PPARG inverse agonists and uses thereof

Abstract

The present invention provides compounds of Formula (I): # imgabs0 #, and pharmaceutically acceptable salts and compositions thereof, which are useful in the treatment of various diseases associated with PPARG.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 317,737, filed on March 8, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] PPARγ (PPARG) is a type II ligand-dependent nuclear hormone receptor (belonging to the PPAR nuclear receptor subfamily) that forms an essential heterodimer with the retinoid X receptor (RXR) to exert its effects. PPARG is mainly expressed in adipose tissue, colon, macrophages, and urothelial layer. PPARG is known as the master regulator of adipogenesis, responsible for regulating adipocyte differentiation, fatty acid storage, and glucose metabolism. Studies have also shown that PPARG plays an important role in macrophage metabolism and inflammation, and it is induced by IL4 and controls glutamine metabolism. In normal urothelium, PPARG is essential for its homeostasis and regeneration.

[0004] The role of PPARG in cancer was initially inferred from genomic studies that identified PAX8-PPARG chromosomal rearrangements in follicular thyroid carcinoma. More recently, PPARG has been 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 an increased incidence of urothelial carcinoma. Most cancers of the urothelium are urothelial carcinomas, which are classified as non-muscle-invasive urothelial carcinoma (NMIUC, 70%), muscle-invasive urothelial carcinoma (MIUC, 25%), or metastatic urothelial carcinoma (MUC, 5%). MIUC is usually diagnosed de novo but may also arise from the 10% to 20% of NMIUC cases that eventually progress. MIUC is a heterogeneous and aggressive disease with a five-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 association of molecular subtypes with urothelial differentiation. Several molecular classifications of MIUC have been proposed, with the luminal subtype being distinguished by activated PPARG. First-line treatment is chemotherapy, with several options for cases not amenable to chemotherapy or as second-line treatment, but treatment options are limited and overall survival is low.

[0005] There is a need to develop effective PPARG modulators to treat cancers such as NMIUC, MIUC and MUC and related diseases. Summary of the invention

[0006] Provided herein are compounds having Formula I:

[0007]

[0008] and pharmaceutically acceptable salts and compositions thereof, wherein R 1 , R 2 , R 3 , X, Y and Z are as described herein. In one aspect, the disclosed compounds of Formula I and their pharmaceutically acceptable salts can modulate PPARG (e.g., as agonists, such as inverse agonists), and can be used in various therapeutic applications, such as treating cancer. Therefore, their use for treating diseases responsive to PPARG inhibition is also included.

[0009] Also included are pharmaceutical compositions comprising the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof, and methods for their preparation. DETAILED DESCRIPTION

[0010] 1. Overall description of the compound

[0011] In a first embodiment, provided herein is a compound of Formula I:

[0012]

[0013] X, Y and Z are each independently selected from N and -CR 4 ;

[0014] R 1 is selected from phenyl, heterocyclyl and heteroaryl, each of which is optionally substituted by 1 to 3 selected from R 5 The group substitution;

[0015] R 2 Selected from halogen, -SR a 、-SOR a 、-SO2R a 、-OR a and -SO(=NR a )R b ;

[0016] R 3 is selected from cyano and nitro;

[0017] R 4 is selected from hydrogen, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy and hydroxy;

[0018] R 5 is selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, cyano, oxo, -(C1-C4) alkyl, OR a 、-(C1-C4)alkylC(O)R a 、-(C1-C4)alkylC(O)ORa 、-C(O)NR a R b 、-(C1-C4)alkylC(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-NR a R b 、-(C1-C4)alkylNR a R b 、-C(O)NR a SO3H, -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)2NR a R b 、-C(S)R a 、-S(O)2R a 、-S(O)R a 、-C(S)OR a 、-C(S)NR a R b 、-NR a C(S)R b 、-SR a , -O(phenyl), phenyl, heterocyclyl and heteroaryl, wherein the phenyl, heterocyclyl, heteroaryl and phenyl on -O(phenyl) are each optionally and independently substituted by 1 to 3 selected from R 6 The group substitution;

[0019] R 6 is selected from halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, nitro, oxo, cyano, -(C1-C4) alkyl, OR d 、-(C1-C4)alkylC(O)R d 、-(C1-C4)alkylC(O)OR d 、-C(O)NR d R e 、-(C1-C4)alkylC(O)NR d R e、-C(O)R d 、-C(O)OR d 、-NR d R e 、-(C1-C4)alkylNR d R e 、-C(O)NR d SO3H, -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)2NR d R e 、-C(S)R d 、-S(O)2R d 、-S(O)R d 、-C(S)OR d 、-C(S)NR d R e 、-NR d C(S)R e and-SR d ;and

[0020] R a , R b , R c , R d and R e Each is independently selected from hydrogen, (C1-C4)alkyl and halo(C1-C4)alkyl.

[0021] 2. definition

[0022] When used to describe a chemical group that may have multiple points of attachment, the hyphen (-) indicates the point of attachment of the group to the variable it defines. For example, -NR b C(O)OR c and-NR b C(S)OR c Indicates that the point of attachment of the group occurs at the nitrogen atom.

[0023] The terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) and iodine (iodo, -I).

[0024] The term "alkyl" used alone or as part of a larger moiety (eg, "haloalkyl," etc.) refers to a saturated straight-chain or branched monovalent hydrocarbon radical.

[0025] "Alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented as -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy and butoxy.

[0026] The term "haloalkyl" includes monohalo, polyhalo and perhaloalkyl groups wherein the halogen is independently selected from fluorine, chlorine, bromine and iodine.

[0027] "Haloalkoxy" is a haloalkyl group attached to another moiety through an oxygen atom, for example -OCHF2 or -OCF3.

[0028] The term oxo denotes a =0 group.

[0029] The term "heteroaryl" used alone or as part of a larger moiety refers to a 5- to 12-membered aromatic group containing 1-4 heteroatoms selected from N, O and S. Heteroaryl can be monocyclic or bicyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bicyclic heteroaryl includes groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, imidazopyridinyl, benzoxazolyl, benzoxadiazolyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It should be understood that when specified, optional substituents on the heteroaryl may be present in any substitutable position, and include, for example, the position at which the heteroaryl is attached.

[0030] The term "heterocyclic group" refers to a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O and S. It can be a monocyclic, bicyclic (e.g., bridged, fused or spirocyclic bicyclic) or tricyclic. The heterocyclic ring can be connected to its side group by any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyridonyl, pyrrolidinone, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. The heterocyclic group can be a monocyclic or bicyclic ring. The term "heterocyclyl" also includes, for example, an unsaturated heterocyclic group fused to another unsaturated heterocyclic group or an aryl or heteroaryl ring, such as tetrahydronaphthyridine, indolinone, dihydropyrrole triazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It should also be understood that, when specified, optional substituents on the heterocyclic group may be present in any substitutable position, and include, for example, the position where the heterocyclic group is attached (e.g., in the case of an optionally substituted heterocyclic group or an optionally substituted heterocyclic group).

[0031] The term "spiro" refers to two rings that share one ring atom (eg, carbon).

[0032] The term "fused" refers to two rings that share two adjacent ring atoms with each other.

[0033] The term "bridged" refers to two rings that share three ring atoms with each other.

[0034] The terms "subject" and "patient" are used interchangeably and refer to mammals 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.

[0035] "Inhibit," "inhibition," or "inhibiting" includes a decrease in the baseline activity of a biological activity or process.

[0036] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or condition, or one or more symptoms thereof, as described herein. In certain aspects, treatment may be performed after the onset of one or more symptoms, i.e., therapeutic treatment. In other aspects, treatment may be performed in the absence of symptoms. For example, susceptible individuals may be treated before symptoms develop (e.g., in view of a history of symptoms and / or in view of exposure to a particular organism, or other predisposing factors), i.e., prophylactic treatment. Treatment may also be continued after symptom relief, e.g., to delay its recurrence.

[0037] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or carrier that does not destroy the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants or carriers that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0038] When used in medicine, the salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic salts or basic / cationic salts. Suitable pharmaceutically 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 salts of organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). The compounds of the present invention having an acidic group (e.g., a carboxylic acid) can form pharmaceutically acceptable salts with a pharmaceutically acceptable base. Suitable pharmaceutically 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 quaternary ammonium groups also contain counterions, such as chlorides, bromides, iodides, acetates, perchlorates, and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, and salts formed with amino acids (e.g., glutamic acid).

[0039] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that will elicit a desired or beneficial biological or medical response in a subject, for example, a dosage of 0.01-100 mg / kg body weight / day.

[0040] 3. Compound

[0041] In a second embodiment, X, Y and Z in the compound of Formula I or a pharmaceutically acceptable salt thereof are each -CR 4 ; or X and Z are each -CR s and Y is N, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a second embodiment, X, Y and Z in the compound of Formula I or a pharmaceutically acceptable salt thereof are each -CR 4 , wherein the remaining variables are as described above for Formula I.

[0042] In a third embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 4 is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl and (C1-C4)alkoxy, wherein the remaining variables are as described above for Formula I or as described in the second embodiment. Alternatively, as part of a third embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 4 is hydrogen, wherein the remainder of the variables are as described above for Formula I or as in the second embodiment.

[0043] In a fourth embodiment, R 3 is cyano, wherein the remainder of the variables are as described above for Formula I or as in the second or third embodiment.

[0044] In a fifth embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 2 Selected from halogen, -SR a 、-SOR a 、-SO2R a and -SO(=NR a )R b , wherein the remaining variables are as described above for Formula I or as described in the second, third or fourth embodiment. Alternatively, as part of a fifth embodiment, R in a compound of Formula I or a pharmaceutically acceptable salt thereof is 2 Selected from -SO2R a and-SR a , wherein the remaining variables are as described above for Formula I or as described in the second, third or fourth embodiment. In another alternative, as part of the fifth embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 2 is selected from -SO2Me, SCF3, -SO2CH2CF3 and -SO2CF3, wherein the remainder of the variables are as described above for Formula I or as described in the second, third or fourth embodiment.

[0045] In a sixth embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 1is selected from phenyl and heteroaryl, each of which is optionally substituted by 1 to 3 selected from R 5 wherein the remaining variables are as described above for Formula I or as described in the second, third, fourth or fifth embodiment. Alternatively, as part of a sixth embodiment, R in a compound of Formula I or a pharmaceutically acceptable salt thereof is 1 is selected from phenyl, pyridyl, isoquinolyl, pyrazolopyridyl, each of which is optionally substituted by 1 to 3 selected from R 5 wherein the remaining variables are as described above for Formula I or as described in the second, third, fourth or fifth embodiment.

[0046] In a seventh embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 is selected from halogen, oxo, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, -(C1-C4) alkyl, OR a 、-(C1-C4)alkylC(O)R a 、-(C1-C4)alkylC(O)OR a 、-C(O)NR a R b 、-(C1-C4)alkylC(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-NR a R b 、-(C1-C4)alkylNR a R b NR a C(O)R b 、-NR a C(O)OR b 、-NR c C(O)N a R b 、-NR c S(O)2NR a R b 、-S(O)2R a 、-S(O)R a 、-SR a , -O(phenyl), phenyl, heterocyclyl and heteroaryl, wherein the phenyl, heterocyclyl, heteroaryl and phenyl on -O(phenyl) are each optionally and independently substituted by 1 to 3 selected from R 6 wherein the remaining variables are as described above for Formula I or as described in the second, third, fourth, fifth or sixth embodiment. Alternatively, as part of the seventh embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 5selected from halogen, halo(C1-C4)alkyl, cyano, oxo, -O(phenyl), heterocyclyl and heteroaryl, wherein the phenyl on the heterocyclyl, heteroaryl and -O(phenyl) is each optionally and independently replaced by 1 to 3 selected from R 6 wherein the remaining variables are as described above for Formula I or as described in the second, third, fourth, fifth or sixth embodiment. In another alternative, as part of the seventh embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 is selected from cyano, chloro, fluoro, CF3, oxo, methyl, pyridyl, piperazinyl, pyrazolyl and -O(phenyl), wherein the remaining variables are as described above for Formula I or as described in the second, third, fourth, fifth or sixth embodiment.

[0047] In an eighth embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 6 is selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, -(C1-C4)alkyl, OR d 、-(C1-C4)alkylC(O)OR d 、-NR d R e 、-(C1-C4)alkylNR d R e 、-C(O)NR d R e 、-(C1-C4)alkylC(O)NR d R e 、-C(O)R d 、-C(O)OR d 、-S(O)2R d 、-S(O)R d and-SR d , wherein the remaining variables are as described above for Formula I or as described in the second, third, fourth, fifth, sixth or seventh embodiment. Alternatively, as part of an eighth embodiment, R in a compound of Formula I or a pharmaceutically acceptable salt thereof is 6 is selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, oxo, -C(O)R d , wherein the remaining variables are as described above for Formula I or as described in the second, third, fourth, fifth, sixth or seventh embodiment. In another alternative, as part of the eighth embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 6 is selected from methyl, CF3, -CHCF2, oxo, chloro, and C(O)CH3, wherein the remainder of the variables are as described above for Formula I or as described in the second, third, fourth, fifth, sixth or seventh embodiment.

[0048] Compounds having Formula I are further disclosed in the embodiments and are encompassed by the present disclosure. Pharmaceutically acceptable salts and neutral forms thereof are also included.

[0049] 4. Use, preparation and administration

[0050] The compounds and compositions described herein are generally useful for modulating the activity of PPARG. In some aspects, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein inhibit the activity of PPARG. In some aspects, the compounds and pharmaceutically acceptable salts disclosed herein are agonists of PPARG. In some aspects, the compounds and pharmaceutically acceptable salts disclosed herein are agonists of PPARG. In some aspects, the compounds and pharmaceutically acceptable salts disclosed herein are inverse agonists of PPARG. In one aspect, an "inverse agonist" refers to an agent that binds to the same receptor binding site (e.g., a binding site of a nuclear receptor (e.g., PPARG)) as an agonist, and not only antagonizes the effects of the agonist, but also produces an opposite effect by inhibiting spontaneous receptor signaling (when present).

[0051] In some aspects, the compounds and pharmaceutically acceptable salts disclosed herein overcome the activated state of PPARG function caused by changes in PPARG activity (mutation, amplification or overexpression) or RXRA activating mutations. In some aspects, the compounds and pharmaceutically acceptable salts disclosed herein improve the inhibitory state (NCOR1 recruitment) to a degree higher than that of previously disclosed PPARG modulators (e.g., previous inverse agonists). Such results are produced even in the context of mutations. For example, see the table in the Examples section that qualitatively evaluates NCOR1 recruitment and PPARG target gene inhibition in HT1197.

[0052] In some aspects, the compounds and pharmaceutical compositions described herein can be used to treat diseases associated with PPARG function. Thus, provided herein are methods for treating diseases associated with PPARG function, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof.

[0053] Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the disclosed compound or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with PPARG function. Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the disclosed compound or a pharmaceutically acceptable salt thereof, for treating a disease associated with PPARG.

[0054] In one aspect, the disease associated with PPARG is cancer. In some aspects, cancer is associated with upregulated peroxisome proliferator-activated receptor (PPAR) signaling pathways. In some aspects, the upregulated PPAR signaling pathway is associated with one or more selected from Uroplakin1A (UPK1A), Uroplakin IB (UPK1B), Uroplakin (UPK2), Keratin 20 (KRT20), GATA Binding Protein 3 (GATA3), Nuclear Receptor Corepressor 1 (NCOR1), Nuclear Receptor Corepressor2 (NCOR2), Fatty Acid Binding Protein 4 (FABP4), Forkhead Box Al (FOXA1), CD36 molecule (CD36), Acyl-CoA Oxidase 1 (ACOX1), 3-Hydroxy-3-Methylglutaryl-CoA synthetase 2 (3-Hydroxy-3-Methylglutaryl-CoA synthetase 2, HMGCS2), Acyl-CoA Synthetase Long-Chain Family Member 5 (ACSL5), Arachidonate 5-Lipoxygenase (ALOX5), Acyl-CoA Synthetase Long-Chain Family Member 1 (ACSL1), and Angiopoietin Like 4 (ANGPTL4) genes were increased in the presence of leukemia cells.

[0055] In some aspects, 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, kidney 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 aspect, the cancer treated by the compounds described herein, their pharmaceutically acceptable salts, and pharmaceutical compositions is urothelial cancer, such as non-muscle-invasive urothelial cancer, muscle-invasive urothelial cancer, and metastatic urothelial cancer.

[0056] In addition to cancer, other uses are contemplated, including, for example, metabolic diseases (e.g., osteoporosis, rickets, arthritis, obesity, type I and type II diabetes), lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia, osteoporosis, rickets, arthritis inflammatory diseases (e.g., inflammatory skin diseases such as psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus), pulmonary diseases (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), restenosis after invasive surgery, cardiomyopathy, myocardial fibrosis, congestive heart failure, neoplastic diseases, and angiogenesis and neovascularization in renal diseases.

[0057] In certain aspects, pharmaceutical compositions as described herein are formulated for use by patients in need of the compositions. Pharmaceutical compositions as described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or by implantable storage capsules. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of pharmaceutical compositions as described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art.

[0058] In some aspects, the pharmaceutical composition is administered orally.

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

[0060] Example

[0061] Chemical synthesis

[0062] The following representative examples are intended to help illustrate the present disclosure and are not intended to be limiting and should not be construed as limiting the scope of the present invention.

[0063] Starting Materials

[0064]

[0065] 5-Cyano-2-(trifluoromethylsulfonyl)benzoyl chloride :

[0066] Step 1, methyl 5-cyano-2-(trifluoromethylsulfonyl)benzoate : CuBr (150mg, 1.05mmol, 0.1 equivalent) and 1,10-phenanthroline (377mg, 2.09mmol, 0.2 equivalent) were added to a solution of 5-cyano-2-iodo-benzoic acid methyl ester (3.0g, 10.5mmol, 1.0 equivalent) and trifluoromethylsulfonyl silver (2.18g, 10.5mmol, 1.0 equivalent) in DMF (30mL). The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was diluted with water (60mL) and extracted with ethyl acetate (3×30mL). The organic layers were combined, washed with brine (2×25mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (13:1 petroleum ether: ethyl acetate) to obtain the title compound (1.22g, 43% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.31 (d, J = 1.6 Hz, 1H), 7.86-7.82 (m, 1H), 7.81-7.78 (m, 1H), 4.00 (s, 3H).

[0067] Step 2, 5-cyano-2-(trifluoromethylsulfonyl)benzoic acid : To a solution of methyl 5-cyano-2-(trifluoromethylsulfonyl)benzoate (1.2 g, 4.59 mmol, 1.0 equiv) in THF (12 mL) was added a solution of LiOH·H2O (193 mg, 4.59 mmol, 1.0 equiv) in water (3 mL). The reaction mixture was stirred at 20°C for 2 hours. The pH of the reaction mixture was adjusted to 2-3 with HCl (2 M). The mixture was filtered, the filter cake was washed with water (2×100 mL), and dried under vacuum to give the title compound (1.02 g, 4.13 mmol, 90.0% yield) as a yellow solid. LCMS [M-1] = 246.0. 1 H NMR (400MHz, DMSO-d6) δ = 8.40 (d, J = 2.0 Hz, 1H), 8.14 (dd, J = 2.0, 8.4 Hz, 1H), 7.85 (s, 1H).

[0068] Step 3, 5-cyano-2-(trifluoromethylsulfonyl)benzoyl chloride : A mixture solution of 5-cyano-2-(trifluoromethylsulfonyl)benzoic acid (210 mg, 849.54 μmol, 1 eq.) in SOCl (2 mL) was degassed with N, and the mixture was stirred at 80° C. for 2 hours under N. The reaction mixture was concentrated under reduced pressure to give the title compound (226 mg, crude product) as a pale white solid.

[0069]

[0070] 2-Chloro-5-cyano-benzoyl chloride : SOCl2 (1.0 mL) was added to a solution of 2-chloro-5-cyanobenzoic acid (75.0 mg, 413 μmol, 1.0 equiv). The mixture was stirred at 80°C for 0.5 h. The solution was concentrated under reduced pressure to give the title compound (83.0 mg, crude product) as a white solid. The product was used directly in the next step.

[0071]

[0072] 5-Chloro-2-cyano-pyridine-4-carbonyl chloride To a solution of 5-chloro-2-cyano-pyridine-4-carboxylic acid (1.45 g, 7.94 mmol, 1 eq) was added SOCl2 (15 mL), and the mixture was stirred for 2 h at 100° C. The mixture was concentrated to give the title compound (1.59 g, 99% yield) as a white solid, which was used directly in the next step.

[0073]

[0074] 5-Cyano-2-methylsulfonyl-benzoyl chloride

[0075] Step 1, 5-cyano-2-(methylsulfonyl)benzoic acid : CuI (105mg, 551μmol, 0.1 equivalent), K3PO4 (1.75g, 8.27mmol, 1.5 equivalents) and sodium methanesulfonate (843mg, 8.27mmol, 1.5 equivalents) are added to a DMF (4mL) solution of 2-chloro-5-cyanobenzoic acid (1.0g, 5.51mmol, 1.0 equivalents). The mixture is stirred at 100°C for 16 hours. The reaction mixture is quenched by adding HCl (1M, 24mL) at 15°C. The mixture is filtered, and concentrated under reduced pressure to obtain the title compound (713mg, 3.17mmol, 57.4% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ14.52-13.87(m,1H),8.57-7.88(m,3H),3.46(br s,3H).

[0076] Step 2, 5-cyano-2-methylsulfonyl-benzoyl chloride : A solution of 5-cyano-2-(methylsulfonyl)benzoic acid (100 mg, 444 μmol, 1.0 equivalent) in SOCl2 (1.5 mL) was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (108 mg, crude product) as a brown solid. The material was used directly in the next step without further purification.

[0077]

[0078] 3,5-Difluoro-4-(6-methylpyridin-3-yl)aniline :

[0079] To a solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.2 g, 913 μmol, 1.0 equiv) in dioxane (6.0 mL) and water (2.0 mL) was added 4-bromo-3,5-difluoroaniline (233 mg, 913 μmol, 1.0 equiv), K2CO3 (379 mg, 2.7 mmol, 3.0 equiv) and Pd(dppf)Cl2·CH2Cl2 (74.5 mg, 91.2 μmol, 0.1 equiv). The mixture was degassed with N2 and then stirred at 80°C under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5:1 to 4:1 petroleum ether:ethyl acetate) to give the title compound (144 mg, 70.8% yield, 98.9% purity) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (s, 1H), 7.64 (br d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.41-6.19 (m, 2H), 3.98 (br s, 2H), 2.60 (s, 3H).

[0080]

[0081] 4-(6-(Difluoromethyl)pyridin-3-yl)-3,5-difluoroaniline :

[0082] The title compound was prepared starting from 2-difluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine using a procedure similar to that used to prepare 3,5-difluoro-4-(6-methylpyridin-3-yl)aniline. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.72 (s, 1H), 7.91 (br d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.87-6.51 (t, J = 55.2 Hz, 1H), 6.38-6.23 (m, 2H), 4.27-3.82 (m, 2H).

[0083]

[0084] 6-(4-Amino-2,6-difluorophenyl)isoindolin-1-one :

[0085] The title compound was prepared starting from 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one using a procedure similar to that used to prepare 3,5-difluoro-4-(6-methylpyridin-3-yl)aniline. 1 H NMR (400 MHz, methanol-d4) δ 7.74 (s, 1H), 7.62-7.54 (m, 2H), 6.37-6.27 (m, 2H), 4.55-4.50 (m, 2H), 3.21 (s, 3H).

[0086]

[0087] 6-(4-Amino-2,6-difluorophenyl)-2-methylisoindolin-1-one :

[0088] The title compound was prepared starting from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one using a procedure similar to that used for 3,5-difluoro-4-(6-methylpyridin-3-yl)aniline. 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),7.79-7.43(m,3H),6.43-6.15(m,2H),5.89(s,2H),4.40(s,2H).

[0089]

[0090] 3,5-Difluoro-4-(1-methyl-1H-pyrazol-4-yl)aniline :

[0091] The title compound was prepared using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as the starting material in a similar manner to that used to prepare 3,5-difluoro-4-(6-methylpyridin-3-yl)aniline. LCMS: [M+1] = 210.1. 1 H NMR (400MHz, DMSO-d6) δ7.86 (s, 1H), 7.60 (s, 1H), 6.27 (br d, J = 11.4Hz, 2H), 5.70 (s, 2H), 3.86 (s, 3H).

[0092]

[0093] 5-Chloro-2-cyano-N-(3,5-difluorophenyl)isonicotinamide :

[0094] To a solution of 3,5-difluoroaniline (200 mg, 1.55 mmol, 1.0 equiv) in ethyl isopropionate (2 mL) was added a solution of 5-chloro-2-cyano-pyridine-4-carbonyl chloride (311 mg, 1.55 mmol, 1.0 equiv) in ethyl isopropionate (2 mL) at 20 ° C. The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (40 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (3 mL) at 25 ° C to give the title compound (178 mg, 39% yield) as a white solid. LCMS [M-1] = 292.0. 1 H NMR (methanol-d4, 400 MHz) δ 8.8-8.9 (m, 1H), 8.15 (s, 1H), 7.3-7.4 (m, 2H), 6.7-6.8 (m, 1H).

[0095]

[0096] 2-Cyano-N-(3,5-difluorophenyl)-5-((2,2,2-trifluoroethyl)thio)isonicotinamide :

[0097] To a solution of 2,2,2-trifluoroethane-1-thiol (75.5 μL, 851 μmol, 2.5 equiv) in DMF (1 mL) was added NaH (34.1 mg, 851 μmol, 2.5 equiv; 60% oil dispersion) at 0°C. The mixture was stirred at 0°C for 20 minutes, and then 5-chloro-2-cyano-N-(3,5-difluorophenyl)isonicotinamide (100 mg, 340 μmol, 1.0 equiv) was added to the mixture at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The mixture was added to water (5 mL). The resulting suspension was filtered, and the filter cake was washed with water (3×10 mL). The solid was concentrated under reduced pressure to give the title compound (120 mg, 94% yield) as a white solid. LCMS [M+1] = 374.1.

[0098] 1 H NMR (400MHz, DMSO-d6) δ = 11.12 (s, 1H), 9.10 (s, 1H), 8.35 (s, 1H), 7.41 (dd, J = 2.0, 9.0Hz, 2H), 7.13-7.03 (m, 1H), 4.39 (q, J = 10.2Hz, 2H).

[0099]

[0100] 3-(4-Chlorophenoxy)-5-fluoroaniline :

[0101] Step 1, 1-(4-chlorophenoxy)-3-fluoro-5-nitrobenzene: N2 was passed into a mixture of 4-chlorophenol (2.4 g, 18.9 μmol, 1.0 equiv.), 1,3-difluoro-5-nitrobenzene (3.0 g, 18.9 μmol, 1.0 equiv.) and Cs2CO3 (9.2 g, 28.3 μmol, 1.5 equiv.) in DMA (30 mL) to degas. Then, the mixture was stirred at 65 ° C for 8 hours under N2. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was washed with brine (3×100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate in petroleum ether: ethyl acetate solution) to give the title compound (2.96 g, 59% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.70-7.63 (m, 1H), 7.60 (d, J=0.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.10-6.96 (m, 3H).

[0102] Step 2, 3-(4-chlorophenoxy)-5-fluoroaniline : To a solution of 1-(4-chlorophenoxy)-3-fluoro-5-nitrobenzene (500 mg, 1.9 μmol, 1.01.0 equivalent) in ethanol (5 mL) was added NH4Cl (500 mg, 9.3 μmol, 5.0) in water (2.5 mL) and iron (0) (522 mg, 9.3 μmol, 5.0 equivalent). The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine (2×5 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (420 mg, 94% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.31 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.07 (d, J = 1.5 Hz, 3H), 4.59-2.48 (m, 2H).

[0103] Example 1

[0104]

[0105] N-(3-chloro-4-cyanophenyl)-5-cyano-2-(methylsulfonyl)benzamide

[0106] N-(3-chloro-4-cyanophenyl)-5-cyano-2-(methylsulfonyl)benzamide: To a mixture of 4-amino-2-chlorobenzonitrile (80 mg, 524 μmol, 1.0 equivalent) in isopropyl acetate (3.2 mL) was added a solution of 5-cyano-2-methylsulfonyl-benzoyl chloride (153 mg, 629 μmol, 1.2 equivalent). The mixture was degassed and purged with N2, then stirred at 80 ° C for 16 hours under N2. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (3 × 10 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. The reaction mixture was purified by preparative HPLC column (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: 20%-60% acetonitrile in water (+ formic acid)) to obtain the title compound (96.6 mg, 50.4% yield) as a white solid. LCMS [M-1] = 358.0. 1 H NMR(400MHz,DMSO-d6)δ11.36(br s,1H),8.43(d,J=1.3Hz,1H),8.31(dd,J=1.5,8.1Hz,1H),8.21(d,J=8.3Hz,1H),8. 09(d,J=1.8Hz,1H),7.99(d,J=8.5Hz,1H),7.68(dd,J=1.9,8.6Hz,1H),3.44(s,3H).

[0107] The compounds in Table 1 were prepared according to Scheme 1 using procedures similar to those described in Example 1.

[0108] Table 1

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] Embodiment 31

[0122]

[0123] 2-Cyano-N-(3,5-difluorophenyl)-5-(methylsulfonyl)isonicotinamide :

[0124] Sodium methanesulfonate (10.4 mg, 102 μmol, 1.5 equiv) was added to a solution of 5-chloro-2-cyano-N-(3,5-difluorophenyl)isonicotinamide (20 mg, 68.1 μmol, 1.0 equiv) in NMP (0.5 mL) at 0 °C. The solution was then stirred at 20 °C for 36 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (3:1 petroleum ether: ethyl acetate) to give the title compound (15.7 mg, 68% yield) as a white solid. LCMS[M+1]=337.9. 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.04-9.00 (m, 1H), 8.73 (s, 1H), 7.85 (s, 1H), 7.10 (br d, J = 6.6 Hz, 2H), 6.57 (br t, J = 8.8 Hz, 1H), 3.41 (s, 3H).

[0125]

[0126] Embodiment 33

[0127]

[0128] 5-Cyano-N-(3,5-difluorophenyl)-2-((2,2,2-trifluoroethyl)sulfonyl)benzamide

[0129] Step 1, 5-cyano-N-(3,5-difluorophenyl)-2-iodo-benzamide: A mixture solution of 5-cyano-2-iodo-benzoic acid (1.0 g, 3.66 mmol, 1.0 equivalent) in SOCl2 (10 mL) was degassed with N2 and then stirred at 100 ° C for 2 hours under N2. The mixture was concentrated under reduced pressure to give 5-cyano-2-iodo-benzoyl chloride (1.0 g, crude product) as a light yellow solid. The crude product was used directly in the next step. To a solution of isopropyl acetate (5 mL) of 3,5-difluoroaniline (443 mg, 3.43 mmol, 1.0 equivalent) was added a solution of isopropyl acetate (10 mL) of 5-cyano-2-iodo-benzoyl chloride (1.0 g, 3.43 mmol, 1.0 equivalent). The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was diluted with isopropyl acetate (10 mL), filtered, and the filter cake was washed with isopropyl acetate (3×10 mL). The solid was concentrated under reduced pressure. The residue was triturated with DCM at 25°C for 30 min to give the title compound (390 mg, 30% yield) as a white solid. LCMS [M+1] = 385.1.

[0130] Step 2, 5-cyano-N-(3,5-difluorophenyl)-2-((2,2,2-trifluoroethyl)thio)benzamide :

[0131] To a solution of 5-cyano-N-(3,5-difluorophenyl)-2-iodo-benzamide (200 mg, 520.7 μmol, 1.0 equiv) in DMSO (2 mL) was added NaH (20.8 mg, 521 μmol, 1.0 equiv; 60% oil dispersion). The mixture was stirred at 20 ° C for 0.5 hours, and then CuI (9.9 mg, 52 μmol, 0.1 equiv) and 2,2,2-trifluoroethanethiol (46.2 μL, 521 μmol, 1.0 equiv) were added to the mixture. The reaction mixture was stirred at 100 ° C for 4 hours. The reaction was quenched by adding saturated NH4Cl aqueous solution (8 mL), and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (6:1 to 5:1 petroleum ether:ethyl acetate) to give the title compound (140 mg, 72% yield) as a white solid.

[0132] LCMS [M+1] = 373.1. 1 H NMR (400 MHz, methanol-d4) δ 7.96 (s, 1H), 7.84 (s, 2H), 7.41-7.32 (m, 2H), 6.74 (tt, J = 2.4, 9.2 Hz, 1H), 3.93 (q, J = 9.8 Hz, 2H).

[0133] Step 3, 5-cyano-N-(3,5-difluorophenyl)-2-((2,2,2-trifluoroethyl)sulfonyl)benzamide: To a solution of 5-cyano-N-(3,5-difluorophenyl)-2-((2,2,2-trifluoroethyl)thio)benzamide (140 mg, 376.0 μmol, 1.0 eq) in DCM (6 mL) was added m-CPBA (458 mg, 2.26 mmol, 6.0 eq; 85% purity) at 0 °C. The mixture was stirred at 40 °C for 16 h. The reaction was quenched by the addition of a solution of Na2SO3 (300 mg) in H2O (10 mL) at 20 °C and stirred at 20 °C for 0.5 h. The reaction mixture was then extracted with DCM (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: 45-64% acetonitrile in water (+ formic acid)) to give the title compound (38.6 mg, 26% yield) as a white solid. LCMS [M+1] = 404.9. 1 H NMR (400MHz, DMSO-d6) δ11.27(br s,1H),8.51(br s,1H),8.40-8.20(m,2H),7.38(br d,J=4.6Hz,2H),7.07(br s,1H),5.33-4.91(m,2H).

[0134]

[0135] Biochemistry and cell-based assays

[0136] PPARγ-NCOR1 recruitment assay :

[0137] The compound potency (EC 50) and the maximum extent of NCOR1 recruitment to PPARG, the assay measured the binding of a biotinylated NCOR1 ID2 peptide (biotin-GHSFADPASNLGLEDIIRKALMG-amide) to the PPARG / RXRA LBD heterodimer. Specifically, 20 μl of TR-FRET master mix consisting of 2 nM WT PPARG LBD (expressed in E. coli, His-TEV-Q203-Y477; UniprotID P37231-2), 2 nM WT RXRA LBD or mutant S427F RXRA LBD (expressed in E. coli, Flag-TEV-E228-T462; P19793-1), 50 nM NCOR1, 80 nM rosiglitazone, 25 nM streptavidin-d2 (Cisbio), and 0.3 nM Anti-His 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 a 384-well plate. Tb (Cisbio), 384-well plates also contained 60 nL of compound in 0.3% fcDMSO (v / v) for 10-point dose response titrations in duplicate. The mixture was incubated for 3 h and then read on an EnVision plate reader (PerkinElmer) using Ex / Em 615 / 665. To determine the potency of NCOR1 recruitment (EC 50 ) and extent, TR-FRET ratios were normalized to the mean ratio of DMSO control wells (0%) and the mean maximum ratio of the positive control compound (T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide); defined as 100%) in CDDVault and analyzed using the Levenberg-Marquardt algorithm.

[0138] PPARγ-MED1 blocking assay :

[0139] The compound potency (IC 50) and the maximal extent to which MED1 repel PPARG, the assay measures the binding of a biotinylated MED1 LxxLL peptide (biotin-VSSMAGNTKNHPMLMNLLKDNPAQ-amide) to the PPARG / RXRA LBD heterodimer. Specifically, 20 μl of TR-FRET master mix consisting of 2 nM WT PPARG LBD (expressed in E. coli, His-TEV-Q203-Y477; Uniprot ID P37231-2), 2 nM WT RXRA LBD (expressed in E. coli, Flag-TEV-E228-T462; P19793-1), 350 nM NCOR1, 80 nM rosiglitazone, 175 nM streptavidin-d2 (Cisbio), and 0.3 nM Anti-His 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 a 384-well plate. Tb (Cisbio), 384-well plates also contained 60 nL of DMSO solution (0.3% fcDMSO (v / v)) of the compound for duplicate 10-point dose response titrations. The mixture was incubated for 3 hours and then read on an EnVision plate reader (Perkin Elmer) using Ex / Em 615 / 665. To determine the potency of MED1 exclusion (IC 50 ) and extent, TR-FRET ratios were normalized to the mean ratio of DMSO control wells (defined as 0%) and the mean minimum ratio of the positive control compound (GW9662 (2-chloro-5-nitrobenzanilide); defined as 100%) in CDD Vault and analyzed using the Levenberg-Marquardt algorithm.

[0140] Bladder cancer drug efficacy trial

[0141] In 5637 (PPARG amplification) and HT1197 (RXRA S427F mutation) cells, quantitative PCR was used to evaluate the regulation of PPARG target genes. Cells were treated with PPARG inverse agonists for 24 hours before analyzing FABP4 (IDT, Cat: Hs.PT 58.20106818) and ANGPTL4 (IDT, Cat: Hs.PT 58.25480012) expression, and the expression of the housekeeping gene TBP (IDT, Cat: Hs.PT 58v.39858774) was used to normalize expression between samples. Quantitative PCR was performed using the ABI QuantStudio 7Flex Reaction system. Data were analyzed and reported relative to the DMSO control group using the comparative Ct method (ΔΔCt).

[0142] Table 1

[0143] For the PPARG-NCOR recruitment assay, EC 50 The percentages of NCOR recruitment are 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 percentages of NCOR recruitment are as follows: A: >100% (>control compound, T907), B: <100% (<control compound, T907).

[0144] For the PPARG-MED1 recruitment assay, EC 50 The percentages of MED1 blocking are 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 percentages of MED1 blocking are as follows: A: >100% (>control compound, GW9662), B: <100% (<control compound, GW9662).

[0145] For HT1197 cell assays, EC 50 The values ​​are 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 percentage of inhibition of the PPARG target gene ANGPTL4 at 100 nM compound concentration is expressed as a percentage of the DMSO control experiment.

[0146]

[0147]

[0148] Although we have described some embodiments, it is apparent that our basic examples can be modified to provide other embodiments utilizing the compounds and methods of the present invention. It should be understood, therefore, that the scope of the invention will be defined by the appended claims rather than by the specific embodiments illustrated.

[0149] The contents of all references cited in this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are hereby incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are given the meanings commonly understood by those of ordinary skill in the art.

Claims

1. A compound having formula I: or a pharmaceutically acceptable salt thereof, wherein: X, Y and Z are each independently selected from N and -CR 4 ; R 1 is selected from phenyl, heterocyclyl and heteroaryl, each of which is optionally substituted by 1 to 3 selected from R 5 The group substitution; R 2 Selected from halogen, -SR a 、-SOR a 、-SO2R a 、-OR a and -SO(=NR a )R b ; R 3 is selected from cyano and nitro; R 4 is selected from hydrogen, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy and hydroxy; R 5 is selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, cyano, oxo, -(C1-C4) alkyl, OR a 、-(C1-C4)alkylC(O)R a 、-(C1-C4)alkylC(O)OR a 、-C(O)NR a R b 、-(C1-C4)alkylC(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-NR a R b 、-(C1-C4)alkylNR a R b 、-C(O)NR a SO3H, -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)2NR a R b 、-C(S)R a 、-S(O)2R a 、-S(O)R a 、-C(S)OR a 、-C(S)NR a R b 、-NR a C(S)R b 、-SR a , -O(phenyl), phenyl, heterocyclyl and heteroaryl, wherein the phenyl, heterocyclyl, heteroaryl and phenyl on -O(phenyl) are each optionally and independently substituted by 1 to 3 selected from R 6 The group substitution; R 6 is selected from halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, nitro, oxo, cyano, -(C1-C4) alkyl, OR d 、-(C1-C4)alkylC(O)R d 、-(C1-C4)alkylC(O)OR d 、-C(O)NR d R e 、-(C1-C4)alkylC(O)NR d R e 、-C(O)R d 、-C(O)OR d 、-NR d R e 、-(C1-C4)alkylNR d R e 、-C(O)NR d SO3H, -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)2NR d R e 、-C(S)R d 、-S(O)2R d 、-S(O)R d 、-C(S)OR d 、-C(S)NR d R e 、-NR d C(S)R e and-SR d ;and R a , R b , R c , R d and R e Each is independently selected from hydrogen, (C1-C4)alkyl and halo(C1-C4)alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are each -CR 4 ; or X and Z are each -CR s And Y is N.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are each -CR 4 .

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 4 is selected from hydrogen, (C1-C4)alkyl, halogenated (C1-C4)alkyl and (C1-C4)alkoxy.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4 For hydrogen.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 3 It is cyano.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 2 Selected from halogen, -SR a 、-SOR a 、-SO2R a and -SO(=NR a )R b .

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 2 Selected from -SO2R a and-SR a .

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 2 Selected from -SO2Me, SCF3, -SO2CH2CF3 and -SO2CF3.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 1 is selected from phenyl and heteroaryl, each of which is optionally substituted by 1 to 3 selected from R 5 The group is substituted.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 is selected from phenyl, pyridyl, isoquinolyl, pyrazolopyridyl, each of which is optionally substituted by 1 to 3 selected from R 5 The group is substituted.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 5 is selected from halogen, oxo, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, -(C1-C4) alkyl, OR a 、-(C1-C4)alkylC(O)R a 、-(C1-C4)alkylC(O)OR a 、-C(O)NR a R b 、-(C1-C4)alkylC(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-NR a R b 、-(C1-C4)alkylNR a R b NR a C(O)R b 、-NR a C(O)OR b 、-NR c C(O)N a R b 、-NR c S(O)2NR a R b 、-S(O)2R a 、-S(O)R a 、-SR a , -O(phenyl), phenyl, heterocyclyl and heteroaryl, wherein the phenyl, heterocyclyl, heteroaryl and phenyl on -O(phenyl) are each optionally and independently substituted by 1 to 3 selected from R 6 The group is substituted.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R 5 selected from halogen, halo(C1-C4)alkyl, cyano, oxo, -O(phenyl), heterocyclyl and heteroaryl, wherein the phenyl on the heterocyclyl, heteroaryl and -O(phenyl) is each optionally and independently replaced by 1 to 3 selected from R 6 The group is substituted.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 5 Selected from cyano, chloro, fluoro, CF3, oxo, methyl, pyridyl, piperazinyl, pyrazolyl and -O(phenyl).

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 6 is selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, -(C1-C4)alkyl, OR d 、-(C1-C4)alkylC(O)OR d 、-NR d R e 、-(C1-C4)alkylNR d R e 、-C(O)NR d R e 、-(C1-C4)alkylC(O)NR d R e 、-C(O)R d 、-C(O)OR d 、-S(O)2R d 、-S(O)R d and-SR d .

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 6 is selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, oxo and -C(O)R d .

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 6 Selected from methyl, CF3, -CHCF2, oxo, chloro and C(O)CH3.

18. The compound of claim 1, wherein the compound is selected from Or a pharmaceutically acceptable salt of any of the above compounds.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

20. A method of treating a cancer responsive to PPARG inhibition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein the cancer is selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, kidney cancer, brain cancer, and hematopoietic cancer.

22. The method of claim 20 or 21, wherein the cancer is bladder cancer.

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