituted with 0-4 Rc.

85. The compound of claim 81, wherein R5is selected from:

86. The compounds of any one of claims 81-85, wherein R6is selected from:

87. The compound of any one of claims 81-86, wherein R6Ais a C1-6 alkyl substituted with 0-2RB88. The compound of any one of claims 81-86, wherein R6Ais a 3- to 6-membered carbocyclic or heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

89. The compound of any one of claims 81-86, wherein R6Ais an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

90. The compound of any one of claims 81-86, wherein R6Ais a 5- or 6-membered heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

91. The compound of any one of claims 81-86, wherein R6Ais a 5- or 6-membered aryl or heteroaryl group comprising 0-3 heteroatoms, substituted with 0-2 RB.

92. The compound of any one of claims 81-86, wherein R6Ais a 5 : 6-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

93. The compound of any one of claims 81-86, wherein R6Ais a 6 : 5-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

94. A compound having the structural Formula (VI):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinR5is C4-C5 carbocyclic or heterocyclic ring, optionally substituted with 0-4 Rc;R6Bis selected from 5- or 6-membered heterocyclic comprising 0-3 heteroatoms, or 8- to 10-membered heterocyclic comprising 0-5 heteroatoms, 5- or 6-membered aryl or heteroaryl comprising 0-3 heteroatoms, and 8- to 10-membered bicyclic aryl or heteroaryl comprising 0-5 heteroatoms, each optionally substituted with 0-2 RB;RBis selected from halo, CN, R, OR, NRR’, C(O)NRR’ and OC(O)NRR’, or 5- or 6- membered aryl or heteroaryl comprising 0-3 heteroatoms;Rcis selected from halo, CN, R, OR and NRR’ ; and each of R and R’ is independently selected from H, unsubstituted or substituted C1-6 alkyl, 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.The compound of claim 94, wherein R5is C1-5 alkyl.The compound of claim 94, wherein R5is C4 carbocyclic ring, optionally substituted with 0-4 Rc.The compound of claim 94, wherein R5is C5 carbocyclic ring, optionally substituted with 0-4 Rc. wherein R5is selected from:

99. The compound of any one of claims 94-98, wherein R6Bis a 3 - to 6-membered carbocyclic or heterocyclic group comprising 0-3 heteroatoms, substituted with 0-2 RB.

100. The compound of any one of claims 94-98, wherein R6Bis an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

101. The compound of any one of claims 94-98, wherein R6Bis a 5- or 6-membered aryl or heteroaryl group comprising 0-3 heteroatoms, substituted with 0-2 RB.

102. The compound of any one of claims 94-98, wherein R6Bis an 8- to 10-membered bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

103. The compound of claim 102, wherein R6Bis a 5 : 6-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

104. The compound of claim 102, wherein R6Bis a 6 : 5-membered fused bicyclic aryl or heteroaryl group comprising 0-5 heteroatoms, substituted with 0-2 RB.

105. The compound of any of claims 1-104, having one or more deuterium atoms in place of hydrogen.

106. A pharmaceutical composition comprising a compound according to any one of claims 1-105 and a pharmaceutically acceptable excipient, carrier, or diluent.

107. The pharmaceutical composition of claim 106, being suitable for oral administration.

108. A unit dosage form comprising a pharmaceutical composition according to claim 106 or 107.

109. The unit dosage form of claim 108, being in the form of a tablet or capsule.

110. 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 1-103.

111. The method of claim 110, 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.1 J 2 The method of claim 110, 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.

113. The method of any one of claims 110-112, wherein the subj ect being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

114. Use of a compound according to any one of claims 1-105, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

115. The use of claim 114, wherein the disease or disorder is cancer.

116. The use of claim 115, 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.

117. The use of claim 115, 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.

118. A method for making a compound of any one claims 1-105.

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