PPARG inverse agonists and uses thereof

Abstract

Compounds of formula (I), as well as pharma- ceutically acceptable salts and compositions thereof, are provided that are useful for treating a variety of conditions associated with PPARG. TIFF2025508272000080.tif2133

Description

[Technical field]

[0001] Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 274,596, filed November 2, 2021, and U.S. Provisional Application No. 63 / 347,671, filed June 1, 2022, the entire contents of each of which are incorporated by reference herein. [Background technology]

[0002] PPAR gamma (PPARG) is a type II ligand-dependent nuclear hormone receptor (belonging to the PPAR nuclear receptor subfamily) that functions as an obligate heterodimer with the retinoid X receptor (RXR). PPARG is expressed primarily in adipose tissue, colon, macrophages and the luminal layer of the urothelium. PPARG is known as a master regulator of adipogenesis and functions to regulate adipocyte differentiation, fatty acid storage and glucose metabolism. PPARG has also been shown to play an important role in macrophage metabolism and inflammation induced by IL4, controlling glutamine metabolism. In normal urothelium, PPARG is essential for its homeostasis and renewal.

[0003] The role of PPARG in cancer was originally inferred from genomic studies that identified PAX8-PPARG chromosomal rearrangements in follicular thyroid carcinoma. More recently, PPARG was found to be overexpressed and genetically altered in the luminal subtype of urothelial carcinoma. This is consistent with reports that long-term use of PPARG agonists is associated with increased incidence of urothelial carcinoma. The majority of urothelial carcinomas are urothelial carcinomas, which are classified as either non-muscle invasive urothelial carcinoma (NMIUC, 70%), muscle invasive urothelial carcinoma (MIUC, 25%) or metastatic urothelial carcinoma (MUC, 5%). MIUC is usually newly diagnosed, but 10-20% of NMIUC cases may eventually progress. MIUC is a heterogeneous and aggressive disease associated with a 5-year survival rate of 60% for patients with localized disease and less than 10% for patients with distant metastases. The molecular understanding of NMIUC and MIUC has improved significantly, including the relationship between molecular subtypes and urothelial differentiation. Several molecular classes of MIUC have been proposed, with an activated PPARG signature prominent in the luminal subtype. First-line treatment is chemotherapy, and although there are several options for chemotherapy-ineligible or second-line patients, options are limited and overall survival is poor.

[0004]

[0004] There is a need to develop effective PPARG modulators for treating cancers such as NMIUC, MIUC and MUC, and related conditions. Summary of the Invention [Means for solving the problem]

[0005] As used herein, the compound of formula I

[0006] [ka]

[0007] and pharma- ceutically acceptable salts and compositions thereof, 1 , R 2, R 3 , R 4 , R 5 , R 6 , R 7 , X, q and r are as described herein. In one embodiment, the disclosed compounds of formula I and their pharma- ceutically acceptable salts modulate PPARG (e.g., as agonists, such as inverse agonists) and are useful in various therapeutic applications, such as in the treatment of cancer. Thus, their use for treating diseases that respond to the inhibition of PPARG is included.

[0008] Also included are pharmaceutical compositions comprising the disclosed compounds of Formula I and pharma ceutically acceptable salts thereof, as well as methods for their preparation. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern (XRPD) for crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile. [Diagram 2] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram of Form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 1. Overview of the compound In a first embodiment, a compound of formula I

[0011] [ka]

[0012] or a pharma- ceutically acceptable salt thereof (In the formula, R 1 is hydrogen, halo, (C1 ~C 4 ) alkyl or hydroxyl; X is S, SO, SO 2 , or -SONH, R 2 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, or halo(C 1 -C 4 ) alkyl, R 3 is cyano or nitro, R 4 is hydrogen, halo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkoxy or hydroxyl, R 5 Ha, halo, halo (C 1 ~C 4 ) alkyl or cyano; R 6 Ha, halo, halo (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkyl or cyano; R 7 Halo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 )alkoxy, -(C 1 ~C 4 ) Alkyl OR a , -(C 1 ~C 4 )AlkylC(O)R a , -(C 1 ~C 4 )AlkylC(O)OR a , -C(O)NR a R b , -(C 1 ~C4 )AlkylC(O)NR a R b , -C(O)R a , -C(O)OR a , -NR a R b , -(C 1 ~C 4 ) Alkyl NR a R b , -C(O)NR a SO 3 H, -NR a C(O)R b , -NR a C(O)OR b , -NR a C(S)OR b , -NR c C(O)N a R b , -NR c C(S)NR a R b , -NR c S(O) 2 NR a R b , -C(S)R a , -S(O) 2 R a , -S(O)R a , -C(S)OR a , -C(S)NR a R b , -NR a C(S)R b , -SR a , phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl, each of said phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl being optionally and independently selected from R 8 is substituted with 1 to 3 groups selected from R 8 Halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 )alkoxy, nitro, oxo, cyano, -(C1 ~C 4 ) Alkyl OR d , -(C 1 ~C 4 )AlkylC(O)R d , -(C 1 ~C 4 )AlkylC(O)OR d , -C(O)NR d R e , -(C 1 ~C 4 )AlkylC(O)NR d R e , -C(O)R d , -C(O)OR d , -NR d R e , -(C 1 ~C 4 ) Alkyl NR d R e , -C(O)NR d SO 3 H, -NR d C(O)R e , -NR d C(O)OR e , -NR d C(S)OR e , -NR f C(O)N d R e , -NR f C(S)NR d R e , -NR f S(O) 2 NR d R e , -C(S)R d , -S(O) 2 R d , -S(O)R d , -C(S)OR d , -C(S)NR d R e , -NR d C(S)R e and -SR d is selected from R a , R b , R c , R d , R e and R fare each independently hydrogen or (C 1 ~C 4 ) alkyl, q and r are each independently 0 or 1. is provided.

[0013] 2.Definition When used in connection with describing a chemical group that may have multiple points of attachment, a hyphen (-) refers to the point of attachment of the group to the variable for which it is defined. For example, -NR b C(O)OR c and -NR b C(S)OR c means that the point of attachment for this group occurs on the nitrogen atom.

[0014] The terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0015] The term "alkyl", whether used alone or as part of a larger moiety such as "haloalkyl", means a saturated straight or branched chain monovalent hydrocarbon radical. "Alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C 1 ~C 4 )Alkoxy" includes methoxy, ethoxy, proproxy and butoxy.

[0016] The term "haloalkyl" includes mono-, poly- and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine, bromine and iodine. "Haloalkoxy" is, for example, -OCHF 2 Or -OCF 3 and the like are haloalkyl groups that are attached to another moiety through an oxygen atom.

[0017] The term oxo means the group ═O. The term "5-7 membered heteroaryl" used alone or as part of a larger moiety refers to a 5-7 membered aromatic group containing 1-4 heteroatoms selected from N, O and S. Monocyclic heteroaryls include, 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 the heteroaryl group may be present at any substitutable position, including, for example, the position at which the heteroaryl is attached.

[0018] The term "4-6 membered heterocyclyl" refers to a 4-6 membered saturated or partially unsaturated heterocycle containing 1-4 heteroatoms independently selected from N, O and S. The heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom resulting in a stable structure. Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, oxetanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl and tetrahydropyrimidinyl. Optional substituents on the heterocyclyl group can be present at any substitutable position, including the position at which the heterocyclyl is attached.

[0019] The disclosed compounds may exist in one or more tautomeric forms, such as those below, and are included herein.

[0020] [ka]

[0021]

[0020] As used herein, "crystalline" refers to a solid form of a compound in which there is long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of its powder X-ray diffraction pattern.

[0022]

[0021] Unless otherwise specified, crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is a single crystalline form, which means that 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile exists as a single crystal or as multiple crystals, each crystal having the same crystalline form (i.e., form A).

[0023]

[0022] The 2-theta values ​​of the powder X-ray diffraction patterns for the crystalline forms described herein may vary slightly from instrument to instrument, and also depend on variations in sample preparation and batch-to-batch variations due to factors such as temperature changes, sample substitution, and the presence or absence of an internal standard. Therefore, unless otherwise specified, the XRPD patterns / assignments shown herein are not to be taken as absolute and may vary by ±0.2 degrees. It is well known in the art that this variability accounts for the above factors and does not prevent the unambiguous identification of the crystalline forms. Unless otherwise specified, the 2-theta values ​​provided herein were obtained using Cu Kα1 radiation.

[0024]

[0023] For example, the temperature values ​​of DSC peaks herein may vary slightly from instrument to instrument and are also dependent on variations in sample preparation, batch-to-batch variations, and environmental factors. Thus, unless otherwise defined, the temperature values ​​given herein are not to be construed as absolute and may vary by ±5 degrees or ±2 degrees.

[0025]

[0024] "Substantially the same XRPD pattern" or "substantially similar powder X-ray diffraction pattern" as defined in the drawings means that, for comparative purposes, at least 90% of the peaks shown are present. It is further understood that, for comparative purposes, some variability in peak intensities from those shown is permitted, such as ±0.2 degrees.

[0026]

[0025] The terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0027]

[0026] The terms "inhibit," "inhibition," or "inhibiting" include a reduction in the baseline activity of a biological activity or process.

[0027] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of, or preventing the progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered asymptomatically. 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 exposure to a particular organism or other susceptibility factor), i.e., prophylactic treatment. Treatment may also be continued after symptoms have disappeared, e.g., to delay their recurrence.

[0028] The term "pharmaceutical 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 can 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, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

[0029]

[0029] For use in medicine, the salts of the compounds described herein refer to non-toxic "pharmaceutical acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutical acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutical acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present teachings having an acidic group, such as a carboxylic acid, can form pharmaceutical acceptable salts with a pharmaceutical acceptable base(s). Suitable pharmaceutical acceptable base salts include, for example, ammonium salts, alkali metal salts (e.g., sodium and potassium salts), and alkaline earth metal salts (e.g., magnesium and calcium salts). Compounds having a quaternary ammonium group also include counterions 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.

[0030]

[0030] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that elicits a desired or beneficial biological or medical response in a subject, for example, a dosage of between 0.01 and 100 mg / kg body weight / day.

[0031] 3.Compound In a second embodiment, the compound of formula I is represented by formula II

[0032] [ka]

[0033] or a pharma- ceutically 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 a compound of formula II a

[0034] [ka]

[0035] or a pharma- ceutically acceptable salt thereof, wherein the variables are as described above for formula I. Alternatively, as part of the second embodiment, the compound of formula I is represented by formula III

[0036] [ka]

[0037] or a pharma- ceutically acceptable salt thereof, wherein the variables are as described above for formula I. Alternatively, as part of the second embodiment, the compound of formula I is represented by formula III a

[0038] [ka]

[0039] or a pharma- ceutically acceptable salt thereof, wherein the variables are as described above for formula I. Alternatively, as part of the second embodiment, the compound of formula I is represented by formula IV

[0040] [ka]

[0041] or a pharma- ceutically acceptable salt thereof, wherein the variables are as described above for formula I. Alternatively, as part of the second embodiment, the compound of formula I is represented by formula IV a

[0042] [ka]

[0043] or a pharma- ceutically acceptable salt thereof, in which the variables are as described above for Formula I. In a third embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 1 is hydrogen, and the remainder of the variables are as described above for Formula I.

[0044] In a fourth embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 3 is cyano, and the remainder of the variables are as described above for Formula I or the third embodiment.

[0045] In a fifth embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 4 is hydrogen, and the remaining variables are as described above for Formula I, or any one of the third or fourth embodiments.

[0046] In a sixth embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 5 is halo or cyano, and the remaining variables are as described above for Formula I, or any one of the third, fourth or fifth embodiments. Alternatively, as part of the sixth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, 5 is halo, and the remaining variables are as described above for Formula I, or any one of the third, fourth or fifth embodiments. Alternatively, as part of the sixth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, 5 is chloro or fluoro, and the remaining variables are as described above for Formula I, or any one of the third, fourth or fifth embodiments. Alternatively, as part of the sixth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, 5 is fluoro, and the remaining variables are as described above for Formula I, or any one of the third, fourth or fifth embodiments.

[0047] In a seventh embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 6 is halo, and the remaining variables are as described above for Formula I, or any one of the third through sixth embodiments. Alternatively, as part of the seventh embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, 6 is fluoro or chloro, and the remaining variables are as described above for Formula I, or any one of the third through sixth embodiments. Alternatively, as part of the seventh embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, 6 is fluoro, and the remaining variables are as described above for Formula I or any one of the third through sixth embodiments.

[0048] In an eighth embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 7 Ha, halo, halo (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )alkoxy, -(C 1 ~C 4 ) Alkyl OR a , -C(O)NR a R b , phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl, each of said phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl being optionally and independently selected from R 8 and the remaining variables are as described above for Formula I, or any one of the third through seventh embodiments. Alternatively, as part of the eighth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is 7 Ha, halo, halo (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkyl, (C 1~C 4 )alkoxy, -(C 1 ~C 4 ) Alkyl OR a , -C(O)NR a R b , phenyl, pyridinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, pyrazolyl, and oxetanyl, each of said phenyl, pyridinyl, pyrazolyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, piperidinyl, and oxetanyl may optionally and independently be selected from R 8 and the remaining variables are as described above for Formula I, or any one of the third through seventh embodiments. Alternatively, as part of the eighth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is 7 Ha, halo, halo (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )alkoxy, -(C 1 ~C 4 ) Alkyl OR a , -C(O)NR a R b , phenyl, pyridinyl, pyrazolyl, and oxetanyl, each of said phenyl, pyridinyl, pyrazolyl, and oxetanyl being optionally and independently selected from R 8 and the remaining variables are as described above for Formula I, or any one of the third through seventh embodiments. Alternatively, as part of the eighth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is 7 is pyrazolyl, pyridinyl, or piperazinyl, each of which is optionally and independently selected from R 8 and the remaining variables are as described above for Formula I, or any one of the third through seventh embodiments. In yet another alternative, as part of the eighth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is 7may optionally and independently be R 8 and the remaining variables are as described above for formula I or any one of the third through seventh embodiments.

[0049] In a ninth embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 8 Halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) alkoxy, oxo, and cyano, and the remaining variables are as described above for Formula I or any one of the third through eighth embodiments. Alternatively, as part of the ninth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is 8 Halo(C 1 ~C 4 ) alkyl, and the remaining variables are as described above for Formula I, or any one of the third through eighth embodiments. Alternatively, as part of the ninth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is 8 is (C 1 ~C 4 ) alkyl, and the remaining variables are as described above for Formula I or any one of the third through eighth embodiments.

[0050] In a tenth embodiment, R in a compound of formula I or II or a pharma- ceutically acceptable salt thereof is 2 Halo(C 1 ~C 4 ) alkyl or (C 1 ~C 4 ) alkyl, and the remaining variables are as described above for Formula I, or any one of the third through ninth embodiments. Alternatively, as part of the tenth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is2 (C 1 ~C 4 ) alkyl, and the remaining variables are as described above for Formula I, or any one of the third through ninth embodiments. Alternatively, as part of the tenth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is 2 is CH 3 , C.H. 2 CH 3 , C.F. 3 CH 2 , C.F. 3 , CH(CH 3 ) 2 or CH 2 CH(CH 3 ) 2 and the remaining variables are as described above for Formula I or any one of the third through ninth embodiments. Alternatively, as part of the tenth embodiment, R in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, 2 CH 3 and the remainder of the variables are as described above for Formula I or any one of the third through ninth embodiments.

[0051] In an eleventh embodiment, X in the compound of formula I or II or a pharma- ceutically acceptable salt thereof is SO 2 and the remaining variables are as described above for Formula I or any one of the third through tenth embodiments.

[0052]

[0041] Compounds having formula I and II are further disclosed in the examples and are included in the present disclosure. Pharmaceutically acceptable salts and neutral forms thereof are also included. In certain embodiments, one or more hydrogen atoms on the compounds disclosed herein can be replaced by deuterium.

[0053] 4.Crystal morphology

[0042] Also provided herein is 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile of crystalline form A. Also provided herein is a pharmaceutical composition comprising 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile of crystalline form A. Further provided is the use of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile of crystalline form A for treating diseases that are responsive to the inhibition of PPARG.

[0054]

[0043] In one embodiment, provided herein is 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile of crystalline form A, the crystalline form being characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 18.8° and 19.8°. Alternatively, 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile of crystalline form A, the crystalline form being characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 18.8° and 19.8°. In another alternative, crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 18.8°, and 19.8°. In yet another alternative, crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, and 12.7°. In yet another alternative, the crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, and 19.8°. In yet another alternative, the crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by at least three powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 17.7°, 18.8°, 19.8°, and 22.2°.In yet another alternative, the crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 17.7°, 18.8°, 19.8°, and 22.2°. In yet another alternative, the crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 17.7°, 18.8°, 19.8°, and 22.2°. In yet another alternative, the crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 17.7°, 18.8°, 19.8°, and 22.2°. In yet another alternative, the crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 17.7°, 18.8°, 19.8°, and 22.2°. In yet another alternative, crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by at least 3, at least 4, at least 5, at least 6, at least 8, at least 9, or at least 10 peaks selected from those in Table 1. In yet another alternative, crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by an XRPD substantially similar to that in FIG.In yet another alternative, crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by a differential scanning calorimetry (DSC) having an endotherm at 304° C. (onset temperature), and the crystalline form may also include an XRPD peak at a 2Θ angle selected from any of those described above. In yet another alternative, crystalline form A of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile is characterized by a differential scanning calorimetry (DSC) substantially similar to FIG. 2, and crystalline form 1 may also include an XRPD peak at a 2Θ angle selected from any of those described above.

[0055] [Table 1]

[0056] 6. General Methods In one aspect, as part of the twelfth embodiment, the compound of formula I is of formula A

[0057] [ka]

[0058] wherein L is a leaving group and the remaining variables are as described above for a compound of formula I or any one of the third to ninth embodiments, by reacting a compound of formula I with XR 2 with a corresponding sulfur nucleophile to form a 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 the twelfth embodiment, the compound of formula A can be prepared by a method comprising reacting the compound of formula A with a corresponding sulfur nucleophile to form a 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 the twelfth embodiment, the compound of formula A can be prepared by reacting the compound of formula A with a corresponding sulfur nucleophile to form a compound of formula I. 2 O, Cu(OAc) 2In some aspects, as part of the twelfth embodiment, the compound of formula A reacts with a sulfur nucleophile in the presence of a copper catalyst, such as CuBr, CuCl, etc. In some aspects, as part of the twelfth embodiment, the compound of formula A reacts with a sulfur nucleophile in the presence of a copper ligand, such as an organic base (e.g., proline, quinolone-8-ol, hydroxyproline, N-Me glycine, and dimethylglycine). In some aspects, in the twelfth embodiment, q and r are each 0. In some aspects, in the twelfth embodiment, XR 2 teeth - S(O) 2 CH 3 Like - S(O) 2 (C 1 ~C 4 ) alkyl. In some aspects, as part of the twelfth embodiment, the compound of formula A is reacted with a sulfur nucleophile in the presence of an organic solvent, such as a polar aprotic solvent (e.g., DMSO, DMF, NMP, and DMA). ... 3 PO 4 , K 2 CO 3 , NaHCO 3 , K 2 HPO 4 , Na 2 CO 3 , Na 3 PO 4 , Li 3 PO 4 , reacts with sulfur nucleophiles in the presence of bases such as KOtBu and KHMDS. In some aspects, the compound of formula I in the twelfth embodiment is 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile. In some aspects, the compound of formula I in the twelfth embodiment is crystalline form A 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile as defined by one or more of the XRPD peaks defined herein.

[0059] In one aspect, as part of the thirteenth embodiment, a compound of formula A

[0060] [ka]

[0061] wherein L is a leaving group and the remaining variables are as described above for a compound of formula I or any one of the third to ninth embodiments, comprising:

[0062] [ka]

[0063] In some aspects, the base in the eleventh embodiment is selected from the group consisting of LiOtBu, LiOH, NaOH, KOH, and CsOH·H. 2 In some aspects, the compound of the eleventh embodiment having formula B is reacted with a base in the presence of an organic solvent, such as a polar aprotic solvent, such as THF, 2-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, in the thirteenth embodiment, q and r are each 0. In some aspects, the compound of formula A in the thirteenth embodiment is

[0064] [ka]

[0065] In some aspects, the compound of formula B in the thirteenth embodiment is

[0066] [ka]

[0067] It is. In one aspect, as part of the fourteenth embodiment, a compound of formula B

[0068] [ka]

[0069] wherein L is a leaving group such as a halogen leaving group (e.g., chloro), and the remaining variables are as described above for a compound of formula I or any one of the third to ninth embodiments, comprising:

[0070] [ka]

[0071] The compound having the formula D

[0072] [ka]

[0073] In some aspects, in the fourteenth embodiment, q and r are each 0. In some aspects, in the fourteenth embodiment, the compound of formula B is

[0074] [ka]

[0075] In some aspects, the compound of formula C in the fourteenth embodiment is

[0076] [ka]

[0077] In some aspects, the compound of formula D in the fourteenth embodiment is

[0078] [ka]

[0079] where L is as defined above. In one aspect, as part of the fifteenth embodiment, a compound of formula C

[0080] [ka]

[0081] wherein the remaining variables are as described above for the compounds of formula I or any one of the third, sixth, seventh or eighth embodiments, comprising:

[0082] [ka]

[0083] (In the formula, L v is a leaving group such as a halogen (e.g., fluoro) with an ammonia ion, such as from ammonium hydroxide, to form a compound having formula C. In some aspects, the compound having formula E is reacted with an ammonia ion, such as from ammonium hydroxide, in the presence of an organic solvent, such as a polar aprotic solvent or a polar protic solvent, such as THF, 2-MeTHF, IPA, toluene, acetonitrile, DMP, NMP, CPME, and MTBE. In some aspects, the compound having formula E is reacted with an ammonia ion, such as from ammonium hydroxide, in the presence of 2-MeTHF. In some aspects, in a fifteenth embodiment, q and r are each 0. In some aspects, the compound of formula C in the fifteenth embodiment is

[0084] [ka]

[0085] In some aspects, the compound of formula E in the fifteenth embodiment is

[0086] [ka]

[0087] It is. In one aspect, as part of the sixteenth embodiment, a compound of formula D

[0088] [ka]

[0089] wherein L is a leaving group such as, for example, a halogen leaving group (e.g., chloro), and the remaining variables are as described above for formula I or any one of the fourth or fifth embodiments, comprising:

[0090] [ka]

[0091] With a chlorinating agent, such as thionyl chloride, a compound of formula D in a sixteenth embodiment is provided.

[0092] [ka]

[0093] In some aspects, the compound of formula F in the sixteenth embodiment is

[0094] [ka]

[0095] It is. In one aspect, as part of the seventeenth embodiment, a compound of formula G

[0096] [ka]

[0097] where L is a leaving group such as a halogen leaving group (e.g., chloro) and R 4 is as described above for any one of formula I or the fourth or fifth embodiment, comprising the steps of:

[0098] [ka]

[0099] The compound having the formula: 2 , Pd 2 (dba) 3 In some aspects, as part of the seventeenth embodiment, the method includes reacting with a palladium catalyst such as, for example, dppb, tBu 3 HBF 4 , dppp, Ph 3 P, XantPhos, dppf, AmgenPHOS, DPEPhos, RuPHOS, R-BINAP, (o-tol) 3 P, S-PHOS, X-Phos, tBu-XPhos and Ph 2 -CH 2 CH 2 -(2-Pyr)). Solvents: DMAc, tBuOH, DMAc / water, and tBuOH / water. In some aspects, the compound of formula G in the seventeenth embodiment is

[0100] [ka]

[0101] In some aspects, the compound of formula H in the seventeenth embodiment is

[0102] [ka]

[0103] It is. Other methods of preparation are disclosed in the Exemplification section and are included as part of this invention.

[0104] 6. Use, Formulation and Administration

[0051] The compounds and compositions described herein are generally useful for modulating the activity of PPARG. In some embodiments, the compounds, pharma- ceutically acceptable salts, and pharmaceutical compositions described herein inhibit the activity of PPARG. In some embodiments, the compounds and pharma- ceutically acceptable salts disclosed herein are agonists of PPARG. In some embodiments, the compounds and pharma- ceutically acceptable salts disclosed herein are agonists of PPARG. In some embodiments, the compounds and pharma- ceutical acceptable salts disclosed herein are inverse agonists of PPARG. In one embodiment, an "inverse agonist" refers to an agent that binds to the same receptor binding site as an agonist (e.g., the binding site of a nuclear receptor such as PPARG) and exerts the opposite effect by not only antagonizing the effect of the agonist, but also suppressing spontaneous receptor signaling (if present).

[0105] In some aspects, the compounds and pharma- ceutically acceptable salts disclosed herein overcome the activated state of PPARG function resulting from altered PPARG activity (mutation, amplification or overexpression) or RXRA-activating mutation. In some aspects, the compounds and pharma- ceutically acceptable salts disclosed herein increase the repressed state (NCOR1 recruitment) to a greater extent than previously disclosed PPARG regulators, such as previous inverse agonists. Such results occur even in the context of mutants. For example, see the table in the Examples section that qualitatively evaluates NCOR1 recruitment and repression of PPARG target genes in HT1197.

[0106] In some aspects, the compounds and pharmaceutical compositions described herein are useful for treating disorders associated with PPARG function. Thus, provided herein is a method for treating disorders associated with PPARG function, comprising administering to a subject in need of treatment of the disorder a therapeutically effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein or a pharma- ceutically acceptable salt thereof.

[0107]

[0054] Also provided is the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for treating a disorder associated with PPARG function.Also provided is a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, or a disclosed compound or a pharma- ceutically acceptable salt thereof, for use in treating a disorder associated with PPARG.

[0108] In one aspect, the PPARG-associated disorder is cancer. In some aspects, the cancer is associated with an upregulated peroxisome proliferator-activated receptor (PPAR) signaling pathway. In some aspects, the upregulated PPAR signaling pathway is associated with increased expression of one or more genes selected from uroplakin 1A (UPK1A), uroplakin IB (UPK1B), uroplakin (UPK2), keratin 20 (KRT20), GATA binding protein 3 (GAT A3), nuclear receptor corepressor 1 (NCORl), nuclear receptor corepressor 2 (NCOR2), fatty acid binding protein 4 (FABP4), forkhead box A1 (FOXA1), CD36 molecule (CD36), acyl-CoA oxidase 1 (ACOX1), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), acyl-CoA synthase long chain family member 5 (ACSL5), arachidonate 5-lipoxygenase (ALOX5), acyl-CoA synthase long chain family member 1 (ACSL1), and angiopoietin-like 4 (ANGPTL4).

[0109] In some embodiments, the cancer treated by the compounds described herein, their pharmaceutically acceptable salts and pharmaceutical compositions 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 hematopoietic cancer (e.g., lymphoma, multiple myeloma and leukemia). In one embodiment, the cancer treated by the compounds described herein, their pharmaceutically acceptable salts and pharmaceutical compositions is urothelial cancer, e.g., non-muscle invasive urothelial cancer, muscle invasive urothelial cancer and metastatic urothelial cancer.

[0110]

[0057] Other uses besides cancer are contemplated, such as angiogenesis and neovascularization in metabolic diseases (e.g. osteoporosis, rickets, arthropathy, obesity, type 1 and type 2 diabetes), lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic nephropathy, diabetic complications, hyperuricemia, osteoporosis, rickets, arthropathy, inflammatory diseases (e.g. inflammatory skin diseases such as psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus), pulmonary disorders (e.g. asthma and chronic obstructive pulmonary disease), autoimmune diseases, neurodegenerative diseases (e.g. multiple sclerosis, Alzheimer's disease and Parkinson's disease), cardiovascular diseases (e.g. selected from atherosclerosis, venous and arterial occlusive diseases), stenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, neoplastic diseases and renal diseases.

[0111] In certain aspects, the pharmaceutical compositions described herein are formulated for administration to a patient in need of such compositions. The pharmaceutical compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally or via a subcutaneously implanted reservoir. The term "parenterally" as used herein includes subcutaneous, intravenous, intramuscular, intraarterial, intrasynovial, 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 suspensions. These suspensions may be formulated by techniques well known in the art using suitable dispersing or wetting agents and suspending agents.

[0112]

[0059] In some aspects, the pharmaceutical composition is administered orally. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of the compounds described herein in the composition will also depend on the particular compound in the pharmaceutical composition.

[0113] Example chemical synthesis The following representative examples are intended to help illustrate the present disclosure, but they are not intended, and should not be construed, to limit the scope of the invention.

[0114] Typical starting materials used were obtained from commercial sources or prepared in other instances unless otherwise noted.

[0063] DSC, Mettler Toledo DSC 3+ Samples (1-5 mg) were weighed directly into 40 μL sealed aluminum pans with a pinhole and analyzed according to the following parameters:

[0115] [Table 2]

[0116]

[0064] XRPD samples were analyzed using a Bruker D8 ADVANCE X-ray diffractometer using copper radiation (Cu Kα, λ = 1.54060 Å). The generator was operated at a voltage of 40 KV and an amperage of 40 mA. Data were collected with a scan range of 4-40°, a step size of 0.02°, a scan speed of 10° / min, and a sample rotation speed of 15 rpm.

[0117] Preparation of compounds The compounds claimed herein were prepared according to the procedures outlined in the following schemes.

[0118]

[0066]

[0119] [ka]

[0120]

[0067] Quinolones such as S6 can be prepared by the general synthetic methodology shown in Scheme 1. Compounds of formula S2 can be prepared from aniline S1 by treatment with acetonitrile, boron trichloride, aluminum trichloride and HCl in an organic solvent such as dichloromethane. Treatment of acetylaniline S2 with acyl chloride S3 gives intermediates of formula S4. Quinolones such as S5 can then be prepared by treatment of S4 at elevated temperature with hydroxide base in an organic solvent such as dioxane. The chloride on S5 can then be displaced with a sulfur-based nucleophile to generate S6 via SNAr reaction or copper catalysis. Acyl chloride S3 can be prepared from the corresponding acid by treatment with thionyl chloride and oxalyl chloride in an organic solvent such as dichloromethane.

[0121]

[0068]

[0122] [ka]

[0123] Certain quinolone analogs S6 can also be prepared via a two-step process consisting of nucleophilic addition of a thiol to S5, followed by oxidation of the thioether S7.

[0070]

[0124] [ka]

[0125] Certain quinolone analogs S6 can also be prepared via a three-step process consisting of acylation of S2 with S8 to give S9, cyclization of amide S9 to give quinolone S7, and oxidation of the thioether of S7.

[0126] Preparation of Starting Materials

[0127] [ka]

[0128] 1-(6-amino-2,4-difluoro-3-(4-methylpiperazin-1-yl)phenyl)ethan-1-one Step 1. 1-(3-bromo-2,6-difluoro-4-nitrophenyl)-4-methylpiperazine: To a solution of 2-bromo-3,4,5-trifluoro-1-nitrobenzene (5 g, 19.5 mmol, 1.0 equiv.) in DMSO (50 mL), was added K 2 CO 3 (4.05 g, 29.3 mmol, 1.5 equiv) and 1-methylpiperazine (1.96 g, 19.5 mmol, 2.2 mL, 1.0 equiv) were added. The mixture was stirred at 20 °C for 16 h. LCMS showed that compound 1 was completely consumed and one main peak with the desired mass was detected. The suspension was filtered through a Celite pad and the pad cake was washed with EtOAc (10 mL × 3). The filtrate was diluted with EtOAc (20 mL × 3) and H 2 The combined organic layers were washed with brine (15 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 1-(3-bromo-2,6-difluoro-4-nitrophenyl)-4-methylpiperazine as a yellow solid (6.5 g, 99.0% yield). 1H NMR (400 MHz, chloroform-d) δ 7.66 (dd, J = 1.8, 11.8 Hz, 1H), 3.40 (br t, J = 4.8 Hz, 4H), 2.59 - 2.50 (m, 4H), 2.36 (s, 3H).

[0129] Step 2. 2-Bromo-3,5-difluoro-4-(4-methylpiperazin-1-yl)aniline: To a solution of 1-(3-bromo-2,6-difluoro-4-nitrophenyl)-4-methylpiperazine (6.5 g, 19.3 mmol, 1.0 equiv) in EtOH (40 mL) was added H 2 NH in O (20 mL) and Fe (5.40 g, 96.7 mmol, 5.0 equiv.) 4 A solution of 1000 ml of 1,000 ml of ethyl acetate (5.17 g, 96.7 mmol, 5.0 equiv.) was added. The mixture was stirred at 80° C. for 2 h. LCMS showed that compound 2 was completely consumed and one main peak with the desired mass was detected. The suspension was filtered through a Celite pad and the pad cake was washed with EtOAc (50 mL×3). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with EtOAc (10 mL×3) and H 2 The combined organic layers were washed with brine (5 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 2-bromo-3,5-difluoro-4-(4-methylpiperazin-1-yl)aniline as a yellow solid (4.5 g, 76.0% yield). 1 H NMR (400 MHz, chloroform-d) δ 6.27 (br s, 2H), 6.11 (dd, J = 1.8, 12.8 Hz, 1H), 3.17 - 3.01 (m, 4H), 2.57 (d, J = 8.8 Hz, 3H), 2.35 (s, 3H), 2.30 - 2.30 (m, 1H), 1.41 - 1.16 (m, 3H). Step 3, 1-(6-amino-2,4-difluoro-3-(4-methylpiperazin-1-yl)phenyl)ethan-1-one: To a solution of tributyl(1-ethoxymethyl)stannane (10.5 g, 29.0 mmol, 3.0 equiv.) and 2-bromo-3,5-difluoro-4-(4-methylpiperazin-1-yl)aniline (3 g, 9.80 mmol, 1.0 equiv.) in toluene (30 mL) was added Pd(PPh 3 ) 4 (1.13 g, 980 umol, 0.1 equiv.) was added. The mixture was stirred at 120° C. for 16 h. LCMS showed that compound 3 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was quenched by the addition of KF solution (30 mL) at 20° C. and stirred for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the intermediate 2-(1-ethoxymethyl)-3,5-difluoro-4-(4-methylpiperazin-1-yl)aniline (8.8 g) as a dark brown oil. 2.H 2 To a solution of 2-(1-ethoxymethyl)-3,5-difluoro-4-(4-methylpiperazin-1-yl)aniline (8.8 g, 29.60 mmol, 1 equiv.) in 2H2O (3.0 mL) was added HOAc (26.4 mL). The mixture was stirred at 20° C. for 3 h. LCMS showed that the intermediate was completely consumed. The reaction mixture was cooled to 20° C. with NaHCO 3 The mixture was quenched by the addition of EtOAc (50 mL) and NaOH (20 mL). The resulting mixture was extracted with EtOAc (50 mL×4). The combined organic layers were washed with brine (80 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , DCM / MeOH=50 / 1 to 30 / 31) to give the title compound as a yellow solid (0.68 g, yield 8.53%). 1H NMR (400 MHz, chloroform-d) δ = 6.27 (br s, 2H), 6.11 (dd, J =2.0, 12.8 Hz, 1H), 3.10 (br d, J = 4.0 Hz, 4H), 2.63 - 2.50 (m, 6H), 2.35 (s, 3H), 2.04 (s, 1H).

[0130] [ka]

[0131] 5-Cyano-2-(methylthio)benzoyl chloride Step 1. Methyl 2-chloro-5-cyanobenzoate: To a solution of 2-chloro-5-cyano-benzoic acid (10 g, 55.0 mmol, 1.0 equiv.) was added SOCl 2 (82.0 g, 689.2 mmol, 50 mL, 12.5 equiv.) was added. The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in THF (50 mL) and added to MeOH (50 mL). The reaction mixture was cooled to room temperature and concentrated with NaHCO 3 (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and 2 SO 4 It was dried at rt, filtered and concentrated under reduced pressure to give the title compound as a white solid (9 g, 84% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 2.0, 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H).

[0132] Step 2, 5-Cyano-2-methylsulfanyl-benzoic acid: To a solution of NaSMe (35.83 g, 511 mmol, 2.5 equiv) in DMF (400 mL) was added dropwise a solution of methyl 2-chloro-5-cyano-benzoate (40 g, 205 mmol, 1.0 equiv) in DMF (400 mL) at 0° C. Then the mixture was stirred at 0° C. for 3 h. The pH of the reaction mixture was adjusted to pH=1 with HCl (1M). The mixture was filtered and the filter cake was dried under vacuum to give the title compound as a white solid (30 g, 76% yield). LCMS [M-1]=192.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.53 (br s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 2.0, 8.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 2.46 (s, 3H).

[0133] Step 3: 5-cyano-2-(methylthio)benzoyl chloride: SOCl 2 A solution of 5-cyano-2-(methylthio)benzoic acid (4.2 g, 22.0 mmol, 1.0 equiv) in (56 mL) was stirred at 80° C. for 1 h. The mixture was concentrated under reduced pressure to give the title compound as a yellow solid (4.6 g, 99% yield). The product was used without further purification.

[0134] [ka]

[0135] 1-(6-amino-2,4-difluoro-3-iodo-phenyl)ethenone: To a solution of 1-(2-amino-4,6-difluoro-phenyl)ethanone (10.0 g, 58.4 mmol, 1.0 equiv.) in DCM (100 mL) was added N-iodosuccinimide (14.4 g, 64.2 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with brine and diluted with Na 2 SO4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0-33% ethyl acetate in petroleum ether) to give the title compound as a brown solid (6.5 g, 37% yield). LCMS [M+1]=297.7. 1 H NMR (400 MHz, chloroform-d) δ 6.70 - 6.43 (m, 2H), 6.26 (dd, J = 1.8, 9.6 Hz, 1H), 2.61 (d, J = 9.0 Hz, 3H).

[0136] [ka]

[0137] 2-Chloro-5-cyanobenzoic acid: 2-Chloro-5-iodobenzoic acid (6.0 g, 21.2 mmol, 1.0 equiv.) was combined with tert-butanol (18 g), water (24 g), potassium carbonate (2.94 g, 21.2 mmol, 1.0 equiv.), potassium ferrocyanide trihydrate (4.49 g, 10.6 mmol, 0.5 equiv.). The mixture was stirred for 1 hour, after which tris(dibenzylideneacetone)dipalladium(0) (0.097 g, 0.1 mmol, 0.005 equiv.), 1,4-bis(diphenylphosphino)butane (0.091 g, 0.2 mmol, 0.01 equiv.) and a mixture of tert-butanol (6.0 g) and water (6.0 g) were added. The mixture was adjusted to 75° C. for 17 hours and then cooled to 20° C. Ammonium pyrrolidine dithiocarbamate (1.80 g, 11.0 mmol, 0.5 equiv.) was charged followed by water (1.8 g) and the mixture was adjusted to 45° C. and stirred for 20 hours. The mixture was cooled to 25° C., filtered through diatomaceous earth and rinsed with water (18 g). The filtrate was extracted twice with methyl tert-butyl ether (2×18 g) and the aqueous layer was combined with ethyl acetate (54 g) and adjusted to 20° C. A 2N HCl solution (48 g) was added dropwise over 4 hours at 20° C. The mixture was stirred for 1 hour and then the bottom aqueous layer was removed. The organic layer was washed with water (30 g) and treated with activated charcoal (0.2 g) for 5 hours and then removed by filtration and rinsing with ethyl acetate (12 g). The filtrate was concentrated under vacuum to 12 mL, then acetone (24 g) was charged and the process repeated. The solution was then concentrated to 12 mL, then a final charge of acetone (12 g) was made. The mixture was adjusted to 35° C. for 2 hours, then 0.2 N HCl (90 g) was charged over 4 hours. The mixture was aged at 35° C. for an additional 3 hours, then adjusted to 25° C. over 5 hours and held for 3 hours. The slurry was filtered, washed with water (12 g) and then dried at 50° C. to produce the title compound (2.7 g, 71% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.91 (br, 1H), 8.24 (d, J = 4 Hz, 1H), 8.02 (m, 1H), 7.80 (d, J = 8 Hz, 1H).

[0138] Example 1

[0139] [ka]

[0140] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile Scheme 1. 2-Chloro-5-cyanobenzoyl chloride:

[0085] SOCl 2 A solution of 2-chloro-5-cyano-benzoic acid (2.5 g, 13.8 mmol) in (25 mL) was stirred for 1 h at 80° C. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to give the title compound as a yellow solid (2.8 g, crude), which was used directly in the next step.

[0141] Scheme 1, Step 1. 1-(2-amino-4,6-difluorophenyl)ethanone:

[0087] CH 3 A solution of 3,5-difluoroaniline (8.9 g, 68.9 mmol, 1.0 equiv) in CN (85 mL) was added to BCl at 0 °C. 3 (1M, 72.4 mL, 1.05 equiv.) was then added. 3 (10.1 g, 75.8 mmol, 4.1 mL, 1.1 equiv) was added in three portions to the mixture, and then the mixture was stirred at 80° C. for 16 h. The mixture was cooled to 0° C., then aqueous HCl (4 M, 80 mL) was added, and the mixture was stirred at 80° C. for 2 h. The mixture was cooled to room temperature and extracted with EtOAc (2×150 mL). The combined organic layers were washed with saturated aqueous NaHCO 3 Wash with solution (2 x 50 mL) and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid (8.0 g, 68% yield). LCMS: [M+H] + (C 8 H 7 F 2The calculated value for NO) is m / z = 172.0, the observed value is m / z = 172.1. 1 H NMR (400 MHz, CDCl 3 ), δ 6.5 (br s, 2H), 6.0 - 6.2 (m, 2H), 2.6 (d, J = 8.4 Hz, 3H).

[0142] Scheme 1, Step 2. N-(2-acetyl-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide: To a solution of 1-(2-amino-4,6-difluoro-phenyl)ethanone (2 g, 11.7 mmol, 1.0 equiv) in THF (20 mL) was added NaH (467 mg, 11.7 mmol, 60% dispersion in oil, 1.0 equiv) at 0° C. The mixture was stirred for 30 min, after which a solution of 2-chloro-5-cyano-benzoyl chloride (2.6 g, 12.8 mmol, 1.1 equiv) in THF (10 mL) was added dropwise. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NH 4 It was quenched by the addition of Cl (15 mL), diluted with water (20 mL) and filtered. The filter cake was triturated with EtOAc (20 mL) and filtered to give the title compound as a white solid (2.4 g, 61% yield). LCMS: [M+H] + (C 16 H 9 F 3 N 2 O 2 ) The calculated value for m / z = 335.0, the observed value is m / z = 335.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.2 (s, 1H), 8.1 (d, J = 2.0 Hz, 1H), 8.0 (dd, J = 8.4, 2.2 Hz, 1H), 7.8 (d, J = 8.4 Hz, 1H), 7.5 - 7.5 (m, 1H), 7.3 (ddd, J = 11.2, 8.8, 2.2 Hz, 1H), 2.5 - 2.6 (m, 3H).

[0143] Scheme 1, Step 3. 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile: To a solution of N-(2-acetyl-3,5-difluoro-phenyl)-2-chloro-5-cyano-benzamide (2.5 g, 7.5 mmol, 1.0 equiv.) in dioxane (40 mL) was added NaOH (3.0 g, 74.7 mmol, 10.0 equiv.). The mixture was stirred at 110° C. for 1.5 h. The pH of the reaction mixture was adjusted to 5 with aqueous HCl (1 M), then diluted with water (30 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with Na 2 SO 4 The crude residue was purified by preparative HPLC (column: Welch Xtimate C18 250 × 70 mm × 10 um; mobile phase: 15–45% acetonitrile in water (10 mM NH 4 HCO 3 )) which gave, after concentration under reduced pressure, the title compound as a white solid (570 mg, 24% yield, 98% purity). LCMS: [M+H] + (C 16 H 7 ClF 2 N 2 Calculated for m / z = 317.0, found m / z = 317.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.2 - 10.3 (m, 1H), 8.2 (d, J = 2.0 Hz, 1H), 8.0 (dd, J = 8.4, 2.0 Hz, 1H), 7.9 (d, J = 8.4 Hz, 1H), 7.0 - 7.2 (m, 2H), 6.1 (s, 1H).

[0144] Scheme 1, Step 4. 3-(5,7-Difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile: To a mixture of 4-chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (100 mg, 316 μmol, 1.0 equiv.) in DMSO (3 mL), sodium methanesulfinate (41.9 mg, 411 μmol, equiv.), K 3 PO 4 (67.0 mg, 316 μmol, 1.0 equiv.), CuI (6.0 mg, 32 μmol, 0.1 equiv.) and quinolin-8-ol (4.6 mg, 32 μmol, 0.1 equiv.) were added to N 2 The mixture was stirred at 120° C. for 24 hours. The reaction mixture was cooled to 10° C. and cooled to 37° C. 2 The mixture was diluted with 20 mL of 2H2O (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: water (+NH 4 HCO 3 ) to give the title compound as a white crystalline solid (37.4 mg, 33% yield, 99.3% purity) characterized as crystalline form A. LCMS [M+1]=361.0. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.36 (d, J = 8.4 Hz, 1H), 8.20 (dd, J = 1.6, 8.4 Hz, 1H), 8.13 (d, J = 1.4 Hz, 1H), 7.06 (br d, J = 9.4 Hz, 1H), 6.99 (ddd, J = 2.4, 9.4, 11.8 Hz, 1H), 6.31 (s, 1H), 3.20 (s, 3H).

[0145] Alternative synthesis of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile

[0146] [ka]

[0147] Step 1. 1-(2-amino-4,6-difluorophenyl)ethanone: A mixture of 1-(2,4,6-trifluorophenyl)ethan-1-one (10.0 g, 57.4 mmol, 1.0 equiv.) and 28% aqueous ammonium hydroxide (28.0 g, 459.5 mmol, 8.0 equiv.) in 2-methyltetrahydrofuran (30 g) was heated to 105° C. for 23 hours. The mixture was cooled to 25° C. and charged with toluene (80 g). The layers were separated and the organic layer was concentrated under vacuum to 30 mL. Toluene (30 g) was charged to the organic layer followed by two washes with 3N HCl (2×30 g) and 5% aqueous NaHCO. 3 (30 g). The organic layer was concentrated under vacuum to 20 mL and then charged with isopropyl acetate (80 g). The mixture was concentrated again to 20 mL and charged with isopropyl acetate (30 g) to yield the title compound as a solution in isopropyl acetate (assay yield 82%).

[0148] Step 2. N-(2-acetyl-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide: A solution of 2-chloro-5-cyano-benzoic acid (6.0 g, 33.0 mmol, 1.1 equiv.) in toluene was adjusted to 80° C. and added SOCl 2(6.9 g, 58.4 mmol, 2.0 equiv) was charged over 1 h. The mixture was stirred at 80° C. for 6 h, then cooled and concentrated under vacuum to 10 mL. Isopropyl acetate (35 g) was charged and the mixture was concentrated once more to 10 mL. The charge of isopropyl acetate (35 g) and concentration to 10 mL was repeated, followed by a final charge of isopropyl acetate (10 g). The mixture was adjusted to 45° C. and a solution of 1-(2-amino-4,6-difluorophenyl)ethanone (5.0 g, 29.2 mmol, 1.0 equiv, 35 mL as a solution in isopropyl acetate) in isopropyl acetate was charged over 2 h. The mixture was adjusted to 80° C. and stirred for 12 h, then cooled to 25° C. and filtered. The solid was rinsed twice with isopropyl acetate (2×25 g) and twice with n-heptane (2×25 g) and then dried at 50° C. to yield the title compound (8.7 g, 89% yield).

[0149] Step 3. 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile Lithium tert-butoxide (1.4 g, 17.9 mmol, 1.2 equiv.) was added to a mixture of N-(2-acetyl-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide (5.0 g, 14.9 mmol, 1.0 equiv.) and 2-methyltetrahydrofuran (100 g). The mixture was conditioned at 75° C. for 22 hours and then cooled to 20° C. Dimethyl sulfoxide (20 g) was charged and the mixture was conditioned at 40° C. for 2 hours. 1N HCl solution (50 g) was added slowly and the mixture was stirred at 40° C. for an additional 3 hours. The mixture was cooled to 5° C. over 3 hours and stirred for an additional 16 hours. The slurry was filtered and the solid was washed twice with water (2×10 g) and twice with acetone (2×10 g). The wet solid was then slurry washed in acetone (40 g) at 50° C. for 3 hours, then cooled to 5° C. and stirred for an additional 3 hours. The slurry was filtered and the solid was rinsed with acetone (10 g). The solid was dried at 55° C. to give the title compound (4.8 g, 80% yield).

[0150] Step 4. 3-(5,7-Difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile To a solution of 4-chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (10.0 g, 31.6 mmol, 1 equiv.) in dimethyl sulfoxide (65 g), sodium methanesulfinate (3.89 g, 37.9 mmol, 1.2 equiv.), tripotassium phosphate (10.1 g, 47.4 mmol, 1.5 equiv.), copper(I) iodide (0.60 g, 3.16 mmol, 0.1 equiv.) and L-proline (0.36 g, 3.16 mmol, 0.1 equiv.). The mixture was stirred at 25° C. for 4 hours and then quenched with 5% aqueous ammonium hydroxide (50 g). The mixture was stirred for 4 hours, after which 1N HCl (300 g) was added and stirred for an additional 12 hours. The solid was filtered and washed with water (2 x 50 g). The solid was then slurry washed in water (150 g) at 50°C for 14 hours and then cooled to 25°C for filtration. The wet solid was then slurry washed in acetone (80 g) at 50°C for 3 hours and then cooled to 5°C for 3 hours and aged for 2 hours and then filtered and washed with acetone (20 g). The solid was dried at 50°C to produce the title compound (7.1 g, 61% yield). HRMS: [M+H] + (C 17 H 10 F 2 N 2 O 3 S) calculated m / z = 361.0453, observed m / z = 361.0453. 1 H NMR (500 MHz, MeOH-d 4) δ 8.50 (d, J = 8.3 Hz, 1H), 8.33 (dd, J = 8.3, 1.6 Hz, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 9.4 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.46 (s, 1H), 3.34 (s, 3H). The XRPD pattern of the resulting product, 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile, characterized as Form A, is shown in Figure 1. The DSC curve is shown in Figure 2 and shows an endothermic transition occurring at approximately 304 °C.

[0151] The compounds in Table 2 were prepared according to Scheme 1 using procedures similar to those described in Example 1.

[0152] [Table 3]

[0153] Example 4

[0154] [ka]

[0155] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2,2,2-trifluoroethyl)sulfonyl)-benzonitrile Scheme 2, Step 1. 3-(5,7-Difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2,2,2-trifluoroethyl)thio)benzonitrile: To a solution of 2,2,2-trifluoroethane-1-thiol (780 mg, 6.72 mmol, 596 μL, 1.0 equiv) in THF (1 mL) was added NaH (242 mg, 6.05 mmol, 60% purity, 0.9 equiv). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent to give sodium 2,2,2-trifluoroethanethiolate (850 mg, crude) as a white solid. Next, a solution of 4-chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (600 mg, 1.89 mmol, 1.0 equiv.) and sodium 2,2,2-trifluoroethanethiol (809 mg, 6.63 mmol, 3.5 equiv.) in DMSO (10 mL) was added with K 2 CO 3 (576 mg, 4.17 mmol, 2.2 equiv.) and CuI (36 mg, 190 μmol, 0.1 equiv.) were added. The mixture was stirred at 100° C. for 16 h. The residue was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5:1 to 1:1 petroleum ether:ethyl acetate gradient) to give the title compound (120 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0156] Scheme 2, Step 2. 3-(5,7-Difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2,2,2-trifluoroethyl)sulfonyl)-benzonitrile: Acetone (1 mL), H 2To a mixture of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2,2,2-trifluoroethyl)thio)benzonitrile (100 mg, 252 μmol, 1 equiv.) in 2HO (0.6 mL), MeOH (0.75 mL) and THF (0.75 mL) was added oxone (930 mg, 1.51 mmol, 3.0 equiv.) at 20 °C. 2 The mixture was stirred at 60° C. for 24 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna 80×30 mm×3 um; mobile phase: 20-50% acetonitrile in water (+HCl)) to give the title compound as a white solid (5.4 mg, 4.9% yield, 97.9% purity). LCMS [M+1]=328.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 - 8.34 (m, 2H), 8.33 - 8.27 (m, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.23 (br s, 1H), 6.65 - 6.20 (m, 1H), 5.12 (q, J = 9.8 Hz, 2H).

[0157] Example 5

[0158] [ka]

[0159] Scheme 2, Step 2. 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2,2,2-trifluoroethyl)sulfinyl)benzonitrile:

[0109] Acetone (1 mL) H 2To a mixture of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2,2,2-trifluoroethyl)thio)benzonitrile (50 mg, 126 μmol, 1.0 equiv.) in 2H2O (0.6 mL), MeOH (0.75 mL) and THF (0.75 mL) was added oxone (77.6 mg, 126 μmol, 1.0 equiv.) at 20 °C. 2 The mixture was stirred at 20° C. for 16 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna 80×30 mm×3 um; mobile phase: 25-55% acetonitrile in water (+HCl)) to give the title compound as a white solid (15.0 mg, 28% yield, 97.7% purity). LCMS [M+1]=412.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.50 - 11.93 (m, 1H), 8.58 - 8.18 (m, 3H), 7.51 - 7.08 (m, 2H), 6.54 - 5.88 (m, 1H), 4.85 - 3.96 (m, 2H).

[0160] Example 6

[0161] [ka]

[0162] Scheme 2, Step 1. 3-(5,7-Difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile: To a mixture of 4-chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (500 mg, 1.58 mmol, 1.0 equiv.) in DMSO (8 mL), NaSMe (387 mg, 5.53 mmol, 3.5 equiv.), K 2CO 3 (480 mg, 3.48 mmol, 2.2 equiv.) and CuI (30 mg, 158 μmol, 0.1 equiv.) were added to N 2 The mixture was then heated at 100 °C for 16 h under N 2 The reaction mixture was added to water (50 mL), stirred at 25° C. for 30 min, and then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: 30-60% acetonitrile in water (+formic acid)) to give the title compound as a white solid (220 mg, 41% yield, 96.9% purity). LCMS [M+1]=329.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.00 (br s, 1H), 8.05 - 7.90 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.23 - 7.02 (m, 2H), 5.99 (s, 1H), 2.54 (s, 3H).

[0163] Example 7

[0164] [ka]

[0165] Scheme 2, Step 2. 3-(5,7-Difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfinyl)benzonitrile: To a mixture of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile (50 mg, 152 μmol, 1.0 equiv.) in DCM (2 mL) was added m-CPBA (31 mg, 152 μmol, 85% purity, 1.0 equiv.) at 20° C., and the mixture was then incubated at 20° C. for 1 h with N 2 The reaction mixture was stirred under reduced pressure at 25° C.3 (20 mL) of saturated aqueous NaHCO 3 (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was triturated with MTBE (5 mL) to give the title compound as a white solid (30 mg, 43% yield, 98.6% purity). LCMS [M+1]=345.0. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.37 (br d, J = 8.2 Hz, 1H), 8.25 - 8.16 (m, 2H), 7.35 - 7.22 (m, 1H), 7.13 - 7.03 (m, 1H), 6.85 - 6.54 (m, 1H), 3.03 - 2.80 (m, 3H).

[0166] Example 8

[0167] [ka]

[0168] Scheme 2, Step 2. 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(S-methylsulfonimidoyl)benzonitrile: To a mixture of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile (50 mg, 152 μmol, 1.0 equiv.) in MeOH (1 mL) was added ammonium carbamate (59.4 mg, 761 μmol, 5.0 equiv.) at 20° C., followed by addition of PhI(OAc) in MeOH (0.5 mL). 2(123 mg, 381 μmol, 2.5 equiv) was added dropwise to the mixture. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: 1-40% acetonitrile in water (+formic acid)-ACN) to give the title compound as a yellow solid (22.6 mg, 37.6% yield, 99.8% purity). LCMS [M+1]=360.1. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.41 (d, J = 8.2 Hz, 1H), 8.17 (dd, J = 1.8, 8.2 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.11 - 6.92 (m, 2H), 6.30 (s, 1H), 3.21 (s, 3H).

[0169] Example 9

[0170] [ka]

[0171] 3-(7-chloro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile Step 1, 1-(2-amino-4-chlorophenyl)ethanone: H 2 To a solution of 1-(4-chloro-2-nitrophenyl)ethanone (35 g, 175 mmol, 1.0 equiv.) in 2H2O (350 mL) and acetic acid (350 mL) was added iron(0) (39.1 g, 701 mmol, 4.0 equiv.). The mixture was stirred at 100 °C for 2 h. The suspension was filtered through a Celite pad and the filter cake was washed with ethyl acetate (3 x 100 ml). The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and H2O. 2 The mixture was diluted with 2×O (500 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic layers were then washed with saturated aqueous NaHCO 3 , washed with brine, and then washed with anhydrous Na2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded the title compound as a dark brown solid (27.7 g, crude). This material was used in the next step without further purification. LCMS [M+1]=170.2. 1 H NMR (400 MHz, chloroform-d) δ 7.61 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 6.59 (br d, J = 8.6 Hz, 1H), 6.39 (br s, 2H), 2.54 (s, 3H). Step 2, N-(2-acetyl-5-chlorophenyl)-5-cyano-2-(methylthio)benzamide: To a solution of 1-(2-amino-4-chlorophenyl)ethenone (6.7 g, 39.6 mmol, 1.0 equiv) in isopropyl acetate (300 mL) was added 5-cyano-2-methylsulfanyl-benzoyl chloride (8.4 g, 39.6 mmol, 1.0 equiv). The mixture was stirred at 80° C. for 6 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (500 mL). The filter cake was dried under vacuum and triturated with MeOH at 25° C. for 0.5 h to give the title compound as a white solid (10 g, 70% yield). LCMS [M+1]=345.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.90 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.14 - 8.05 (m, 2H), 7.97 (dd, J = 1.8, 8.4 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 2.2, 8.5 Hz, 1H), 2.64 (s, 3H), 2.52 (s, 3H). Step 3, 3-(7-chloro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile: To a solution of N-(2-acetyl-5-chlorophenyl)-5-cyano-2-(methylthio)benzamide (9.8 g, 28.4 mmol, 1.0 equiv.) in 2-MeTHF (300 mL) was added LiOH (4.0 g, 171 mmol, 6.0 equiv.). The mixture was stirred at 110° C. for 24 h. The mixture was cooled to room temperature and the pH was adjusted to pH=3 with aqueous 1M HCl. The brown solid that precipitated during the pH adjustment was filtered off and diluted with H 2 O (600 mL) and then dried under vacuum. Trituration with acetonitrile at room temperature for 0.5 h afforded the title compound as a pale yellow solid (6.0 g, crude). LCMS [M+1]=327.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d, J = 8.8 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.65 - 7.56 (m, 2H), 7.40 (dd, J = 1.8, 8.7 Hz, 1H), 6.14 (s, 1H), 2.54 (s, 3H). Step 4, 3-(7-chloro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)-benzonitrile: H 2 O (160 mL), CHCl 3 (80 mL) and acetonitrile (80 mL) were added to a solution of 3-(7-chloro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile (5.0 g, 15.3 mmol, 1.0 equiv.) in NaIO at room temperature. 4 (9.8 g, 45.9 mmol, 3.0 equiv.) and ruthenium trichloride (317 mg, 1.5 mmol, 0.1 equiv.) were added to N 2 C. to 100.degree. C. The mixture was stirred at room temperature for 16 h. The suspension was filtered through filter paper and the pad cake was washed with MeOH (3.times.150 mL). The filtrate was concentrated under reduced pressure. The residue was triturated first with MTBE and then with MeOH at room temperature for 0.5 h to give the title compound as a white solid (2.4 g, 45% yield). LCMS [M+1]=359.0.1 H NMR (400 MHz, DMSO-d 6 ) δ 12.10 (br s, 1H), 8.33 (br d, J = 10.2 Hz, 3H), 8.13 (br d, J = 7.8 Hz, 1H), 7.54 (br s, 1H), 7.40 (br d, J = 6.8 Hz, 1H), 6.21 (br s, 1H), 3.35 - 3.28 (m, 3H).

[0172] Example 10

[0173] [ka]

[0174] 3-(7-chloro-5-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)-benzonitrile Step 1. 1-(2-amino-4-chloro-6-fluorophenyl)ethanone: A solution of 3-chloro-5-fluoroaniline (20 g, 137 mmol, 1.0 equiv.) in p-xylene (40 mL) was added to BCl at 0-5° C. 3 (1M, 182.7 mL, 1.3 equiv) was added over 2 h. The mixture was allowed to warm to room temperature within 0.5 h and stirred at room temperature for 10 min. Then acetonitrile (57.8 mL, 1.10 mol, 8 equiv) was added dropwise over 20 min at room temperature. The mixture was stirred at room temperature for 10 min and then p-xylene (45 mL) was added. Then AlCl 3 (10.2 g, 76.9 mmol, 0.5 equiv) was added and the reaction mixture was stirred at room temperature for 1 h and then at 75-77 °C for an additional 12 h. Aqueous HCl (4N, 200 mL) was then added to the mixture and the mixture was stirred at 80 °C for 4 h. The mixture was poured into water (800 mL) and extracted with ethyl acetate (1.5 L). The organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50:1 to 20:1 petroleum ether:ethyl acetate) to give the title compound as a pale yellow solid (4.6 g, 18% yield). LCMS [M+1]=188.0 / 190.0. 1 H NMR (400 MHz, chloroform-d) δ 6.53 - 6.41 (m, 2H), 6.36 (dd, J = 2.0, 11.8 Hz, 2H), 2.58 (d, J = 8.4 Hz, 3H).

[0175] Step 2. N-(2-acetyl-5-chloro-3-fluorophenyl)-5-cyano-2-(methylthio)benzamide: To a solution of 1-(2-amino-4-chloro-6-fluorophenyl)ethanone (4.1 g, 21.8 mmol, 1 equiv) in isopropyl acetate (48 mL) was added 5-cyano-2-(methylthio)benzoyl chloride (4.6 g, 21.8 mmol, 1.0 equiv). The mixture was stirred at 80° C. for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with acetonitrile (30 mL) at room temperature to give the title compound as a white solid (5.5 g, 70% yield). LCMS [M+1]=363.0 / 364.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.03 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.95 (dd, J = 1.8, 8.4 Hz, 1H), 7.63 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 1.8, 10.5 Hz, 1H), 3.42 (s, 1H), 2.54 (d, J = 3.8 Hz, 3H). Step 3, 3-(7-chloro-5-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile: To a solution of N-(2-acetyl-5-chloro-3-fluorophenyl)-5-cyano-2-(methylthio)benzamide (5 g, 13.7 mmol, 1.0 equiv.) in 2-MeTHF (50 mL) was added LiOH (495 mg, 20.6 mmol, 1.5 equiv.). The mixture was stirred at 100° C. for 16 h. The mixture was cooled to room temperature. The pH of the reaction mixture was adjusted to pH=3 with aqueous 2N HCl. The precipitate formed during the pH adjustment was filtered off and the filter cake was dried under vacuum. The residue was triturated with ethyl acetate at room temperature to give the title compound as a white solid (3.8 g, 78% yield). LCMS [M+1]=345.0 / 347.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.01 (br s, 1H), 8.01 - 7.95 (m, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.40 (br s, 1H), 7.25 (br d, J = 10.8 Hz, 1H), 6.02 (br s, 1H), 2.54 (s, 3H).

[0176] Step 4. 3-(7-chloro-5-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile: acetone (16.8 mL), H 2 To a solution of 3-(7-chloro-5-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)-benzonitrile (3.2 g, 9.2 mmol, 1.0 equiv.) in 2H2O (9.6 mL), THF (12 mL) and MeOH (12 mL) was added oxone (28.5 g, 46.4 mmol, 5.0 equiv.). The mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with Na 2 SO 3 (3 equiv.) in water. The reaction mixture was diluted with H 2The crude residue was triturated with MTBE (2×150 mL) at room temperature, followed by MeOH (2×150 mL) at room temperature to give the title compound as an off-white solid (2.3 g, 65.4% yield). LCMS [M+1]=377.0 / 379.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.15 (br s, 1H), 8.43 - 8.22 (m, 3H), 7.62 - 7.17 (m, 2H), 6.38 - 6.02 (m, 1H), 3.47 - 3.25 (m, 3H).

[0177] Example 11

[0178] [ka]

[0179] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((trifluoromethyl)sulfonyl)benzonitrile Step 1. Methyl 5-cyano-2-iodo-benzoate: To a solution of 5-cyano-2-iodo-benzoic acid (4.0 g, 14.6 mmol, 1.0 equiv) in MeOH (30 mL) was added H 2 SO 4 (1.2 mL, 22.8 mmol, 1.6 equiv) was added. The mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and extracted with anhydrous Na 2 SO 4 The mixture was dried at rt, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (4.0 g, 95% yield). 1H NMR (400 MHz, chloroform-d) δ 8.16 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 2.0, 8.2 Hz, 1H), 3.98 (s, 3H).

[0180] Step 2. Methyl 5-cyano-2-(trifluoromethylsulfanyl)benzoate: To a mixture of methyl 5-cyano-2-iodo-benzoate (1.5 g, 5.2 mmol, 1.0 equiv.) and trifluoromethylsulfanylsilver (1.1 g, 5.2 mmol, 1.0 equiv.) in DMF (15 mL), copper(I) bromide (75.0 mg, 523 μmol, 0.1 equiv.) and 1,10-phenanthroline (188.3 mg, 1.1 mmol, 0.2 equiv.) were added at room temperature with N 2 The mixture was heated at 80° C. for 16 h under N 2 The reaction mixture was poured into ice water (250 mL) and stirred for 30 min. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with aqueous NaHCO 3 (2 x 100 ml), and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100:1 to 14:1 petroleum ether:ethyl acetate) to give the title compound as a white solid (1.2 g, 88% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 1.5 Hz, 1H), 7.89 - 7.74 (m, 2H), 4.00 (s, 3H).

[0181] Step 3. 5-Cyano-2-(trifluoromethylsulfanyl)benzoic acid: THF (12 mL) and H 2 A mixture of methyl 5-cyano-2-(trifluoromethylsulfanyl)benzoate (1.2 g, 4.6 mmol, 1.0 equiv.) in 20HO (3 mL) was added to LiOH H at room temperature. 2 O (231 mg, 5.5 mmol, 1.2 equiv.) 2The mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to pH=4-5 with aqueous 1N HCl. THF was removed under reduced pressure. The precipitate was filtered off and dried under vacuum to give the title compound as a white solid (1.0 g, 90% yield). LCMS [M-1]=246.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.93 - 13.99 (m, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.15 (dd, J = 2.0, 8.6 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H).

[0182] Step 4, N-(2-acetyl-3,5-difluoro-phenyl)-5-cyano-2-(trifluoromethylsulfanyl)benzamide: SOCl 2 (5 mL) was added to a flask containing 5-cyano-2-(trifluoromethylsulfanyl)benzoic acid (1.0 g, 4.1 mmol, 1.0 equiv.) at room temperature with N 2 The mixture was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure to give 5-cyano-2-(trifluoromethylsulfanyl)benzoyl chloride as a white solid (1.1 g, crude), which was used in the next step of the reaction without further purification.

[0183] To a mixture of 1-(2-amino-4,6-difluoro-phenyl)ethanone (644 mg, 3.8 mmol, 1.0 equiv.) in isopropyl acetate (15 mL), 5-cyano-2-(trifluoromethylsulfanyl)benzoyl chloride (1.1 g, 4.14 mmol, 1.1 equiv.) was added at room temperature in N 2 The mixture was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure and the crude product was triturated with acetonitrile at room temperature for 30 minutes to give the title compound as a white solid (1.2 g, 77% yield). LCMS [M+1]=401.1. 1H NMR (400 MHz, chloroform-d) δ 12.63 (br s, 1H), 8.53 - 8.43 (m, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 1.8, 8.4 Hz, 1H), 6.73 (ddd, J = 2.6, 8.2, 12.2 Hz, 1H), 2.72 (d, J = 8.6 Hz, 3H). Step 5. 3-(5,7-difluoro-4-oxo-1H-quinolin-2-yl)-4-(trifluoromethylsulfanyl)benzonitrile: To a mixture of N-(2-acetyl-3,5-difluoro-phenyl)-5-cyano-2-(trifluoromethylsulfanyl)benzamide (1.2 g, 3.0 mmol, 1.0 equiv.) in 2-MeTHF (18 mL), LiOH (71.8 mg, 3.0 mmol, 1.0 equiv.) at room temperature was added to the mixture. 2 The mixture was heated at 80° C. for 32 h under N 2 The mixture was stirred under reduced pressure. The reaction mixture was diluted with water (10 mL) and then concentrated to remove 2-MeTHF. The pH of the mixture was adjusted to pH=4-5 with aqueous 1N HCl. The precipitate that formed during the pH adjustment was filtered off and then triturated with acetonitrile at room temperature for 30 min to give the title compound as a white solid (930 mg, 80% yield). LCMS [M+1]=383.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.10 (br s, 1H), 8.34 (d, J = 1.4 Hz, 1H), 8.17 (br d, J = 11.8 Hz, 2H), 7.34 - 6.92 (m, 2H), 6.11 (br s, 1H).

[0184] Step 6, 3-(5,7-difluoro-4-oxo-1H-quinolin-2-yl)-4-(trifluoromethylsulfonyl)benzonitrile: CHCl 3 (7 mL), ACN (7 mL) and H 23-(5,7-Difluoro-4-oxo-1H-quinolin-2-yl)-4-(trifluoromethylsulfanyl)benzonitrile (700 mg, 1.8 mmol, 1.0 equiv.) and RuCl in 2H2O (14 mL). 3 (38 mg, 183.1 μmol, 0.1 equiv.) was added to a mixture of NaIO at room temperature. 4 (1.2 g, 5.5 mmol, 3.0 equiv.) 2 The mixture was stirred at room temperature for 16 hours. The reaction was cooled to room temperature and cooled to room temperature. 2 SO 3 (15 mL) of saturated aqueous solution and stirred at room temperature for 1 h. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100×40 mm×3 um; mobile phase: 25-65% acetonitrile in water (+ formic acid modifier)) to give the title compound as a white solid (100 mg, 13% yield). LCMS [M+1]=415.0. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.51 (d, J = 8.2 Hz, 1H), 8.39 - 8.28 (m, 2H), 7.08 - 6.95 (m, 2H), 6.22 (br s, 1H).

[0185] Example 12

[0186] [ka]

[0187] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(isopropylsulfonyl)benzonitrile Step 1, 5-Cyano-2-isopropylsulfanyl-benzoic acid: To a solution of propane-2-thiol (2.3 mL, 25.5 mmol, 2.5 equiv.) in DMF (20 mL) was added NaH (1.0 g, 25.5 mmol, 2.5 equiv.; 60% dispersion in oil). The reaction mixture was stirred at room temperature for 1 h, after which methyl 2-chloro-5-cyano-benzoate (2.0 g, 10.2 mmol, 1.0 equiv.) was added to the mixture. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by H 2 O (2 eq.) and the pH of the solution was adjusted to pH=4 with aqueous 1N HCl. The precipitate formed during the pH adjustment was filtered off and triturated with MTBE at room temperature for 10 min to give the title compound as a light yellow solid (2.0 g, 88% yield). LCMS: [M-1]=220.1. 1 H NMR (400 MHz, chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 1.8, 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 3.60 (td, J = 6.6, 13.4 Hz, 1H), 1.45 (d, J = 6.6 Hz, 6H).

[0188] Step 2, N-(2-acetyl-3,5-difluoro-phenyl)-5-cyano-2-isopropylsulfanyl-benzamide: SOCl 2A solution of 5-cyano-2-isopropylsulfanyl-benzoic acid (500 mg, 2.2 mmol, 1.0 equiv) in 1 mL of isopropyl acetate was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give 5-cyano-2-isopropylsulfanyl-benzoyl chloride as a yellow solid (542 mg, crude). This material was used in the next step of the reaction without further purification. To a solution of 1-(2-amino-4,6-difluoro-phenyl)ethanone (350 mg, 2.05 mmol, 1.0 equiv) in isopropyl acetate (10 mL) was added 5-cyano-2-isopropylsulfanyl-benzoyl chloride (539 mg, 2.2 mmol, 1.1 equiv). The mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated and the resulting residue was triturated with acetonitrile at room temperature for 10 min to give the title compound as a pale yellow solid (570 mg, 74% yield). LCMS [M+1]=375.1. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.73 (d, J = 1.6 Hz, 1H), 8.67 (dd, J = 1.8, 8.2 Hz, 1H), 8.54 - 8.44 (m, 2H), 7.96 (ddd, J = 2.4, 9.0, 11.4 Hz, 1H), 4.51 (td, J = 6.6, 13.2 Hz, 1H), 3.36 (d, J = 5.4 Hz, 3H), 2.08 (d, J = 6.8 Hz, 6H).

[0189] Step 3, 3-(5,7-difluoro-4-oxo-1H-quinolin-2-yl)-4-isopropylsulfanyl-benzonitrile: To a solution of N-(2-acetyl-3,5-difluoro-phenyl)-5-cyano-2-isopropylsulfanyl-benzamide (470 mg, 1.2 mmol, 1.0 equiv.) in dioxane (10 mL) was added LiOH (45 mg, 1.8 mmol, 1.5 equiv.). The reaction mixture was stirred at 110° C. for 10 h. The pH of the reaction mixture was adjusted to pH=1 with aqueous 1M HCl. The precipitate formed during the pH adjustment was filtered off and then triturated with acetonitrile at room temperature for 10 min to give the title compound as a white solid (400 mg, 89% yield). LCMS [M+1]=357.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.15 - 11.98 (m, 1H), 7.98 - 7.90 (m, 2H), 7.71 (d, J = 8.2 Hz, 1H), 7.12 (m, 2H), 5.97 (s, 1H), 3.75 (m, 1H), 1.26 (d, J = 6.6Hz, 6H).

[0190] Step 4, 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(isopropylsulfonyl)benzonitrile: To a solution of 3-(5,7-difluoro-4-oxo-1H-quinolin-2-yl)-4-isopropylsulfanyl-benzonitrile (150 mg, 421 μmol, 1.0 equiv.) in DCM (5.0 mL) was added m-CPBA (256 mg, 1.2 mmol, 3.0 equiv.; 85% purity). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H 2 Na in O (5.0 mL) 2 SO 3 (300 mg). The reaction mixture was extracted with DCM (2×5 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80×40 mm×3 um; mobile phase: 25-45% acetonitrile in water (+HCl modifier)) to give the title compound as a white solid (41.2 mg, 25% yield). LCMS [M+1]=389.1. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.33 - 8.29 (dd, J = 8.0 Hz, 1H), 8.24 - 8.19 (dd, J = 1.4 Hz, J = 8.0 Hz, 1H), 8.16 (d, J = 1.4 Hz,1H), 7.14 - 7.08 (m, 1H), 7.07 - 7.02 (m, 1H), 6.37 (s, 1H), 3.40 (quintet, J = 6.8 Hz, 1H), 1.26 - 1.20 (m, 6H).

[0191] Example 13

[0192] [ka]

[0193] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(isobutylsulfonyl)benzonitrile This compound was prepared in a similar manner as described in Example 12 using 2-methylpropane-1-thiol as the starting material. LCMS [M+1]=403.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 2H), 8.14 (s, 1H), 7.03 (br d, J = 10.0 Hz, 1H), 6.95 (br s, 1H), 6.11 (s, 1H), 3.58 (br d, J = 6.0 Hz, 2H), 2.09 - 1.98 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H).

[0194] Example 14

[0195] [ka]

[0196] 3-(5,7-difluoro-6-(1-methyl-1H-pyrazol-4-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile Step 1, 1-[6-amino-2,4-difluoro-3-(1-methylpyrazol-4-yl)phenyl]ethenone: A solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (500 mg, 2.4 mmol, 1.0 equiv.) and 1-(6-amino-2,4-difluoro-3-iodo-phenyl)ethanone (714 mg, 2.4 mmol, 1.0 equiv.) in dioxane (7.5 mL) was added to 10 mL of H 2 O at room temperature. 2 O (2.5 mL) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (196 mg, 240 μmol, 0.1 equiv.) 2 CO 3 A solution of (664 mg, 4.8 mmol, 2.0 equiv.) was dissolved in N 2 The mixture was heated at 80° C. for 16 h under N 2 The mixture was stirred under reduced pressure. The residue was poured into ice water (100 mL) and ethyl acetate (100 mL) and stirred for 10 min. The mixture was filtered through a pad of Celite. The organic phase was separated, washed with brine (2×20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 4°C, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100:1 to 5:1 petroleum ether:ethyl acetate). The crude product was triturated with petroleum ether at room temperature for 10 min to give the title compound as a yellow solid (200 mg, 33% yield). LCMS [M+1] = 252.2. 1H NMR (400 MHz, chloroform-d) δ 7.84 (s, 1H), 7.71 (s, 1H), 6.40 (br t, J = 5.6 Hz, 2H), 6.25 (dd, J = 1.6, 12.6 Hz, 1H), 3.97 (s, 3H), 2.64 (d, J = 9.0 Hz, 3H).

[0197] Step 2, N-[2-acetyl-3,5-difluoro-4-(1-methylpyrazol-4-yl)phenyl]-2-chloro-5-cyano-benzamide: To a mixture of 1-[6-amino-2,4-difluoro-3-(1-methylpyrazol-4-yl)phenyl]ethanone (200 mg, 796 μmol, 1.0 equiv.) in isopropyl acetate (1.5 mL) was added 2-chloro-5-cyano-benzoyl chloride (195 mg, 876 μmol, 1.1 equiv.) at room temperature. 2 The mixture was stirred at 80° C. for 8 hours. The mixture was filtered and concentrated under reduced pressure. The residue was triturated with water at room temperature and then with acetonitrile to give the title compound as a pale yellow solid (300 mg, 91% yield). LCMS [M+1]=415.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.03 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 8.05 (dd, J = 2.0, 8.3 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.50 (d, J = 11.2 Hz, 1H), 3.93 (s, 3H), 2.59 (d, J = 3.8 Hz, 3H).

[0198] Step 3, 4-Chloro-3-[5,7-difluoro-6-(1-methylpyrazol-4-yl)-4-oxo-1H-quinolin-2-yl]benzonitrile: To a mixture of N-[2-acetyl-3,5-difluoro-4-(1-methylpyrazol-4-yl)phenyl]-2-chloro-5-cyano-benzamide (300 mg, 723 μmol, 1.0 equiv.) in dioxane (1 mL) was added LiOH (19.0 mg, 796 μmol, 1.1 equiv.) at room temperature. 2 The mixture was stirred at 110° C. for 12 hours. The residue was poured into ice water (100 mL), stirred for 30 minutes, and filtered. The filter cake was triturated with acetonitrile at room temperature to give the title compound as a pale yellow solid (240 mg, 82% yield). LCMS [M+1]=397.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.10 (s, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.09 (dd, J = 2.0, 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.22 (d, J = 11.5 Hz, 1H), 6.06 (d, J = 1.5 Hz, 1H), 3.95 - 3.91 (m, 3H).

[0199] Step 4, 3-[5,7-difluoro-6-(1-methylpyrazol-4-yl)-4-oxo-1H-quinolin-2-yl]-4-methylsulfonyl-benzonitrile: Sodium methanesulfinate (37.0 mg, 363 μmol, 1.2 equiv.), 4-chloro-3-[5,7-difluoro-6-(1-methylpyrazol-4-yl)-4-oxo-1H-quinolin-2-yl]benzonitrile (120 mg, 302 μmol, 1.0 equiv.) and K in DMF (3 mL). 3 PO 4 (96.3 mg, 453.7 μmol, 1.5 equiv.) was added to a mixture of CuI (5.8 mg, 30.2 μmol, 0.1 equiv.) at room temperature with N 2The mixture was stirred at 100° C. for 2 hours. The mixture was quenched by addition of aqueous ammonia solution and then stirred for 30 minutes. The pH of the mixture was adjusted to pH=3-4 with aqueous 1N HCl. The precipitate formed during the pH adjustment was filtered off and then purified by preparative HPLC (column: Phenomenex Luna C18 200×40 mm×10 um; mobile phase: 20-50% acetonitrile in water (+ formic acid modifier)) to give the title compound as a white solid (60 mg, 45% yield). LCMS [M+1]=441.0. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ 8.28 (s, 2H), 8.25 - 8.21 (m, 1H), 8.21 - 8.14 (m, 1H), 7.85 (s, 1H), 7.45 - 7.07 (m, 1H), 6.23 - 6.16 (m, 1H), 3.91 (s, 3H), 3.31 (br s, 3H).

[0200] Example 15

[0201] [ka]

[0202] 3-(5,7-difluoro-6-(6-methylpyridin-3-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile This compound was prepared in a similar manner as described in Example 14 using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 1-(6-amino-2,4-difluoro-3-iodophenyl)ethanone as starting materials. LCMS [M+1]=452.0. 1 H NMR (400 MHz, DMSO-d 6) δ 12.55 - 11.94 (m, 1H), 8.57 (br s, 1H), 8.40 - 8.26 (m, 3H), 7.85 (br d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.37 - 7.11 (m, 1H), 6.45 - 5.90 (m, 1H), 3.32 (s, 3H), 2.55 (s, 3H).

[0203] Biochemical and cellular assays PPARγ-NCOR1 recruitment assay: Compound potency (EC 50 ) and the maximal extent of NCOR1 recruitment to PPARG was assessed with a TR-FRET binding assay measuring the association of a biotinylated NCOR1 ID2 peptide (biotin-GHSFADPASNLGLEDIIRKALMG-amide) to the PPARG / RXRA LBD heterodimer. Specifically, 20 microliters of TR-FRET master mix consisting of 2 nM WT PPARG LBD (E. coli expressed, His-TEV-Q203-Y477; Uniprot ID P37231-2), 2 nM WT RXRA LBD or mutant S427F RXRA LBD (E. coli expressed, Flag-TEV-E228-T462; P19793-1), 50 nM NCOR1, 80 nM rosiglitazone, 25 nM streptavidin-d2 (Cisbio) and 0.3 nM anti-His Tb (Cisbio) in 25 mM MOPS pH 7.4, 25 mM KCl, 1 mM EDTA, 0.01% BSA, 0.01% Tween-20 and 1 mM TCEP was added to 60 μL of compound (0.3% fc) in DMSO. Ten-point dose response titrations of DMSO (v / v) were added to 384-well plates in duplicate. The mixtures were incubated for 3 hours and read on an EnVision plate reader (Perkin Elmer) at Ex / Em 615 / 665. Potency (EC 50To determine the extent of NCOR1 recruitment, TR-FRET ratios were normalized to the average ratio of DMSO control wells (0%) and to the average maximum ratio of a positive control compound (T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide); defined as 100%) in the CDD Vault and analyzed using the Levenberg-Marquardt algorithm.

[0204] PPARγ-MED1 Blockade Assay: Compound potency (IC 50 ) and the maximal extent of MED1 repulsion towards PPARG was assessed in a TR-FRET binding assay measuring the association of biotinylated MED1 LxxLL peptide (biotin- VSSMAGNTKNHPMLMNLLKDNPAQ-amide) to the PPARG / RXRA LBD heterodimer. Specifically, 20 microliters of TR-FRET master mix consisting of 2 nM WT PPARG LBD (E. coli expressed, His-TEV-Q203-Y477; Uniprot ID P37231-2), 2 nM WT RXRA LBD (E. coli expressed, Flag-TEV-E228-T462; P19793-1), 350 nM NCOR1, 80 nM rosiglitazone, 175 nM streptavidin-d2 (Cisbio) and 0.3 nM anti-His Tb (Cisbio) in 25 mM MOPS pH 7.4, 25 mM KCl, 1 mM EDTA, 0.01% BSA, 0.01% Tween-20 and 1 mM TCEP was added to 60 μL of the compounds in DMSO (0.3% DMSO). Ten-point reaction titrations of fc (v / v) were added to a 384-well plate containing duplicates. The mixtures were incubated for 3 hours and read on an EnVision plate reader (Perkin Elmer) at Ex / Em 615 / 665. The potency of MED1 repulsion (IC 50To determine the degree of FRET concentration, TR-FRET ratios were normalized to the average ratio of DMSO control wells (0%) and to the average minimum ratio for a positive control compound (GW9662 (2-chloro-5-nitrobenzanilide); defined as 100%) in the CDD Vault and analyzed using the Levenberg-Marquardt algorithm.

[0205] Bladder Cancer Pharmacodynamic Assay 5637 (PPARG amplified) and HT1197 (RXRA S427F mutant) cells were used to evaluate the regulation of PPARG target genes using quantitative PCR. After treating cells with PPARG inverse agonists for 24 hours, FABP4 (IDT, Catalog No. Hs.PT 58.20106818) and ANGPTL4 (IDT, Catalog No. Hs.PT 58.25480012) expression was analyzed, using the expression of housekeeping gene TBP (IDT, Catalog No. Hs.PT 58v.39858774) to normalize expression across samples. Quantitative PCR was performed using an ABI QuantStudio 7 Flex reaction system. Data was analyzed and reported against DMSO control using the comparative Ct method (ΔΔCt).

[0206] Table 3 For the PPARG-NCOR recruitment assay, EC 50 The concentrations were expressed as follows: A: <10 nM, B: 10-100 nM, C: 100-1,000 nM, D: 1,000-10,000 nM, E: >10,000 nM. The percentage of NCOR recruitment was expressed as follows: A: >100% (> control compound, T907), B: <100% (< control compound, T907).

[0207] For PPARG-MED1 recruitment assay, EC 50were expressed as follows: A: <10 nM, B: 10-100 nM, C: 100-1,000 nM, D: 1,000-10,000 nM, E: >10,000 nM. The % of MED1 blockade was expressed as follows: A: >100% (> control compound, GW9662), B: <100% (< control compound, GW9662).

[0208] For the HT1197 cell assay, EC 50 are expressed as follows: A: <10 nM, B: 10-100 nM, C: 100-1,000 nM, D: 1,000-10,000 nM, E: >10,000 nM, ND: not determined. The % inhibition of ANGPTL4, PPARG target genes at a compound concentration of 100 nM is expressed as a percentage of the DMSO control experiment.

[0209] [Table 4]

[0210]

[0165] Although a number of embodiments have been described, it is apparent that our basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be appreciated that the scope of the present invention is defined by the scope of the appended claims, rather than by the specific embodiments shown by way of example.

[0211]

[0166] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are given the meaning commonly known to those skilled in the art.

Claims

1. Formula I 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, R １ is hydrogen, halo, (C １ ~C ４ ) alkyl or hydroxyl; X is S, SO, SO ２ or -SONH, R ２ is (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, or halo (C １ -C ４ ) alkyl, R ３ is cyano or nitro, R ４ is hydrogen, halo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy or hydroxyl; R ５ Ha, halo, halo (C １ ~C ４ ) alkyl or cyano; R ６ Ha, halo, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkyl or cyano; R ７ Halo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) alkyl OR ａ , -(C １ ~C ４ ) alkylC(O)R ａ , -(C １ ~C ４ ) alkylC(O)OR ａ , —C(O)NR ａ R ｂ , -(C １ ~C ４ ) alkylC(O)NR ａ R ｂ , -C(O)R ａ , -C(O)OR ａ , -NR ａ R ｂ , -(C １ ~C ４ ) alkylNR ａ R ｂ , —C(O)NR ａ SO ３ H, -NR ａ C(O)R ｂ , -NR ａ C(O)OR ｂ , -NR ａ C(S)OR ｂ , -NR ｃ C(O)N ａ R ｂ , -NR ｃ C(S)NR ａ R ｂ , -NR ｃ S (O) ２ NR ａ R ｂ , -C(S)R ａ , -S(O) ２ R ａ , -S(O)R ａ , -C(S)OR ａ , -C(S)NR ａ R ｂ , -NR ａ C(S)R ｂ , -SR ａ , phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl, each of said phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl optionally and independently selected from R ８ is substituted with 1 to 3 groups selected from R ８ Halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, nitro, oxo, cyano, -(C １ ~C ４ ) alkyl OR ｄ , -(C １ ~C ４ ) alkylC(O)R ｄ , -(C １ ~C ４ ) alkylC(O)OR ｄ , —C(O)NR ｄ R ｅ , -(C １ ~C ４ ) alkylC(O)NR ｄ R ｅ , -C(O)R ｄ , -C(O)OR ｄ , -NR ｄ R ｅ , -(C １ ~C ４ ) alkylNR ｄ R ｅ , —C(O)NR ｄ SO ３ H, -NR ｄ C(O)R ｅ , -NR ｄ C(O)OR ｅ , -NR ｄ C(S)OR ｅ , -NR ｆ C(O)N ｄ R ｅ , -NR ｆ C(S)NR ｄ R ｅ , -NR ｆ S (O) ２ NR ｄ R ｅ , -C(S)R ｄ , -S(O) ２ R ｄ , -S(O)R ｄ , -C(S)OR ｄ , -C(S)NR ｄ R ｅ , -NR ｄ C(S)R ｅ and -SR ｄ is selected from R ａ , R ｂ , R ｃ , R ｄ , R ｅ and R ｆ are each independently hydrogen or (C １ ~C ４ ) alkyl, q and r are each independently 0 or 1. (i) the compound is of formula II 【Chemistry 2】 or a pharmaceutically acceptable salt thereof; Optionally, the compound is of formula II a 【Transformation 3】 or a pharmaceutically acceptable salt thereof; (ii) the compound is of formula III 【Chemistry 4】 or a pharmaceutically acceptable salt thereof; Optionally, the compound is of formula IIIa 【Transformation 5】 or a pharmaceutically acceptable salt thereof; or (iii) the compound is of formula IV 【Transformation 6】 or a pharmaceutically acceptable salt thereof; Optionally, the compound is of formula IV a 【Transformation 7】 or a pharmaceutically acceptable salt thereof; The compound of claim 1.

3. R １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen and / or R 3 is cyano.

4. (i) R ５ is halo or cyano, preferably R 5 is halo, more preferably R 5 is chloro or fluoro, even more preferably R 5 is fluoro; and / or (ii) R 6 is halo, preferably R 6 is fluoro or chloro, even more preferably R 6 is fluoro; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. R ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

6. R ７ But, halo, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) alkyl OR ａ , —C(O)NR ａ R ｂ , phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl, each of said phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl optionally and independently selected from R ８ or R 7 is halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, —(C 1 -C 4 )alkylOR a , —C(O)NR a R b , phenyl, pyridinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, pyrazolyl, and oxetanyl, each of said phenyl, pyridinyl, pyrazolyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, piperidinyl, and oxetanyl optionally and independently substituted with 1 to 3 groups selected from R 8 ; or R 7 is pyrazolyl, pyridinyl, or piperazinyl, each of which is optionally and independently substituted with 1 to 3 groups selected from R 8 ; or R 7 is pyrazolyl optionally and independently substituted with 1 to 3 groups selected from R 8 ; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. R ８ But, Halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) selected from alkoxy, oxo, and cyano; or R 8 is halo(C 1 -C 4 )alkyl; or R 8 is (C 1 -C 4 ) alkyl; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. R ２ Halo (C １ ~C ４ ) alkyl or (C １ ~C ４ ) alkyl; R 2 is (C 1 -C 4 ) alkyl; R2 is CH3, CH2CH3, CF3CH2, CF3, CH(CH3)2 or CH2CH(CH3)2; or R 2 is CH 3 ; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

9. X is SO ２ 3. The compound of claim 1 or 2, wherein:

10. If the compound has the structural formula: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 2. The compound of claim 1, wherein:

11. A compound having the structural formula: 【Chemistry 9】 2. The compound of claim 1, wherein:

12. Crystalline form A has the structural formula: 【Chemistry 10】 A compound of the formula The crystalline form is characterized by at least three powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 18.8°, and 19.8°; or characterized by at least four powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 18.8°, and 19.8°; and / or characterized by powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 18.8°, and 19.8°; or characterized by powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, and 12.7°; or characterized by powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, and 19.8°; or characterized by powder X-ray diffraction peaks at 2Θ angles selected from 6.1°, 9.3°, 12.7°, 17.7°, 18.8°, 19.8° and 22.2°; The compound.

13. 13. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a crystalline form of the compound of claim 12, and a pharmaceutically acceptable carrier, optionally for use in a method for treating a cancer responsive to inhibition of PPARG in a subject, wherein the cancer is selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, renal cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, kidney cancer, brain cancer and hematopoietic cancer, preferably the cancer is bladder cancer.

14. 13. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or a crystalline form of the compound according to claim 12, for use in a method of treating a cancer responsive to inhibition of PPARG in a subject, The cancer is selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, renal cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, kidney cancer, brain cancer and hematopoietic cancer, preferably the cancer is bladder cancer; The compound or a pharmaceutically acceptable salt thereof, or a crystalline form of the compound.

15. 10. A process for preparing a compound having formula I according to claim 1, comprising: Formula A 【Chemistry 11】 wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , q and r are as defined in claim 1, and L is a leaving group. The compound of XR ２ wherein R 2 is as defined in claim 1 ) with a corresponding sulfur nucleophile to form said compound of formula I.

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