PPARG inverse agonists and their uses

Abstract

Compounds of formula (I): TIFF2025508542000019.tif3350 and pharma- ceutically acceptable salts and compositions thereof are provided.

Description

[Technical field]

[0001] Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 317,740, filed March 8, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] PPARγ (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 predominantly expressed in adipose tissue, colon, macrophages, and the luminal layer of the urothelium. PPARG is known as a master regulator of adipogenesis, functioning in controlling adipocyte differentiation, fatty acid storage, and glucose metabolism. PPARG has also been shown to play an important role in macrophage metabolism and inflammation, where it is induced by IL4 and regulates glutamine metabolism. In normal urothelium, PPARG is critical for its homeostasis and regeneration.

[0003] The role of PPARG in cancer was initially inferred from genomic studies that identified PAX8-PPARG chromosomal rearrangements in follicular thyroid cancer. 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 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 up to 10-20% of NMIUC cases may eventually progress. MIUC is a heterogeneous, aggressive disease associated with 5-year survival rates ranging from 60% in patients with localized disease to less than 10% in patients with distant metastases. Molecular understanding of NMIUC and MIUC has improved significantly, including molecular subtypes and association with urothelial differentiation. Several molecular classes of MIUC have been proposed, whereby the activated PPARG signature is a distinctive feature in the luminal subtype. First-line treatment is chemotherapy, with several options in chemotherapy-ineligible or second-line, but treatment options are limited and overall survival is poor. Summary of the Invention [Problem to be solved by the invention]

[0004]

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

[0005] Formula I:

[0006] [ka]

[0007] [In the formula, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , W, X, Y, Z, q and r are as described herein], and pharma- ceutically acceptable salts and compositions thereof are provided 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 a variety of therapeutic applications, such as, for example, the treatment of cancer. Thus, their use for treating diseases responsive to inhibition of PPARG is included.

[0008] Also included are pharmaceutical compositions comprising the disclosed compounds of Formula I and their pharma ceutically acceptable salts, as well as methods for their preparation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] 1. General description of the compound In a first embodiment, a compound of formula I:

[0010] [ka]

[0011] [In the formula, X, Y and Z each independently represent N and -CR 4 Selected from; W is O and CR a R b Selected from; R 1 is selected from hydrogen, halo, (C1-C4) alkyl, and hydroxyl; R 2 ,Halo,-SR a , -SOR a , -SO2R a , -OR a , and -SO(=NR a )Rb Selected from; R 3 is selected from cyano and nitro; R 4 is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and hydroxyl; R 5 is selected from phenyl, heterocyclyl, and heteroaryl, each of which is 8 optionally substituted with 1 to 3 groups selected from; R 6 and R 7 each independently represents halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, cyano, oxo, -(C1-C4)alkylOR a , -(C1-C4) alkylC(O)R a , -(C1-C4) alkyl C(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)Ra , -C(S)OR a , -C(S)NR a R b , -NR a C(S)R b , -SR a , phenyl, heterocyclyl, and heteroaryl, each of said phenyl, heterocyclyl, and heteroaryl being optionally independently selected from R 9 substituted with 1 to 3 groups selected from; R 8 and R 9 each independently represents halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, nitro, oxo, cyano, -(C1-C4)alkylOR d , -(C1-C4) alkylC(O)R d , -(C1-C4) alkyl C(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 Selected from; R a , R b , R c , R d , and R e are each independently selected from hydrogen, (C1-C4)alkyl, and halo(C1-C4)alkyl; and q and r are each independently 0 or 1; or a pharma- ceutically acceptable salt thereof. 2.Definition When used in connection with describing a chemical group that may have multiple points of attachment, the hyphen (-) designates the point of attachment of the group to the variable for which the group 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 is on the nitrogen atom.

[0012] The terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0013] The term "alkyl," used alone or as part of a larger moiety, such as, for example, "haloalkyl," means a saturated, straight or branched, monovalent hydrocarbon radical.

[0014]

[0011] "Alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0015] The term "haloalkyl" includes mono-, poly- and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine, bromine and iodine.

[0013] A "haloalkoxy" is a haloalkyl group that is attached to another moiety through an oxygen atom, such as, for example, --OCHF2 or --OCF3.

[0016] The term oxo refers to the group ═O. The term "heteroaryl" used alone or as part of a larger moiety refers to a 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. Heteroaryl groups can be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, imidazopyridinyl, benzoxazolyl, benzoxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. When specified, it will be understood that optional substituents on heteroaryl groups can be present at any substitutable position, including, for example, the position at which the heteroaryl is attached.

[0017] The term "heterocyclyl" refers to a 5-12 membered saturated or partially unsaturated heterocycle containing 1-4 heteroatoms independently selected from N, O, and S. It may be monocyclic, bicyclic (e.g., bridged, fused, or spiro bicyclic), or tricyclic. The heterocycle may be attached to its pendant group at 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, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. Heterocyclyl groups may be monocyclic or bicyclic. The term "heterocyclyl" also includes, for example, unsaturated heterocyclic groups fused to another unsaturated heterocyclic group or to an aryl or heteroaryl ring, such as tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane, and the like. It will also be understood that, where specified, optional substituents on a heterocyclyl group may be present at any substitutable position, including, for example, the position at which the heterocyclyl is attached (e.g., in the case of an optionally substituted heterocyclyl or an optionally substituted heterocyclyl).

[0018] The term "spiro" refers to two rings that share one ring atom (eg, carbon). The term "fused" refers to two rings which share two adjacent ring atoms with each other.

[0019] The term "bridged" refers to two rings which share three ring atoms with each other.

[0020] The disclosed compounds may exist in one or more tautomeric forms, for example, and are included herein:

[0020] [ka]

[0021]

[0021] 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.), agricultural livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Generally, the subject is a human in need of treatment.

[0022]

[0022] The terms "inhibit," "inhibition," or "inhibiting" include a reduction in the baseline activity of a biological activity or process.

[0023] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of a disease or disorder, or one or more symptoms thereof, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or exposure to a particular organism or other susceptibility factors), i.e., prophylactic treatment. Treatment can also be continued after symptoms have resolved, e.g., to delay their recurrence.

[0023]

[0024] The term "pharmaceutical acceptable carrier" refers to non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that is incorporated.The pharmaceutical acceptable carrier, adjuvant and vehicle that can be used in the compositions described herein include, but are not limited to, ion exchanger, alumina, aluminum stearate, lecithin, serum protein, such as human serum albumin, etc.; buffer substances, such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicic acid, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat.

[0024]

[0025] 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 salts or basic / cationic salts. Suitable pharmaceutical acceptable salt addition salts of the compounds described herein include, for example, salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, etc.) and salts of organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.). Compounds of the present teachings with acidic groups, such as carboxylic acids, can form pharmaceutical acceptable salts with pharmaceutical acceptable bases. Suitable pharmaceutical acceptable base salts include, for example, ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts) and alkaline earth metal salts (e.g., magnesium salts and calcium salts). Compounds with a quaternary ammonium group also include a counteranion, such as chloride, bromide, iodide, acetate, perchlorate, etc. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids, such as glutamic acid.

[0025]

[0026] 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, e.g., a dosage of 0.01 to 100 mg / kg body weight / day. 3.Compound

[0027] In a second embodiment, R in a compound of formula I or a pharma- ceutically acceptable salt thereof is 1 is hydrogen, and the remainder of the variables are as described above for formula I.

[0026]

[0028] In a third embodiment, X, Y, and Z in the compound of formula I or a pharma- ceutically acceptable salt thereof are each -CR 4 and the remainder of the variables are as described above for Formula I or the second embodiment.

[0027]

[0029] In a fourth embodiment, R in a compound of formula I or a pharma- ceutically acceptable salt thereof is 4 is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, and (C1-C4)alkoxy, and the remainder of the variables are as described above for Formula I, or the second or third embodiment. Alternatively, as part of the fourth embodiment, R in a compound of Formula I, or a pharma- ceutically acceptable salt thereof, 4 is hydrogen, and the remainder of the variables are as described above for Formula I, or the second or third embodiment.

[0028]

[0030] In a fifth embodiment, R in a compound of formula I 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 second, third, or fourth embodiment.

[0029]

[0031] In a sixth embodiment, R in a compound of formula I or a pharma- ceutically acceptable salt thereof is 2 ,Halo,-SR a , -SOR a , -SO2R a , and -SO(=NR a )R b and the remaining variables are as described above for Formula I or the second, third, fourth or fifth embodiment. Alternatively, as part of the sixth embodiment, R in a compound of Formula I or a pharma- ceutically acceptable salt thereof is selected from 2 is -SO2R a and the remaining variables are as described above for Formula I or the second, third, fourth or fifth embodiment. In another alternative embodiment, as part of the sixth embodiment, R in the compound of Formula I or a pharma- ceutically acceptable salt thereof is 2 is chloro and -SO2Me, and the remainder of the variables are as described above for Formula I or the second, third, fourth or fifth embodiment.

[0030]

[0032] In a seventh embodiment, R in a compound of formula I, or a pharma- ceutically acceptable salt thereof, 6is halo, oxo, cyano, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, -(C1-C4) alkyl OR d , -(C1-C4) alkyl C(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 and the remainder of the variables are as described above for Formula I or the second, third, fourth, fifth or sixth embodiment.

[0031]

[0033] In an eighth embodiment, r in the compound of formula I, or a pharma- ceutically acceptable salt thereof, is 0, and the remaining variables are as described above for formula I, or the second, third, fourth, fifth, sixth, or seventh embodiment.

[0032]

[0034] In a ninth embodiment, q in the compound of formula I, or a pharma- ceutically acceptable salt thereof, is 1, and the remainder of the variables are as described above for formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0033]

[0035] In a tenth aspect, R in a compound of formula I, or a pharma- ceutically acceptable salt thereof, 7 is halo, oxo, cyano, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, -(C1-C4) alkyl OR d , -(C1-C4) alkyl C(O)OR d , -NR d R e , -(C1-C4) alkylNRd 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 and the remaining variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. Alternatively, as part of the tenth embodiment, R in a compound of Formula I or a pharma- ceutically acceptable salt thereof is selected from 7 is halo, and the remaining variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. In another alternative embodiment, as part of the tenth embodiment, R in a compound of Formula I or a pharma- ceutically acceptable salt thereof is 7 is fluoro, and the remainder of the variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment.

[0034]

[0036] In an eleventh embodiment, W in the compound of formula I, or a pharma- ceutically acceptable salt thereof, is selected from O and CH2, and the remaining variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. Alternatively, as part of the eleventh embodiment, W in the compound of formula I, or a pharma- ceutically acceptable salt thereof, is O, and the remaining variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0035]

[0037] In a twelfth embodiment, R in a compound of formula I or a pharma- ceutically acceptable salt thereof is 5 is selected from phenyl and monocyclic heteroaryl, each of which is R 8and the remaining variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment. Alternatively, as part of the twelfth embodiment, R in a compound of Formula I or a pharma- ceutically acceptable salt thereof is 5 is selected from phenyl and pyrazolyl, each of which is optionally substituted with 1 to 3 groups selected from R8, and the remainder of the variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment.

[0036]

[0038] In a thirteenth aspect, R in a compound of formula I, or a pharma- ceutically acceptable salt thereof, 8 is halo, oxo, cyano, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, -(C1-C4) alkyl OR d , -(C1-C4) alkyl C(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 and the remainder of the variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment. Alternatively, as part of the thirteenth embodiment, R in a compound of Formula I, or a pharma- ceutically acceptable salt thereof, is selected from 8is selected from halo and (C1-C4)alkyl, and the remainder of the variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment. In another alternative embodiment, as part of the thirteenth embodiment, R in a compound of Formula I or a pharma- ceutically acceptable salt thereof is 8 is selected from halo and (C1-C4)alkyl, and the remainder of the variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment. In another alternative embodiment, as part of the thirteenth embodiment, R in a compound of Formula I or a pharma- ceutically acceptable salt thereof is 8 is selected from chloro and methyl, and the remainder of the variables are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment.

[0037]

[0039] Compounds having Formula I are further disclosed in the Examples and are included in this disclosure, including pharma- ceutically acceptable salts thereof as well as neutral forms. 4. Use, Formulation and Administration

[0040] 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 suppress 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- ceutical 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, "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, e.g., PPARG) and exerts the opposite effect by not only antagonizing the action of the agonist, but also suppressing spontaneous receptor signaling (if present).

[0038]

[0041] In some embodiments, the compounds and pharma- ceutical acceptable salts disclosed herein overcome the activation state of PPARG function resulting from altered PPARG activity (mutation, amplification or overexpression) or RXRA-activating mutation. In some embodiments, the compounds and pharma-ceutical acceptable salts disclosed herein increase the repression state (recruitment of NCOR1) to a greater extent than previously disclosed PPARG modulators, such as prior inverse agonists. Such results also occur in the context of mutations. For example, see the table in the Exemplification section that qualitatively evaluates the recruitment of NCOR1 and the repression of PPARG target genes in HT1197.

[0039]

[0042] In some aspects, the compounds and pharmaceutical compositions described herein are useful for treating disorders related to PPARG function.Therefore, the method for treating disorders related to PPARG function is provided herein, comprising administering to a subject in need thereof a therapeutically effective amount of the compounds described herein or its pharmaceutical acceptable salt, or the pharmaceutical composition comprising the disclosed compounds or its pharmaceutical acceptable salt.

[0040]

[0043] Also provided is the use of the compound described herein or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising the disclosed compound or its pharmaceutically acceptable salt, for the manufacture of a medicament for treating disorders related to PPARG function.Also provided is the use of the compound described herein or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising the disclosed compound or its pharmaceutically acceptable salt, for treating disorders related to PPARG function.

[0041]

[0044] In one embodiment, the disorder associated with PPARG is cancer. In some embodiments, the cancer is associated with an upregulated peroxisome proliferator-activated receptor (PPAR) signaling pathway. In some embodiments, the upregulated PPAR signaling pathway is associated with uroplakin 1A (UPK1A), uroplakin IB (UPK1B), uroplakin (UPK2), keratin 20 (KRT20), GATA binding protein 3 ( ... A3), nuclear receptor corepressor 1 (NCORl), nuclear receptor corepressor 2 (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 (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).

[0042]

[0045] In some embodiments, the cancers treated by the compounds, pharmacologic salts thereof, and pharmaceutical compositions described herein are 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 tumor, and hematopoietic cancer (e.g., lymphoma, multiple myeloma, and leukemia). In one embodiment, the cancers treated by the compounds, pharmacologic salts thereof, and pharmaceutical compositions described herein are urothelial cancer, such as non-muscle invasive urothelial cancer, muscle invasive urothelial cancer, and metastatic urothelial cancer.

[0043]

[0046] Other uses besides cancer are also contemplated, including angiogenesis and neovascularization in metabolic diseases (e.g., osteoporosis, arthritis, arthropathy, obesity, type I and type II diabetes), lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia, osteoporosis, arthritis, 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), restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, neoplastic diseases, and renal diseases.

[0044]

[0047] In some 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 an implanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, topical, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the pharmaceutical compositions described herein may be an aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0045]

[0048] In some aspects, the pharmaceutical composition is administered orally.

[0049] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular 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 particular disease being treated. The amount of the compound described herein in the composition will also depend on the particular compound in the pharmaceutical composition. EXAMPLES

[0046] chemical synthesis

[0050] The representative examples presented below are intended to help illustrate the disclosure and are not intended to, and should not be construed as, limiting the scope of the invention.

[0047] Starting materials

[0048] [ka]

[0049]

[0051] 1-(2-amino-4-chloro-6-fluorophenyl)ethan-1-one: To a solution of 3-chloro-5-fluoroaniline (20.0 g, 137 mmol, 1.0 equiv) in p-xylene (40.0 mL), BCl3 (182.7 mL, 1 M, 1.33 equiv) was added over 2 h at 0-5 °C, then the mixture was warmed to 22 °C for 0.5 h, stirred at 20-22 °C for 10 min, then acetonitrile (57.8 mL, 1.1 mol, 8.0 equiv) was added dropwise to the mixture over 20 min at 25 °C. The mixture was stirred at 20-22 °C for 10 min, then p-xylene (44.8 mL) was added to the mixture. AlCl3 (10.3 g, 76.9 mmol, 4.2 mL, 0.56 equiv) was then added to the mixture in one portion. The mixture was stirred at 22°C for 1 h, then at 75-77°C for 12 h. HCl (4N, 200mL) was added and the reaction mixture was stirred at 80°C for 4 h. The mixture was poured into water (800mL) and extracted with ethyl acetate (1.500L). The organic phase was washed with brine (100mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1-20:1) to give the title compound (4.6g, 18% yield) as a light yellow solid. LCMS [M+1]=188.0 / 190.0. 1 H NMR (chloroform-d, 400 MHz) δ 6.31-6.52 (m, 4H), 2.58 (d, J = 8.4 Hz, 3H).

[0050] [ka]

[0051]

[0052] 5-Cyano-2-(methylthio)benzoyl chloride

[0053] Step 1, methyl 2-chloro-5-cyano-benzoate: To a solution of 2-chloro-5-cyanobenzoic acid (10 g, 55.0 mmol, 1.0 equiv.) was added SOCl2 (82.0 g, 689.2 mmol, 50 mL, 12.5 equiv.). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in THF (50 mL) and added to MeOH (50 mL). The residue was diluted with saturated aqueous NaHCO3 (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce the title compound (9 g, 84% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) 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).

[0052]

[0054] 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. The mixture was then 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 (30 g, 76% yield) as a white solid. 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).

[0053]

[0055] Step 3, 5-cyano-2-(methylthio)benzoyl chloride: A solution of 5-cyano-2-(methylthio)benzoic acid (4.2 g, 22.0 mmol, 1.0 equiv) in SOCl2 (56 mL) was stirred at 80° C. for 1 h. The mixture was concentrated under reduced pressure to yield the title compound (4.6 g, 99% yield) as a yellow solid. The product was used without further purification.

[0054] [ka]

[0055]

[0056] 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile

[0057] Scheme 1. 2-Chloro-5-cyanobenzoyl chloride:

[0058] A solution of 2-chloro-5-cyanobenzoic acid (2.5 g, 13.8 mmol) in SOCl2 (25 mL) was stirred at 80° C. for 1 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to yield the title compound (2.8 g, crude) as a yellow solid, which was used directly in the next step.

[0056]

[0059] Step 1. 1-(2-amino-4,6-difluorophenyl)ethanone:

[0060] To a solution of 3,5-difluoroaniline (8.9 g, 68.9 mmol, 1.0 equiv) in CH3CN (85 mL) was added BCl3 (1 M, 72.4 mL, 1.05 equiv) at 0 °C. Then AlCl3 (10.1 g, 75.8 mmol, 4.1 mL, 1.1 equiv) was added in three portions to the mixture, and the mixture was then stirred at 80 °C for 16 h. The mixture was cooled to 0 °C, and 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 x 150 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce the title compound (8.0 g, 68% yield) as a light yellow solid. LCMS: [M+H] +Calculated for (C8H7F2NO) requiring m / z = 172.0 and found m / z = 172.1. 1 H NMR (400 MHz, CDCl3), δ 6.5 (br s, 2H), 6.0 - 6.2 (m, 2H), 2.6 (d, J = 8.4 Hz, 3H).

[0057]

[0061] Step 2. N-(2-acetyl-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide:

[0062] 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. After the mixture was stirred for 30 min, 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 quenched at 15° C. by the addition of saturated aqueous NH4Cl (15 mL), diluted with water (20 mL) and filtered. The filter cake was triturated with EtOAc (20 mL) and filtered to yield the title compound (2.4 g, 61% yield) as a white solid. LCMS: [M+H] + Calculated for (C 16 H9F3N2O2) was found to have m / z = 335.0, whereas m / z = 335.0 was required. 1 H NMR (400 MHz, DMSO-d6) 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).

[0058]

[0063] Step 3. 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile:

[0064] 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), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a crude residue, which was purified by preparative HPLC (column: Welch Xtimate C18 250×70 mm×10 um; mobile phase: 15-45% acetonitrile in water (10 mM NH4HCO3)). This gave the title compound (570 mg, 24% yield, 98% purity) as a white solid after concentration under reduced pressure. LCMS: calculated for [M+H]+, (C 16 H7ClF2N2O) was expected to have m / z = 317.0 and was found to have m / z = 317.0. 1 H NMR (400 MHz, DMSO-d6) 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).

[0059] Example 1

[0060] [ka]

[0061]

[0065] 3-(5-(4-chlorophenoxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile

[0066] Step 1, 2-Bromo-1-(4-chlorophenoxy)-5-fluoro-3-nitro-benzene:

[0067] To a mixture of 2-bromo-1,5-difluoro-3-nitro-benzene (20.0 g, 84.0 mmol, 1.0 equiv.) and 4-chlorophenol (10.8 g, 84.0 mmol, 8.2 mL, 1.0 equiv.) in DMA (50 mL) was added Cs2CO3 (30.1 g, 92.4 mmol, 1.1 equiv.) in one portion at RT under N2. The mixture was stirred at 65° C. for 5 h. The reaction mixture was poured into ice water (500 mL) and stirred for 10 min. The aqueous phase was extracted with MTBE (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% petroleum ether) to give a mixture of the title compound and 2-bromo-5-(4-chlorophenoxy)-1-fluoro-3-nitro-benzene (15.8 g, 45.6 mmol) as a yellow oil. The mixture of regioisomers was carried on to the next step. 1 H NMR (400 MHz, chloroform-d) δ 8.01 - 7.93 (m, 1H), 7.77 (dd, J = 2.4, 7.7 Hz, 1H), 7.47 (t, J = 1.9 Hz, 1H), 7.43 - 7.42 (m, 1H), 7.44 - 7.40 (m, 3H), 7.35 - 7.27 (m, 2H), 7.08 - 6.99 (m, 4H), 6.93 (d, J = 8.9 Hz, 1H), 6.76 (dd, J = 2.8, 9.0 Hz, 1H).

[0062]

[0068] Step 2, 2-Bromo-3-(4-chlorophenoxy)-5-fluoro-aniline:

[0069] To a mixture of 2-bromo-5-(4-chlorophenoxy)-1-fluoro-3-nitro-benzene and 2-bromo-1-(4-chlorophenoxy)-5-fluoro-3-nitro-benzene (14.8 g, 42.7 mmol, 1.0 equiv.) and iron(0) (11.9 g, 213.5 mmol, 5.0 equiv.) in ethanol (300 mL) was added a solution of NH4Cl (11.4 g, 213.5 mmol, 5.0 equiv.) in water (100 mL) in one portion at RT under N2. The mixture was stirred at 80° C. for 1 h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to 1 / 3 of the original volume. The resulting solution was diluted with water (200 mL) and the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 50:1 to 8:1) to give the title compound (7.0 g, 52% yield) as a yellow oil and the undesired regioisomer 2-bromo-5-(4-chlorophenoxy)-3-fluoro-aniline (3.3 g, 24% yield) as a yellow oil. LCMS [M-1]=314.1 / 315.9. 1 H NMR (400 MHz, chloroform-d) δ = 7.34 - 7.28 (m, 2H), 6.98 - 6.91 (m, 2H), 6.29 (dd, J = 2.5, 10.0 Hz, 1H), 6.03 (dd, J = 1.5, 2.5 Hz, 1H), 3.81 (br s, 2H).

[0063]

[0070] Step 3, 1-(2-amino-6-(4-chlorophenoxy)-4-fluorophenyl)ethan-1-one:

[0071] To a mixture of 2-bromo-3-(4-chlorophenoxy)-5-fluoroaniline (1 g, 3.16 mmol, 1.0 equiv) and tributyl(1-ethoxyvinyl)stannane (586 μL, 1.74 mmol, 0.55 equiv) in toluene (10 mL) was added Pd(PPh3)4 (365 mg, 316 μmol, 0.1 equiv) at RT under N2. The mixture was stirred at 120° C. for 4 h under N2. The reaction was then cooled to RT and an additional portion of tributyl(1-ethoxyvinyl)stannane (586.4 μL, 1.74 mmol, 0.55 equiv) was added. The mixture was stirred at 120° C. for 12 h. The reaction mixture was poured into aqueous KF solution (20 mL) and stirred for 2 h. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to yield 3-(4-chlorophenoxy)-2-(1-ethoxyvinyl)-5-fluoroaniline (2.1 g, crude) as a brown oil which was used in the next step without further purification.

[0064]

[0072] A solution of 3-(4-chlorophenoxy)-2-(1-ethoxyvinyl)-5-fluoroaniline (970 mg, crude) in acetic acid (18 mL) and water (2 mL) was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and then treated with a saturated aqueous solution of NaHCO3 (70 mL) at 20 °C. The aqueous layer was extracted with ethyl acetate (4 × 50 mL) and 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 (petroleum ether:ethyl acetate = 10:1 to 5:1) to produce the title compound (530 mg, 60% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.40 - 7.33 (m, 2H), 7.04 - 6.99 (m, 2H), 6.52 - 6.11 (m, 2H), 6.08 (dd, J = 2.4, 10.4 Hz, 1H), 5.76 (dd, J = 2.4, 10.0 Hz, 1H), 2.59 (s, 3H).

[0065]

[0073] Step 4, N-(2-acetyl-3-(4-chlorophenoxy)-5-fluorophenyl)-5-cyano-2-(methylthio)benzamide:

[0074] To a solution of 1-(2-amino-6-(4-chlorophenoxy)-4-fluorophenyl)ethan-1-one (200 mg, 715 μmol, 1.0 equiv.) in isopropyl acetate (3 mL) was added 5-cyano-2-methylsulfanyl-benzoyl chloride (151 mg, 715 μmol, 1.0 equiv.). The mixture was stirred at 80° C. for 16 h. The mixture was filtered and the filter cake was reacted with MTBE at RT for 1 h to produce the title compound (200 mg, 62% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 12.04 (s, 1H), 8.35 (dd, J = 2.4, 11.1 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 1.8, 8.4 Hz, 1H), 7.45 - 7.39 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 6.32 (dd, J = 2.4, 9.4 Hz, 1H), 2.69 (s, 3H), 2.54 (s, 3H).

[0066]

[0075] Step 5, 3-(5-(4-chlorophenoxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile:

[0076] To a solution of N-(2-acetyl-3-(4-chlorophenoxy)-5-fluorophenyl)-5-cyano-2-(methylthio)benzamide (200 mg, 440 μmol, 1.0 equiv.) in 2-MeTHF (5 mL) was added LiOH (11.6 mg, 484 μmol, 1.1 equiv.). The mixture was stirred at 95° C. for 14 h. The pH of the solution was adjusted to pH=1 with 1M aqueous HCl. The solid precipitated from the solution was filtered off and triturated with acetonitrile at RT to yield the title compound (200 mg, crude) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.94 - 7.86 (m, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.23 (br d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.79 - 6.69 (m, 2H), 2.60 (s, 3H).

[0067]

[0077] Step 6, 3-(5-(4-chlorophenoxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile:

[0078] To a solution of 3-(5-(4-chlorophenoxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile (110 mg, 252 μmol, 1 equiv.) in acetone (2.8 mL), water (1.6 mL), THF (2 mL) and MeOH (2 mL) was added oxone (774 mg, 1.26 mmol, 5 equiv.). The reaction mixture was stirred at 40° C. for 1.5 h. The reaction mixture was quenched by the addition of a saturated solution of Na2SO3 (800 mg) in water (10 mL) at RT. The aqueous layer was extracted with DCM (2×10 mL) and the combined organic phase was 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: 1-50% acetonitrile (+ formic acid) in water) to give the title compound (49.1 mg, 42% yield) as a white solid. LCMS [M+1]=469.0. 1H NMR (400 MHz, methanol-d4) δ 8.37 (d, J = 8.0 Hz, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.00 (br d, J = 8.4 Hz, 1H), 6.55 (br d, J = 9.4 Hz, 1H), 6.32 - 6.22 (m, 1H), 3.20 (s, 3H).

[0068] Example 2

[0069] [ka]

[0070]

[0079] 4-Chloro-3-(5-(4-chlorophenoxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile

[0071]

[0080] Step 1, N-(2-acetyl-3-(4-chlorophenoxy)-5-fluorophenyl)-2-chloro-5-cyanobenzamide:

[0081] To a solution of 1-(2-amino-6-(4-chlorophenoxy)-4-fluorophenyl)ethanone (100 mg, 358 μmol, 1.0 equiv.) in isopropyl acetate (2.0 mL) was added 2-chloro-5-cyano-benzoyl chloride (78.6 mg, 393 μmol, 1.1 equiv.). The reaction mixture was then stirred at 80° C. for 12 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with acetonitrile to yield the title compound (85 mg, 51% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 11.89 - 11.79 (m, 1H), 8.33 (dd, J = 2.4, 10.8 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.73 - 7.71 (dd, J = 2.0, 8.0 Hz, 1H), 7.64 - 7.62 (d, J = 8.4 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.06 - 7.03 (m, 2H), 6.36 - 6.33 (dd, J = 2.4, 9.4 Hz, 1H), 2.68 (s, 3H).

[0072]

[0082] Step 2, 4-chloro-3-(5-(4-chlorophenoxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile:

[0083] To a solution of N-(2-acetyl-3-(4-chlorophenoxy)-5-fluorophenyl)-2-chloro-5-cyanobenzamide (80 mg, 181 μmol, 1.0 equiv.) in 2-MeTHF (1.0 mL) was added LiOH (8.64 mg, 361 μmol, 2.0 equiv.). The reaction mixture was stirred at 80° C. under N2 for 16 h. The pH of the reaction mixture was adjusted to pH=3 with 1M aqueous HCl. The precipitate formed during pH adjustment was collected by filtration. The crude product was triturated with acetonitrile to yield the title compound (36 mg, 46% yield) as a white solid. LCMS [M+1]=424.9. 1 H NMR (400 MHz, methanol-d4) δ 8.07 - 8.04 (m, 1H), 7.95 - 7.91 (m, 1H), 7.85 - 7.81 (m, 1H), 7.42 - 7.37 (m, 2H), 7.07 - 7.02 (m, 3H), 6.59 - 6.54 (m, 1H), 6.21 (br s, 1H).

[0073] Example 3

[0074] [ka]

[0075]

[0084] 3-(7-Fluoro-5-((1-methyl-1H-pyrazol-4-yl)oxy)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile

[0076]

[0085] Step 1, N-(2-acetyl-3,5-difluoro-phenyl)-5-cyano-2-methylsulfanyl-benzamide:

[0086] To a solution of 1-(2-amino-4,6-difluoro-phenyl)ethanone (400 mg, 2.34 mmol, 1.0 equiv) in isopropyl acetate (10 mL) was added 5-cyano-2-methylsulfanyl-benzoyl chloride (544 mg, 2.57 mmol, 1.1 equiv). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to produce the title compound (540 mg, 67% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.03 (m, 1H), 7.96 (m, 1H), 7.58-7.54 (m, 2H), 7.27 (m, 1H), 2.50 (s, 3H), 2.49 (s, 3H).

[0077]

[0087] Step 2, 3-(5,7-difluoro-4-oxo-1H-quinolin-2-yl)-4-methylsulfanyl-benzonitrile:

[0088] To a solution of N-(2-acetyl-3,5-difluoro-phenyl)-5-cyano-2-methylsulfanyl-benzamide (100 mg, 288.7 μmol, 1.0 equiv.) in dioxane (2 mL) was added LiOH (6.9 mg, 289 μmol, 1.0 equiv.). The mixture was stirred at 110° C. for 2 h. The pH of the reaction mixture was adjusted to pH=1 with 1M aqueous HCl. A precipitate formed during the pH adjustment. The precipitate was filtered off and the filter cake was dried under vacuum to yield the title compound (80 mg, 84% yield) as a yellow solid.

[0078]

[0089] Step 3, 3-(7-fluoro-5-((1-methyl-1H-pyrazol-4-yl)oxy)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile:

[0090] To a solution of 1-methyl-1H-pyrazol-4-ol (300 mg, 3.06 mmol, 1.0 equiv.) in THF (2.0 mL) was added NaH (122 mg, 3.06 mmol, 1.0 equiv.; 60% dispersion in oil). The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to yield sodium 1-methylpyrazol-4-yl)oxy (368 mg, crude) as a white solid.

[0079]

[0091] To a solution of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile (400 mg, 1.22 mmol, 1.0 equiv) in DMF (2.0 mL) was added (1-methylpyrazol-4-yl)oxysodium (365.7 mg, 3.05 mmol, 2.5 equiv). The reaction mixture was stirred at 100° C. for 16 h. The pH of the reaction mixture was adjusted to pH=1 with 1M aqueous HCl. A precipitate formed during the pH adjustment and was filtered off. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: 10-50% acetonitrile (+formic acid) in water) to produce the title compound (65.0 mg, 13% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 7.85 (dd, J = 1.6, 8.4 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 6.90 (dd, J = 1.8, 9.2 Hz, 1H), 6.59 (dd, J = 2.2, 10.8 Hz, 1H), 6.25 (br s, 1H), 3.92 (s, 3H), 2.64 - 2.49 (m, 3H).

[0080]

[0092] Step 4, 3-(7-fluoro-5-((1-methyl-1H-pyrazol-4-yl)oxy)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile:

[0093] To a solution of 3-(7-fluoro-5-((1-methyl-1H-pyrazol-4-yl)oxy)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylthio)benzonitrile (50 mg, 123 μmol, 1.0 equiv.) in acetone (3.5 mL), water (2.0 mL), MeOH (2.5 mL) and THF (2.5 mL) was added oxone (378 mg, 615 μmol, 5.0 equiv.) and the reaction mixture was stirred at 30° C. for 3.5 h. The reaction mixture was quenched by the addition of a saturated solution of Na2SO3 (9 mg) in water (1.0 mL) at 20° C. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with acetonitrile to give the title compound (14.3 mg, 26% yield) as a white solid. LCMS [M+1]=439.1. 1 H NMR (400 MHz, methanol-d4) δ 8.37 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 1.4, 8.2 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.68 (s, 1H), 7.46 (s, 1H), 6.87 (br d, J = 7.0 Hz, 1H), 6.60 (dd, J = 1.8, 10.8 Hz, 1H), 6.30 (br s, 1H), 3.92 (s, 3H), 3.24 - 3.18 (m, 3H).

[0081] Example 4

[0082] [ka]

[0083]

[0094] 3-(7-chloro-5-((1-methyl-1H-pyrazol-4-yl)oxy)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile

[0095] The title compound was prepared in a similar manner as described for 3-(7-fluoro-5-((1-methyl-1H-pyrazol-4-yl)oxy)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile (Example 3) using N-(2-acetyl-5-chloro-3-fluorophenyl)-5-cyano-2-(methylthio)benzamide as the starting material. LCMS [M+1]=455.0. 1 H NMR (400 MHz, methanol-d4) δ 8.37 (d, J = 8.2 Hz, 1H), 8.20 (br d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 7.20 (br s, 1H), 6.77 (s, 1H), 6.31 (br s, 1H), 3.93 (s, 3H), 3.21 (br s, 3H).

[0084] Example 5

[0085] [ka]

[0086]

[0096] 4-Chloro-3-(5-((6-chloropyridin-3-yl)oxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile:

[0097] To a solution of 6-chloropyridin-3-ol (105 mg, 810.5 μmol, 1.0 equiv.) in THF (2 mL) was added NaH (32.4 mg, 811 μmol, 1.0 equiv.; 60% dispersion in oil) at 0° C., and the mixture was then stirred for 2 h at 20° C. The mixture was concentrated under reduced pressure to produce (6-chloro-3-pyridyl)oxysodium (123 mg, crude) as a white solid.

[0087]

[0098] To a solution of 4-chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (100 mg, 235 μmol, 1.0 equiv.) in DMF (1.5 mL) was added (6-chloro-3-pyridyl)oxysodium (61.4 mg, 474 μmol, 1.0 equiv.). The mixture was stirred at 100° C. for 20 h. The mixture was quenched with saturated aqueous NH4Cl and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: 20-50% acetonitrile (+formic acid) in water) to produce the title compound (16.9 mg, 10% yield) as a yellow solid. LCMS [M+1]=426.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.15 - 12.08 (m, 1H), 8.22 (d, J = 1.3 Hz, 1H), 8.10 - 8.04 (m, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.49 - 7.39 (m, 1H), 7.37 - 7.31 (m, 1H), 7.28 - 7.17 (m, 1H), 7.03 (br d, J = 9.7 Hz, 1H), 5.96 (s, 1H).

[0088] Example 6

[0089] [ka]

[0090]

[0099] 4-Chloro-3-(5-((4-chlorobenzyl)oxy)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile:

[0100] To a solution of 4-chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (500 mg, 1.58 mmol, 1.0 equiv.) in DMF (7 mL) was added (4-chlorophenyl)methanol (270 mg, 1.89 mmol, 1.2 equiv.) and potassium tert-butoxide (532 mg, 4.74 mmol, 3.0 equiv.). The mixture was stirred at 100° C. for 16 h. The reaction mixture was diluted with water and ethyl acetate. The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 5:1). The residue was then purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: 45-75% acetonitrile (+formic acid) in water) to yield the title compound (22.0 mg, 3.2% yield) as a white solid. LCMS [M+1]=438.9. 1 H NMR (400 MHz, chloroform-d) δ 9.96 - 9.15 (m, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.63 - 7.60 (m, 1H), 7.49 - 7.44 (m, 4H), 7.40 (dd , J = 1.8, 10.1 Hz, 1H), 7.04 (s, 1H), 6.79 (dd, J = 2.0, 10.0 Hz, 1H), 5.30 (s, 2H).

[0091] Example 7

[0092] [ka]

[0093]

[0101] 3-(5-(4-chlorobenzyl)-7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile

[0094]

[0102] Step 1, 1-Bromo-5-fluoro-2-iodo-3-nitrobenzene:

[0103] To a mixture of 2-bromo-4-fluoro-6-nitroaniline (2.0 g, 8.5 mmol, 1.0 equiv) in H2SO4 (25.8 mL, 50% purity) and H2O (6.5 mL) was added NaNO2 (769 mg, 11.2 mmol, 1.3 equiv) in portions at 0 °C under N2. After the mixture was stirred at 0 °C for 30 min, KI (3.7 g, 22.3 mmol, 2.6 equiv) was added to the mixture and the resulting mixture was stirred at 0 °C for 40 min. The reaction mixture was poured into ice water (200 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (200 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 20:1) to yield the title compound (2.5 g, yield 50%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.66 (dd, J = 2.8, 7.4 Hz, 1H), 7.36 (dd, J = 2.8, 7.3 Hz, 1H).

[0095]

[0104] Step 2, 3-Bromo-5-fluoro-2-iodoaniline:

[0105] To a mixture of 1-bromo-5-fluoro-2-iodo-3-nitro-benzene (2.5 g, 6.5 mmol, 90.0% pure, 1.0 equiv) and NH4Cl (1.74 g, 32.52 mmol, 5.0 equiv) in ethanol (30 mL) and H2O (10 mL) under N2 at 20 °C, Fe (1.8 g, 32.5 mmol, 5.0 equiv) was added in one portion. The mixture was stirred at 80 °C for 2 h. The mixture was filtered over a pad of Celite and the filtrate was concentrated in vacuo. The residue was poured into ice water (200 mL). The aqueous phase was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1-10:) to give the title compound (2.0 g, yield 97%) as a light yellow solid. LCMS [M+1]=315.8. 1 H NMR (400 MHz, chloroform-d) δ 6.84 (dd, J = 2.6, 8.2 Hz, 1H), 6.41 (dd, J = 2.6, 10.2 Hz, 1H), 4.48 (br s, 2H).

[0096]

[0106] Step 3, 3-Bromo-2-(1-ethoxyvinyl)-5-fluoro-aniline:

[0107] To a mixture of 3-bromo-5-fluoro-2-iodo-aniline (7.0 g, 22.2 mmol, 1.0 equiv.) and tributyl(1-ethoxyvinyl)stannane (8.8 g, 24.4 mmol, 1.1 equiv.) in toluene (100 mL) was added Pd(PPh3)4 (2.6 g, 2.2 mmol, 0.1 equiv.) in one portion at 20° C. under N2. The mixture was stirred at 120° C. for 16 h under N2. The mixture was cooled to 20° C., then aqueous KF solution (100 mL) was added and the mixture was stirred at 20° C. for 4 h. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 20:1) to give the title compound (4.2 g, 73% yield) as a yellow solid. LCMS [M-1]=258.0. 1 H NMR (400 MHz, chloroform-d) δ 6.71 (dd, J = 2.4, 8.3 Hz, 1H), 6.35 (dd, J = 2.4, 10.4 Hz, 1H), 4.56 (d, J = 2.2 Hz, 1H), 4.29 (d, J = 2.2 Hz, 1H), 4.18 (br s, 2H), 3.91 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H).

[0097]

[0108] Step 4, 1-(2-amino-6-bromo-4-fluoro-phenyl)ethanone:

[0109] To a mixture of 3-bromo-2-(1-ethoxyvinyl)-5-fluoro-aniline (4.2 g, 16.2 mmol, 1.0 equiv) in acetic acid (72 mL) was added H2O (8 mL) in one portion under N2 at 20 °C. The mixture was stirred at 20 °C for 10 h. The mixture was concentrated under reduced pressure and then a saturated aqueous solution of NaHCO3 (200 mL) was added. The aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 99:1 to 20:1) to give the title compound (1.9 g, 51% yield) as a yellow solid. LCMS [M-1] = 229.9. 1 H NMR (400 MHz, chloroform-d) δ 6.71 (dd, J = 2.4, 8.2 Hz, 1H), 6.34 (dd, J = 2.4, 10.4 Hz, 1H), 4.89 (br s, 2H), 2.66 (s, 3H).

[0098]

[0110] Step 5, 1-[2-amino-6-[(4-chlorophenyl)methyl]-4-fluoro-phenyl]ethenone:

[0111] To 1-(2-amino-6-bromo-4-fluoro-phenyl)ethanone (1.0 g, 4.3 mmol, 1.0 equiv.), K3PO4 (1.8 g, 8.6 mmol, 2.0 equiv.) and 2-[(4-chlorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 5.2 mmol, 1.2 equiv.) in ethanol (8 mL) / HO (2 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (342 mg, 431 μmol, 0.1 equiv.) at 20 °C under N2. The mixture was stirred at 80 °C under N2 for 16 h. The mixture was cooled to 20 °C and filtered through a pad of Celite. The filtrate was diluted with water (200 mL) and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 20:1) to give the title compound (274 mg, 23% yield) as a yellow oil. LCMS [M+1]=278.0. 1 H NMR (400 MHz, chloroform-d) δ 7.29 - 7.24 (m, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.30 (dd, J = 2.4, 10.2 Hz, 1H), 6.20 (dd, J = 2.4, 9.6 Hz, 1H), 4.59 (br s, 2H), 3.98 (s, 2H), 2.40 (s, 3H).

[0099]

[0112] Step 6, N-[2-acetyl-3-[(4-chlorophenyl)methyl]-5-fluoro-phenyl]-5-cyano-2-methylsulfanyl-benzamide:

[0113] A mixture of 1-[2-amino-6-[(4-chlorophenyl)methyl]-4-fluoro-phenyl]ethanone (220 mg, 792 μmol, 1.0 equiv.) and 5-cyano-2-methylsulfanyl-benzoyl chloride (184 mg, 871 μmol, 1.1 equiv.) in isopropyl acetate (1 mL) was stirred at 80° C. for 16 h. The mixture was cooled to 20° C. and then concentrated under reduced pressure. H2O (10 mL) was added to the residue and the mixture was stirred at 20° C. for 10 min. The precipitate was filtered off in vacuo. The crude product was triturated with acetonitrile at 20° C. for 30 min to yield the title compound (260 mg, 73% yield) as a white solid. LCMS [M+1]=453.1. 1 H NMR (400 MHz, chloroform-d) δ 9.29 (s, 1H), 8.02 (dd, J = 2.4, 10.4 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.70 (dd, J = 1.8, 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.70 (dd, J = 2.4, 8.8 Hz, 1H), 4.09 (s, 2H), 2.55 (s, 3H), 2.48 (s, 3H).

[0100]

[0114] Step 7, 3-[5-[(4-chlorophenyl)methyl]-7-fluoro-4-oxo-1H-quinolin-2-yl]-4-methylsulfanyl-benzonitrile:

[0115] To a mixture of N-[2-acetyl-3-[(4-chlorophenyl)methyl]-5-fluoro-phenyl]-5-cyano-2-methylsulfanyl-benzamide (250 mg, 552 μmol, 1.0 equiv.) in dioxane (3 mL) under N2 at 20° C. was added LiOH (14.5 mg, 607 μmol, 1.1 equiv.). The mixture was stirred at 110° C. for 5 h. The mixture was cooled to 20° C. and then diluted with H2O (20 mL). The pH of the mixture was adjusted to pH=4-5 with 1N aqueous HCl. The precipitate formed was filtered off and washed with water. The crude solid was triturated with acetonitrile for 1 h to yield the title compound (200 mg, 83% yield) as a white solid. LCMS [M+1]=435.1. 1 H NMR (400 MHz, methanol-d4) δ 7.83 (dd, J = 1.6, 8.4 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.27 - 7.22 (m, 2H), 7.22 - 7.17 (m, 2H), 7.14 (dd, J = 2.6, 9.2 Hz, 1H), 6.92 (dd, J = 2.4, 9.8 Hz, 1H), 6.18 (s, 1H), 4.80 (s, 2H), 2.54 (s, 3H).

[0101]

[0116] Step 8, 3-[5-[(4-chlorophenyl)methyl]-7-fluoro-4-oxo-1H-quinolin-2-yl]-4-methylsulfonyl-benzonitrile: To a mixture of 3-[5-[(4-chlorophenyl)methyl]-7-fluoro-4-oxo-1H-quinolin-2-yl]-4-methylsulfanyl-benzonitrile (100 mg, 230 μmol, 1.0 equiv.) in acetone (1.4 mL) / H2O (0.8 mL) / THF (1 mL) / MeOH (1 mL) was added oxone (424 mg, 690 μmol, 3.0 equiv.) with N2 at RT. The mixture was stirred at 50° C. for 16 h. After the mixture was cooled to RT, saturated aqueous Na2SO3 (3 mL) was added. The resulting mixture was stirred at RT for 10 min. The aqueous phase was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (5 mL), dried over anhydrous 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: [35-65% acetonitrile (+ formic acid) in water] to yield the title compound (28 mg, 26% yield) as a white solid. LCMS[M+1]=467.0. 1 H NMR (400 MHz, methanol-d4) δ 8.36 (d, J = 8.2 Hz, 1H), 8.19 (dd, J = 1.6, 8.2 Hz, 1H), 8.14 - 8.08 (m, 1H), 7.28 - 7.23 (m, 2H), 7.23 - 7.17 (m, 2H), 7.09 (dd, J = 2.4, 9.2 Hz, 1H), 6.92 (dd, J = 2.0, 9.6 Hz, 1H), 6.21 (s, 1H), 4.81 (s, 2H), 3.17 (s, 3H).

[0102] Biochemical and cellular assays

[0117] PPARγ-NCOR1 Recruitment Assay:

[0118] Compound potency of NCOR1 recruitment to PPARG (EC 50) and maximum extent was assessed in a TR-FRET binding assay measuring the association of a biotinylated NCOR1 ID2 peptide (biotin-GHSFADPASNLGLEDIIRKALMG-amide) to the PPARG / RXRA LBD heterodimer. In detail, 20 microliters of TR-FRET consisting of 2 nM WT PPARG LBD (expressed in Escherichia coli (e. coli), His-TEV-Q203-Y477; Uniprot ID 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 Tb (Cisbio) in 25 mM MOPS (pH 7.4), 25 mM KCl, 1 mM EDTA, 0.01% BSA, 0.01% Tween-20, 1 mM TCEP was added to 60 nL DMSO (0.3% fc). The mixture was incubated for 3 hours and read on an EnVision plate reader (Perkin Elmer) at Ex / Em 615 / 665. 50 To determine the extent of DMSO and NCOR1 recruitment, TR-FRET ratios were normalized to the average ratio of DMSO control wells (0%) and the average maximum ratio of a positive control compound in the CDD Vault (T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide); defined as 100%) and analyzed using the Levenberg-Marquardt algorithm.

[0103]

[0119] PPARγ-MED1 Blockade Assay:

[0120] Compound potency of MED1 against PPARG (IC 50) and maximum extent 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. In detail, 20 microliters of TR-FRET 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 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 DMSO (0.3% DMSO). The mixture was incubated for 3 hours and read on an EnVision plate reader (Perkin Elmer) at Ex / Em 615 / 665. The potency of MED1 repulsion (IC 50 To determine the degree of FRET, TR-FRET ratios were normalized to the average ratio of DMSO control wells (0%) and the average minimum ratio of a positive control compound in the CDD Vault (GW9662 (2-chloro-5-nitrobenzanilide); defined as 100%) and analyzed using the Levenberg-Marquardt algorithm.

[0104]

[0121] Bladder Cancer Pharmacodynamic Assay

[0122] 5637 (PPARG amplified) and HT1197 (RXRA S427F mutant) cells were used to assess the regulation of PPARG target genes using quantitative PCR. Cells were treated with PPARG inverse agonists for 24 hours before analysis of FABP4 (IDT, Cat:Hs.PT 58.20106818) and ANGPTL4 (IDT, Cat:Hs.PT 58.25480012) expression, and expression across samples was normalized using the expression of the housekeeping gene TBP (IDT, Cat:Hs.PT 58v.39858774). Quantitative PCR was performed using an ABI QuantStudio 7 Flex Reaction system. Data were analyzed and reported relative to DMSO controls using the comparative Ct method (ΔΔCt).

[0105] Table 1

[0123] For PPARG-NCOR recruitment 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. NCOR mobilization % is expressed as follows: A: >100% (> control compound T907), B: <100% (< control compound T907).

[0106]

[0124] For PPARG-MED1 recruitment 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. % MED1 blockade is expressed as follows: A: >100% (> control compound GW9662), B: <100% (< control compound GW9662).

[0107]

[0125] For 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 tested. The % inhibition of ANGPTL4, a PPARG target gene, at 100 nM compound concentration is expressed as a percentage of the DMSO control experiment.

[0108] [Table 1]

[0109]

[0126] The inventors have described many embodiments, and it is clear that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be understood that the scope of the present invention is not to be defined by the specific embodiments shown by way of example, but rather by the appended claims.

[0110]

[0127] 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 accorded the meaning commonly known to those skilled in the art.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, X, Y and Z are each independently N and -CR ４ Selected from: W is O and CR ａ R ｂ Selected from: R １ is hydrogen, halo, (C １ ~C ４ ) alkyl, and hydroxyl; R ２ is halo, -SR ａ , -SOR ａ , -SO ２ R ａ , -OR ａ , and -SO(=NR ａ ) R ｂ Selected from: R ３ is selected from cyano and nitro; R ４ is hydrogen, halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, and hydroxyl; R ５ is selected from phenyl, heterocyclyl, and heteroaryl, each of which is R ８ optionally substituted with 1 to 3 groups selected from R ６ and R ７ are each independently halo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkoxy, cyano, oxo, -(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, heterocyclyl, and heteroaryl, each of said phenyl, heterocyclyl, and heteroaryl optionally and independently selected from R ９ substituted with 1 to 3 groups selected from R ８ and R ９ are each independently 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 Selected from: R ａ , R ｂ , R ｃ , R ｄ , and R ｅ are each independently hydrogen, (C １ ~C ４ ) alkyl, and halo(C １ ~C ４ ) alkyl; q and r are each independently 0 or 1; or a pharmaceutically acceptable salt thereof.

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

3. X, Y, and Z are each -CR ４ 3. The compound of claim 1 or 2, wherein:

4. R ４ is hydrogen, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, and (C １ ~C ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

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

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

7. R ２ But, halo, -SR ａ , -SOR ａ , -SO ２ R ａ , and -SO(=NR ａ ) R ｂ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

8. R ２ halo and -SO ２ R ａ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

9. R ２ chloro and -SO ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from: Me.

10. R ６ However, halo, oxo, cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) alkyl OR ｄ , -(C １ ~C ４ ) alkylC(O)OR ｄ , -NR ｄ R ｅ , -(C １ ~C ４ ) alkylNR ｄ R ｅ , —C(O)NR ｄ R ｅ , -(C １ ~C ４ ) alkylC(O)NR ｄ R ｅ , -C(O)R ｄ , -C(O)OR ｄ , -S(O) ２ R ｄ , -S(O)R ｄ , and -SR ｄ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

11. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein r is 0.

12. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein q is 1.

13. R ７ However, halo, oxo, cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) alkyl OR ｄ , -(C １ ~C ４ ) alkylC(O)OR ｄ , -NR ｄ R ｅ , -(C １ ~C ４ ) alkylNR ｄ R ｅ , —C(O)NR ｄ R ｅ , -(C １ ~C ４ ) alkylC(O)NR ｄ R ｅ , -C(O)R ｄ , -C(O)OR ｄ , -S(O) ２ R ｄ , -S(O)R ｄ , and -SR ｄ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

14. R ７ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is halo.

15. R ７ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

16. W is O and CH ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

17. 3. The compound of claim 1 or 2, wherein W is O, or a pharmaceutically acceptable salt thereof.

18. R ５ is selected from phenyl and monocyclic heteroaryl, each of which is R ８ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 groups selected from:

19. R ５ is selected from phenyl and pyrazolyl, each of which is R ８ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 groups selected from:

20. R ８ However, halo, oxo, cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) alkyl OR ｄ , -(C １ ~C ４ ) alkylC(O)OR ｄ , -NR ｄ R ｅ , -(C １ ~C ４ ) alkylNR ｄ R ｅ , —C(O)NR ｄ R ｅ , -(C １ ~C ４ ) alkylC(O)NR ｄ R ｅ , -C(O)R ｄ , -C(O)OR ｄ , -S(O) ２ R ｄ , -S(O)R ｄ , and -SR ｄ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

21. R ８ However, halo and (C １ ~C ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

22. R ８ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is selected from chloro and methyl. 【Request Item 23】 【Chemistry 2-1】 【Chemistry 2-2】 The compound of claim 1 selected from: or any of the above pharmaceutically acceptable salts thereof.

24. 24. A pharmaceutical composition comprising a compound of claim 1, 2, or 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. 24. A compound according to claim 1, 2, or 23, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer responsive to inhibition of PPARG in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound according to claim 1, 2, or 23, or a pharmaceutically acceptable salt thereof.

26. 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, 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.

27. 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein the cancer is bladder cancer.

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