Patent Description:
PPARgamma (PPARG) is a type II ligand-dependent nuclear hormone receptor (belonging to the PPAR nuclear receptor subfamily) that functions as an obligate heterodimer with retinoid X receptors (RXRs). PPARG is predominantly expressed in adipose tissue, colon, macrophages and the luminal layers of the urothelium. PPARG is known as a master regulator of adipogenesis, functioning to regulate adipocyte differentiation, fatty acid storage and glucose metabolism. PPARG has also been shown to play an important role in the metabolism and inflammation of macrophages, where it is induced by IL4 and controls glutamine metabolism. In the normal urothelium, PPARG is critical for its homeostasis and regeneration.

The role for PPARG in cancer was originally inferred from genomic studies that identified a PAX8-PPARG chromosomal rearrangement in follicular thyroid carcinomas. More recently, PPARG has been found to be over-expressed and genetically altered in the luminal subtype of urothelial cancer. This is consistent with reports that long-term use of PPARG agonists is associated with an increased incidence of urothelial cancer. Most urothelial cancers are urothelial carcinoma, which are classified as either non-muscle-invasive urothelial cancer (NMIUC, <NUM>%), muscle-invasive urothelial cancer (MIUC, <NUM>%) or metastatic urothelial cancer (MUC, <NUM>%). MIUC is usually diagnosed de novo but may arise from the <NUM> to <NUM>% of NMIUC cases that eventually progress. MIUC is a heterogeneous and aggressive disease, associated with a five-year survival rate of <NUM>% for patients with localized disease and less than <NUM>% for patients with distant metastases. Molecular understanding of NMIUC and MIUC has improved significantly, including the association between molecular subtypes and urothelial differentiation. Several molecular classes of MIUC have been proposed, whereby an activated PPARG signature features prominently in the luminal subtypes. First-line treatment is chemotherapy with several options in chemo-ineligible or second line, but treatment options are limited with poor overall survival rates. A PPAR agonist is disclosed in <CIT>.

The need exists to develop effective PPARG modulators for treating cancers such as NMIUC, MIUC, and MUC, and related conditions.

Provided herein are compounds having the Formula I:
<CHM>
and pharmaceutically acceptable salts and compositions thereof, wherein R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, X, q and r are as described herein. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof modulate PPARG (e.g., as agonists such as inverse agonists, and are useful in a variety of therapeutic applications such as, for example, in treating cancer. As such, their uses for treating diseases responsive to the inhibition of PPARG are included.

Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the disclosed compounds of Formula I, as well as methods for their preparation are also included.

In a first embodiment, provided herein is a compound of Formula <NUM>:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein:.

When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NRbC(O)ORc and -NRbC(S)ORc mean that the point of attachment for this group occurs on the nitrogen atom.

The terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

The term "alkyl" when used alone or as part of a larger moiety, such as "haloalkyl", and the like, means saturated straight-chain or branched monovalent hydrocarbon radical.

"Alkoxy" means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C<NUM>-C<NUM>)alkoxy" includes methoxy, ethoxy, proproxy, and butoxy.

The term "haloalkyl" includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

"Haloalkoxy" is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., -OCHF<NUM> or -OCF<NUM>.

The term "<NUM>- to <NUM>-membered heteroaryl" used alone or as part of a larger moiety refers to a <NUM>- to <NUM>-membered aromatic radical containing <NUM>-<NUM> heteroatoms selected from N, O, and S. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.

The term "<NUM>- to <NUM>-membered heterocyclyl" means a <NUM>- to <NUM>-membered saturated or partially unsaturated heterocyclic ring containing <NUM> to <NUM> heteroatoms independently selected from N, O, and S. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, oxetanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. Optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.

The disclosed compounds may exist in one or more tautomeric forms, such as those below, and are included herein.

As used herein, "crystalline" refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern.

Unless otherwise specified, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is a single crystalline form, meaning that <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form (i.e., Form A).

The <NUM>-theta values of the X-ray powder diffraction patterns for the crystalline form described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation due to factors such as temperature variation, sample displacement, and the presence or absence of an internal standard. Therefore, unless otherwise defined, the XRPD patterns / assignments recited herein are not to be construed as absolute and can vary ± <NUM> degrees. It is well known in the art that this variability will account for the above factors without hindering the unequivocal identification of a crystal form. Unless otherwise specified, the <NUM>-theta values provided herein were obtained using Cu Kα1 radiation.

Temperature values, e.g., for DSC peaks herein may vary slightly from one instrument to another and also depending on variations in sample preparation, batch to batch variation, and environmental factors. Therefore, unless otherwise defined, temperature values recited herein are not to be construed as absolute and can vary ± <NUM> degrees or ± <NUM> degrees.

"Substantially the same XRPD pattern" or "an X-ray powder diffraction pattern substantially similar to" a defined figure means that for comparison purposes, at least <NUM>% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed, such as ± <NUM> degrees.

The terms "subject" and "patient" may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

The term "inhibit," "inhibition" or "inhibiting" includes a decrease in the baseline activity of a biological activity or process.

As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

For use in medicines, the salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts. " Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methane sulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that will elicit a desired or beneficial biological or medical response of a subject e.g., a dosage of between <NUM> - <NUM>/kg body weight/day.

In a second embodiment, the compound of Formula I is of the Formula <NUM>:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I. Alternatively, as part of a second embodiment, the compound of Formula I is of the Formula IIa:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I. In another alternative, as part of a second embodiment, the compound of Formula I is of the Formula III:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I. In another alternative, as part of a second embodiment, the compound of Formula I is of the Formula IIIa:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I. In another alternative, as part of a second embodiment, the compound of Formula I is of the Formula IV:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I. In another alternative, as part of a second embodiment, the compound of Formula I is of the Formula IVa:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

In a third embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is hydrogen, wherein the remaining variables are as described above for Formula I.

In a fourth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is cyano, wherein the remaining variables are as described above for Formula I or the third embodiment.

In a fifth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the third or fourth embodiments.

In a sixth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo or cyano, wherein the remaining variables are as described above for Formula I or any one of the third, fourth, or fifth embodiments. Alternatively, as part of a sixth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo, wherein the remaining variables are as described above for Formula I or any one of the third, fourth, or fifth embodiments. In another alternative, as part of a sixth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is chloro or fluoro, wherein the remaining variables are as described above for Formula I or any one of the third, fourth, or fifth embodiments. In another alternative, as part of a sixth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is fluoro, wherein the remaining variables are as described above for Formula I or any one of the third, fourth, or fifth embodiments.

In a seventh embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo, wherein the remaining variables are as described above for Formula I or any one of the third to sixth embodiments. Alternatively, as part of a seventh embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is fluoro or chloro, wherein the remaining variables are as described above for Formula I or any one of the third to sixth embodiments. In another alternative, , as part of a seventh embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is fluoro, wherein the remaining variables are as described above for Formula I or any one of the third to sixth embodiments.

In an eighth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, -(C<NUM>-C<NUM>)alkylORa, -C(O)NRaRb, phenyl, <NUM>- to <NUM>-membered heterocyclyl, and <NUM>- to <NUM>-membered heteroaryl, wherein each of said phenyl, <NUM>- to <NUM>-membered heterocyclyl, and <NUM>-to <NUM>-membered heteroaryl are optionally and independently substituted with <NUM> to <NUM> groups selected from R<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to seventh embodiments. Alternatively, as part of an eighth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, -(C<NUM>-C<NUM>)alkylORa, -C(O)NRaRb, phenyl, pyridinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, pyrazolyl, and oxetanyl, wherein each of said phenyl, pyridinyl, pyrazolyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, piperidinyl, and oxetanyl are optionally and independently substituted with <NUM> to <NUM> groups selected from R<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to seventh embodiments. In another alternative, as part of an eighth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, -(C<NUM>-C<NUM>)alkylORa, - C(O)NRaRb, phenyl, pyridinyl, pyrazolyl, and oxetanyl, wherein each of said phenyl, pyridinyl, pyrazolyl, and oxetanyl are optionally and independently substituted with <NUM> to <NUM> groups selected from R<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to seventh embodiments. In another alternative, as part of an eighth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is pyrazolyl, pyridinyl, or piperazinyl, each of which optionally and independently substituted with <NUM> to <NUM> groups selected from R<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to seventh embodiments. In yet another alternative, as part of an eighth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is pyrazolyl optionally and independently substituted with <NUM> to <NUM> groups selected from R<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to seventh embodiments.

In a ninth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is selected from halo, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkoxy, oxo, and cyano, wherein the remaining variables are as described above for Formula I or any one of the third to eighth embodiments. Alternatively, as part of an ninth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo(C<NUM>-C<NUM>)alkyl, wherein the remaining variables are as described above for Formula I or any one of the third to eighth embodiments. In another alternative, as part of an ninth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is (C<NUM>-C<NUM>)alkyl, wherein the remaining variables are as described above for Formula I or any one of the third to eighth embodiments.

In a tenth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is halo(C<NUM>-C<NUM>)alkyl or (C<NUM>-C<NUM>)alkyl, wherein the remaining variables are as described above for Formula I or any one of the third to ninth embodiments. Alternatively, as part of a tenth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is (C<NUM>-C<NUM>)alkyl, wherein the remaining variables are as described above for Formula I or any one of the third to ninth embodiments. In another alternative, as part of a tenth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is CH<NUM>, CH<NUM>CH<NUM>, CF<NUM>CH<NUM>, CF<NUM>, CH(CH<NUM>)<NUM>, or CH<NUM>CH(CH<NUM>)<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to ninth embodiments. In another alternative, as part of a tenth embodiment, R<NUM> in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is CH<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to ninth embodiments.

In an eleventh embodiment, X in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof is SO<NUM>, wherein the remaining variables are as described above for Formula I or any one of the third to tenth embodiments.

Compounds having the Formula I and II are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. In certain aspects, one or more hydrogen atoms on a compound disclosed herein may be replaced by deuterium.

Also provided herein is crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile. Also provided herein are pharmaceutical compositions comprising crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile. Further provided is the use of crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile for treating diseases responsive to the inhibition of PPARG.

In one aspect, provided herein is crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile, wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. Alternatively, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by at least six x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by x-ray powder diffraction peaks at 2Θ angles selected from <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>°. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by at least three, at least four, at least five, at least six, at least eight, at least nine, or at least <NUM> peaks selected from those in Table <NUM>. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by an XRPD substantially similar to <FIG>. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by a Differential Scanning Calorimetry (DSC) with a endotherm at <NUM> (onset temperature), wherein the crystalline form may also comprise XRPD peaks at 2Θ angles selected from any of those described above. In yet another alternative, crystalline Form A of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile is characterized by a Differential Scanning Calorimetry (DSC) substantially similar to <FIG>, wherein the crystalline Form <NUM> may also comprise XRPD peaks at 2Θ angles selected from any of those described above.

In one aspect, as part of a twelfth embodiment, compounds of Formula I can be prepared by a process comprising: reacting a compound of Formula A:
<CHM>
wherein L is a leaving group, and wherein the remaining variables are as described above for the compound of Formula I or any one of the third to ninth embodiments, with the corresponding sulfur nucleophile of XR<NUM> to form the compound of Formula I. In some aspects, the leaving group in the twelfth embodiment, is a halogen leaving group such as chloro. In some aspects, as part of a twelfth embodiment, the compound of Formula A is reacted with the sulfur nucleophile in the presence of a copper catalyst such as, e.g., a copper(I) catalyst (e.g. CuI) or copper(II) catalyst (e.g., Cu<NUM>O, Cu(OAc)<NUM>, CuBr, CuCl, and the like. In some aspects, as part of a twelfth embodiment, the compound of Formula A is reacted with the sulfur nucleophile in the presence of a copper ligand such as e.g., an organic base(e.g., proline, quinolone-<NUM>-ol, hydroxyproline, N-Me glylcine, and dimethyl glycine). In some aspects, q and r are each <NUM> in the twelfth embodiment. In some aspects, XR<NUM> in the twelfth embodiment is -S(O)<NUM>(C<NUM>-C<NUM>)alkyl such as -S(O)<NUM>CH<NUM>. In some aspects, as part of a twelfth embodiment, the compound of Formula A is reacted with the sulfur nucleophile in the presence of an organic solvent such as polar aprotic solvent (e.g., DMSO, DMF, NMP and DMA). In some aspects, as part of a twelfth embodiment, the compound of Formula A is reacted with the sulfur nucleophile in the presence of a base such as K<NUM>PO<NUM>, K<NUM>CO<NUM>, NaHCO<NUM>, K<NUM>HPO<NUM>, Na<NUM>CO<NUM>, Na<NUM>PO<NUM>, Li<NUM>PO<NUM>, KOtBu and KHMDS. In some aspects, the compound of Formula I in the twelfth embodiment is <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile. In some aspects, the compound of Formula I in the twelfth embodiment is crystalline Form A <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile as defined by one or more of the XRPD peaks defined herein.

In one aspect, as part of a thirteenth embodiment, provided is a process for preparing a compound having the Formula A:
<CHM>
wherein L is a leaving group, and wherein the remaining variables are as described above for the compound of Formula I or any one of the third to ninth embodiments, said process comprising: reacting a compound having the Formula B:
<CHM>
with a base. In some aspects, the base in the eleventh embodiment is an inorganic base such as LiOtBu, LiOH, NaOH, KOH and CsOH·H<NUM>O. In some aspects, the compound having the Formula B the eleventh embodiment is reacted with the base in the presence of an organic solvent such as a polar aprotic solvent like THF, <NUM>-MeTHF, CPME, dioxane, and NMP. In some aspects, the base in the eleventh embodiment is LiOtBu. In some aspects, the leaving group in the thirteenth embodiment is a halogen leaving group such as chloro. In some aspects, q and r are each <NUM> in the thirteenth embodiment. In some aspects, the compound of Formula A in the thirteenth embodiment, is
<CHM>
In some aspects, the compound of Formula B in the thirteenth embodiment, is
<CHM>.

In one aspect, as part of a fourteenth embodiment, provided is a process for preparing a compound having the Formula B:
<CHM>
wherein L is a leaving group such as a halogen leaving group (e.g., chloro), and wherein the remaining variables are as described above for the compound of Formula I or any one of the third to ninth embodiments, said process comprising: reacting a compound having the Formula C:
<CHM>
with a compound having the Formula D:
<CHM>
In some aspects, q and r are each <NUM> in the fourteenth embodiment. In some aspects, the compound of Formula B in the fourteenth embodiment, is
<CHM>. In some aspects, the compound of Formula C in the fourteenth embodiment, is
<CHM>
In some aspects, the compound of Formula D in the fourteenth embodiment, is
<CHM>
wherein L is as defined above.

In one aspect, as part of a fifteenth embodiment, provided is a process for preparing a compound having the Formula C:
<CHM>
wherein the remaining variables are as described above for the compound of Formula I or any one of the third, sixth, seventh, or eighth embodiments, said process comprising reacting a compound having the Formula E:
<CHM>
where Lv is a leaving group such as e.g., a halogen (e.g., fluoro), with ammonia ion such as from ammonium hydroxide to form the compound having the Formula C. In some aspects, the compound having the Formula E is reacted with ammonia ion such as from ammonium hydroxide in the presence of an organic solvent such as a polar aprotic or polar protic solvent like THF, <NUM>-MeTHF, IPA, toluene, acetonitrile, DMP, NMP, CPME and MTBE. In some aspects, the compound having the Formula E is reacted with ammonia ion such as from ammonium hydroxide in the presence of <NUM>-MeTHF. In some aspects, q and r are each <NUM> in the fifteenth embodiment. In some aspects, the compound of Formula C in the fifteenth embodiment, is
<CHM>
In some aspects, the compound of Formula E in the fifteenth embodiment, is
<CHM>.

In one aspect, as part of a sixteenth embodiment, provided is a process for preparing a compound having the Formula D:
<CHM>
wherein L is a leaving group such as e.g., a halogen leaving group (e.g., chloro) and wherein the remaining variables are as described above for Formula I or any one of the fourth or fifth embodiments, said process comprising reacting a compound having the Formula F:
<CHM>
with a chlorinating agent such as e.g., thionyl chloride. In some aspects, the compound of Formula D in the sixteenth embodiment, is
<CHM>
In some aspects, the compound of Formula F in the sixteenth embodiment, is
<CHM>.

In one aspect, as part of a seventeenth embodiment, provided is a process for preparing a compound having the Formula G:
<CHM>
wherein L is a leaving group such as a halogen leaving group (e.g., chloro) and R<NUM> is as described above for Formula I or any one of the fourth or fifth embodiments, said process comprising reacting a compound having the Formula H:
<CHM>
with a palladium catalyst such as e.g., Pd(OAc)<NUM>, Pd<NUM>(dba)<NUM>. In some aspects, as part of a seventeenth embodiment, the process further comprises the addition of a palladium coupling ligand such as e.g., dppb, tBu<NUM>HBF<NUM>, dppp, Ph<NUM>P, XantPhos, dppf, AmgenPHOS, DPEPhos, RuPHOS, R-BINAP, (o-tol)<NUM>P, S-PHOS, X-Phos, tBu-XPhos, and Ph<NUM>-CH<NUM>CH<NUM>-(<NUM>-Pyr)). Solvent: DMAc, tBuOH, DMAc/water, and tBuOH/water. In some aspects, the compound of Formula G in the seventeenth embodiment, is
<CHM>
In some aspects, the compound of Formula H in the seventeenth embodiment, is
<CHM>.

Other processes of preparation are disclosed in the exemplification section and are included as part of the present invention.

The compounds and compositions described herein are generally useful for modulating the activity of PPARG. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein inhibit the activity PPARG. In some aspects, the compounds and pharmaceutical acceptable salts disclosed herein are agonists of PPARG. In some aspects, the compounds and pharmaceutical acceptable salts disclosed herein are agonists of PPARG. In some aspects, the compounds and pharmaceutical acceptable salts disclosed herein are inverse agonists of PPARG. In one aspect, "inverse-agonists" refer to agents that bind to the same receptor binding site as a agonist (e.g., the binding site of a nuclear receptor such as PPARG) and not only antagonizes the effects of an agonist but, moreover, exerts the opposite effect by suppressing spontaneous receptor signaling (when present).

In some aspects, the compounds and pharmaceutical acceptable salts disclosed herein overcome the activated state of PPARG function resulting from alteration in PPARG activity (mutation, amplification or overexpression) or from RXRA activating mutations. In some aspect, the compounds and pharmaceutical acceptable salts disclosed herein increase the repressive state (NCOR1 recruitment) to a higher degree than previously disclosed PPARG modulators such as prior inverse agonists. Such results even arise in the mutant context. See e.g., the table qualitatively assessing NCOR1 recruitment and repression of PPARG target genes in HT1197 in the Exemplification section.

In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disorder associated with PPARG function. Thus, provided herein are methods of treating a disorder associated with PPARG function, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.

Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder associated with PPARG function. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a disorder associated with PPARG.

In one aspect, the disorder associated with PPARG is cancer. In some aspects, the cancer is associated with an up-regulated peroxisome proliferator-activated receptor (PPAR) signaling pathway. In some aspects, the up-regulated PPAR signaling pathway is associated with increased expression of one or more genes selected from Uroplakin 1A (UPK1A), Uroplakin IB (UPK1B), Uroplakin (UPK2), Keratin <NUM> (KRT20), GATA Binding Protein <NUM> (GAT A3), Nuclear Receptor Corepressor <NUM> (NCORI), Nuclear Receptor Corepressor <NUM> (NCOR2), Fatty Acid Binding Protein <NUM> (FABP4), Forkhead Box Al (FOXA1), CD36 Molecule (CD36), Acyl-CoA Oxidase <NUM> (ACOX1), <NUM>-Hydroxy-<NUM>-Methylglutaryl-CoA Synthase <NUM> (HMGCS2), Acyl-CoA Synthetase Long-Chain Family Member <NUM> (ACSL5), Arachidonate <NUM> -Lipoxygenase (ALOX5), Acyl-CoA Synthetase Long-Chain Family Member <NUM> (ACSL1), and Angiopoietin Like <NUM> (ANGPTL4).

In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, renal cancer, bladder cancer, testicular cancer, urothelial cancer (e.g., non-muscle-invasive urothelial cancer, muscle-invasive urothelial cancer, metastatic urothelial cancer), skin cancer, melanoma, colon cancer, kidney cancer, brain cancer and a hematopoietic cancer (e.g., lymphoma, multiple myeloma and leukemia). In one aspect, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is urothelial cancer such as non-muscle-invasive urothelial cancer, muscle-invasive urothelial cancer, and metastatic urothelial cancer.

Other uses besides cancer are contemplated and include e.g., metabolic diseases (e.g., osteoporosis, rachitis, arthrosis, obesity, type I and type II diabetes mellitus), lipid metabolism disorder, pancreatitis, glucose metabolism disorder, diabetic neuropathy, diabetic complications, hyperuricemia, osteoporosis, rachitis, arthrosis inflammatory diseases (e.g., inflammatory skin diseases such as psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitides and pruritus), pulmonary disorders (e.g., asthma and chronic obstructive pulmonary disease), autoimmune disease, neurodegenerative disease (e.g., multiple sclerosis, Alzheimer's disease, and Parkinson's disease), cardiovascular diseases (e.g., selected from atherosclerosis, venous and arterial occlusive diseases), restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in neoplastic diseases and renal diseases.

In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

In some aspects, the pharmaceutical compositions are administered orally.

A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.

The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention.

General starting materials used were obtained from commercial sources or prepared in other examples, unless otherwise noted.

DSC was performed using a Mettler Toledo DSC<NUM>+. The sample (<NUM>-<NUM>) was weighed directly in a <NUM>µL hermetic aluminum pan with a pinhole and analyzed according to the parameters below:.

XRPD samples were analyzed using a Bruker D8 ADVANCE X-ray diffractometer using copper radiation (Cu Kα, λ = <NUM>Å). The generator was operated at a voltage of <NUM> KV and an amperage of <NUM> mA. Data were collected with a scanning range of <NUM> to <NUM>° with a step size of <NUM>°, scanning speed of <NUM> °/minute and a sample rotation speed of <NUM> rpm.

The compounds claimed herein were prepared following the procedures outlined in the following schemes.

Quinolones like S6 may be prepared by the general synthetic methods shown in Scheme <NUM>. Compounds of formula S2 may be prepared from the anilines S1 by treatment with acetonitrile, boron trichloride, aluminum trichloride and HCl in an organic solvent such as dichloromethane. Treatment of the acetylaniline S2 with an acyl chloride S3 yields intermediates of formula S4. Quinolones like S5 may then be prepared by treatment of S4 with a hydroxide base in an organic solvent such as dioxane at elevated temperature. The chloride on S5 may then be replaced with sulfur-based nucleophiles to provide S6. via an SNAr reaction or via a copper catalysis. Acyl chlorides S3 may be prepared from the corresponding acid by treatment with thionyl chloride or oxalyl chloride in an organic solvent such as dichloromethane.

Certain quinolone analogues S6 may also be prepared via a two-step process consisting of nucleophile addition of a thiol to S5 followed by oxidation of the thioether S7. <CHM>
<CHM>.

Certain quinolone analogues S6 may also be prepared a three-step process consisting of acylation of S2 with S8 to yield S9, cyclization amide S9 to yield quinolones S7, and oxidation of the thioether of S7.

Step <NUM>, <NUM>-(<NUM>-bromo-<NUM>,<NUM>-difluoro-<NUM>-nitrophenyl)-<NUM>-methylpiperazine: To a solution <NUM>-bromo-<NUM>,<NUM>,<NUM>-trifluoro-<NUM>-nitrobenzene (<NUM>, <NUM> mmol, <NUM> eq) in DMSO (<NUM>) was added K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>-methylpiperazine (<NUM>, <NUM> mmol, <NUM>, <NUM> eq). The mixture was stirred at <NUM> for <NUM> hrs. LCMS showed compound <NUM> was consumed completely and one main peak with desired mass was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (<NUM> * <NUM>). The filtrate was extracted with EtOAc (<NUM> * <NUM>) and H<NUM>O (<NUM>). The combined organic layers were washed with brine (<NUM>), dried over anhydrous Na<NUM>SO<NUM>, filtered and concentrated under reduced pressure to give <NUM>-(<NUM>-bromo-<NUM>,<NUM>-difluoro-<NUM>-nitrophenyl)-<NUM>-methylpiperazine (<NUM>, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-bromo-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)aniline: To a solution of <NUM>-(<NUM>-bromo-<NUM>,<NUM>-difluoro-<NUM>-nitrophenyl)-<NUM>-methylpiperazine (<NUM>, <NUM> mmol, <NUM> eq) in EtOH (<NUM>) was added a solution of NH<NUM>Cl (<NUM>, <NUM> mmol, <NUM> eq) in H<NUM>O (<NUM>) and Fe (<NUM>, <NUM> mmol, <NUM> eq). The mixture was stirred at <NUM> for <NUM> hrs. LCMS showed compound <NUM> was consumed completely and one main peak with desired mass was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (<NUM> * <NUM>). The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was extracted with EtOAc (<NUM> * <NUM>) and H<NUM>O (<NUM>). The combined organic layers were washed with brine (<NUM>), dried over anhydrous Na<NUM>SO<NUM>, filtered and concentrated under reduced pressure to give <NUM>-bromo-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)aniline (<NUM>, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (br s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). Step <NUM>, <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)phenyl)ethan-<NUM>-one: To a solution of tributyl(<NUM>-ethoxyvinyl)stannane (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>-bromo-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)aniline (<NUM>, <NUM> mmol, <NUM> eq) in toluene (<NUM>) was added Pd(PPh<NUM>)<NUM> (<NUM>, <NUM> umol, <NUM> eq). The mixture was stirred at <NUM> for <NUM> hrs. LCMS showed compound <NUM> was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of KF solution (<NUM>) at <NUM> and stirred for <NUM> hrs. The mixture was diluted with water (<NUM>) and extracted with EtOAc (<NUM> * <NUM>). The combined organic layers were washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated under reduced pressure to give intermediate <NUM>-(<NUM>-ethoxyvinyl)-<NUM>, <NUM>-difluoro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl) aniline (<NUM>) as a black brown oil. To a solution of <NUM>-(<NUM>-ethoxyvinyl)-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)aniline (<NUM>, <NUM> mmol, <NUM> eq) in H<NUM>O (<NUM>) was added HOAc (<NUM>). The mixture was stirred at <NUM> for <NUM> hrs. LCMS showed the intermediate was consumed completely. The reaction mixture was quenched by addition NaHCO<NUM> aq (<NUM>) and NaOH (<NUM>) at <NUM>. The resulting mixture was extracted with EtOAc (<NUM> * <NUM>). The combined organic layers were washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO<NUM>, DCM/MeOH =<NUM>/<NUM> to <NUM>/<NUM>) to afford the title compound (<NUM>, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ = <NUM> (br s, <NUM>), <NUM> (dd, J =<NUM>, <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, methyl <NUM>-chloro-<NUM>-cyano-benzoate: To a solution of <NUM>-chloro-<NUM>-cyano-benzoic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) was added SOCl<NUM> (<NUM>, <NUM> mmol, <NUM>, <NUM> equiv. The reaction mixture was stirred at <NUM> for <NUM> hour. The reaction mixture was cooled to RT and concentrated under reduced. The residue was dissolved in THF (<NUM>) and added to MeOH (<NUM>). The reaction mixture was cooled to RT and quenched with a saturated aqueous solution of NaHCO<NUM> (<NUM>) and extracted with ethyl acetate (<NUM> x <NUM>). The combined organic layers were washed with brine, dried over Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure to afford the title compound (<NUM>, <NUM>% yield) as a white solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-cyano-<NUM>-methylsulfanyl-benzoic acid: To a solution of NaSMe (<NUM>, <NUM> mmol, <NUM> equiv. ) in DMF (<NUM>) was added dropwise a solution of methyl <NUM>-chloro-<NUM>-cyano-benzoate (<NUM>, <NUM> mmol, <NUM> equiv. ) in DMF (<NUM>) at <NUM>. Then the mixture was stirred at <NUM> for <NUM> hours. The pH of the reaction mixture was adjusted to pH = <NUM> with HCl (<NUM>). The mixture was filtered and the filter cake was dried over under vacuum to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M-<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d6) δ <NUM> (br s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-cyano-<NUM>-(methylthio) benzoyl chloride: A solution of <NUM>-cyano-<NUM>-(methylthio) benzoic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) in SOCl<NUM> (<NUM>) was stirred at <NUM> for <NUM> hour. The mixture was concentrated under reduced pressure to afford the title compound (<NUM>, <NUM>% yield) as a yellow solid. The product was used without further purification.

<NUM>-(<NUM>-amino-<NUM>,<NUM> -difluoro-<NUM>-iodo-phenyl)ethenone: To a solution of <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluoro-phenyl)ethanone (<NUM>, <NUM> mmol, <NUM> equiv. ) in DCM (<NUM>) was added N-iodosuccinimide (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at RT for <NUM> hours. The reaction mixture was diluted with water (<NUM>) and extracted with DCM (<NUM> x <NUM>). The combined organic layers were washed with brine, dried over Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (<NUM>-<NUM>% ethyl acetate in petroleum ether) to afford the title compound (<NUM>, <NUM>% yield) as a brown solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

<NUM>-chloro-<NUM>-cyanobenzoic acid: <NUM>-chloro-<NUM>-iodobenzoic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) was combined with tert-butanol (<NUM>), water (<NUM>), potassium carbonate (<NUM>, <NUM> mmol, <NUM> equiv. ), potassium ferrocyanide trihydrate (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred for <NUM> hour before addition of tris(dibenzylideneacetone)dipalladium(<NUM>) (<NUM>, <NUM> mmol, <NUM> equiv. ), <NUM>,<NUM>-bis(diphenylphosphino)butane (<NUM>, <NUM> mmol, <NUM> equiv. ) and a mixture of tert-butanol (<NUM>) and water (<NUM>). The mixture was adjusted to <NUM> for <NUM> hours before cooling to <NUM>. Ammonium pyrrolidinedithiocarbamate (<NUM>, <NUM> mmol, <NUM> equiv. ) was charged followed by water (<NUM>) and the mixture was adjusted to <NUM> and stirred for <NUM> hours. The mixture was cooled to <NUM> and filtered through diatomite and rinsed with water (<NUM>). The filtrate was extracted twice with methyl tert-butyl ether (<NUM> x <NUM>) and the aqueous layer was combined with ethyl acetate (<NUM>) and adjusted to <NUM>. A 2N HCl solution (<NUM>) was added dropwise over <NUM> hours at <NUM>. The mixture was stirred for one hour before the bottom aqueous layer was removed. The organic layer was washed with water (<NUM>) and treated with activated carbon (<NUM>) for <NUM> hours before removal by filtration and rinsing with ethyl acetate (<NUM>). The filtrate was concentrated to <NUM> under vacuum before charging acetone (<NUM>) and the process repeated. The solution was then concentrated to <NUM> before a final charge of acetone (<NUM>). The mixture was adjusted to <NUM> for <NUM> hours before charging <NUM>. 2N HCl (<NUM>) over <NUM> hours. The mixture was aged an additional <NUM> hours at <NUM> before adjusting to <NUM> over <NUM> hours and holding for <NUM> hours. The slurry was filtered and washed with water (<NUM>) before drying at <NUM> to deliver the title compound (<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

A solution of <NUM>-chloro-<NUM>-cyano-benzoic acid (<NUM>, <NUM> mmol) in SOCl<NUM> (<NUM>) was stirred at <NUM> for <NUM> hour. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to afford the title compound (<NUM>, crude) as a yellow solid, the product was used directly in next step.

To a solution of <NUM>,<NUM>-difluoroaniline (<NUM>, <NUM> mmol, <NUM> equiv. ) in CH<NUM>CN (<NUM>) was added BCl<NUM> (<NUM>, <NUM>, <NUM> equiv. ) at <NUM>. Then AlCl<NUM> (<NUM>, <NUM> mmol, <NUM>, <NUM> equiv. ) was added to the mixture in three portions and the mixture was then stirred at <NUM> for <NUM> hours. The mixture was cooled to <NUM> and then aqueous HCl (<NUM>, <NUM>) was added and the mixture was stirred at <NUM> for <NUM> hours. The mixture was cooled to room temperature and extracted with EtOAc (<NUM> x <NUM>). The combined organic layers were washed with saturated aqueous NaHCO<NUM> solution (<NUM> x <NUM>), dried over Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure to afford the title compound (<NUM>, <NUM>% yield) as a light-yellow solid. LCMS: calculated for [M+H]+ (C<NUM>H<NUM>F<NUM>NO) requires m/z = <NUM>, found m/z = <NUM>. <NUM>H NMR (<NUM>, CDCl<NUM>), δ <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a solution of <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluoro-phenyl)ethanone (<NUM>, <NUM> mmol, <NUM> equiv. ) in THF (<NUM>) was added NaH (<NUM>, <NUM> mmol, <NUM>% dispersion in oil, <NUM> equiv. ) at <NUM>. The mixture was stirred for <NUM> minutes before the dropwise addition of a solution of <NUM>-chloro-<NUM>-cyano-benzoyl chloride (<NUM>, <NUM> mmol, <NUM> equiv. ) in THF (<NUM>). The mixture was stirred at room temperature for <NUM> hours. The reaction mixture was quenched by the addition saturated aqueous NH<NUM>Cl (<NUM>) at <NUM>, diluted with water (<NUM>), and filtered. The filter cake was triturated with EtOAc (<NUM>) and filtered to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS: calculated for [M+H]+ (C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>) requires m/z = <NUM>, found m/z = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of N-(<NUM>-acetyl-<NUM>,<NUM>-difluoro-phenyl)-<NUM>-chloro-<NUM>-cyano-benzamide (<NUM>, <NUM> mmol, <NUM> equiv. ) in dioxane (<NUM>) was added NaOH (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The pH of the reaction mixture was adjusted to <NUM> with aqueous HCl (<NUM>) and then diluted with water (<NUM>) and extracted with EtOAc (<NUM> x <NUM>). The combined organic layers were washed with brine (<NUM> x <NUM>), dried over Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure to afford a crude residue that was purified by preparative HPLC (column: Welch Xtimate C18 <NUM> x <NUM> x <NUM>; mobile phase: <NUM>-<NUM>% acetonitrile in water (<NUM> NH<NUM>HCO<NUM>)). This afforded the title compound (<NUM>, <NUM>% yield, <NUM>% purity) as a white solid after concentration under reduced pressure. LCMS: calculated for [M+H]+ (C<NUM>H<NUM>ClF<NUM>N<NUM>O) requires m/z = <NUM>, found m/z = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

To a mixture of <NUM>-chloro-<NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)benzonitrile (<NUM>, <NUM>µmol, <NUM> equiv. ) in DMSO (<NUM>) were added sodium methanesulfinate (<NUM>, <NUM>µmol, equiv. ), K<NUM>PO<NUM> (<NUM>, <NUM>µmol, <NUM> equiv. ), CuI (<NUM>, <NUM>µmol, <NUM> equiv. ) and quinolin-<NUM>-ol (<NUM>, <NUM>µmol, <NUM> equiv. ) at <NUM> under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was diluted with H<NUM>O (<NUM>) and extracted with ethyl acetate (<NUM> X <NUM>). The combined organic layers were washed with brine (<NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 <NUM>*<NUM>*<NUM>; Mobile phase: <NUM>%-<NUM>% acetonitrile in water (+NH<NUM>HCO<NUM>)) to afford the title compound (<NUM>, <NUM>% yield, <NUM>% purity) as a white crystalline solid, characterized as crystalline Form A. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

A mixture of <NUM>-(<NUM>,<NUM>,<NUM>-trifluorophenyl)ethan-<NUM>-one (<NUM>, <NUM> mmol, <NUM> equiv. ) in <NUM>-methyltetrahydrofuran (<NUM>) and <NUM>% aqueous ammonium hydroxide (<NUM>, <NUM> mmol, <NUM> equiv. ) was heated to <NUM> for <NUM> hours. The mixture was cooled to <NUM> and toluene (<NUM>) was charged. The layers were separated and the organic layer was concentrated to <NUM> under vacuum. Toluene (<NUM>) was charged to the organic layer before washing twice with 3N HCl (<NUM> x <NUM>) and once with <NUM>% aqueous NaHCO<NUM> (<NUM>). The organic layer was concentrated to <NUM> under vacuum before charging isopropyl acetate (<NUM>). The mixture was again concentrated to <NUM> and isopropyl acetate (<NUM>) was charged to deliver the title compound as a solution in isopropyl acetate (<NUM>% assay yield).

A solution of <NUM>-chloro-<NUM>-cyano-benzoic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) in toluene was adjusted to <NUM> and SOCl<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) was charged over <NUM> hour. The mixture was stirred for <NUM> hours at <NUM> before cooling and concentrating under vacuum to <NUM>. Isopropyl acetate (<NUM>) was charged and the mixture was concentrated to <NUM> once again. The charge of isopropyl acetate (<NUM>) and concentration to <NUM> was repeated before a final charge of isopropyl acetate (<NUM>). The mixture was adjusted to <NUM> and a solution of <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluorophenyl)ethanone in isopropyl acetate (<NUM>, <NUM> mmol, <NUM> equiv. , <NUM> as a solution in isopropyl acetate) was charged over <NUM> hours. The mixture was adjusted to <NUM> and stirred for <NUM> hours before cooling to <NUM> and filtering. The solids were rinsed twice with isopropyl acetate (<NUM> x <NUM>) and twice with n-heptane (<NUM> x <NUM>) before drying at <NUM> to deliver the title compound (<NUM>, <NUM>% yield).

Lithium tert-butoxide (<NUM>, <NUM> mmol, <NUM> equiv. ) was added to a mixture of N-(<NUM>-acetyl-<NUM>,<NUM>-difluorophenyl)-<NUM>-chloro-<NUM>-cyanobenzamide (<NUM>, <NUM> mmol, <NUM> equiv. ) and <NUM>-methyltetrahydrofuran (<NUM>). The mixture was adjusted to <NUM> for <NUM> hours before cooling to <NUM>. Dimethyl sulfoxide (<NUM>) was charge and the mixture adjusted to <NUM> for <NUM> hours. A 1N HCl solution (<NUM>) was slowly added and the mixture stirred for an additional <NUM> hours at <NUM>. The mixture was cooled to <NUM> over <NUM> hours and stirred for an additional <NUM> hours. The slurry was filtered and the solids washed twice with water (<NUM> x <NUM>) and twice with acetone (<NUM> x <NUM>). The wet solids were then slurry washed in acetone (<NUM>) at <NUM> for <NUM> hours before cooling to <NUM> and stirring for an additional <NUM> hours. The slurry was filtered and the solids rinsed with acetone (<NUM>). The solids were dried at <NUM> to deliver the title compound (<NUM>, <NUM>% yield).

To a solution of <NUM>-chloro-<NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)benzonitrile (<NUM>, <NUM> mmol, <NUM> equiv. ) in dimethyl sulfoxide (<NUM>) was added sodium methanesulfinate (<NUM>, <NUM> mmol, <NUM> equiv. ), tripotassium phosphate (<NUM>, <NUM> mmol, <NUM> equiv. ), copper(I) iodide (<NUM>, <NUM> mmol, <NUM> equiv. ) and L-proline (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours then quenched with <NUM>% aqueous ammonium hydroxide (<NUM>). The mixture was stirred for <NUM> hours before addition of 1N HCl (<NUM>) and an additional <NUM> hours of stirring. The solids were filtered and washed with water (<NUM> x <NUM>). The solids were then slurry washed in water (<NUM>) at <NUM> for <NUM> hours before cooling to <NUM> for filtration. The wet solids were then slurry washed in acetone (<NUM>) at <NUM> for <NUM> hours before cooling to <NUM> over <NUM> hours and ageing <NUM> hours before filtration and washing with acetone (<NUM>). The solids were dried at <NUM> to deliver the title compound (<NUM>, <NUM>% yield). HRMS: calculated for [M+H]+ (C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S) requires m/z = <NUM>, found m/z = <NUM>. <NUM>H NMR (<NUM>, MeOH-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). The XRPD pattern of the resulting product, <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile, characterized as Form A, the XRPD for which is shown in <FIG>. The DSC curve is shown in <FIG> and indicated an endothermic transition with onset of about <NUM>.

The compounds in Table <NUM> were prepared following Scheme <NUM> using similar procedures to those described for Example <NUM>.

Scheme <NUM>, step <NUM>. <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-((<NUM>,<NUM>,<NUM>-trifluoroethyl)thio)benzonitrile: To a solution of <NUM>,<NUM>,<NUM>-trifluoroethane-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM>µL, <NUM> equiv. ) in THF (<NUM>) was added NaH (<NUM>, <NUM> mmol, <NUM>% purity, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hr. The reaction mixture was concentrated under reduced pressure to remove solvent to give sodium <NUM>,<NUM>,<NUM>-trifluoroethanethiolate (<NUM>, crude) as a white solid. Then, to a solution of <NUM>-chloro-<NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)benzonitrile (<NUM>, <NUM> mmol, <NUM> equiv. ) and sodium <NUM>,<NUM>,<NUM>-trifluoroethanethiolate (<NUM>, <NUM> mmol, <NUM> equiv. ) in DMSO (<NUM>) was added K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) and CuI (<NUM>, <NUM>µmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hrs. The residue was diluted with water (<NUM>) and extracted with EtOAc (<NUM> X <NUM>). The combined organic layers were washed with brine (<NUM>), dried over anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient of <NUM>:<NUM> to <NUM>:<NUM> petroleum ether:ethyl acetate) to afford the title compound (<NUM>, crude) as yellow solid which used directly in next step without any more purification.

To a mixture of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-((<NUM>,<NUM>,<NUM>-trifluoroethyl)thio)benzonitrile (<NUM>, <NUM>µmol, <NUM> equiv. ) in acetone (<NUM>), H<NUM>O (<NUM>), MeOH (<NUM>) and THF (<NUM>) was added Oxone (<NUM>, <NUM> mmol, <NUM> equiv. ) in two portions at <NUM> under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction was diluted with water (<NUM>) and extracted with EtOAc (<NUM> X <NUM>). The combined organic layers were washed with brine (<NUM>), dried over anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Phenomenex Luna <NUM>*<NUM>*<NUM>; Mobile phase: <NUM>-<NUM>% acetonitrile in water (+HCl)) to afford the title compound (<NUM>, <NUM>% yield, <NUM>% purity) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>).

To a mixture of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-((<NUM>,<NUM>,<NUM>-trifluoroethyl)thio)benzonitrile (<NUM>, <NUM>µmol, <NUM> equiv. ) in acetone (<NUM>) H<NUM>O (<NUM>) MeOH (<NUM>) and THF (<NUM>) was added Oxone (<NUM>, <NUM>µmol, <NUM> equiv. ) at <NUM> under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction was diluted with water (<NUM>) and extracted with EtOAc (<NUM> X <NUM>). The combined organic layers were washed with brine (<NUM>), dried over anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Phenomenex Luna <NUM>*<NUM>*<NUM>; Mobile phase: <NUM>-<NUM>% acetonitrile in water (+HCl)) to afford the title compound (<NUM>, <NUM>% yield, <NUM>% purity) as white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a mixture of <NUM>-chloro-<NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)benzonitrile (<NUM>, <NUM> mmol, <NUM> equiv. ) in DMSO (<NUM>) was added NaSMe (<NUM>, <NUM> mmol, <NUM> equiv. ), K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) and CuI (<NUM>, <NUM>µmol, <NUM> eq) at <NUM> under N<NUM>, and then the mixture was stirred at <NUM> for <NUM> hours under N<NUM>. The reaction mixture was added to water (<NUM>) and stirred at <NUM> for <NUM> mins, then extracted with ethyl acetate (<NUM> X <NUM>). The combined organic layers were washed with brine (<NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Phenomenex Luna C18 <NUM>*<NUM>*<NUM>; Mobile phase: <NUM>-<NUM>% acetonitrile in water (+formic acid)) to afford the title compound (<NUM>, <NUM>% yield, <NUM>% purity) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a mixture of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylthio)benzonitrile (<NUM>, <NUM>µmol, <NUM> equiv. ) in DCM (<NUM>) was added m-CPBA (<NUM>, <NUM>µmol, <NUM>% purity, <NUM> equiv. ) at <NUM>, and then the mixture was stirred at <NUM> for <NUM> hour under N<NUM>. The reaction mixture was quenched by the addition of a saturated aqueous solution of NaHSO<NUM> (<NUM>) at <NUM>, and then diluted with NaHCO<NUM> (<NUM>) and extracted with DCM (<NUM> X <NUM>). The combined organic layers were dried over Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE (<NUM>) to afford the title compound (<NUM>, <NUM>% yield, <NUM>% purity) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a mixture of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylthio)benzonitrile (<NUM>, <NUM>µmol, <NUM> equiv. ) in MeOH (<NUM>) was added ammonium carbamate (<NUM>, <NUM>µmol, <NUM> equiv. ) at <NUM>, then PhI(OAc)<NUM> (<NUM>, <NUM>µmol, <NUM> equiv. ) in MeOH (<NUM>) was added to the mixture dropwise. The resulting mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 <NUM>*<NUM>*<NUM>; Mobile phase: <NUM>-<NUM>% acetonitrile in water (+formic acid)-ACN) to afford the title compound (<NUM>, <NUM>% yield, <NUM>% purity) as a yellow solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-(<NUM>-amino-<NUM>-chlorophenyl)ethanone: To a solution of <NUM>-(<NUM>-chloro-<NUM>-nitrophenyl)ethanone (<NUM>, <NUM> mmol, <NUM> equiv. ) in H<NUM>O (<NUM>) and acetic acid (<NUM>) was added iron (<NUM>) (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The suspension was filtered through a pad of Celite and the filter cake was washed with ethyl acetate (<NUM> x <NUM>). The filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (<NUM>) and H<NUM>O (<NUM>), and the layers were separated. The aqueous layer was extracted with ethyl acetate (<NUM> x <NUM>). The combined organic layers were then washed with saturated aqueous NaHCO<NUM>, brine, dried over anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure to afford the title compound (<NUM>, crude) as a black-brown solid. This material was used in next step without further purification. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, N-(<NUM>-acetyl-<NUM>-chlorophenyl)-<NUM>-cyano-<NUM>-(methylthio)benzamide: To a solution of <NUM>-(<NUM>-amino-<NUM>-chlorophenyl)ethenone (<NUM>, <NUM> mmol, <NUM> equiv. ) in isopropyl acetate (<NUM>) was added <NUM>-cyano-<NUM>-methylsulfanyl-benzoyl chloride (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The mixture was cooled to RT and filtered. The filter cake was washed with ethyl acetate (<NUM>). The filter cake was dried under vacuum and triturated with MeOH at <NUM> for <NUM> hours to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-(<NUM>-chloro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylthio)benzonitrile: To a solution of N-(<NUM>-acetyl-<NUM>-chlorophenyl)-<NUM>-cyano-<NUM>-(methylthio)benzamide (<NUM>, <NUM> mmol, <NUM> equiv. ) in <NUM>-MeTHF (<NUM>) was added LiOH (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The mixture was cooled to RT and the pH was adjusted to pH = <NUM> with aqueous <NUM> HCl. The brown solid that precipitated during the pH adjustment was filtered off and washed with H<NUM>O (<NUM>), and then dried under vacuum. Trituration with acetonitrile at RT for <NUM> hours afforded the title compound (<NUM>, crude) as a light-yellow solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-(<NUM>-chloro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)-benzonitrile: To a solution of <NUM>-(<NUM>-chloro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylthio)benzonitrile (<NUM>, <NUM> mmol, <NUM> equiv. ) in H<NUM>O (<NUM>), CHCl<NUM> (<NUM>), and acetonitrile (<NUM>) was added NaIO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) and ruthenium trichloride (<NUM>, <NUM> mmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at RT for <NUM> hours. The suspension was filtered through a filter paper and the pad cake was washed with MeOH (<NUM> x <NUM>). The filtrate was concentrated under reduced pressure. The residue was triturated with first with MTBE and then with MeOH at RT for <NUM> hours to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>).

Step <NUM>, <NUM>-(<NUM>-amino-<NUM>-chloro-<NUM>-fluorophenyl)ethanone: To a solution of <NUM>-chloro-<NUM>-fluoroaniline (<NUM>, <NUM> mmol, <NUM> equiv. ) in p-xylene (<NUM>) was added BCl<NUM> (<NUM>, <NUM>, <NUM> equiv. ) at <NUM>-<NUM> over <NUM> hours. The mixture was warmed up to RT within <NUM> hours and stirred at RT for <NUM> minutes. Then acetonitrile (<NUM>, <NUM> mol, <NUM> equiv. ) was added dropwise at RT over <NUM> minutes. The mixture was stirred at RT for <NUM> minutes, then p-xylene (<NUM>) was added. Then AlCl<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) was added and the reaction mixture was stirred at RT for <NUM> hour and then stirred at <NUM>-<NUM> for another <NUM> hours. Then aqueous HCl (<NUM> N, <NUM>) was added to the mixture and the mixture was stirred at <NUM> for <NUM> hours. The mixture was poured into water (<NUM>) and extracted with ethyl acetate (<NUM>). The organic phase was washed with brine (<NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (<NUM>:<NUM> to <NUM>:<NUM> petroleum ether:ethyl acetate) to afford the title compound (<NUM>, <NUM>% yield) as a light-yellow solid. LCMS [M+<NUM>] = <NUM>/<NUM>. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, N-(<NUM>-acetyl-<NUM>-chloro-<NUM>-fluorophenyl)-<NUM>-cyano-<NUM>-(methylthio)benzamide: To a solution of <NUM>-(<NUM>-amino-<NUM>-chloro-<NUM>-fluorophenyl)ethanone (<NUM>, <NUM> mmol, <NUM> equiv. ) in isopropyl acetate (<NUM>) was added <NUM>-cyano-<NUM>-(methylthio)benzoyl chloride (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with acetonitrile (<NUM>) at RT to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M+<NUM>] = <NUM>/<NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, <NUM>-(<NUM>-chloro-<NUM>-fluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylthio)benzonitrile: To a solution of N-(<NUM>-acetyl-<NUM>-chloro-<NUM>-fluorophenyl)-<NUM>-cyano-<NUM>-(methylthio)benzamide (<NUM>, <NUM> mmol, <NUM> equiv. ) in <NUM>-MeTHF (<NUM>) was added LiOH (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The mixture was cooled to RT. The pH of the reaction mixture was adjusted to pH = <NUM> with aqueous 2N HCl. The precipitate that formed during the pH adjustment was filtered off and the filter cake was dried under vacuum. The residue was triturated with ethyl acetate at RT to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M+<NUM>] = <NUM>/<NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-(<NUM>-chloro-<NUM>-fluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylsulfonyl)benzonitrile: To a solution of <NUM>-(<NUM>-chloro-<NUM>-fluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(methylthio)-benzonitrile (<NUM>, <NUM> mmol, <NUM> equiv. ) in acetone (<NUM>), H<NUM>O (<NUM>), THF (<NUM>) and MeOH (<NUM>) was added Oxone (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was cooled to RT and quenched with an aqueous solution of Na<NUM>SO<NUM> (<NUM> equiv. The reaction mixture was diluted with H<NUM>O (<NUM>) and filtered. The filter cake was washed with water and dried under reduced pressure. Trituration of the crude residue with MTBE (<NUM> x <NUM>) at RT and then trituration with MeOH (<NUM> x <NUM>) at RT afforded the title compound (<NUM>, <NUM>% yield) as off-white solid. LCMS [M+<NUM>] = <NUM>/<NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Step <NUM>, methyl <NUM>-cyano-<NUM>-iodo-benzoate: To a solution of <NUM>-cyano-<NUM>-iodo-benzoic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) in MeOH (<NUM>) was added H<NUM>SO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM> x <NUM>). The combined organic layers were washed with brine, dried over anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure to afford the title compound (<NUM>, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, Methyl <NUM>-cyano-<NUM>-(trifluoromethylsulfanyl) benzoate: To a mixture of methyl <NUM>-cyano-<NUM>-iodo-benzoate (<NUM>, <NUM> mmol, <NUM> equiv. ) and trifluoromethylsulfanylsilver (<NUM>, <NUM> mmol, <NUM> equiv. ) in DMF (<NUM>) was added copper(I)bromide (<NUM>, <NUM>µmol, <NUM> equiv. ) and <NUM>,<NUM>-phenanthroline (<NUM>, <NUM> mmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours under N<NUM>. The reaction mixture was poured into ice-water (<NUM>) and stirred for <NUM> minutes. The aqueous phase was extracted with ethyl acetate (<NUM> x <NUM>). The combined organic layers were washed with aqueous NaHCO<NUM> (<NUM> x <NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (<NUM>:<NUM> to <NUM>:<NUM> petroleum ether:ethyl acetate) to afford the title compound (<NUM>, <NUM>% yield) as white solid. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Step <NUM>, <NUM>-cyano-<NUM>-(trifluoromethylsulfanyl) benzoic acid: To a mixture of methyl <NUM>-cyano-<NUM>-(trifluoromethylsulfanyl) benzoate (<NUM>, <NUM> mmol, <NUM> equiv. ) in THF (<NUM>) and H<NUM>O (<NUM>) was added LiOH·H<NUM>O (<NUM>, <NUM> mmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at RT for <NUM> hours. The pH of the reaction mixture was adjusted to pH = <NUM>-<NUM> with aqueous <NUM> N HCl. The THF was removed under reduced pressure. The precipitate was filtered off and dried under vacuum to afford the title compound (<NUM>, <NUM>% yield) as white solid. LCMS [M-<NUM>] =<NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, N-(<NUM>-acetyl-<NUM>,<NUM>-difluoro-phenyl) -<NUM> -cyano-<NUM>- (trifluoromethylsulfanyl) benzamide: SOCl<NUM> (<NUM>) was added to a flask containing <NUM>-cyano-<NUM>-(trifluoromethylsulfanyl) benzoic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours. The mixture was concentrated under reduced pressure to afford <NUM>-cyano-<NUM>-(trifluoromethylsulfanyl)benzoyl chloride (<NUM>, crude) as white solid which was used in the next phase of the reaction without further purification.

To a mixture of <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluoro-phenyl) ethanone (<NUM>, <NUM> mmol, <NUM> equiv. ) in isopropyl acetate (<NUM>) was added <NUM>-cyano-<NUM>-(trifluoromethylsulfanyl) benzoyl chloride (<NUM>, <NUM> mmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours. The mixture was concentrated under reduced pressure and the crude product was triturated with acetonitrile at RT for <NUM> minutes to afford the title compound (<NUM>, <NUM>% yield) as white solid LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>-quinolin-<NUM>-yl)-<NUM>-(trifluoromethylsulfanyl) benzonitrile: To a mixture of N-(<NUM>-acetyl-<NUM>,<NUM>-difluoro-phenyl)-<NUM>-cyano-<NUM>-(trifluoromethylsulfanyl) benzamide (<NUM>, <NUM> mmol, <NUM> equiv. ) in <NUM>-MeTHF (<NUM>) was added LiOH (<NUM>, <NUM> mmol, <NUM> equiv. ) in at RT under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours under N<NUM>. The reaction mixture was diluted with water (<NUM>) and then concentrated to remove <NUM>-MeTHF. The pH of the mixture was adjusted to pH = <NUM>-<NUM> with aqueous 1N HCl. The precipitate that formed during the pH adjustment was filtered off and then triturated with acetonitrile at RT for <NUM> minutes to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>).

Step <NUM>, <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>-quinolin -<NUM>-yl)-<NUM>-(trifluoromethylsulfonyl)benzonitrile: To a mixture of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>-quinolin-<NUM>-yl)-<NUM>-(trifluoromethylsulfanyl) benzonitrile (<NUM>, <NUM> mmol, <NUM> equiv. ) and RuCl<NUM> (<NUM>, <NUM>µmol, <NUM> equiv. ) in CHCl<NUM> (<NUM>), ACN (<NUM>) and H<NUM>O (<NUM>) was added NaIO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) in one portion at RT under N<NUM>. The mixture was stirred at RT for <NUM> hours. The reaction was quenched with a saturated aqueous solution of Na<NUM>SO<NUM> (<NUM>) and stirred at RT for <NUM> hour. The aqueous phase was extracted with ethyl acetate (<NUM> x <NUM>). The combined organic layers were washed with brine, dried with anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 <NUM> x <NUM> x <NUM>; mobile phase: <NUM>-<NUM>% acetonitrile in water (+formic acid modifier)) to afford the title compound (<NUM>, <NUM>% yield) as white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>).

Step <NUM>, <NUM>-cyano-<NUM>-isopropylsulfanyl-benzoic acid: To a solution of propane-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM> equiv. ) in DMF (<NUM>) was added NaH (<NUM>, <NUM> mmol, <NUM> equiv. ; <NUM>% dispersion in oil). The reaction mixture was stirred at RT for <NUM> hour before methyl <NUM>-chloro-<NUM>-cyano-benzoate (<NUM>, <NUM> mmol, <NUM> equiv. ) was added to the mixture. The resulting mixture was stirred at RT for <NUM> hours. The reaction was quenched with H<NUM>O (<NUM> equiv. ) and the pH of the solution was adjusted to pH = <NUM> with aqueous 1N HCl. The precipitate that formed during the pH adjustment was filtered off and triturated with MTBE at RT for <NUM> minutes to afford the title compound (<NUM>, <NUM>% yield) as a pale-yellow solid. LCMS: [M-<NUM>] = <NUM>. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>).

Step <NUM>, N-(<NUM>-acetyl-<NUM>,<NUM>-difluoro-phenyl)-<NUM>-cyano-<NUM>-isopropylsulfanyl-benzamide: A solution of <NUM>-cyano-<NUM>-isopropylsulfanyl-benzoic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) in SOCl<NUM> (<NUM>) was stirred at <NUM> for <NUM> hour. The reaction mixture was concentrated under reduced pressure to afford <NUM>-cyano-<NUM>-isopropylsulfanyl-benzoyl chloride (<NUM>, crude) as a yellow solid. This material was used in the next phase of the reaction without further purification. To a solution of <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluoro-phenyl)ethanone (<NUM>, <NUM> mmol, <NUM> equiv. ) in isopropyl acetate (<NUM>) was added <NUM>-cyano-<NUM>-isopropylsulfanyl-benzoyl chloride (<NUM>, <NUM> mmol, <NUM> equiv. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was concentrated, and the resulting residue was triturated with acetonitrile at RT for <NUM> minutes to afford the title compound (<NUM>, <NUM>% yield) as a pale-yellow solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>-quinolin-<NUM>-yl)-<NUM>-isopropylsulfanyl-benzonitrile: To a solution of N-(<NUM>-acetyl-<NUM>,<NUM>-difluoro-phenyl)-<NUM>-cyano-<NUM>-isopropylsulfanyl-benzamide (<NUM>, <NUM> mmol, <NUM> equiv. ) in dioxane (<NUM>) was added LiOH (<NUM>, <NUM> mmol, <NUM> equiv. The reaction mixture was stirred at <NUM> for <NUM> hours. The pH of the reaction mixture was adjusted pH = <NUM> with aqueous <NUM> HCl. The precipitate that formed during the pH adjustment was filtered off and then triturated with acetonitrile at RT for <NUM> minutes to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) <NUM><NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(isopropylsulfonyl)benzonitrile: To a solution of <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>-quinolin-<NUM>-yl)-<NUM>-isopropylsulfanyl-benzonitrile (<NUM>, <NUM>µmol, <NUM> equiv. ) in DCM (<NUM>) was added m-CPBA (<NUM>, <NUM> mmol, <NUM> equiv. ; <NUM>% purity). The reaction mixture was stirred at RT for <NUM> hours. The reaction mixture was quenched by the addition of Na<NUM>SO<NUM> (<NUM>) in H<NUM>O (<NUM>). The reaction mixture was extracted with DCM (<NUM> x <NUM>). The combined organic layers were dried over Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 <NUM> x <NUM> x <NUM>; mobile phase: <NUM>-<NUM>% acetonitrile in water (+ HCl modifier)) to afford the title compound (<NUM>, <NUM>% yield) as a white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> - <NUM> (dd, J = <NUM>, <NUM>), <NUM> - <NUM> (dd, J = <NUM> Hz, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>-(<NUM>,<NUM>-difluoro-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM>-yl)-<NUM>-(isobutylsulfonyl)benzonitrile This compound was prepared in a similar manner to that described for Example <NUM>, using <NUM>-methylpropane-<NUM>-thiol as the starting material. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, <NUM>-[<NUM>-amino-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpyrazol-<NUM>-yl)phenyl]ethenone: To a solution of <NUM>-methyl-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)pyrazole (<NUM>, <NUM> mmol, <NUM> equiv. ) and <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluoro-<NUM>-iodo-phenyl)ethanone (<NUM>, <NUM> mmol, <NUM> equiv. ) in dioxane (<NUM>) was added a solution of K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) in H<NUM>O (<NUM>) and Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> (<NUM>, <NUM>µmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours under N<NUM>. The residue was poured into ice-water (<NUM>) and ethyl acetate (<NUM>) stirred for <NUM> minutes. The mixture was filtered through a pad of celite. The organic phase was separated and washed with brine (<NUM> x <NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (<NUM>:<NUM> to <NUM>:<NUM> petroleum ether:ethyl acetate). The crude product was triturated with petroleum ether at RT for <NUM> minutes to afford the title compound (<NUM>, <NUM>% yield) as yellow solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, N-[<NUM>-acetyl-<NUM>,<NUM>-difluoro-<NUM>- (<NUM>-methylpyrazol-<NUM>-yl)phenyl]-<NUM>-chloro-<NUM>-cyano-benzamide: To a mixture of <NUM>-[<NUM>-amino-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpyrazol-<NUM>-yl)phenyl]ethanone (<NUM>, <NUM>µmol, <NUM> equiv. ) in isopropyl acetate (<NUM>) was added <NUM>-chloro-<NUM>-cyano-benzoyl chloride (<NUM>, <NUM>µmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at <NUM>° C for <NUM> hours. The mixture was filtered and concentrated under reduced pressure. The residue was triturated with water and then acetonitrile at RT to afford the title compound (<NUM>, <NUM>% yield,) as light-yellow solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step <NUM>, <NUM>-chloro-<NUM>-[<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpyrazol-<NUM>-yl)-<NUM>-oxo-<NUM>-quinolin-<NUM>-yl]benzonitrile: To a mixture of N-[<NUM>-acetyl-<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpyrazol-<NUM>-yl)phenyl]-<NUM>-chloro-<NUM>- cyano-benzamide (<NUM>, <NUM>µmol, <NUM> equiv. ) in dioxane (<NUM>) was added LiOH (<NUM>, <NUM>µmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours. The residue was poured into ice-water (<NUM>), stirred for <NUM> minutes and filtered. The filter cake was triturated with acetonitrile at RT to afford the title compound (<NUM>, <NUM>% yield) as light-yellow solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

Step <NUM>, <NUM>-[<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpyrazol-<NUM>-yl)-<NUM>-oxo-<NUM>-quinolin -<NUM>-yl]-<NUM>-methylsulfonyl-benzonitrile: To a mixture of sodium methanesulfinate (<NUM>, <NUM>µmol, <NUM> equiv. ), <NUM>-chloro-<NUM>-[<NUM>,<NUM>-difluoro-<NUM>-(<NUM>-methylpyrazol-<NUM>-yl)-<NUM>-oxo-<NUM>-quinolin-<NUM>-yl]benzonitrile (<NUM>, <NUM>µmol, <NUM> equiv. ) and K<NUM>PO<NUM> (<NUM>, <NUM>µmol, <NUM> equiv. ) in DMF (<NUM>) was added CuI (<NUM>, <NUM>µmol, <NUM> equiv. ) at RT under N<NUM>. The mixture was stirred at <NUM> for <NUM> hours. The mixture was quenched by the addition of aqueous ammonia solution and then stirred for <NUM> minutes. The pH of the mixture was adjusted to pH =<NUM>-<NUM> with aqueous 1N HCl. The precipitate that formed during the pH adjustment was filtered off and then purified by preparative HPLC (column: Phenomenex Luna C18 <NUM> x <NUM> x <NUM>; mobile phase: <NUM>-<NUM>% acetonitrile in water (+formic acid modifier)) to afford the title compound (<NUM>, <NUM>% yield) as white solid. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>+D<NUM>O) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>).

This compound was prepared in a similar manner to that described for Example <NUM> using <NUM>-methyl-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)pyridine and <NUM>-(<NUM>-amino-<NUM>,<NUM>-difluoro-<NUM>-iodophenyl)ethanone as the starting materials. LCMS [M+<NUM>] = <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM> Hz, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Compound potency (EC<NUM>) and maximal extent of NCOR1 recruitment to PPARG were assessed a TR-FRET binding assay measuring association of a biotinylated NCOR1 ID2 peptide (Biotin-GHSFADPASNLGLEDIIRKALMG-amide) to PPARG/RXRA LBD heterodimer. Specifically, a <NUM> microliters of TR-FRET master mix consisting of <NUM> WT PPARG LBD (e. coli expressed, His-TEV-Q203-Y477; Uniprot ID P37231-<NUM>), <NUM> WT RXRA LBD or mutant S427F RXRA LBD (e. coli expressed, Flag-TEV-E228-T462; P19793-<NUM>), <NUM> NCOR1, <NUM> Rosiglitazone, <NUM> streptavidin-d2 (Cisbio) and <NUM> Anti-His Tb (Cisbio) in <NUM> MOPS pH <NUM>, <NUM> KC1, <NUM> EDTA, <NUM>% BSA, <NUM>% Tween-<NUM> and <NUM> TCEP was added to <NUM>-well plates containing duplicate <NUM>-point dose response titrations of compounds in <NUM> nL DMSO (<NUM>% f. DMSO (v/v)). Mixtures were incubated for <NUM> hours and read in an EnVision plate reader (Perkin Elmer) with Ex/Em <NUM>/<NUM>. To determine the potency (EC<NUM>) and extent of NCOR1 recruitment, TR-FRET ratios were normalized to the average ratio of DMSO control wells (<NUM>%) and to the average maximum ratio for positive control compound (T0070907 (<NUM>-chloro-<NUM>-nitro-N-<NUM>-pyridinyl-benzamide); defined as <NUM>%) in CDD Vault and analyzed using the Levenberg-Marquardt algorithm.

Compound potency (IC<NUM>) and maximal extent of MED1 repulsion to PPARG were assessed a TR-FRET binding assay measuring association of a biotinylated MED1 LxxLL peptide (Biotin- VSSMAGNTKNHPMLMNLLKDNPAQ-amide) to PPARG/RXRA LBD heterodimer. Specifically, a <NUM> microliters of TR-FRET master mix consisting of <NUM> WT PPARG LBD (e. coli expressed, His-TEV-Q203-Y477; Uniprot ID P37231-<NUM>), <NUM> WT RXRA LBD (e. coli expressed, Flag-TEV-E228-T462; P19793-<NUM>), <NUM> NCOR1, <NUM> Rosiglitazone, <NUM> streptavidin-d2 (Cisbio) and <NUM> Anti-His Tb (Cisbio) in <NUM> MOPS pH <NUM>, <NUM> KC1, <NUM> EDTA, <NUM>% BSA, <NUM>% Tween-<NUM> and <NUM> TCEP was added to <NUM>-well plates containing duplicate <NUM>-point dose response titrations of compounds in <NUM> nL DMSO (<NUM>% DMSO f. Mixtures were incubated for <NUM> hours and read in an EnVision plate reader (Perkin Elmer) with Ex/Em <NUM>/<NUM>. To determine the potency (IC<NUM>) and extent of MED1 repulsion, TR-FRET ratios were normalized to the average ratio of DMSO control wells (<NUM>%) and to the average minimum ratio for positive control compound (GW9662 (<NUM>-chloro-<NUM>-nitrobenzanilide); defined as <NUM>%) in CDD Vault and analyzed using the Levenberg-Marquardt algorithm.

<NUM> (PPARG amplified) and HT1197 (RXRA S427F mutation) cells were used for assessment of modulation of PPARG target genes using quantitative PCR. Cells were treated for <NUM> hours with PPARG inverse agonists prior to analysis of FABP4 (IDT, Cat: Hs. PT <NUM>) and ANGPTL4 (IDT, Cat: Hs. PT <NUM>) expression, with expression of the housekeeping gene TBP (IDT, Cat: Hs. <NUM>) used to normalize expression across samples. Quantitative PCR was performed using an ABI QuantStudio <NUM> Flex Reaction system. Data were analyzed and reported relative to DMSO control using the comparative Ct method (ΔΔCt).

For the PPARG-MED1 recruitment assay the EC<NUM> is expressed as follows, A: <<NUM>, B: <NUM>-<NUM>, C: <NUM>-<NUM>,<NUM>, D: <NUM>,<NUM>-<NUM>,<NUM>, E: ><NUM>,<NUM>. The % MED1 blockade is expressed as follows, A: ><NUM>% (> the control compound, GW9662), B: <<NUM>% (< the control compound, GW9662).

For the HT1197 cell assay the EC<NUM> is expressed as follows, A: <<NUM>, B: <NUM>-<NUM>, C: <NUM>-<NUM>,<NUM>, D: <NUM>,<NUM>-<NUM>,<NUM>, E: ><NUM>,<NUM>, ND: not determined. The % inhibition of ANGPTL4, a PPARG target gene, at <NUM> compound concentration is expressed as percentage of a DMSO control experiment.

While we have described a number of embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claim 1:
A compound having the Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein
R<NUM> is hydrogen, halo, (C<NUM>-C<NUM>)alkyl, or hydroxyl;
X is S, SO, SO<NUM>, or -SONH;
R<NUM> is (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, or halo(C<NUM>-C<NUM>)alkyl;
R<NUM> is cyano or nitro;
R<NUM> is hydrogen, halo, (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, or hydroxyl;
R<NUM> is halo, halo(C<NUM>-C<NUM>)alkyl, or cyano;
R<NUM> is halo, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkyl, or cyano;
R<NUM> is halo, (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkoxy, -(C<NUM>-C<NUM>)alkylORa, -(C<NUM>-C<NUM>)alkylC(O)Ra, -(C<NUM>-C<NUM>)alkylC(O)ORa, -C(O)NRaRb, -(C<NUM>-C4)alkylC(O)NRaRb, -C(O)Ra, -C(O)ORa, -NRaRb, -(C<NUM>-C<NUM>)alkylNRaRb, -C(O)NRaSO<NUM>H, - NRaC(O)Rb, -NRaC(O)ORb, -NRaC(S)ORb, -NRcC(O)NaRb, -NRcC(S)NRaRb, - NRcS(O)<NUM>NRaRb, -C(S)Ra, -S(O)<NUM>Ra, -S(O)Ra, -C(S)ORa, -C(S)NRaRb, -NRaC(S)Rb, -SRa, phenyl, <NUM>- to <NUM>-membered heterocyclyl, and <NUM>- to <NUM>-membered heteroaryl, wherein each of said phenyl, <NUM>- to <NUM>-membered heterocyclyl, and <NUM>- to <NUM>-membered heteroaryl are optionally and independently substituted with <NUM> to <NUM> groups selected from R<NUM>
R<NUM> is selected from halo, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkoxy, nitro, oxo, cyano, -(C<NUM>-C<NUM>)alkylORd, -(C<NUM>-C<NUM>)alkylC(O)Rd, -(C<NUM>-C4)alkylC(O)ORd, -C(O)NRdRe, -(C<NUM>-C<NUM>)alkylC(O)NRdRe, -C(O)Rd, -C(O)ORd, -NRdRe, - (C<NUM>-C<NUM>)alkylNRdRe, -C(O)NRdSO<NUM>H, -NRdC(O)Re, -NRdC(O)ORe, -NRdC(S)ORe, - NRfC(O)NdRe, -NRfC(S)NRdRe, -NRfS(O)<NUM>NRdRe, -C(S)Rd, -S(O)<NUM>Rd, -S(O)Rd, -C(S)ORd, - C(S)NRdRe, -NRdC(S)Re, and -SRd;
Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen or (C<NUM>-C<NUM>)alkyl; and
q and r are each independently <NUM> or <NUM>.