PPARG inverse agonist and its use

Abstract

Compounds of formula (I), as well as pharma- ceutically acceptable salts and compositions thereof, are provided that are useful for treating a variety of conditions associated with PPARG. TIFF2024508908000113.tif3157

Description

[Technical Field]

[0001] Related applications

[0001] This application claims the benefit of priority under U.S. Provisional Application No. 63 / 155,410, filed on 2 March 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002]

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

[0003]

[0003] The role of PPARG in cancer was originally inferred from genomic studies that identified PAX8-PPARG chromosomal rearrangements in follicular thyroid carcinoma. More recently, PPARG has been found to be overexpressed and genetically modified 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. The majority of urothelial carcinomas are urothelial carcinomas and are classified into one of the following: non-muscle-invasive urothelial carcinoma (NMIUC, 70%), muscle-invasive urothelial carcinoma (MIUC, 25%), or metastatic urothelial carcinoma (MUC, 5%). MIUC is usually diagnosed at new age, but 10-20% of NMIUC cases may eventually progress. MIUC is a heterogeneous and invasive disease and is associated with a 60% 5-year survival rate for patients with localized disease and less than 10% for patients with distant metastases. The molecular understanding of NMIUC and MIUC has improved significantly, including the relationship between molecular subtypes and urothelial differentiation. Several molecular classes of MIUC have been proposed, characterized by a prominent activated PPARG signature in the luminal subtype. The first-line treatment is chemotherapy, and while there are some options for chemotherapy-ineligible patients or second-line treatments, these options are limited, and overall survival is poor.

[0004]

[0004] There is a need to develop effective PPARG modulators to treat cancers such as NMIUC, MIUC, and MUC, as well as related conditions. [Overview of the Initiative]

[0005]

[0005] In this specification, Formula I

[0006] [ka]

[0007] Compounds having, as well as pharmaceutically acceptable salts and compositions thereof (wherein R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , q and r are as described herein), are provided. In one aspect, the disclosed compounds of Formula I and their pharmaceutically acceptable salts modulate PPARG (e.g., as an agonist such as a reverse agonist) and are useful in various therapeutic applications such as, for example, in the treatment of cancer. Accordingly, these uses for treating diseases responsive to the inhibition of PPARG are included.

[0008]

[0006] Also included are pharmaceutical compositions comprising the disclosed compounds of Formula I and their pharmaceutically acceptable salts, and methods for their preparation.

Mode for Carrying Out the Invention

[0009] 1. Overview of the Compound

[0007] In a first embodiment, Formula I

[0010]

Chemical formula

[0011] of the compound or its pharmaceutically acceptable salt (wherein, R 1 is hydrogen, halo, (C1-C4)alkyl or hydroxyl, R 2 is halo, R 3 is cyano or nitro, R 4 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)alkoxy or hydroxyl, R 5 is halo, halo(C1-C4)alkyl or cyano, R 6 is halo, halo(C1-C4)alkyl, (C1-C4)alkyl or cyano, R 7This includes halo, (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 -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 , phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl, and each of the phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl is optionally and independently R 8 Replaced by 1 to 3 elements selected from, R 8is 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)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 selected from R a R b R c R d R e and R f are each independently hydrogen or (C1-C4)alkyl, q and r are each independently 0 or 1) It will be provided.

[0012] 2.Definition

[0008] When used in connection with describing a chemical group that may have multiple bond points, the hyphen (-) refers to the bond point of the group to the variable part in which it is defined. For example, -NR b C(O)OR c and -NR b C(S)OR c This means that the bonding site for this group occurs on the nitrogen atom.

[0013]

[0009] The terms "halo" and "halogen" refer to atoms selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iod, -I).

[0014]

[0010] The term "alkyl" means a saturated linear or branched monovalent hydrocarbon group when used alone or as part of a larger term such as "haloalkyl".

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

[0015]

[0012] The term "haloalkyl" includes mono, poly, and perhaloalkyl groups in which the halogen is independently selected from fluorine, chlorine, bromine, and iodine.

[0013] A "haloalkoxy" is a haloalkyl group that is bonded to another part via an oxygen atom, such as -OCHF2 or -OCF3.

[0016]

[0014] The term oxo means =O group.

[0015] The term “5- to 7-membered heteroaryl,” used alone or as part of a larger term, refers to a 5- to 7-membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. Examples of monocyclic heteroaryls include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetradinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, and pyrazinyl. Any optional substituent on the heteroaryl group may be located at any substitutable position, such as the position to which the heteroaryl is bonded.

[0017]

[0016] The term "4-6 membered heterocyclyl" refers to a 4-6 membered saturated or partially unsaturated heterocycle containing 1-4 heteroatoms independently selected from N, O, and S. A heterocyclyl ring can bond to its pendant group at any heteroatom or carbon atom to form a stable structure. Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. Any optional substituent on the heterocyclyl group may be located at any substitutable position, such as the position where the heterocyclyl is bonded.

[0018]

[0017] The disclosed compounds may exist in one or more tautomer forms, such as the following, and are included herein.

[0019] [ka]

[0020]

[0018] The terms “subject” and “patient” may be used interchangeably and refer to mammals requiring treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human being requiring treatment.

[0021]

[0019] The terms “inhibit,” “inhibit,” or “the act of inhibiting” include reduction of biological activity or baseline activity of a process.

[0020] As used herein, the terms “treatment,” “to treat,” and “to treat” mean to reverse, alleviate, delay the onset of, or prevent the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, the treatment may be administered after the onset of one or more symptoms, i.e., it may be a therapeutic treatment. In other embodiments, the treatment may be administered asymptomatically. For example, the treatment may be administered to a susceptible individual before the onset of symptoms (e.g., in light of symptom history and / or exposure to a particular organism or other susceptibility factor), i.e., it may be a prophylactic treatment. The treatment may also be continued after the disappearance of symptoms, for example, to delay their recurrence.

[0022]

[0021] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound being formulated together. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffering substances, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partially 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 silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0023]

[0022] For use in pharmaceuticals, salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of this teaching having an acidic group such as a carboxylic acid can form a pharmaceutically acceptable salt using a pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include, for example, ammonium salts, alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts). Compounds having a quaternary ammonium group also include counterions such as chloride, bromide, iodide, acetic acid, and perchloric acid. Other examples of such salts include hydrochlorides, hydrobroms, sulfates, methanesulfons, nitrates, benzoates, and salts containing amino acids such as glutamic acid.

[0024]

[0023] The term “effective dose” or “therapeutic effective dose” refers to the amount of the compound described herein that elicits a desired or beneficial biological or medical response in a subject, for example, a dosage between 0.01 and 100 mg / kg body weight / day.

[0025] 3.Compound

[0024] In the second embodiment, the compound of formula I is formula II

[0026] [ka]

[0027] The compound or a pharmaceutically acceptable salt thereof, the variable part is as described above for formula I.

[0025] In the third embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof2 This is chloroform, and the remaining variable part is as described above for formula I.

[0028]

[0026] In the fourth embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof 3 The first component is cyano, and the remaining variable components are as described above for Formula I or the third embodiment.

[0029]

[0027] In the fifth embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof 1 R is hydrogen, fluoro, hydroxyl, or methyl, and the remaining variable is as described above for Formula I or the third or fourth embodiment. Alternatively, as part of the fifth embodiment, R in a compound of Formula I or II or a pharmaceutically acceptable salt thereof. 1 R is hydrogen, fluoro, hydroxyl, or methyl, and the remaining variable is as described above for Formula I or the third or fourth embodiment. In another option, as part of the fifth embodiment, R in a compound of Formula I or II or a pharmaceutically acceptable salt thereof. 1 is hydrogen, and the remaining variable part is as described above for Equation I or the third or fourth embodiment.

[0030]

[0028] In the sixth embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof 5 R is a halo or cyano, and the remaining variable is as described above for the third, fourth, or fifth embodiment of formula I or the third, fourth, or fifth embodiment. Alternatively, as part of the sixth embodiment, R in the compound of formula I or II or a pharmaceutically acceptable salt thereof. 5 is a halo, and the remaining variable is as described above for the third, fourth, or fifth embodiment of formula I. Alternatively, as part of the sixth embodiment, R in the compound of formula I or II or a pharmaceutically acceptable salt thereof. 5is chloro or fluoro, and the remaining variable is as described above for the third, fourth, or fifth embodiment of formula I. In another option, as part of the sixth embodiment, R in the compound of formula I or II or a pharmaceutically acceptable salt thereof. 5 is fluoro, and the remaining variable part is as described above for Formula I or the third, fourth, or fifth embodiment.

[0031]

[0029] In the seventh embodiment, q in the compound of formula I or II or a pharmaceutically acceptable salt thereof is 1, and the remaining variable is as described above for the third, fourth, fifth or sixth embodiment of formula I.

[0032]

[0030] In the eighth embodiment, r in the compound of formula I or II or a pharmaceutically acceptable salt thereof is 1, and the remaining variable is as described above for the third, fourth, fifth, sixth, or seventh embodiment of formula I. Alternatively, as part of the eighth embodiment, r in the compound of formula I or II or a pharmaceutically acceptable salt thereof is 0, and the remaining variable is as described above for the third, fourth, fifth, sixth, or seventh embodiment of formula I.

[0033]

[0031] In the ninth embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof 6 is a halo, and the remaining variable is as described above for the third, fourth, fifth, sixth, or seventh embodiment of formula I or the third, fourth, fifth, fifth, sixth, or seventh embodiment. Alternatively, as part of the ninth embodiment, R in the compound of formula I or II or a pharmaceutically acceptable salt thereof. 6 is fluoro, and the remaining variable part is as described above for the third, fourth, fifth, sixth, or seventh embodiment of formula I.

[0034]

[0032] In the tenth embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof 7 These are halo, halo(C1~C4)alkyl, (C1~C4)alkyl, (C1~C4)alkoxy, -(C1~C4)alkyl ORa -C(O)NR a R b , phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl, and each of the phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl is optionally and independently R 8 It is substituted with 1 to 3 groups selected from, and the remaining variable is as described above for the third, fourth, fifth, sixth, seventh, eighth or ninth embodiment of formula I or the third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. Alternatively, as part of the tenth embodiment, R in the compound of formula I or II or a pharmaceutically acceptable salt thereof 7 These are halo, halo(C1~C4)alkyl, (C1~C4)alkyl, (C1~C4)alkoxy, -(C1~C4)alkyl OR a -C(O)NR a R b , phenyl, pyridinyl, pyrazolyl and oxetanyl, and each of the phenyl, pyridinyl, pyrazolyl and oxetanyl is optionally and independently R 8 It is substituted with 1 to 3 groups selected from, and the remaining variable is as described above for the third, fourth, fifth, sixth, seventh, eighth or ninth embodiment of formula I or the third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. In another option, as part of the tenth embodiment, R in the compound of formula I or II or a pharmaceutically acceptable salt thereof. 7 These are halo, halo(C1~C4)alkyl, (C1~C4)alkyl, (C1~C4)alkoxy, -(C1~C4)alkyl OR a -(C1~C4)alkylC(O)NR a R b -(C1~C4)alkylC(O)OR a -C(O)NR a R b , phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl, and each of the phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl is optionally and independently R 8It is substituted with 1 to 3 groups selected from, and the remaining variable is as described above for the third, fourth, fifth, sixth, seventh, eighth or ninth embodiment of formula I or the third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. In another option, as part of the tenth embodiment, R in the compound of formula I or II or a pharmaceutically acceptable salt thereof. 7 These are halo, halo(C1~C4)alkyl, (C1~C4)alkyl, (C1~C4)alkoxy, and -(C1~C4)alkylC(O)NR a R b ,-(C1~C4)alkyl OR a -(C1~C4)alkylC(O)OR a -C(O)NR a R b , azetidinil, phenyl, pyridinil, piperazinil, piperidinil, pyridinil, pyrazolyl, tetrahydropyridinil, pyrrolidinil, pyrazolyl, dihydropyridazinil, pyridazinil, imadazolyl, dihydropyridinil, dihydropyrimidinil, pyrimidinil, and oxetanil, and each of the above azetidinil, phenyl, pyridinil, piperazinil, piperidinil, pyridinil, pyrazolyl, tetrahydropyridinil, pyrrolidinil, pyrazolyl, dihydropyridazinil, pyridazinil, imadazolyl, dihydropyridinil, dihydropyrimidinil, pyrimidinil, and oxetanil may, and independently, 8 It is replaced by one to three bases selected from, and the remaining variable part is as described above for the third, fourth, fifth, sixth, seventh, eighth or ninth embodiment of formula I.

[0035]

[0033] In the 11th embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof 8 R is selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, and cyano, and the remaining variable is as described above for the third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment of formula I. Alternatively, as part of the eleventh embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof.8 R is a halo(C1-C4)alkyl, and the remaining variable is as described above for the third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment of formula I. Alternatively, as part of the eleventh embodiment, R in a compound of formula I or II or a pharmaceutically acceptable salt thereof. 8 These are halo, (C1~C4)alkyl, halo(C1~C4)alkyl, (C1~C4)alkoxy, -(C1~C4)alkyl OR d -(C1~C4)alkylNR d R e -(C1~C4)alkylC(O)OR d , halo(C1~C4)alkoxy, -C(O)OR d -(C1~C4)alkylC(O)NR d R e -C(O)NR d R e , oxo, cyano, -C(O)R d , -NR d R e and -S(O)2R d The variable parts are selected from the above, and the remaining variable parts are as described above for the third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment of formula I.

[0036]

[0034] Compounds having formulas I and II are further disclosed in the examples and are included in this disclosure. Their pharmaceutically acceptable salts and neutral forms are also included.

[0037] 4. Use, Formulation, and Administration

[0035] The compounds and compositions described herein are generally useful for modulating PPARG activity. In some embodiments, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein inhibit PPARG activity. In some embodiments, the compounds and pharmaceutically acceptable salts disclosed herein are PPARG agonists. In some embodiments, the compounds and pharmaceutically acceptable salts disclosed herein are PPARG agonists. In some embodiments, the compounds and pharmaceutically acceptable salts disclosed herein are PPARG inverse agonists. In one embodiment, “inverse agonist” refers to a drug that binds to the same receptor binding site as the agonist (e.g., the binding site of a nuclear receptor such as PPARG) and exerts an opposite effect not only by antagonizing the effect of the agonist but also by suppressing spontaneous receptor signaling (if present).

[0038]

[0036] In some embodiments, the compounds and pharmaceutically acceptable salts disclosed herein overcome the activated state of PPARG function resulting from altered PPARG activity (mutation, amplification, or overexpression) or RXRA activating mutations. In some embodiments, the compounds and pharmaceutically acceptable salts disclosed herein increase the repressive state (NCOR1 recruitment) to a greater extent than previously disclosed PPARG regulators such as the aforementioned inverse agonists. Such results occur even in the context of mutants. See, for example, the table in the Exemplary Section for a qualitative assessment of NCOR1 recruitment and repression of PPARG target genes in HT1197.

[0039]

[0037] In some embodiments, the compounds and pharmaceutical compositions described herein are useful for treating disorders related to PPARG function. Accordingly, a method for treating a disorder related to PPARG function is provided herein, comprising the step of administering to a subject in need of treatment of the disorder 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.

[0040]

[0038] The use of pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, or the disclosed compounds or pharmaceutically acceptable salts thereof, for the preparation of pharmaceuticals for treating disorders related to PPARG function is also provided. Pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, or the disclosed compounds or pharmaceutically acceptable salts thereof, for use in treating disorders related to PPARG function are also provided.

[0041]

[0039] In one embodiment, the PPARG-related disorder is cancer. In some embodiments, cancer is related to an upregulated peroxisome proliferator-activated receptor (PPAR) signaling pathway. In some embodiments, upregulated PPAR signaling pathways are associated with increased expression of one or more genes selected from uroplakin 1A (UPK1A), uroplakin IB (UPK1B), uroplakin (UPK2), keratin 20 (KRT20), GATA-binding protein 3 (GATA A3), nuclear receptor corepressor 1 (NCOR1), 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 synthase 2 (HMGCS2), acyl-CoA synthase long chain family member 5 (ACSL5), arachidonic acid 5-lipoxygenase (ALOX5), acyl-CoA synthase long chain family member 1 (ACSL1), and angiopoietin-like 4 (ANGPTL4).

[0042]

[0040] In some embodiments, cancers treated with the compounds described herein, their pharmaceutically acceptable salts and pharmaceutical compositions are selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial carcinoma (e.g., non-muscle-invasive urothelial carcinoma, muscle-invasive urothelial carcinoma, metastatic urothelial carcinoma), skin cancer, melanoma, colon cancer, kidney cancer, brain cancer and hematopoietic cancer (e.g., lymphoma, multiple myeloma and leukemia). In one embodiment, cancers treated with the compounds described herein, their pharmaceutically acceptable salts and pharmaceutical compositions are urothelial carcinomas, e.g., non-muscle-invasive urothelial carcinoma, muscle-invasive urothelial carcinoma and metastatic urothelial carcinoma.

[0043]

[0041] Other uses besides cancer are intended, for example, metabolic diseases (e.g., osteoporosis, rickets, arthritis, obesity, type 1 and type 2 diabetes), lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic nephropathy, diabetic complications, hyperuricemia, osteoporosis, rickets, arthritis, inflammatory diseases (e.g., inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus), lung 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 occlusion), stenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, neoplastic diseases and renal diseases, and angiogenesis and neovascularization.

[0044]

[0042] In certain embodiments, the pharmaceutical compositions described herein are formulated for administration to patients requiring such compositions. The pharmaceutical compositions described herein may be administered orally, parenterally, or by inhalation spray, via topical, intrarectal, nasal, oral, vaginal, or subcutaneous implantable reservoirs. The term “parenterally,” as used herein, includes subcutaneous, intravenous, intramuscular, intraarterial, intrasynovial, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable formulations of the pharmaceutical compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated by techniques well known in the art using suitable dispersants or wetting and suspending agents.

[0045]

[0043] In some embodiments, the pharmaceutical composition is administered orally.

[0044] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, elimination rate, drug combination, and the judgment of the physician performing the treatment and the severity of the specific disease being treated. The amount of the compounds described herein in a composition will also depend on the specific compound in the pharmaceutical composition.

[0046] Example chemical synthesis

[0045] The following representative examples are intended to illustrate the present disclosure and are not intended to limit the scope of the invention, nor should they be construed as such.

[0047]

[0046] Unless otherwise noted, the common starting materials used were obtained from commercial sources or prepared in other instances.

[0048] Preparation of compounds

[0047] The claimed compounds in this specification were prepared according to the procedure outlined in the following scheme.

[0049]

[0048]

[0050] [ka]

[0051]

[0049] Quinolones such as S5 can be prepared by the general synthesis method shown in Scheme 1. Compounds of formula S2 can be prepared from aniline S1 by treatment with acetonitrile, boron trichloride, aluminum trichloride and HCl in an organic solvent such as dichloromethane. Treatment of acetylaniline S2 with a base such as sodium hydride in an organic solvent such as THF, and treatment with acyl chloride S3 yields an intermediate of formula S4. Quinolones such as S5 can then be prepared from S4 by high-temperature treatment with a base such as sodium hydroxide in an organic solvent such as dioxane. Acyl chloride S3 can be prepared from the corresponding acid by treatment with thionyl chloride and oxalyl chloride in an organic solvent such as dichloromethane.

[0052]

[0050]

[0053] [ka]

[0054]

[0051] Quinolones such as S5 can also be prepared by general synthetic methods as shown in Scheme 2. 2-halo-anilines such as S6 can be prepared from aniline S1 by treatment with NIS or NBS in an organic solvent such as acetic acid. Compounds of formula S2 can be prepared from 2-halogen-aniline S6 by high-temperature treatment with tributyl(1-ethoxyvinyl) stannane and a palladium catalyst such as Pd(PPh3)4 in an organic solvent such as toluene, followed by treatment with an acidic aqueous solution such as hydrochloric acid. Treatment of acetylaniline S2 with a base such as sodium hydride in an organic solvent such as THF, and treatment with acyl chloride S3 yields an intermediate of formula S4. Quinolones such as S5 can then be prepared from S4 by high-temperature treatment with a base such as sodium hydroxide in an organic solvent such as dioxane. Acyl chloride S3 can be prepared from the corresponding acid by treatment with thionyl chloride and oxalyl chloride in an organic solvent such as dichloromethane.

[0055]

[0052]

[0056] [ka]

[0057]

[0053] Quinolones such as S5 can also be prepared by general synthetic methods as shown in Scheme 3. Deprotonation of 2-haloaniline S6 with a base such as sodium hydride NaH in an organic solvent such as THF, and treatment with acyl chloride S4 yields the intermediate S7. S7 can be converted to S4 by treatment with tributyl(1-ethoxyvinyl) stannane and a palladium catalyst such as Pd(PPh3)4 in an organic solvent such as toluene, followed by treatment with an acidic aqueous solution. Quinolones such as S5 can then be prepared from S4 by high-temperature treatment with a base such as sodium hydroxide in an organic solvent such as dioxane.

[0058]

[0054]

[0059] [ka]

[0060]

[0055] Quinolones such as S5 can also be prepared by general synthetic methods as shown in Scheme 4. Substituted acetylaniline intermediate S2 can be prepared using various palladium-catalyzed cross-couplings of S8. Treatment of S2 with a base such as sodium hydride in an organic solvent such as THF, and treatment with acyl chloride S3 yields the intermediate of formula S4. Quinolones such as S5 can then be prepared from S4 by high-temperature treatment with a base such as sodium hydroxide in an organic solvent such as dioxane.

[0061]

[0056]

[0062] [ka]

[0063]

[0057] Quinolones such as S5 can also be prepared by general synthetic methods as shown in Scheme 5. Substituted acetylaniline intermediate S2 can be prepared using various palladium-catalyzed cross-couplings of S9. Treatment of S2 with a base such as sodium hydride in an organic solvent such as THF, and treatment with acyl chloride S3 yields the intermediate of formula S4. Quinolones such as S5 can then be prepared from S4 by high-temperature treatment with a base such as sodium hydroxide in an organic solvent such as dioxane.

[0064]

[0058]

[0065] [ka]

[0066]

[0059] Quinolones such as S13 can be prepared by general synthetic methods as shown in Scheme 6. Treatment of S10 with an amine yields intermediate S11, which can be converted to intermediate S12 and quinolone S13 using the methods described herein.

[0067]

[0060]

[0061] Preparation of starting materials

[0068] [ka]

[0069]

[0062] 2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine:

[0063] To a solution of 4-bromo-3,5-difluoroaniline (1.0 g, 4.8 mmol, 1.0 equivalent) and 4-(trifluoromethyl)phenylboronic acid (1.37 g, 7.21 mmol, 1.5 1.0 equivalents) in dioxane (9 mL) and H2O (3 mL), Pd(dppf)Cl2.CH2Cl2 (392 mg, 480 μmol, 0.1 equivalent) and K2CO3 (1.99 g, 14.4 mmol, 3.0 1.0 equivalent) were added. The mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1~5:1) to obtain the title compound as a white solid (1.2 g, 91% yield). LCMS:[M+H] + (C 13 The calculated value for H8F5N is m / z = 274.1, while the measured value is m / z = 274.0. 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 6.34 - 6.27 (m, 2H), 4.00 (br s, 2H).

[0064]

[0070] [ka]

[0071]

[0065] 4-amino-5-iodo-2-(trifluoromethyl)benzonitrile:

[0066] To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (1.0 g, 5.37 mmol, 1.0 equivalent) in THF (10 mL) and MeOH (10 mL), NIS (1.2 g, 5.37 mmol, 1.0 equivalent) and 4-methylbenzenesulfonic acid hydrate (1.02 g, 5.37 mmol, 1.0 equivalent) were added. The mixture was stirred at 20°C for 16 hours. The reaction product was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3 × 20 mL) and H2O (20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: siRNA = 100:1 to 10:1) to obtain the title compound as a yellow solid (1.3 g, yield 78%). LCMS: [M + H] + The calculated mass value for (C8H4F3IN2) is m / z = 312.9, while the measured value is also m / z = 312.9. 1 H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 6.99 (s, 1H), 4.89 (br s, 2H).

[0072] [ka]

[0073]

[0067] 2-Bromo-3,5-difluoro-4-(pyridine-4-yl)aniline

[0068] Step 1, 3,5-difluoro-4-(pyridine-4-yl)aniline: This material was prepared using 4-pyridylboronic acid as a starting material in the same manner as described for 2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.67 - 8.61 (m, 2H), 7.38 (dd, J = 1.6, 4.6 Hz, 2H), 6.38 - 6.23 (m, 2H), 4.07 (br s, 2H).

[0069] Step 2. To a solution of 3,5-difluoro-4-(pyridine-4-yl)aniline (850 mg, 4.1 mmol, 1.0 equivalent) in 2-bromo-3,5-difluoro-4-(pyridine-4-yl)aniline:THF (10 mL), N-bromosuccinimide (660 mg, 3.7 mmol, 0.9 equivalent) at -5°C was added. The mixture was stirred at -5°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (3:1~1:1 petroleum ether:ethyl acetate) to obtain the title compound as a pale yellow solid (1.0 g, yield 85.1%).

[0074] 1 ¹H NMR (400 MHz, chloroform-d): δ 8.67 (d, J = 5.0 Hz, 2H), 7.41 - 7.33 (m, 2H), 6.45 (dd, J = 1.8, 11.4 Hz, 1H), 4.56 (br s, 2H).

[0075] [ka]

[0076]

[0070] 1-(4-amino-2,6-difluorophenyl)pyrrolidine-2-one

[0071] Step 1, 1-(2,6-difluoro-4-nitrophenyl)pyrrolidine-2-one: To a mixture of pyrrolidine-2-one (1.43 mL, 18.6 mmol, 1.1 equivalents) in DMF (10 mL), NaH (1.22 g, 30.4 mmol, 1.8 equivalents; 60% dispersion) at 0°C was added under N2. The mixture was stirred at 0°C for 20 minutes, and then 1,2,3-trifluoro-5-nitrobenzene (3.0 g, 16.9 mmol, 1 equivalent) at 0°C was added to the mixture. The mixture was stirred at 0°C for 3 hours. The reaction mixture was poured into saturated NH4Cl aqueous solution (20 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10:1-5:1 petroleum ether:ethyl acetate) to obtain the title compound as a pale yellow solid (3.5 g, yield 85%). 1 H NMR (400 MHz, methanol-d4) δ 8.09 - 8.01 (m, 2H), 3.87 (t, J = 7.0 Hz, 2H), 2.62 - 2.55 (m, 2H), 2.32 (quintet, J = 7.6 Hz, 2H).

[0072] Step 2, 1-(4-amino-2,6-difluorophenyl)pyrrolidine-2-one: To a mixture of 1-(2,6-difluoro-4-nitrophenyl)pyrrolidine-2-one (1.5 g, 6.19 mmol, 1.0 equivalent) in EtOH (4 mL) and water (1 mL), iron(0) (1.73 g, 30.9 mmol, 5.0 equivalent) and NH4Cl (1.66 g, 30.9 mmol, 5.0 equivalent) at 20°C were added under N2 conditions. The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow solid (950 mg, yield 72%). 1H NMR (400 MHz, methanol-d4) δ 6.36 - 6.22 (m, 2H), 3.74 - 3.65 (m, 2H), 2.57 - 2.48 (m, 2H), 2.23 (quintet, J = 7.6 Hz, 2H).

[0077] [ka]

[0078]

[0073] 2-bromo-3,5-difluoro-6-methylaniline

[0074] Step 1, N-(4,6-difluoro-3-methyl-2-nitrophenyl)acetamide: To a mixture of N-(2,4-difluoro-5-methylphenyl)acetamide (1.5 g, 8.1 mmol, 1.0 equivalent) in H2SO4 (15 mL), a mixture of HNO3 (1.1 mL, 24.3 mmol, 3.0 equivalent) at 0°C and H2SO4 (1.5 mL) was added dropwise under N2. The mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into ice-cold water (40 mL), the precipitated solid was filtered, and washed with water (2 × 100 mL). The solid residue was dissolved in ethyl acetate (300 mL) and washed with aqueous NaHCO3 (2 × 40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100:1 to 20:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (1.4 g, 75% yield). LCMS[M+1] = 231.0.

[0079]

[0075] Step 2, N-(4,6-difluoro-3-methyl-2-nitroaniline:MeOH) (5.0 mL) was mixed with N-(4,6-difluoro-3-methyl-2-nitrophenyl)acetamide (1.4 g, 6.1 mmol, 1.0 equivalent), to which HCl (12 M, 9.8 mL, 19.3 equivalents) at 20°C was added dropwise under N2 conditions. The mixture was stirred at 90°C for 16 hours. The residue was poured into ice water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50:1~10:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (1.1 g, yield 92%). 1 H NMR (400 MHz, chloroform-d) δ 7.01 (dd, J = 8.8, 10.2 Hz, 1H), 4.99 (br s, 2H), 2.34 (dd, J = 1.2, 2.4 Hz, 3H).

[0080]

[0076] Step 3, 4,6-difluoro-3-methyl-2-nitroaniline (1.1 g, 5.85 mmol, 1.0 equivalent) and CuBr2 (2.61 g, 11.7 mmol, 548 uL, 2.0 equivalent) were added in one batch to a mixture of 4,6-difluoro-3-methyl-2-nitroaniline (1.1 g, 5.85 mmol, 1.0 equivalent) and CuBr2 (2.61 g, 11.7 mmol, 548 uL, 2.0 equivalent) in 2-bromo-1,5-difluoro-4-methyl-3-nitrobenzene:MeCN (15 mL) under N2 conditions. The mixture was stirred at 20 °C for 16 hours. The mixture was filtered, concentrated under reduced pressure, then poured into DCM and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (50:1-10:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (1.3 g, yield 88%). 1 ¹H NMR (400 MHz, chloroform-d): δ 7.06 (t, J = 8.4 Hz, 1H), 2.28 - 2.22 (m, 3H).

[0081]

[0077] Step 4, To a mixture of 2-bromo-1,5-difluoro-4-methyl-3-nitrobenzene (1.3 g, 5.2 mmol, 1.0 equivalent) in 2-bromo-3,5-difluoro-6-methylaniline:EtOH (13 mL) and water (6.5 mL), NH4Cl (1.4 g, 25.8 mmol, 5.0 equivalent) and iron(0) (2.0 g, 36.1 mmol, 7.0 equivalent) at 20°C were added all at once under N2. The mixture was stirred at 80°C for 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50:1~20:1 petroleum ether:ethyl acetate) to obtain the title compound as a white solid (650 mg, yield 57%). LCMS[M+1] = 223.8. 1 ¹H NMR (400 MHz, chloroform-d): δ 6.35 (t, J = 9.2 Hz, 1H), 4.33 (br s, 2H), 2.09 (s, 3H).

[0082] [ka]

[0083]

[0078] 1-(6-amino-3-bromo-2,4-difluorophenyl)ethane-1-one:

[0079] Step 1, To a solution of 1-(2-amino-4,6-difluorophenyl)ethane-1-one in BCl3 (55.4 mL, 426 mmol, 1.1 equivalents), a solution of 3,5-difluoroaniline (49.9 g, 426 mmol, 1.1 equivalents) in DCE (850 mL) at 0°C was added dropwise over 15 minutes, maintaining a temperature between 0 and 10°C. Acetonitrile (61.14 mL, 1.16 mol, 3.0 equivalents) was added dropwise to the mixture over 2 to 3 minutes, and then AlCl3 (56.80 g, 426.00 mmol, 1.1 equivalents) was added gradually over 10 minutes, maintaining a temperature between 0 and 10°C between the addition of both reagents. The mixture was then refluxed at 80°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to 0°C and then quenched with 4N HCl (500 mL). The mixture was stirred at 80°C for 2 hours. The reaction mixture was extracted with DCM (3 × 400 mL). The combined organic layer was washed with saturated aqueous NaHCO3 (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound as an off-white solid (45 g, yield 67.7%, purity 99.7%). LCMS[M+1] = 172.1. 1 H NMR (400 MHz, CDCl3) δ 6.3 - 6.7 (m, 2H), 6.1 - 6.2 (m, 2H), 2.6 - 2.6 (m, 3H).

[0084]

[0080] Step 2, 1-(2-amino-4,6-difluorophenyl)ethanone (40 g, 234 mmol, 1.0 equivalent) in a mixture of 1-(6-amino-3-bromo-2,4-difluorophenyl)ethanone-1-one:DCM (400 mL) was mixed with N-bromosuccinimide (45.8 g, 257 mmol, 1.1 equivalent) at 20°C under N2 conditions. The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water (50 mL), and the aqueous layer was extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (20:1~12:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (29.9 g, yield 47%). LCMS[M+1] = 249.9 / 251.9. 1 ¹H NMR (400 MHz, chloroform-d): δ 6.71 - 6.46 (m, 2H), 6.26 (dd, J = 1.8, 10.2 Hz, 1H), 2.60 (d, J = 8.6 Hz, 3H).

[0085] [ka]

[0086]

[0081] 1-(6-amino-2,4-difluoro-3-iodophenyl)ethenone: To a solution of 1-(2-amino-4,6-difluorophenyl)ethenone (10.0 g, 58.4 mmol, 1.0 equivalent) in DCM (100 mL), N-iodosuccinimide (14.4 g, 64.2 mmol, 1.1 equivalent) was added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were washed with 300 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (0-33% ethyl acetate in petroleum ether) to obtain the title compound as a brown solid (6.5 g, yield 37%). LCMS[M+1] = 297.7. 1¹H NMR (400 MHz, chloroform-d): δ 6.70 - 6.43 (m, 2H), 6.26 (dd, J = 1.8, 9.6 Hz, 1H), 2.61 (d, J = 9.0 Hz, 3H).

[0087] [ka]

[0088]

[0082] 1-[6-amino-2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethenone: 1-(6-amino-3-bromo-2,4-difluorophenyl)ethenone (10g, 39.99 mmol, 1 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) in toluene (200mL) To a mixture of -2-yl)-1,3,2-dioxaborolane (30.47 g, 119.98 mmol, 3 equivalents), KOAc (7.85 g, 79.99 mmol, 2 equivalents) and [2-(2-aminophenyl)phenyl]-chloropalladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (944.01 mg, 1.20 mmol, 0.03 equivalents) were added under N2 conditions at 20°C. The mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (50:1-15:1 petroleum ether:ethyl acetate) to obtain the title compound as a white solid (5.5 g, yield 46.1%). LCMS[M+1] = 298.1 and 216.1 (boric acid MS). 1 H NMR (400 MHz, methanol-d4) δ 6.21 (dd, J = 1.2, 11.6 Hz, 1H), 2.53 (d, J = 8.8 Hz, 3H), 1.33 (s, 12H).

[0089] [ka]

[0090]

[0083] 1-(6-amino-2,4-difluoro-3-(oxetan-3-yl)phenyl)ethane-1-one: A solution of 1-(6-amino-2,4-difluoro-3-iodophenyl)ethane-1-one (200 mg, 673 μmol, 1.0 equivalent) and 3-iodooxetane (124 mg, 673 μmol, 1.0 equivalent) in DME (2 mL), with NiCl2·glyme (740 ug, 3.3 μmol, 0.005 equivalents) and Na2CO3 (143 mg, 1.3 mmol, 2 equivalents) 4,4'-di-tert-butyl-2,2'-dipyridyl (903 u, 3.3 μmol, 0.005 equivalents), tris(trimethylsilyl)silane (208 uL, 673 μmol, 1.0 equivalent), and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+)-4-tert-butyl-2-(4-tert-butyl-2pyridyl)pyridinehexafluorophosphate (7.6 mg, 6.7 μmol, 0.01 equivalents) were added. The mixture was stirred at 20°C for 2 hours. The residue was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5:1 to 1:1, petroleum ether:ethyl acetate) to obtain the title compound as a white solid (120 mg, 78% yield). 1 ¹H NMR (400 MHz, chloroform-d) δ values: 6.60 - 6.23 (m, 1H), 6.16 (dd, J = 1.8, 12.1 Hz, 1H), 5.07 - 4.96 (m, 2H), 4.96 - 4.86 (m, 2H), 4.63 - 4.42 (m, 1H), 2.58 (d, J = 8.8 Hz, 3H).

[0091] [ka]

[0092]

[0084] 1-(6-amino-2,4-difluoro-3-(methoxymethyl)phenyl)ethane-1-one: To a solution of 1-(6-amino-2,4-difluoro-3-iodophenyl)ethane-1-one (1.5 g, 5.0 mmol, 1.0 equivalent) and tributyl(methoxymethyl) stannan (5.0 g, 15.1 mmol, 3.0 equivalents) in DMF (2 mL), [2-(2-aminophenyl)phenyl]-chloro-palladium-dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (397 mg, 505 μmol, 0.1 equivalent) was added. The mixture was stirred at 100 °C for 16 hours. The reaction product was diluted with water, and the aqueous mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1-2:1 petroleum ether:ethyl acetate) to obtain the title compound as a white solid (770 mg, yield 71%). 1 ¹H NMR (400 MHz, chloroform-d) δ values: 6.69 - 6.37 (m, 2H), 6.16 (dd, J = 1.8, 11.2 Hz, 1H), 4.48 - 4.39 (m, 2H), 3.43 - 3.33 (m, 3H), 2.60 (d, J = 8.8 Hz, 3H).

[0093] [ka]

[0094]

[0085] 3,5-difluoro-2-iodo-4-(1H-pyrazole-1-yl)aniline

[0086] Step 1, 1-(2,6-difluoro-4-nitrophenyl)-1H-pyrazole: To a mixture of 3,4,5-trifluoronitrobenzne (2 g, 11.3 mmol, 1.0 equivalent) and 1H-pyrazole (768.9 mg, 11.3 mmol, 1.0 equivalent) in DMSO (15 mL), K2CO3 (2.34 g, 16.9 mmol, 1.5 equivalent) at 20°C was added under N2. The mixture was stirred at 20°C for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground with MTBE (3 × 50 mL) to obtain the title compound as a white solid (1.7 g, yield 67%). 1 H NMR (400 MHz, DMSO-d6) δ 8.39 - 8.32 (m, 2H), 8.22 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 6.65 (t, J = 2.2 Hz, 1H).

[0095]

[0087] Step 2, 500 mg, 2.22 mmol, 1.0 equivalent of 1-(2,6-difluoro-4-nitrophenyl)-1H-pyrazole (500 mg, 2.22 mmol, 1.0 equivalent) in a mixture of 3,5-difluoro-4-(1H-pyrazole-1-yl)aniline:EtOH (5 mL) and water (1 mL) was mixed with NH4Cl (594 mg, 11.1 mmol, 5.0 equivalents) at 20°C and iron(0) (620 mg, 11.1 mmol, 5.0 equivalents) under N2 conditions. The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was washed with water (3 × 10 mL) to obtain the title compound as a yellow solid (600 mg, crude). 1 ¹H NMR (400 MHz, methanol-d4): δ 7.71 (t, J = 2.0 Hz, 2H), 6.49 (t, J = 2.0 Hz, 1H), 6.39 - 6.27 (m, 2H).

[0096]

[0088] Step 3, 3,5-difluoro-2-iodo-4-(1H-pyrazole-1-yl)aniline: To a mixture of 3,5-difluoro-4-(1H-pyrazole-1-yl)aniline (320 mg, 1.64 mmol, 1.0 equivalent) in acetic acid (1 mL), N-iodosuccinimide (350 mg, 1.56 mmol, 0.95 equivalent) at 20°C was added under N2 conditions. The mixture was stirred at 20°C for 2 hours. The residue was poured into a saturated aqueous solution of NaHCO3 (20 mL). The aqueous mixture was extracted with ethyl acetate (2 × 40 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 (10:1-5:1 petroleum ether:ethyl acetate) to obtain the title compound as a pale yellow solid (450 mg, yield 85.5%). 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 6.77 - 6.51 (m, 1H), 6.46 (t, J = 2.2 Hz, 1H), 6.19 (s, 2H).

[0097] [ka]

[0098]

[0089] 1-(6-amino-2,4-difluoro-3-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-4-yl)phenyl)ethane-1-one:2-(4-bromo-1H-pyrazole-1-yl)-2-methylpropan-1-ol (885 mg, 4.0 mmol, 2 equivalents) and 1 in dioxane (6 mL) and water (2 mL) To a solution of -(6-amino-2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-one (600 mg, 2.0 mmol, 1 equivalent), K2CO3 (837 mg, 6.0 mmol, 3.0 equivalents) and Pd(dppf)Cl2·CH2Cl2 (165 mg, 202 μmol, 0.1 equivalents) were added. The mixture was stirred at 80°C for 16 hours. The reaction product was diluted with water (20 mL), and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether:ethyl acetate) to obtain the title compound as a brown solid (160 mg, yield 26%). 1 H NMR (400 MHz, chloroform-d) δ 7.84 (br d, J = 6.8 Hz, 2H), 7.56 - 7.45 (m, 1H), 6.52 - 6.32 (m, 2H), 6.30 - 6.20 (m, 1H), 3.85 (s, 2H), 2.64 (d, J = 8.8 Hz, 3H), 1.61 (s, 6H).

[0099] [ka]

[0100]

[0090] tert-butyl 4-(3-acetyl-4-amino-2,6-difluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate: This material was prepared in the same manner as described for 3'-acetyl-4'-amino-2',6'-difluoro-[1,1'-biphenyl]-4-carbonitride. 1H NMR (400 MHz, chloroform-d) δ 6.17 (d, J = 1.8 Hz, 1H), 5.73 (br s, 1H), 4.06 (q, J = 2.8 Hz, 2H), 3.62 (t, J = 5.6 Hz, 2H), 2.57 (d, J = 8.8 Hz, 3H), 2.36 (br s, 2H), 1.50 (s, 9H).

[0101] [ka]

[0102]

[0091] tert-butyl 4-(3-acetyl-4-amino-2,6-difluorophenyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-(3-acetyl-4-amino-2,6-difluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.4 mmol, 1 equivalent) in MeOH (5 mL), 10% Pd / C (100 mg, 100 μmol, 0.07 equivalents) at 20°C under N2 conditions was added. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 20°C for 2 hours under an H2 (15 psi) atmosphere. The suspension was filtered through a Celite pad, and the filtration cake was washed with MeOH (3 × 10 mL). The title compound was obtained as a brown solid (500 mg, crude) by concentration of the filtrate under reduced pressure. 1 H NMR (400 MHz, chloroform-d) δ 6.12 (dd, J = 1.6, 12.4 Hz, 1H), 4.23 (br d, J = 12.4 Hz, 2H), 2.99 (tt, J = 3.4, 12.4 Hz, 1H), 2.76 (br t, J = 12.6 Hz, 2H), 2.57 (d, J = 9.1 Hz, 3H), 2.05 - 1.88 (m, 2H), 1.65 (br d, J = 13.4 Hz, 2H), 1.54 - 1.43 (m, 9H).

[0103] [ka]

[0104]

[0092] Ethyl 3-(3-acetyl-4-amino-2,6-difluorophenyl)propanoate

[0093] Step 1, 1-(6-amino-3-bromo-2,4-difluorophenyl) acrylate (0.9 g, 3.60 mmol, 1.0 equivalent) and ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate (2.03 g, 9.00 mmol, 2.5 equivalents) were added to a solution of 1-(6-amino-3-bromo-2,4-difluorophenyl)ethane-1-one (0.9 g, 3.60 mmol, 1.0 equivalent) and ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate (2.03 g, 9.00 mmol, 2.5 equivalents) in3-acetyl-4-amino-2,6-difluorophenyl) acrylate (12 mL) and water (4 mL). Pd(dppf)Cl2·CH2Cl2 (294 mg, 360 μmol, 0.1 equivalent) and K2CO3 (1.49 g, 10.8 mmol, 3.0 equivalent) were added. The mixture was stirred at 100°C for 8 hours under N2. The reaction mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10:1-3:1 petroleum ether:ethyl acetate) to obtain the title compound as a brown solid (0.7 g, 72% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.11 - 7.82 (m, 2H), 7.52 (d, J = 16.4 Hz, 1H), 6.51 (d, J = 13.8 Hz, 1H), 6.34 (d, J = 16.4 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H).

[0105]

[0094] Step 2, Ethyl 3-(3-acetyl-4-amino-2,6-difluorophenyl)propanoate: To a solution of ethyl(E)-3-(3-acetyl-4-amino-2,6-difluorophenyl)acrylate (700 mg, 2.60 mmol, 1.0 equivalent) in EtOH (5 mL) and THF (5 mL), 10% Pd / C (100 mg) was added. The mixture was stirred at 20°C for 16 hours under an H2 (15 Psi) atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (10:1-3:1 petroleum ether:ethyl acetate) to obtain the title compound as a white solid (600 mg, yield 85%). LCMS[M+1] = 272.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (br s, 2H), 6.47 - 6.28 (m, 1H), 4.04 (q, J = 7.2 Hz, 2H), 2.84 - 2.67 (m, 2H), 2.48 (d, J = 8.6 Hz, 5H), 1.16 (t, J = 7.2 Hz, 3H).

[0106] [ka]

[0107]

[0095] 4-amino-2,6-difluoro-3-iodo-N-methylbenzamide

[0096] Step 1, Methyl 4-amino-2,6-difluoro-3-iodobenzoate:

[0097] N-iodosuccinimide (4.8 g, 21.4 mmol, 1.0 equivalent) was added to a solution of methyl 4-amino-2,6-difluorobenzoate (3.8 g, 20.4 mmol, 1.0 equivalent) in acetic acid (40 mL) at 20°C. The reaction mixture was then stirred at 10°C for 0.5 hours. The mixture was quenched with a saturated aqueous solution of Na2S2O3 (50 mL). The aqueous layer was extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, and concentrated to obtain the title compound as a white solid (5.5 g, crude). 1H NMR (400 MHz, DMSO-d6) δ 6.60 - 6.49 (m, 2H), 6.43 (dd, J = 1.4, 13.3 Hz, 1H), 3.77 (s, 3H).

[0108]

[0098] Step 2, 4-amino-2,6-difluoro-3-iodo-N-methylbenzamide:

[0099] A solution of methyl 4-amino-2,6-difluoro-3-iodobenzoate (1 g, 3.1 mmol, 1 equivalent) in methylamine (22.0 mL, 319 mmol, 100 equivalents; 40% solution in water) was stirred at 20°C for 1 hour. The mixture was diluted with H2O (15 mL) and extracted with EA (2 × 20 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (80:1~20:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (800 mg, yield 80%). 1 ¹H NMR (400 MHz, methanol-d4): δ 6.45 - 6.37 (m, 1H), 2.87 (s, 3H).

[0109] [ka]

[0110]

[0100] 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,3-difluorobenzoic acid

[0101] Step 1, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (129.8 mg, 199 μmol, 0.1 equivalent) was added to a solution of methyl 3'-acetyl-4'-amino-2',4,5,6'-tetrafluoro-[1,1'-biphenyl]-3-carboxylate in water (2 mL) and THF (8 mL) containing methyl 5-bromo-2,3-difluorobenzoate (500 mg, 2.0 mmol, 1 equivalent), 1-(6-amino-2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-one (888 mg, 3.0 mmol, 1.5 equivalents) and K3PO4 (846 mg, 3.9 mmol, 2 equivalents). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into water (5 mL) and stirred for 2 minutes. The aqueous phase was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15:1-5:1 petroleum ether:ethyl acetate) to obtain the title compound as a white solid (400 mg, yield 59%). 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 7.72 - 7.78 (m, 1 H) 7.38 - 7.46 (m, 1 H) 6.26 (dd, J = 11.6, 1.53 Hz, 1 H) 3.93 - 4.00 (m, 3 H) 2.60 (d, J = 8.8 Hz, 3 H).

[0111]

[0102] Step 2, Methyl 3'-acetyl-4'-(2-chloro-5-cyanobenzamide)-2',4,5,6'-tetrafluoro-[1,1'-biphenyl]-3-carboxylate: To a mixture of methyl 3'-acetyl-4'-amino-2',4,5,6'-tetrafluoro-[1,1'-biphenyl]-3-carboxylate (240 mg, 703 μmol, 1.0 equivalent) in THF (2 mL), NaH (28.1 mg, 703 μmol, 1.0 equivalent; 60% dispersion in oil) at 0°C was added under N2 conditions. After stirring the mixture at 20°C for 2 minutes, 2-chloro-5-cyanobenzoyl chloride (168.8 mg, 843.9 μmol, 1.2 equivalents) was added under N2 conditions. The mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (20 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was ground over ethyl acetate (3 × 1 mL) at 20°C for 2 minutes, filtered, and concentrated under reduced pressure to obtain the title compound as a white solid (120 mg, 237.7 μmol, yield 33.8%). 1 H NMR (400 MHz, DMSO-d6) δ = 11.23 (s, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.06 (dd, J = 2.0, 8.4 Hz, 2H), 7.94 - 7.81 (m, 2H), 7.64 - 7.52 (m, 1H), 3.91 (s, 3H), 2.58 (d, J = 3.8 Hz, 3H).

[0112]

[0103] Step 3, 110 mg, 217.9 μmol, 1 equivalent of methyl 3'-acetyl-4'-(2-chloro-5-cyanobenzamide)-2',4,5,6'-tetrafluoro-[1,1'-biphenyl]-3-carboxylate (110 mg, 217.9 μmol, 1 equivalent) in a mixture of 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,3-difluorobenzoic acid:dioxane (3 mL) was mixed with 10.4 mg, 435.8 μmol, 1 equivalent of LiOH (20°C) under N2 conditions. The mixture was stirred at 110°C for 2 hours. An additional 5.2 mg, 217.9 μmol, 1 equivalent of LiOH was added, and the reaction was stirred at 110°C for a further 2 hours. The reaction mixture was poured into water (5 mL), and the two aqueous phases were extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was ground with ethyl acetate (3 × 1 mL), filtered, and concentrated under reduced pressure to obtain the title compound as a white solid (65 mg, yield 67%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (t, J=2.6 Hz, 1 H) 8.02 - 8.10 (m, 1 H) 7.90 (d, J=8.4 Hz, 1 H) 7.39 - 7.50 (m, 3 H) 7.26 - 7.32 (m, 1 H).

[0113] [ka]

[0114]

[0104] 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,4-difluorobenzoic acid: This material was prepared using the same synthesis sequence as described for 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,3-difluorobenzoic acid. 1¹H NMR (400 MHz, methanol-d4): δ 8.20 (d, J = 2.2 Hz, 1H), 8.16 - 8.08 (m, 1H), 7.98 - 7.76 (m, 3H), 7.73 - 7.65 (m, 1H), 7.39 - 7.22 (m, 1H).

[0115] [ka]

[0116]

[0105] 4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)picolinic acid: This material was prepared using the same synthetic sequence as described for 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,3-difluorobenzoic acid. 1 H NMR (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 8.86 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.09 (dd, J = 2.0, 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.82 (br d, J = 4.8 Hz, 1H), 7.41 (br d, J = 10.8 Hz, 1H), 6.24 - 6.17 (m, 1H).

[0117] [ka]

[0118]

[0106] 6-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)picolinic acid: This material was prepared using the same synthetic sequence as described for 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,3-difluorobenzoic acid.1 H NMR (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 8.86 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.09 (dd, J = 2.0, 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.82 (br d, J = 4.8 Hz, 1H), 7.41 (br d, J = 10.8 Hz, 1H), 6.24 - 6.17 (m, 1H).

[0119] [ka]

[0120]

[0107] 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2-(trifluoromethyl)benzoic acid: This material was prepared using the same synthetic sequence as described for 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,3-difluorobenzoic acid. 1 H NMR (400 MHz, DMSO-d6) δ 14.41 - 13.33 (m, 1H), 12.60 - 11.96 (m, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.97 - 7.91 (m, 2H), 7.90 - 7.83 (m, 1H), 7.28 (d, J = 9.9 Hz, 1H), 6.13 (br s, 1H).

[0121] [ka]

[0122]

[0108] 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2-fluorobenzoic acid

[0109] Step 1, a mixture of (4-fluoro-3-(methoxycarbonyl)phenyl)boronic acid (600 mg, 3.0 mmol, 1.5 equivalents) and 1-(6-amino-2,4-difluoro-3-iodophenyl)ethane-1-one (600 mg, 2.0 mmol, 1.0 equivalent) in methyl 3'-acetyl-4'-amino-2',4,6'-trifluoro-[1,1'-biphenyl]-3-carboxylate:dioxane (4.5 mL) and water (1.5 mL) was prepared by adding Pd(dppf)Cl2·CH2Cl2 (165 mg, 202 μmol, 0.1 equivalent) and K2CO3 (838 mg, 6.1 mmol, 3.0 equivalents) at 20°C under N2 conditions. The mixture was stirred at 80°C for 12 hours. The reaction mixture was poured into water (20 mL), and the aqueous layer was extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1-2:1 petroleum ether:ethyl acetate) to obtain the title compound as a brown solid (560 mg, yield 83%). 1 H NMR (400 MHz, methanol-d4) δ 7.92 (br d, J = 6.8 Hz, 1H), 7.68 - 7.56 (m, 1H), 7.29 (dd, J = 8.6, 10.6 Hz, 1H), 6.43 (dd, J = 1.6, 12.4 Hz, 1H), 3.98 - 3.87 (m, 3H), 2.55 (d, J = 8.8 Hz, 3H).

[0123]

[0110] Step 2, Methyl 3'-acetyl-4'-(2-chloro-5-cyanobenzamide)-2',4,6'-trifluoro-[1,1'-biphenyl]-3-carboxylate: To a mixture of methyl 3'-acetyl-4'-amino-2',4,6'-trifluoro-[1,1'-biphenyl]-3-carboxylate (490 mg, 1.5 mmol, 1 equivalent) in THF (5 mL), NaH (66.6 mg, 1.7 mmol, 1.1 equivalents; 60% dispersion in oil) and 2-chloro-5-cyanobenzoyl chloride (364 mg, 1.8 mmol, 1.2 equivalents) were added under N2 conditions at 0°C. The mixture was stirred at 20°C for 12 hours. The mixture was added to a saturated aqueous solution of NH4Cl (15 mL), and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was washed with ethyl acetate (2 × 3 mL), filtered, and concentrated under reduced pressure to obtain the title compound as a white solid (540 mg, yield 71%). 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.12 (s, 1H), 8.08 - 8.00 (m, 2H), 7.85 (br d, J = 8.4 Hz, 2H), 7.67 - 7.45 (m, 2H), 3.88 (s, 3H), 2.58 (br d, J = 3.6 Hz, 3H).

[0124]

[0111] Step 3, a mixture of methyl 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2-fluorobenzoate:dioxane (2 mL) and methyl 3'-acetyl-4'-(2-chloro-5-cyanobenzamide)-2',4,6'-trifluoro-[1,1'-biphenyl]-3-carboxylate (540 mg, 1.1 mmol, 1 equivalent) was added under N2 conditions at 20°C. The mixture was stirred at 110°C for 2 hours. The pH of the residue was adjusted to 3-4 with HCl (1 M). Next, the mixture was diluted with water (10 mL) and stirred at 20°C for 10 minutes. The mixture was filtered, and the filtered cake was concentrated under reduced pressure to obtain the crude product. The crude product was washed with acetonitrile (2 × 2 mL), the mixture was filtered, and the filtered cake was concentrated under reduced pressure to obtain the title compound as a white solid (400 mg, 77% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.31 - 12.15 (m, 1H), 8.29 - 8.24 (m, 1H), 8.12 (s, 1H), 8.03 - 7.91 (m, 3H), 7.87 - 7.75 (m, 1H), 7.58 - 7.45 (m, 1H), 7.33 - 7.22 (m, 1H), 6.11 (br s, 1H), 3.89 (s, 3H).

[0125]

[0112] Step 4, 200 mg, 427 μmol, 1 equivalent of methyl 5-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2-fluorobenzoate (200 mg, 427 μmol, 1 equivalent) in THF (2.1 mL) and water (0.9 mL) was mixed with LiOH·H2O (35.8 mg, 853 μmol, 2 equivalents) at 20°C under N2 conditions. The mixture was stirred at 20°C for 6 hours. The reaction mixture was poured into water (10 mL) and the pH was adjusted to 7 with HCl (1 M). The solid was precipitated from the mixture, washed with water (2 mL), then the mixture was filtered, and the filtered cake was dried under vacuum to obtain the title compound as a white solid (180 mg, yield 89%, purity 96%). 1 H NMR (400 MHz, DMSO-d6) δ 13.65 - 13.22 (m, 1H), 12.34 - 11.99 (m, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.10 (dd, J = 2.0, 8.4 Hz, 1H), 8.02 - 7.90 (m, 2H), 7.78 (br d, J = 3.6 Hz, 1H), 7.49 (dd, J = 8.6, 10.6 Hz, 1H), 7.27 (br d, J = 10.0 Hz, 1H), 6.35 - 5.94 (m, 1H).

[0126]

[0113] Example 1

[0127] [ka]

[0128]

[0114] 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0115] Scheme 1. 2-Chloro-5-cyanobenzoyl chloride:

[0116] 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 hour. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to obtain the title compound as a yellow solid (2.8 g, crude), and the product was used directly in the next step.

[0129]

[0117] Scheme 1, Step 1. 1-(2-amino-4,6-difluorophenyl)ethanone:

[0118] To a solution of 3,5-difluoroaniline (8.9 g, 68.9 mmol, 1.0 equivalent) in CH3CN (85 mL), BCl3 (1 M, 72.4 mL, 1.05 equivalent) at 0°C was added. Next, AlCl3 (10.1 g, 75.8 mmol, 4.1 mL, 1.1 equivalent) was added to the mixture in three portions, and the mixture was stirred at 80°C for 16 hours. 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 hours. The mixture was cooled to room temperature and extracted with HCl (2 × 150 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a pale yellow solid (8.0 g, yield 68%). LCMS:[M+H] + The calculated value for (C8H7F2NO) is m / z = 172.0, while the measured value is 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).

[0130]

[0119] Scheme 1, Step 2. N-(2-acetyl-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide:

[0120] A solution of 1-(2-amino-4,6-difluorophenyl)ethanone (2 g, 11.7 mmol, 1.0 equivalent) in THF (20 mL) was mixed with NaH (467 mg, 11.7 mmol, 60% dispersion in oil, 1.0 equivalent) at 0°C. The mixture was stirred for 30 minutes, and then a solution of 2-chloro-5-cyanobenzoyl chloride (2.6 g, 12.8 mmol, 1.1 equivalents) in THF (10 mL) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding saturated aqueous solution NH4Cl (15 mL) at 15°C, diluted with water (20 mL), and filtered. The filtered cake was pulverized with siRNA (20 mL) and filtered to obtain the title compound as a white solid (2.4 g, yield 61%). LCMS:[M+H] + (C 16 The calculated value for H9F3N2O2 is m / z = 335.0, while the measured value is also m / z = 335.0. 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).

[0131]

[0121] Scheme 1, Step 3. 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile: A solution of N-(2-acetyl-3,5-difluoro-phenyl)-2-chloro-5-cyano-benzamide (2.5 g, 7.5 mmol, 1.0 eq) in dioxane (40 mL) was added with NaOH (3.0 g, 74.7 mmol, 10.0 eq). The mixture was stirred at 110 °C for 1.5 h. The pH of the reaction mixture was adjusted to 5 with aqueous HCl solution (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 give a crude residue, which was purified by preparative HPLC (column: Welch Xtimate C18 250×70 mm×10um; mobile phase: 15 - 45% acetonitrile in water (10 mM NH4HCO3)). Thereby, after concentration under reduced pressure, the title compound was obtained as a white solid (570 mg, yield 24%, purity 98%). LCMS: [M+H] + (C 16 The calculated value for H7ClF2N2O) is m / z = 317.0, and the measured value 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).

[0132]

[0123] Example 2

[0133]

Chemical formula

[0134]

[0124] 4-chloro-3-(6,7-dichloro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile

[0135]

[0125] Scheme 1, Step 1. 1-(2-amino-4,5-dichlorophenyl)ethenone:

[0126] To a solution of 3,4-dichloroaniline (2.0 g, 12.4 mmol, 1.0 equivalent) in ACN (20 mL), BCl3 (1 M, 13.0 mL, 1.05 equivalent) at 0°C was added. Next, AlCl3 (1.81 g, 13.58 mmol, 742 μL, 1.1 equivalent) was added in three portions, and the mixture was stirred at 80°C for 16 hours. The mixture was cooled to 0°C, aqueous HCl (4 M, 5 mL) was added, and the mixture was stirred at 80°C for 4 hours. The reaction product was cooled to room temperature, extracted with ethyl acetate, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 30:1 petroleum ether: HCl), and the title compound was obtained as a white solid (170 mg, yield 6.7%). LCMS:[M+H] + The calculated value for (C8H7Cl2NO) is m / z = 204.1, and the measured value is also m / z = 204.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.39 (br s, 2H), 7.02 (s, 1H), 2.52 (s, 3H).

[0136]

[0127] Scheme 1, Step 2. N-(2-acetyl-4,5-dichlorophenyl)-2-chloro-5-cyanobenzamide:

[0128] To a solution of 1-(2-amino-4,5-dichlorophenyl)ethanone (125 mg, 614 μmol, 1.0 equivalent) in DCM (1 mL), room temperature TEA (171 μL, 1.2 mmol, 2.0 equivalents) was added under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, and then 2-chloro-5-cyano-benzoyl chloride (172 mg, 860 μmol, 1.4 equivalents) was added dropwise as a solution in DCM (1 mL). The reaction mixture was stirred at room temperature for 5 hours. The mixture was poured into water (0.5 mL) and stirred for 1 minute. The aqueous phase was extracted with DCM (3 × 3 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was pulverized with MeOH to obtain the title compound as a yellow solid (100 mg, crude). LCMS:[M+H] + (C 16The calculated value for (H9Cl3N2O2) is m / z = 366.9, and the measured value is m / z = 366.9.

[0137]

[0129] Scheme 1, Step 3. 4-Chloro-3-(6,7-dichloro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile:

[0130] To a solution of N-(2-acetyl-4,5-dichlorophenyl)-2-chloro-5-cyanobenzamide (90 mg, 244 μmol, 1.0 equivalent) in dioxane (2.0 mL) was added NaOH (98 mg, 2.5 mmol, 10 equivalents). The mixture was stirred at 110 °C for 1.5 h. The pH of the reaction mixture was adjusted to 5 by the addition of aqueous HCl solution (1 M). The mixture was then diluted with water (2 mL) and extracted with EtOAc (4 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was first purified by preparative TLC (SiO2, 10:1 DCM:MeOH) and then by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 um; mobile phase: 35 - 65% ACN in water (10 mM NH4HCO3)) to give the title compound as a white solid (3.8 mg, yield 4.4%, purity 99%). LCMS: [M+H] + (C 16 The calculated value for (H7Cl3N2O) is m / z = 348.0, and the measured value is m / z = 348.0. 1 1H NMR (400 MHz, MeOH-d4) δ 8.38 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 1.6, 8.4 Hz, 1H), 7.85 - 7.80 (m, 2H), 6.39 (s, 1H).

[0138]

[0131] The compounds in Table 1 were prepared using the same procedures as described for Examples 1 and 2 according to Scheme 1.

[0139]

Table 1-1

[0140] [Table 1-2]

[0141] [Table 1-3]

[0142] [Table 1-4]

[0143]

[0132] Example 9

[0144] [ka]

[0145]

[0133] 2-(2-chloro-5-cyanophenyl)-7-methyl-4-oxo-1,4-dihydroquinoline-6-carbonitrile

[0134] Scheme 2, Step 1. 4-amino-5-iodo-2-methyl-benzonitrile:

[0135] To a solution of 4-amino-2-methyl-benzonitrile (400 mg, 3.0 mmol, 1.0 equivalent) in AcOH (5 mL), NIS (681 mg, 3.0 mmol, 1.0 equivalent) was added. The mixture was then stirred at room temperature for 3 hours. The mixture was quenched with H2O (100 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (10 mL) and brine (5 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 petroleum ether: siRNA) to obtain the title compound as a brown solid (580 mg, crude). LCMS:[M+H] + The calculated value for (C8H7IN2) is m / z = 259.0, and the measured value is also m / z = 259.0. 1H NMR (400 MHz, CDCl3-d) δ 7.92 - 7.73 (m, 1H), 6.59 (s, 1H), 4.54 (br d, J = 1.3 Hz, 2H), 2.40 (s, 3H).

[0146]

[0136] Scheme 2, Step 2. 5-Acetyl-4-amino-2-methyl-benzonitrile:

[0137] To a solution of 4-amino-5-iodo-2-methyl-benzonitrile (450 mg, 1.7 mmol, 1.0 equivalent) and tributyl(1-ethoxyvinyl) stannan (756 mg, 2.1 mmol, 1.2 equivalents) in toluene (12 mL), Pd(PPh3)4 (101 mg, 87.2 μmol, 0.05 equivalent) was added at room temperature. The mixture was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched by adding aqueous HCl (1 N, 2 mL), and stirred at room temperature for 30 minutes. Next, the mixture was added to aqueous KF (20 mL) and stirred at room temperature for 1 hour. Next, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10:1-3:1 petroleum ether:RINKAN) to obtain the title compound as a white solid (160 mg, 53% yield). LCMS:[M+H] + (C 10 H 10 The calculated value for N2O is m / z = 175.1, while the measured value is also m / z = 175.1. 1 H NMR (400 MHz, CDCl3-d) δ 8.12 - 7.90 (m, 1H), 6.53 (s, 1H), 2.59 (s, 3H), 2.46 (s, 3H).

[0147]

[0138] Scheme 2, Step 3. N-(2-acetyl-4-cyano-5-methylphenyl)-2-chloro-5-cyano-benzamide:

[0139] To a solution of 5-acetyl-4-amino-2-methyl-benzonitrile (120 mg, 689 μmol, 1.0 equivalent) in THF (5 mL), NaH (33 mg, 827 μmol, 60% dispersed in oil, 1.2 equivalents) was added. The mixture was stirred at 0°C for 10 minutes, then 2-chloro-5-cyano-benzoyl chloride (165 mg, 825 μmol, 1.2 equivalents) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was slowly poured into a saturated aqueous solution of NH4Cl (5 mL) and stirred for 5 minutes. The aqueous phase was extracted with  (2 × 30 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (2:1 petroleum ether:Â) to obtain the title compound as a white solid (12 mg, 35 μmol, yield 5.2%). LCMS:[M+H] + (C 18 H 12 The calculated value for ClN3O2 is m / z = 338.1, while the measured value is m / z = 338.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H), 8.54 - 8.49 (m, 1H), 8.46 (s, 1H), 8.25 (br s, 1H), 8.12 - 8.05 (m, 1H), 7.89 (br d, J = 8.2 Hz, 1H), 2.68 (br s, 3H), 2.59 (br s, 3H).

[0148]

[0140] Scheme 2, Step 4. 2-(2-chloro-5-cyanophenyl)-7-methyl-4-oxo-1H-quinoline-6-carbonitrile: A solution of N-(2-acetyl-4-cyano-5-methyl-phenyl)-2-chloro-5-cyano-benzamide (10 mg, 29.6 μmol, 1.0 eq) in dioxane (1.0 mL) was added with NaOH (11.8 mg, 296 μmol, 10 eq). The reaction mixture was stirred under a nitrogen atmosphere at 110 °C for 2 h. The pH of the mixture was adjusted to 5 - 6 with 1 N aqueous HCl. The aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 um; mobile phase: 15 - 45% ACN (0.2% FA) in water) to afford the title compound as a white solid (2.3 mg, yield 24%, purity 98%). LCMS: [M + H] + (C 18 H 10 ClN3O), calculated value for m / z = 320.1, found m / z = 320.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.46 - 8.38 (m, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 2.0, 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 6.21 (s, 1H), 2.58 (s, 3H).

[0149]

[0142] The compounds in Table 2 were prepared using the same procedure as described for Example 9 according to Scheme 2.

[0150]

Table 2-1

[0151]

Table 2-2

[0152]

Table 2-3

[0153]

[0143] Example 31

[0154] [ka]

[0155]

[0144] 4-Chloro-3-(7-Chloro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0145] Step 1, 1-(2-amino-4-chlorophenyl)ethane-1-one:

[0146] To a solution of 1-(4-chloro-2-nitrophenyl)ethane-1-one (1.0 g, 5.0 mmol, 1.0 equivalent) in EtOH (9 mL) and H2O (3 mL), iron (powder) (1.4 g, 25.1 mmol, 5.0 equivalents) and NH4Cl (1.3 g, 25.1 mmol, 5.0 equivalents) were added. The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was diluted with water (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (0-50% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (610 mg, yield 72%). 1 H NMR (400 MHz, chloroform-d) δ 7.64 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H), 6.62 (dd, J = 1.8, 8.6 Hz, 1H), 6.36 (br s, 2H), 2.56 (s, 3H).

[0156]

[0147] Step 2, N-(2-acetyl-5-chlorophenyl)-2-chloro-5-cyanobenzamide:

[0148] 2-chloro-5-cyanobenzoic acid (136 mg, 749 μmol, 1.0 equivalent) was treated with SOCl2 (1 mL) at 20°C under N2 conditions. The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to obtain 2-chloro-5-cyano-benzoyl chloride (150 mg, crude) as a white solid. To a solution of 1-(2-amino-4-chlorophenyl)ethane-1-one (100 mg, 590 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (119 μL, 1.5 mmol, 2.5 equivalents) and 2-chloro-5-cyano-benzoyl chloride (142 mg, 708 μmol, 1.2 equivalents) were added. The mixture was stirred at 40°C for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with HCl (1N, 30 mL) and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was ground in ACN (5 mL) at 20°C for 30 minutes to obtain the title compound as a white solid (120 mg, 61% yield). LCMS[M+1] = 333.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 1.6, 3.6 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.45 - 7.40 (m, 1H), 2.63 (s, 3H).

[0157]

[0149] Step 3, 4-chloro-3-(7-chloro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0150] A mixture of N-(2-acetyl-5-chlorophenyl)-2-chloro-5-cyanobenzamide (150 mg, 450 μmol, 1.0 equivalent) in dioxane (2 mL) was to be suddenly mixed with LiOH (10.8 mg, 450 μmol, 1.0 equivalent) at 20 °C under N2 conditions. The mixture was stirred at 110 °C for 5 hours. The mixture was poured into HCl (1 N) and the pH was adjusted to 5. Next, the residue was poured into water (20 mL) and stirred for 30 minutes, then the mixture was filtered. The filtered cake was pulverized with ethyl acetate at 20 °C for 30 minutes, and the precipitate was filtered. The filtered cake was pulverized with DMSO for 30 minutes to obtain the title compound (68 mg, yield 48%). LCMS[M+1] = 314.9 / 316.9. 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (br s, 1H), 8.26 (s, 1H), 8.11 (br dd, J = 8.9, 13.5 Hz, 2H), 7.93 (d, J = 8.3 Hz, 1H), 7.59 (br s, 1H), 7.47 - 7.36 (m, 1H), 6.15 (br s, 1H).

[0158]

[0151] Example 12

[0159] [ka]

[0160]

[0152] 2-(2-chloro-5-cyanophenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-6 ​​carbonitrile

[0153] Scheme 3, Step 1. 2-Chloro-5-cyano-N-(4-cyano-2-iodo-5-(trifluoromethyl)phenyl)benzamide:

[0154] To a solution of 4-amino-5-iodo-2-(trifluoromethyl)benzonitrile (250 mg, 801 μmol, 1.0 equivalent) in THF (1 mL), NaH (32.0 mg, 801 μmol, 60% dispersion in oil, 1.0 equivalent) at 0°C was added. The mixture was stirred for 10 minutes, then 2-chloro-5-cyanobenzoyl chloride (160 mg, 801 μmol, 1.0 equivalent) was added. The mixture was heated to room temperature and then stirred for 16 hours. The reaction was quenched with saturated NH4Cl aqueous solution (10 mL), then extracted with RINKAN (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:siRNA = 4:1) to obtain the title compound as a white solid (100 mg, yield 26%). [MH] + (C 16 The MS mass calculation value for H6ClF3IN3O is m / z = 473.9, while the LCMS measured value is m / z = 474.0. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.88 (s, 1H), 7.68 - 7.62 (m, 1H), 7.52 (d, J = 8.4 Hz, 1H).

[0161]

[0155] Scheme 3, Step 2. 2-Chloro-5-cyano-N-(4-cyano-2-(1-ethoxyvinyl)-5-(trifluoromethyl)phenyl)benzamide:

[0156] To a solution of 2-chloro-5-cyano-N-(4-cyano-2-iodo-5-(trifluoromethyl)phenyl)benzamide (25 mg, 52 μmol, 1.0 equivalent) and tributyl(1-ethoxyvinyl) stannan (23.9 mg, 66.2 μmol, 1.26 equivalents) in toluene (1 mL), Pd(PPh3)4 (6.0 mg, 5.2 μmol, 0.1 equivalent) was added under a nitrogen atmosphere. The mixture was stirred at 120 °C for 16 hours. The mixture was poured into an aqueous solution of KF (50 mL) and stirred for 1 hour. The mixture was then diluted with water (10 mL) and extracted with  (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (18 mg, crude). The crude product was used directly in the next step. LCMS:[MH] - (C 20 H 13 The calculated value for ClF3N3O2 is m / z = 418.1, while the measured value for LCMS is m / z = 418.1.

[0162]

[0157] Scheme 3, Step 3. N-(2-acetyl-4-cyano-5-(trifluoromethyl)phenyl)-2-chloro-5-cyanobenzamide:

[0158] A solution of 2-chloro-5-cyano-N-(4-cyano-2-(1-ethoxyvinyl)-5-(trifluoromethyl)phenyl)benzamide (20 mg, 47.6 μmol, 1.0 equivalent) in HCl / dioxane (2 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO2, petroleum ether:Â=2:1) ​​to obtain the title compound as a white solid (8.0 mg, yield 43%). LCMS:[MH] - (C 18 The calculated value for H9ClF3N3O2 is m / z = 390.0, while the measured value for LCMS is m / z = 390.1. 1H NMR (400 MHz, CDCl3) δ 12.49 - 12.60 (m, 1H), 9.46 (s, 1H), 8.40 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.40, 2.0 Hz, 1H), 7.65 - 7.69 (m, 1H), 2.78 (s, 3H).

[0163]

[0159] Scheme 3, Step 4. 2-(2-chloro-5-cyanophenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-6-carbonitrile:

[0160] A mixture of N-(2-acetyl-4-cyano-5-(trifluoromethyl)phenyl)-2-chloro-5-cyanobenzamide (50 mg, 128 μmol, 1.0 equivalent) and NaOH (51 mg, 1.28 mmol, 10 equivalents) in dioxane (1 mL) was degassed, purged three times with nitrogen, and then the mixture was stirred under a nitrogen atmosphere at 110°C for 1 hour. The pH of the solution was adjusted to 5-6 with aqueous HCl (1 M), and then extracted with  (3 × 5 mL). The combined 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: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%~50%, 8 min) to obtain the title compound as a yellow solid (6.5 mg, yield 14%, purity 99%). LCMS: [MH] - (C 18 The calculated value for H7ClF3N3O is m / z = 372.0, while the measured value using LCMS is also m / z = 372.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.96 (br d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 6.37 (s, 1H).

[0164]

[0161] The compounds in Table 3 were prepared according to Scheme 3 using the same procedure as described in Example 12.

[0165] [Table 3]

[0166]

[0162] Example 35

[0167] [ka]

[0168]

[0163] 4-Chloro-3-(6-(4-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0164] 1-(6-amino-3-bromo-2,4-difluorophenyl)ethan-1-one: To a mixture of 1-(2-amino-4,6-difluorophenyl)ethanone (40 g, 233.7 mmol, 1 equivalent) in DCM (400 mL), N-bromosuccinimide (45.8 g, 257 mmol, 1.1 equivalent) at 20°C was added under N2. The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM (3 × 200 mL). The combined organic layer was washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (4%-8% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (29.9 g, yield 47%). LCMS[M+1] = 249.9. 1 ¹H NMR (400 MHz, chloroform-d): δ 6.71 - 6.46 (m, 2H), 6.26 (dd, J = 1.8, 10.2 Hz, 1H), 2.60 (d, J = 8.6 Hz, 3H).

[0165] Step 1, Scheme 4, 3'-Acetyl-4'-amino-2',6'-difluoro-[1,1'-biphenyl]-4-carbonitrile:

[0166] To a solution of (4-cyanophenyl)boronic acid (176 mg, 1.2 mmol, 1.5 equivalents) and 1-(6-amino-3-bromo-2,4-difluorophenyl)ethane-1-one (200 mg, 800 μmol, 1.0 equivalent) in dioxane (1 mL) and H2O (0.33 mL), K2CO3 (332 mg, 2.40 mmol, 3 equivalents) and Pd(dppf)Cl2·CH2Cl2 (65 mg, 80 μmol, 0.1 equivalents) were added under N2. The mixture was stirred under N2 at 80°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (25% ethyl acetate in petroleum ether) to obtain the title compound as a white solid (200 mg, 92% yield). LCMS[M+1] = 273.1. 1 H NMR (400 MHz, chloroform-d) δ 2.60 (d, J = 9.0 Hz, 3H), 6.28 (dd, J = 11.6, 1.6 Hz, 1H), 6.38 - 6.82 (m, 2H), 7.53 (br d, J=8.4 Hz, 2H), 7.68 - 7.77 (m, 2H).

[0169]

[0167] Step 2, N-(3-acetyl-4'-cyano-2,6-difluoro-[1,1'-biphenyl]-4-yl)-2-chloro-5-cyanobenzamide:

[0168] To a solution of 3'-acetyl-4'-amino-2',6'-difluoro-[1,1'-biphenyl]-4-carbonitrile (200 mg, 734.6 μmol, 1.0 equivalent) in THF (2 mL), NaH (29.4 mg, 735 μmol, 1.0 equivalent; 60% dispersion in oil) was added. Next, 2-chloro-5-cyanobenzoyl chloride (220 mg, 1.10 mmol, 1.5 equivalents) was added, and the mixture was stirred at 0-20°C for 16 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL), and then extracted with ethyl acetate (20 mL). The organic layer was concentrated under reduced pressure to obtain the residue. The crude product was pulverized with ethyl acetate to obtain the title compound as a white solid (220 mg, 69% yield). LCMS[M+1] = 436.0. 1 H NMR (400 MHz, chloroform-d) δ 12.22 (s, 1H), 8.66 (dd, J = 12.2, 1.6 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.77 - 7.86 (m, 3H), 7.71 - 7.77 (m, 1H), 7.62 - 7.68 (m, 1H), 7.59 (br d, J = 8.2 Hz, 2H), 2.70 (d, J = 8.8 Hz, 3H).

[0170]

[0169] Step 3, 4-chloro-3-(6-(4-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0170] NaOH (9.2 mg, 229 μmol, 1.0 equivalent) was added to a solution of N-(3-acetyl-4'-cyano-2,6-difluoro-[1,1'-biphenyl]-4-yl)-2-chloro-5-cyanobenzamide (100 mg, 229 μmol, 1.0 equivalent) in dioxane (2 mL). The mixture was stirred at 110 °C for 1.5 hours. The reaction product was quenched by adding aqueous HCl (1 M), and then diluted with water (5 mL). The mixture was 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 preparative HPLC (column: Phenomenex Luna C18 150×30mm×5um; mobile phase: 25-65% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a white solid (22 mg, yield 23%). LCMS[M+1] = 418.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.25 (br d, J = 1.8 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 8.08 (dd, J = 8.4, 1.8 Hz, 1H,) 8.00 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.28 (br d, J = 10.8 Hz, 1H), 6.15 (br s, 1H).

[0171]

[0171] The compounds in Table 4 were prepared according to Scheme 4 using the same procedure as described in Example 35.

[0172] [Table 4-1]

[0173] [Table 4-2]

[0174] [Table 4-3]

[0175] [Table 4-4]

[0176] [Table 4-5]

[0177] [Table 4-6]

[0178] [Table 4-7]

[0179]

[0172] Example 62

[0180] [ka]

[0181]

[0173] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(1H-pyrazole-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile

[0174] Step 1, 4-bromo-3,5-difluoroaniline (1 g, 4.8 mmol, 1.0 equivalent) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 7.2 mmol, 1.5 equivalent) were added to a solution of 4-bromo-3,5-difluoroaniline (1 g, 4.8 mmol, 1.0 equivalent) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 7.2 mmol, 1.5 equivalent) in dioxane (9 mL) and H2O (3 mL), and K2CO3 (2.0 g, 14.4 mmol, 3.0 equivalent) at 20°C and Pd(dppf)Cl2·CH2Cl2 (393 mg, 481 μmol, 0.1 equivalent) under N2 conditions. The mixture was stirred under N2 at 90°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (17% to 100% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (1.3 g, yield 97%). 1 H NMR (400 MHz, CDCl3) δ 7.99 - 7.92 (m, 2H), 6.33 - 6.24 (m, 2H), 5.42 (dd, J = 2.5, 9.8 Hz, 1H), 4.09 (br dd, J = 2.5, 10.4 Hz, 1H), 3.78 - 3.68 (m, 1H), 2.25 - 2.01 (m, 3H), 1.79 - 1.58 (m, 3H).

[0182]

[0175] Step 2, 2-bromo-3,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)aniline: A solution of N-bromosuccinimide (382 mg, 2.2 mmol, 1.0 equivalent) in THF (3 mL) was added dropwise under N2 conditions to a mixture of 3,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)aniline (600 mg, 2.2 mmol, 1.0 equivalent) in THF (5 mL) at -10°C. The mixture was stirred at -10 to 0°C for 1 hour. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (25% to 100% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (620 mg, yield 81%). 1 H NMR (400 MHz, CDCl3) δ 7.96 (br d, J = 16.2 Hz, 2H), 6.42 (dd, J = 1.8, 12.2 Hz, 1H), 5.44 (dd, J = 2.6, 9.4 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.73 (dt, J = 2.8, 11.2 Hz, 1H), 2.25 - 2.01 (m, 3H), 1.75 - 1.63 (m, 3H).

[0183]

[0176] Step 3, 2-(1-ethoxyvinyl)-3,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)aniline: To a solution of 2-bromo-3,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)aniline (470 mg, 1.3 mmol, 1.0 equivalent) and tributyl(1-ethoxyvinyl) stannan (531 μL, 1.6 mmol, 1.2 equivalents) in toluene (6 mL), Pd(PPh3)4 (152 mg, 131 μmol, 0.1 equivalent) at 20 °C was added under N2 conditions. The mixture was stirred under N2 conditions at 120 °C for 16 hours. The mixture was added to an aqueous solution of KF (30 mL) and then stirred for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% to 100% ethyl acetate in petroleum ether) to obtain the title compound as a yellow oil (270 mg, yield 59%). 1 H NMR (400 MHz, CDCl3) δ 8.03 - 7.89 (m, 2H), 6.57 (d, J = 11.4 Hz, 1H), 6.25 (dd, J = 1.4, 12.6 Hz, 1H), 5.44 (ddd, J = 3.0, 9.4, 12.6 Hz, 1H), 4.19 - 4.01 (m, 1H), 3.80 - 3.65 (m, 2H), 2.63 (d, J = 9.0 Hz, 1H), 2.50 (s, 1H), 2.28 - 2.01 (m, 3H), 1.84 - 1.57 (m, 3H), 1.30 - 1.19 (m, 3H).

[0184]

[0177] Step 4, To a solution of 2-(1-ethoxyvinyl)-3,5-difluoro-4-(1H-pyrazole-4-yl)phenyl)-2-chloro-5-cyanobenzamide:THF (2 mL) containing 2-(1-ethoxyvinyl)-3,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)aniline (230 mg, 658 μmol, 1.0 equivalent), NaH (26.3 mg, 658 μmol, 1.0 equivalent; 60% dispersion in oil) at 0°C was added. The mixture was stirred at 0°C for 5 minutes under N2. Next, 2-chloro-5-cyanobenzoyl chloride (158 mg, 800 μmol, 1.2 equivalents) in THF (1 mL) was added dropwise to the mixture at 0°C, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was quenched by adding HCl aqueous solution (2 M, 1 mL). Next, HCl (12 M, 1 mL) was added to the mixture, and the mixture was stirred at 20°C for 2 hours. The mixture was then diluted with NaHCO3 (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was pulverized with ethyl acetate (5 mL) at 20°C for 20 minutes. The residue was then pulverized with MeOH (5 mL) at 20°C for 20 minutes to obtain the title compound as a yellow solid (100 mg, yield 38%). 1 H NMR (400 MHz, DMSO-d6) δ 13.31 (br s, 1H), 11.01 (br s, 1H), 8.11 (d, J = 1.8 Hz, 2H), 8.04 (dd, J = 2.0, 8.4 Hz, 1H), 7.96 - 7.82 (m, 2H), 7.51 (d, J = 11.6 Hz, 1H), 2.59 (d, J = 3.8 Hz, 3H).

[0185]

[0178] Step 5, 4-chloro-3-(5,7-difluoro-4-oxo-6-(1H-pyrazole-4-yl)-1,4-dihydroquinoline-2-yl)benzamide: To a solution of N-(2-acetyl-3,5-difluoro-4-(1H-pyrazole-4-yl)phenyl)-2-chloro-5-cyanobenzamide (100 mg, 250 μmol, 1.0 equivalent) in dioxane (5 mL), NaOH (49.9 mg, 1.3 mmol, 5.0 equivalent) at 20 °C was added. The mixture was stirred under N2 at 110 °C for 16 hours. The pH of the mixture was adjusted to 6 with aqueous HCl (1 M). Next, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Next, the crude product was ground in 2 mL of water at 20°C for 20 minutes and filtered. The filtered cake was washed with water (3 × 1 mL). The filtered cake was then concentrated to obtain the title compound as a yellow solid (80 mg, crude).

[0186]

[0179] Step 6, 4-chloro-3-(5,7-difluoro-4-oxo-6-(1H-pyrazole-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:DCM (3 mL) was used to prepare a solution of 4-chloro-3-(5,7-difluoro-4-oxo-6-(1H-pyrazole-4-yl)-1,4-dihydroquinoline-2-yl)benzamide (80 mg, 200 μmol, 1.0 equivalent), to which triethylamine (139 μL, 998 μmol, 5 equivalents) and anhydrous trifluoroacetic acid (69 μL, 499 μmol, 2.5 equivalents) at 20°C were added. The mixture was stirred under N2 at 20°C for 1 hour. The pH of the mixture was adjusted to 6 with aqueous HCl (1 M). The reaction mixture was then diluted with water (15 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: 10-50% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a white solid (13.1 mg, yield 17%). LCMS: [M+1]=383.0. 1H NMR (400 MHz, DMSO-d6) δ 13.27 (br s, 1H), 12.09 (br s, 1H), 8.22 (br d, J = 19.8 Hz, 2H), 8.08 (br d, J = 8.4 Hz, 1H), 7.93 (br d, J = 8.4 Hz, 2H), 7.23 (br d, J = 11.6 Hz, 1H), 6.07 (br s, 1H).

[0187]

[0180] Example 63

[0188] [ka]

[0189]

[0181] 4-Chloro-3-(5,7-difluoro-6-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0182] Step 1, 5-(3-acetyl-4-amino-2,6-difluorophenyl)-2-methylpyridazine-3(2H)-one:

[0183] Dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (304 mg, 466 μmol, 0.1 equivalent) was added under N2 conditions at 20°C to a solution of 5-iodo-2-methylpyridazine-3(2H)-one (2.1 g, 7.0 mmol, 1.5 equivalents), 1-(6-amino-2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-one (1.1 g, 4.7 mmol, 1.0 equivalent), and K3PO4 (2.2 g, 10.3 mmol, 2.2 equivalents) in water (25 mL) and THF (99 mL). The mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (10% MeOH in DCM) to obtain the title compound as a brown solid (850 mg, 65% yield). LCMS[M+1] = 280.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 2.0 Hz, 1H), 7.83 (br s, 2H), 7.00 (s, 1H), 6.57 (dd, J = 1.2, 12.8 Hz, 1H), 3.68 (s, 3H), 2.55 - 2.52 (m, 3H).

[0190]

[0184] Step 2, 5-(3-acetyl-2,6-difluoro-4-iodophenyl)-2-methylpyridazine-3(2H)-one:

[0185] A mixture of 5-(3-acetyl-4-amino-2,6-difluorophenyl)-2-methylpyridazine-3(2H)-one (734 mg, 2.6 mmol, 1.0 equivalent) and CuI (1 g, 5.3 mmol, 2.0 equivalents) in acetonitrile (8 mL) was mixed with t-BuONO (949 mg, 9.2 mmol, 1.1 mL, 3.5 equivalents) at 20 °C under N2 conditions. The mixture was stirred at 70 °C for 1 hour. The reaction mixture was diluted with acetonitrile (15 mL). The mixture was concentrated to obtain the crude product. The crude product was pulverized at 25 °C with DCM and MeOH for 30 minutes. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to obtain the title compound as a white solid (565 mg, yield 55%). 1 H NMR (400 MHz, chloroform-d) δ 7.80 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 1.6, 8.6 Hz, 1H), 7.06 (d, J = 1.0 Hz, 1H), 3.85 (s, 3H), 2.60 (d, J = 1.6 Hz, 3H).

[0191]

[0186] Step 3, N-(2-acetyl-3,5-difluoro-4-(1-methyl-6-oxo-1,6-dihydropyridazine-4-yl)phenyl)-2-chloro-5-cyanobenzamide:

[0187] A mixture of 5-(3-acetyl-2,6-difluoro-4-iodophenyl)-2-methylpyridazine-3(2H)-one (200 mg, 513 μmol, 1.0 equivalent), 2-chloro-5-cyanobenzamide (139 mg, 769 μmol, 1.5 equivalent), Cs2CO3 (251 mg, 769 μmol, 1.5 equivalent), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (44.5 mg, 76.9 μmol, 0.15 equivalent) in dioxane (6 mL) was to be mixed with Pd(OAc)2 (11.5 mg, 51.2 μmol, 0.1 equivalent) at 20 °C under N2 conditions. The mixture was stirred at 45 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The precipitated solid from the mixture was filtered off to obtain the title compound as a white solid (102 mg, 45% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.11 (dd, J = 1.6, 9.0 Hz, 2H), 8.05 (dd, J = 2.0, 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 11.2 Hz, 1H), 7.22 (s, 1H), 3.71 (s, 3H), 2.58 (d, J = 3.8 Hz, 3H).

[0192]

[0188] Step 4, 4-Chloro-3-(5,7-difluoro-6-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0189] LiOH (5.4 mg, 226 μmol, 1.0 equivalent) was added under N2 conditions to a solution of N-(2-acetyl-3,5-difluoro-4-(1-methyl-6-oxo-1,6-dihydropyridazine-4-yl)phenyl)-2-chloro-5-cyanobenzamide (100 mg, 226 μmol, 1.0 equivalent) in dioxane (5 mL) at 20°C. The mixture was stirred at 110°C for 30 hours. The pH was adjusted to 5 by adding aqueous HCl (1 M). The solid was precipitated from the solution. The crude product was washed with water at 20°C for 0.5 hours to obtain the title compound as a white solid (34.2 mg, yield 36%). LCMS[M+1] = 425.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 - 12.17 (s, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.14 - 8.01 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.29 (br d, J = 9.2 Hz, 1H), 7.17 (s, 1H), 6.15 (br s, 1H), 3.72 (s, 3H).

[0193]

[0190] Example 64

[0194] [ka]

[0195]

[0191] 4-Chloro-3-(5,7-difluoro-6-(6-(hydroxymethyl)pyridine-3-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0192] 1-(6-amino-2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-one:

[0193] To a mixture of 1-(6-amino-3-bromo-2,4-difluorophenyl)ethanone (10 g, 40.0 mmol, 1.0 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (30.5 g, 120 mmol, 3.0 equivalents) in toluene (200 mL), KOAc (7.85 g, 80.0 mmol, 2.0 equivalents) and [2-(2-aminophenyl)phenyl]-chloropalladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (944.01 mg, 1.20 mmol, 0.03 equivalents) at 20°C were added under N2 conditions. The mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (2%-6% ethyl acetate in petroleum ether) to obtain the title compound as a white solid (5.5 g, 46% yield). LCMS[M+1] = 298.1. 1 H NMR (400 MHz, methanol-d4) δ 6.21 (dd, J = 1.2, 11.6 Hz, 1H), 2.53 (d, J = 8.8 Hz, 3H), 1.33 (s, 12H).

[0196]

[0194] Scheme 5, Step 1. 1-(6-amino-3-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-2,4-difluorophenyl)ethane-1-one:

[0195] To a solution of 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (508.0 mg, 1.7 mmol, 1.0 equivalent) and 1-(6-amino-2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-one (500 mg, 1.7 mmol, 1.0 equivalent) in dioxane (7.5 mL) and water (2.5 mL), K2CO3 (697 mg, 5.1 mmol, 3.0 equivalent) was added, and the mixture was degassed with N2. Pd(dppf)Cl2·CH2Cl2 (137 mg, 168 μmol, 0.1 equivalent) was added, and the mixture was stirred under N2 at 80°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15-20% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (350 mg, 53% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H), 7.80 (br d, J = 7.4 Hz, 1H), 7.68 - 7.61 (m, 1H), 6.60 (br s, 2H), 6.28 (dd, J = 1.4, 11.4 Hz, 1H), 4.93 (s, 2H), 2.61 (d, J = 9.0 Hz, 3H), 1.00 - 0.98 (m, 11H), 0.17 - 0.15 (m, 6H).

[0197]

[0196] Scheme 5, Step 2. N-(2-acetyl-4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-3,5-difluorophenyl)-2-chloro-N-(2-chloro-5-cyanobenzoyl)-5-cyanobenzamide:

[0197] A solution of 1-(6-amino-3-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-2,4-difluorophenyl)ethane-1-one (250 mg, 637 μmol, 1.0 equivalent) in THF (4.0 mL) was mixed with NaH (127 mg, 3.2 mmol, 5.0 equivalents; 60% dispersion in oil) at 0°C. Next, 2-chloro-5-cyanobenzoyl chloride (637 mg, 3.2 mmol, 5.0 equivalents) was added, the solution was degassed with N2, and stirred under N2 at 15°C for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12%-18% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (310 mg, crude). 1 H NMR (400 MHz, chloroform-d) δ 8.64 (s, 1H), 7.98 (d, J = 1.7 Hz, 2H), 7.75 - 7.71 (m, 2H), 7.65 - 7.63 (m, 1H), 7.62 - 7.60 (m, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.16 (dd, J = 1.4, 8.9 Hz, 1H), 4.95 (s, 2H), 2.71 (d, J = 4.2 Hz, 3H), 0.99 (br s, 9H), 0.17 (s, 6H).

[0198]

[0198] N-(2-acetyl-4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide:

[0199] As explained above, in certain cases, it is necessary to remove one acyl group before cyclization to a quinolone when obtaining a dibenzoylation intermediate. Dibenzoylation does not always occur, and in such cases, the steps described herein are not necessary.

[0199]

[0200] To a solution of N-(2-acetyl-4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-3,5-difluorophenyl)-2-chloro-N-(2-chloro-5-cyanobenzoyl)-5-cyanobenzamide (301 mg, 418 μmol, 1.0 equivalent) in isopropanol (5.0 mL), K2CO3 (116 mg, 836 μmol, 2.0 equivalents) was added. The reaction mixture was stirred at 50 °C under N2 for 1 hour. The reaction product was diluted with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (10 mL) and concentrated under reduced pressure. The residue was purified by preparative TLC (25% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (125 mg, yield 54%). 1 H NMR (400 MHz, chloroform-d) δ 12.22 (s, 1H), 8.68 - 8.60 (m, 2H), 7.95 (d, J = 1.8 Hz, 1H), 7.85 (br d, J = 7.4 Hz, 1H), 7.76 - 7.72 (m, 1H), 7.70 (br d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 4.94 (br s, 2H), 2.71 (d, J = 8.8 Hz, 3H), 1.00 (s, 9H), 0.17 (s, 6H).

[0200]

[0201] Scheme 5, Step 3. 3-(6-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-chlorobenzonitrile:

[0202] To a solution of N-(2-acetyl-4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide (150 mg, 270 μmol, 1.0 equivalent) in dioxane (2.0 mL), NaOH (11.0 mg, 270 μmol, 1.0 equivalent) was added. The mixture was stirred for 1.5 hours. The reaction mixture was quenched with 1M aqueous HCl at 15°C, then diluted with water (20 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (25% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (65.0 mg, yield 45%).

[0201]

[0203] 4-Chloro-3-(5,7-difluoro-6-(6-(hydroxymethyl)pyridine-3-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0204] A mixture of 3-(6-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-chlorobenzonitrile (65.0 mg, 121 μmol, 1.0 equivalent) in HCl / dioxane (2.0 mL) was degassed with N2, and the mixture was stirred under N2 at 15°C for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase: 10-40% acetonitrile in water (+0.04% HCl)) to obtain the title compound as a white solid (14.2 mg, yield 28%). LCMS: [M+1] = 424.0. 1H NMR (400 MHz, DMSO-d6) δ 12.74 - 11.84 (m, 1H), 8.77 (s, 1H), 8.31 - 8.19 (m, 2H), 8.10 (dd, J = 2.0, 8.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.36 (br d, J = 10.4 Hz, 1H), 6.19 (br s, 1H), 4.76 (s, 2H).

[0202]

[0205] Example 65

[0203] [ka]

[0204]

[0206] 4-Chloro-3-(5,7-difluoro-6-(2-methyl-1H-imidazole-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0207] The precursor of the title compound, 4-chloro-3-(5,7-difluoro-6-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile, was prepared using 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a starting material, in the same manner as described in Example 64, according to Scheme 5.

[0205]

[0208] 4-Chloro-3-(5,7-difluoro-6-(2-methyl-1H-imidazole-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0209] A solution of 4-chloro-3-(5,7-difluoro-6-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile (60 mg, 114 μmol, 1.0 equivalent) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: 5-35% acetonitrile in water (+NH4HCO3)) to obtain the title compound as a yellow solid (10.3 mg, yield 22%). LCMS[M+1] = 397.0. 1 ¹H NMR (400 MHz, methanol-d4): δ 8.07 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 2.0, 8.3 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.35 (s, 1H), 7.26 - 7.17 (m, 1H), 6.29 (s, 1H), 2.47 (s, 3H).

[0206]

[0210] Example 66

[0207] [ka]

[0208]

[0211] 4-Chloro-3-(5,7-difluoro-6-(2-methyl-1H-imidazole-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0212] The precursor of the title compound, 4-chloro-3-(5,7-difluoro-6-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile, was prepared using 2-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a starting material, in the same manner as described in Example 64, according to Scheme 5.

[0209]

[0213] 4-Chloro-3-(5,7-difluoro-6-(2-methyl-1H-imidazole-4-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile: This compound was prepared in the same manner as described in Example 65. LCMS[M+1] = 397.0. 1 H NMR (400 MHz, methanol-d4) δ 8.09 (d, J = 1.8 Hz, 1H), 7.97 (dd, J = 2.0, 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 0.9 Hz, 1H), 7.41 (dd, J = 1.6, 11.2 Hz, 1H), 6.41 (s, 1H), 2.48 (d, J = 0.6 Hz, 3H).

[0210]

[0214] Example 67

[0211] [ka]

[0212]

[0215] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(2-(trifluoromethyl)-1H-imidazole-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile

[0216] The precursor of the title compound, 4-chloro-3-(5,7-difluoro-4-oxo-6-(2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile was prepared using 4-bromo-2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a starting material, in the same manner as described in Example 64, according to Scheme 5.

[0213]

[0217] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(2-(trifluoromethyl)-1H-imidazole-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0218] This compound was prepared in the same manner as described in Example 65. LCMS[M+1] = 450.9. 1 H NMR (400 MHz, DMSO-d6) δ 13.97-13.77 (m, 1H), 12.24-12.10 (m, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.08 (dd, J = 2.0, 8.4 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.86 - 7.63 (m, 1H), 7.24 (br d, J = 9.0 Hz, 1H), 6.26 - 6.01 (m, 1H).

[0214]

[0219] Example 68

[0215] [ka]

[0216]

[0220] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(6-oxo-1,6-dihydropyrimidine-2-yl)-1,4-dihydroquinoline-2-yl)benzonitrile

[0221] The precursor of the title compound, 4-chloro-3-(5,7-difluoro-6-(4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile, was prepared using 2-chloro-4-((4-methoxybenzyl)oxy)pyrimidine as a starting material, in the same manner as described in Example 64, according to Scheme 5.

[0217]

[0222] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(6-oxo-1,6-dihydropyrimidine-2-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0223] This compound was prepared in the same manner as described in Example 65. LCMS[M+1] = 411.0. 1 H NMR (400 MHz, DMSO-d6) δ 13.46 - 12.96 (m, 1H), 12.33 (br s, 1H), 8.29 (s, 1H), 8.16 - 8.04 (m, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.26 (br d, J = 10.2 Hz, 1H), 6.46 (br s, 1H), 6.16 (s, 1H).

[0224] The compounds in Table 5 were prepared according to Scheme 5, using the same procedure as described in Example 64. Protection of the aryl halides is not always necessary; in these cases, the final step can be omitted.

[0218] [Table 5-1]

[0219] [Table 5-2]

[0220]

[0225] Example 74

[0221] [ka]

[0222]

[0226] 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)benzoic acid

[0227] The precursor of the title compound, tert-butyl3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)benzoate, was prepared according to Scheme 4.

[0223]

[0228] A mixture of tert-butyl 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)benzoate (70 mg, 142 μmol, 1.0 equivalent) in 3 mL of 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)benzoate:HCl / dioxane (3 mL) was stirred at 20 °C for 2 hours. The reaction product was concentrated, and the resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: 40-70% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a white solid (19.6 mg, yield 30%). LCMS[M+1] = 437.0. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 - 13.28 (br s, 1H), 12.14 - 12.27 (br s, 1H), 8.23 ​​- 8.32 (s, 1H), 8.01 - 8.14 (m, 3H), 7.91 - 7.98 (m, 1H), 7.72 - 7.80 (m, 1H), 7.64 - 7.70 (m, 1H), 7.22 - 7.32 (d, J = 10.4, 1H), 6.11 (br s, 1H).

[0224]

[0229] The compounds in Table 6 were prepared according to Scheme 4, using the same procedure as described in Example 74.

[0225] [Table 6]

[0226]

[0230] Example 76

[0227] [ka]

[0228]

[0231] 2-(4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)phenyl)acetic acid

[0232] The precursor of the title compound, methyl 2-(4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)phenyl) acetate, was prepared according to Scheme 4.

[0229]

[0233] 2-(4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)phenyl)acetic acid: To a solution of methyl 2-(4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)phenyl) acetate (30 mg, 64.5 μmol, 1.0 equivalent) in DCE (0.5 mL), Me3SnOH (117 mg, 645 μmol, 10 equivalents) was added. The mixture was stirred at 50°C for 12 hours. The reaction mixture was quenched with HCl (1 M, 2 mL), and the mixture was extracted with DCM (2 × 3 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 80×40mm×3um; mobile phase: 26-54% acetonitrile in water (+0.04% HCl)) to obtain the title compound as a yellow solid (10 mg, yield 34%). LCMS[M+1] = 450.9. 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 2.0, 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.46 - 7.37 (m, 4H), 7.29 (br d, J = 10.4 Hz, 1H), 6.16 (s, 1H), 3.66 (s, 2H).

[0234] Example 77

[0230] [ka]

[0231]

[0235] 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)propanoic acid

[0236] The precursor of the title compound, ethyl 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)propanoate, was prepared according to Scheme 4.

[0232]

[0237] 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)propanoic acid:

[0238] To a solution of ethyl 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)propanoate (55 mg, 132 μmol, 1.0 equivalent) in THF (4 mL) and water (2 mL), LiOH·H2O (27.6 mg, 660 μmol, 5.0 equivalent) was added. The mixture was stirred at 20 °C for 16 hours. The pH of the reaction mixture was adjusted to 3 with HCl aqueous solution (1 M). Next, water (30 mL) was added to the mixture, and a yellow solid was formed, which was filtered off. The solid was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: 20-55% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a white solid (15.8 mg, yield 30%). LCMS[M+1] = 389.0. 1 H NMR (400 MHz, methanol-d4) δ = 8.05 (d, J = 1.8 Hz, 1H), 7.97 - 7.89 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.11 (br d, J = 9.8 Hz, 1H), 6.24 (s, 1H), 3.08 (br t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.8 Hz, 2H).

[0233]

[0239] Example 78

[0234] [ka]

[0235]

[0240] To a solution of 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-N-methylbenzamide:DMF (1 mL) containing 3-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)benzoic acid (60 mg, 137 μmol, 1.0 equivalent), HATU (57.4 mg, 151 μmol, 1.1 equivalent) and DIPEA (119.6 μL, 687 μmol, 5.0 equivalent) were added. Next, methylamine hydrochloride was added (12 mg, 178 μmol, 1.3 equivalent). The mixture was stirred at 20°C for 16 hours. The reaction product was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (15 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 μm; mobile phase: 20-50% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a white solid (11.5 mg, yield 18%). LCMS[M+1] = 450.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (br s, 1H), 8.55 (q, J = 4.1 Hz, 1H), 8.26 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 8.4, 2.0 Hz, 1H), 7.85 - 7.99 (m, 3H), 7.54 - 7.69 (m, 2H), 7.28 (br d, J = 10.2 Hz, 1H), 6.15 (br s, 1H), 2.80 (d, J = 4.6 Hz, 3H).

[0236]

[0241] The compounds in Table 7 were prepared using the same procedure described in Example 78. Acid precursors were prepared according to Scheme 4 using the procedure described in Example 74. Further information on the synthesis of the acid precursors can be found in the section on starting materials.

[0237] [Table 7-1]

[0238] [Table 7-2]

[0239] [Table 7-3]

[0240]

[0242] Example 90

[0241] [ka]

[0242]

[0243] 4-Chloro-3-(6-(1,2-dihydroxyethyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0244] Step 1: A mixture of 1-(6-amino-2,4-difluoro-3-vinylphenyl)ethane-1-one (500 mg, 2.0 mmol, 1.0 equivalent) and potassium trifluoro(vinyl)borate (804 mg, 6.0 mmol, 3.0 equivalents) in 8 mL of dioxane and 2 mL of water was prepared. K3PO4 (849 mg, 4.0 mmol, 2.0 equivalents) and Pd(dppf)Cl2·CH2Cl2 (163 mg, 200 μmol, 0.1 equivalent) were added to this mixture. The mixture was degassed with N2, and then stirred under N2 at 100°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate in petroleum ether) to obtain the title compound as a white solid (380 mg, 96% yield). LCMS[M+1] = 198.1. 1 H NMR (400 MHz, CDCl3) δ 6.6 (dd, J = 18.0, 12.0 Hz, 1H), 6.5 (br s, 2H), 6.2 (dd, J = 12.6, 1.6 Hz, 1H), 5.8 (d, J = 18.0 Hz, 1H), 5.4 (d, J = 12.0 Hz, 1H), 2.6 (d, J = 9.0 Hz, 3H).

[0243]

[0245] Step 2: To a solution of 1-(6-amino-2,4-difluoro-3-vinylphenyl)ethane-1-one (380 mg, 1.9 mmol, 1.0 equivalent) in THF (4 mL), NaH (77.0 mg, 1.9 mmol, 60% purity, 1.0 equivalent) at 0°C was added. Next, a solution of 2-chloro-5-cyanobenzoyl chloride (424 mg, 2.1 mmol, 1.1 equivalent) in THF (3 mL) was added to the mixture. The mixture was degassed with N2 and then stirred under N2 at 20°C for 16 hours. The reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl (10 mL) at 20°C. The mixture was then diluted with water (5 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was pulverized with acetonitrile (5 mL) at 20°C to obtain the title compound as a white solid (535 mg, 77% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.1 (s, 1H), 8.1 (d, J=1.8 Hz, 1H), 8.0 (dd, J=8.4, 2.0 Hz, 1H), 7.8 (d, J=8.4 Hz, 1H), 7.5 (d, J=11.2 Hz, 1H), 6.7 (dd, J=18.0, 11.8 Hz, 1H), 6.0 (d, J=18.2 Hz, 1H), 5.7 (d, J=11.8 Hz, 1H), 2.6 (d, J=4.0 Hz, 3H).

[0244]

[0246] Step 3, 4-chloro-3-(5,7-difluoro-4-oxo-6-vinyl-1,4-dihydroquinoline-2-yl)benzonitrile:NaOH (11.1 mg, 277 μmol, 1.0 equivalent) was added to a solution of N-(2-acetyl-3,5-difluoro-4-vinylphenyl)-2-chloro-5-cyanobenzamide (100 mg, 277 μmol, 1.0 equivalent) in 4-chloro-3-(5,7-difluoro-4-oxo-6-vinyl-1,4-dihydroquinoline-2-yl)benzonitrile:dioxane (2 mL). The mixture was stirred at 110 °C for 2 hours. The pH of the reaction mixture was adjusted to 3 with 1 M HCl (1 M). When the mixture was diluted with water (10 mL), a yellow solid precipitated, which was isolated by filtration. The filtration cake was pulverized with water (10 mL). The resulting solid was pulverized with acetonitrile (20 mL) at 50 °C for 1 hour to obtain the title compound as an off-white solid (50 mg, yield 53%). LCMS[M+1] = 343.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.0 - 12.3 (m, 1H), 8.2 (s, 1H), 8.1 (dd, J = 8.4, 1.8 Hz, 1H), 7.9 (d, J = 8.4 Hz, 1H), 7.1 - 7.2 (m, 1H), 6.7 (dd, J = 17.8, 12.0 Hz, 1H), 6.0 (br d, J = 17.8 Hz, 2H), 5.7 (br d, J = 12.0 Hz, 1H).

[0245]

[0247] Step 4, 4-chloro-3-(6-(1,2-dihydroxyethyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile: To a mixture of K3[Fe(CN)6] (86 mg, 263 μmol, 72 μL, 3.0 equivalents), K2CO3 (36.3 mg, 262.6 μmol, 3.0 equivalents), DABCO (19.3 μL, 175 μmol, 2.0 equivalents), and K2OsO4·2H2O (32.3 mg, 87.5 μmol, 1.0 equivalent) in t-BuOH (2 mL) and water (2 mL), 4-chloro-3-(5,7-difluoro-4-oxo-6-vinyl-1,4-dihydroquinoline-2-yl)benzonitrile (30 mg, 88 μmol, 1.0 equivalent) at 0°C was added. The mixture was stirred under N2 at 20°C for 3 hours. The solution was diluted with ethyl acetate (25 mL), quenched with Na2SO3 (1 g), and stirred for 10 minutes. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with aqueous solutions of 10% HCl (40 mL) and saturated NaHCO3 (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: 1-30% acetonitrile in water (+ 10 mM NH4HCO3)) to obtain the title compound as a white solid (21.0 mg, yield 63%). LCMS[M+1] = 377.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.2 (d, J = 2.0 Hz, 1H), 8.1 (dd, J = 8.4, 2.0 Hz, 1H), 7.9 (d, J = 8.6 Hz, 1H), 7.0 - 7.1 (m, 1H), 6.0 - 6.1 (m, 1H), 5.5 (d, J = 4.8 Hz, 1H), 4.9 - 5.0 (m, 1H), 4.9 (t, J = 5.8 Hz, 1H), 3.7 - 3.8 (m, 1H), 3.6 (dt, J = 10.8, 6.6 Hz, 1H), 3.3 (s, 1H).

[0246]

[0248] Example 91

[0247] [ka]

[0248]

[0249] 4-Chloro-3-(5-fluoro-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-2-yl)benzonitrile

[0250] Step 1: 4-bromo-3-fluoro-2-iodo-5-(trifluoromethyl)aniline:N-iodosuccinimide (1.1 g, 4.9 mmol, 1.1 equivalent) was added to a solution of 4-bromo-3-fluoro-5-(trifluoromethyl)aniline (1.1 g, 4.4 mmol, 1 equivalent) in acetic acid (10 mL) at 20°C. The solution was then stirred at 60°C for 16 hours. The mixture was quenched with a saturated aqueous solution of Na2SO3 (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (80:1~20:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (1.06 g, yield 62%). 1 ¹H NMR (400 MHz, chloroform-d): δ 6.89 (s, 1H), 4.66 - 4.40 (m, 2H).

[0251] Step 2: 1-(6-amino-3-bromo-2-fluoro-4-(trifluoromethyl)phenyl)ethane-1-one:Pd(PPh3)4 (301 mg, 260 μmol, 0.1 equivalent) was added to a solution of 4-bromo-3-fluoro-2-iodo-5-(trifluoromethyl)aniline (1 g, 2.6 mmol, 1.0 equivalent) and tributyl(1-ethoxyvinyl) stannan (1.1 g, 3.1 mmol, 1.0 mL, 1.2 equivalents) in toluene (12 mL) at 20°C. The solution was stirred at 120°C for 16 hours. The solution was quenched with aqueous KF. The mixture was stirred at 20°C for 1 hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (2 × 25 mL) and brine (15 mL), dried over Na₂SO₄, filtered, and concentrated to obtain 4-bromo-2-(1-ethoxyvinyl)-3-fluoro-5-(trifluoromethyl)-aniline as a brown oily substance (900 mg, crude). The crude 4-bromo-2-(1-ethoxyvinyl)-3-fluoro-5-(trifluoromethyl)aniline (900 mg, 2.1 mmol, purity 80%, 1.0 equivalent) was then treated with HCl (10 mL; 4 M in dioxane), and the mixture was stirred at 20°C for 1 hour. The mixture was concentrated to remove the solvent, and the residue was purified by preparative TLC (5:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (395 mg, yield 52%).

[0249]

[0252] Step 3, 1-(2-amino-6-fluoro-4-(trifluoromethyl)phenyl)ethane-1-one (200 mg, 667 μmol, 1 equivalent) was added to a suspension of 10% Pd / C (10 mg, 67 μmol, 0.1 equivalent) in i-PrOH (15 mL) at 20°C. The solution was stirred at 65°C for 24 hours under an H2 (50 psi) atmosphere. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (5:1 petroleum ether:ethyl acetate) to obtain the title compound as a yellow solid (120 mg, yield 81%). 1¹H NMR (400 MHz, chloroform-d): δ 6.69 (s, 1H), 6.57 (dd, J = 1.2, 11.8 Hz, 1H), 6.52 - 6.24 (m, 2H), 2.64 (d, J = 8.2 Hz, 3H).

[0250]

[0253] Steps 4 and 5, 4-chloro-3-(5-fluoro-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0254] Steps 4 and 5 were carried out using 1-(2-amino-6-fluoro-4-(trifluoromethyl)phenyl)ethane-1-one as the starting material, in the same manner as described for steps 2 and 3 and in the preparation of Example 1. The title compound was obtained as a white solid. LCMS[M+1] = 366.9. 1 ¹H NMR (400 MHz, methanol-d4): δ 8.09 (d, J = 1.8 Hz, 1H), 7.94 (br d, J = 2.0 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.71 (br s, 1H), 7.40 - 7.33 (m, 1H), 6.36 (br s, 1H).

[0251]

[0255] Example 92

[0252] [ka]

[0253]

[0256] 4-Chloro-3-(6-(1-(2,3-dihydroxypropyl)-1H-pyrazole-3-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0257] The precursor of the title compound, 3-(6-(1-allyl-1H-pyrazole-3-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-chlorobenzonitrile, was prepared according to Scheme 4.

[0254]

[0258] 4-Chloro-3-(6-(1-(2,3-dihydroxypropyl)-1H-pyrazole-3-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile: 3-(6-(1-allyl-1H-pyrazole-3-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-chlorobenzonitrile (52.2 mg, 142 μmol, 1.0 equivalent) in t-BuOH (1.0 mL) and water (1.0 mL), 1,4-diazabicyclo[2.2.2] To a solution of octane (31.8 mg, 284 μmol, 31 μL, 2.0 equivalents), K2CO3 (59 mg, 426 μmol, 3.0 equivalents), K3[Fe(CN)6] (140 mg, 426 μmol, 117 μL, 3.0 equivalents), and K2OsO4·2H2O (51.6 mg, 140 μmol, 1.0 equivalent), 3-[6-(1-allylpyrazole-3-yl)-5,7-difluoro-4-oxo-1H-quinoline-2-yl]-4-chlorobenzonitrile (60 mg, 142 μmol, 1.0 equivalent) was added. The mixed solution was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna 80×30mm×3um; mobile phase: 20%~50% acetonitrile in water (+0.04% HCl)) to obtain the title compound as a yellow solid (11.1 mg, yield 17%). LCMS[M+1] = 457.0. 1 H NMR (400 MHz, methanol-d4) δ 7.32 (d, J = 1.8 Hz, 1H), 7.18 (dd, J = 2.0, 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.57 (dd, J = 1.4, 10.2 Hz, 1H), 5.90 - 5.81 (m, 2H), 3.62 (dd, J = 4.0, 14.0 Hz, 1H), 3.49 - 3.39 (m, 1H), 3.29 - 3.19 (m, 1H), 2.80 - 2.68 (m, 2H).

[0255]

[0259] Example 93

[0256] [ka]

[0257]

[0260] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(1,2,3,6-tetrahydropyridine-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile

[0261] The precursor of the title compound, tert-butyl 4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate, was prepared according to Scheme 4, using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate as the starting material.

[0258]

[0262] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(1,2,3,6-tetrahydropyridine-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0263] A mixture of tert-butyl 4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (140 mg, 281 μmol, 1.0 equivalent) in DCM (4 mL) was mixed with TFA (0.4 mL) at 20°C under N2 conditions. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under vacuum to obtain a residue. The pH of the residue was adjusted to 7-8 with saturated NaHCO3 solution and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: 5-45% acetonitrile in water (0.2% formic acid)) to obtain the title compound as a white solid (22.3 mg, yield 19%). LCMS[M+2] = 399.0. 1H NMR (400 MHz, methanol-d4) δ = 8.48 (d, J = 2.6 Hz, 1H), 8.05 (s, 1H), 7.98 - 7.90 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 10.4 Hz, 1H), 6.29 (s, 1H), 6.02 (br s, 1H), 3.90 (br d, J = 1.0 Hz, 2H), 3.49 (t, J = 5.8 Hz, 2H), 2.78 - 2.68 (m, 2H).

[0259]

[0264] Example 94

[0260] [ka]

[0261]

[0265] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(piperidine-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0266] The precursor of the title compound, tert-butyl 4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)piperidine-1-carboxylate, was prepared according to Scheme 4, using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate as the starting material.

[0262]

[0267] To a solution of tert-butyl 4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)piperidine-1-carboxylate (170 mg, 340 μmol, 1 equivalent) in DCM (3 mL), TFA (0.3 mL, 4.1 mmol, 11.9 equivalents) at 20°C was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under vacuum to obtain a residue. The pH of the residue was adjusted to 7-8 with NaHCO3 (aq.), and the mixture was then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: 5-40% acetonitrile in water (0.2% formic acid)) to obtain the title compound as a white solid (63 mg, yield 45%). LCMS[M+1] = 400.0. 1 H NMR (400 MHz, methanol-d4) δ 8.04 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 2.1, 8.4 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.15 (dd, J = 1.5, 11.4 Hz, 1H), 6.28 (s, 1H), 3.57 - 3.45 (m, 3H), 3.24 - 3.12 (m, 2H), 2.45 - 2.30 (m, 2H), 2.05 (br d, J = 14.3 Hz, 2H).

[0263]

[0268] Example 95

[0264] [ka]

[0265]

[0269] 3-(6-(1-acetylpiperidine-4-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-chlorobenzonitrile:

[0270] To a solution of 4-chloro-3-(5,7-difluoro-4-oxo-6-(piperidine-4-yl)-1,4-dihydroquinoline-2-yl)benzonitrile (40 mg, 100 μmol, 1 equivalent) in DCM (2 mL), triethylamine (42 μL, 300 μmol, 3 equivalents) and acetic anhydride (8.4 μL, 90.0 μmol, 0.9 equivalents) at 20°C were added. The mixture was stirred under N2 at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: 10-50% acetonitrile in water (0.2% formic acid)) to obtain the title compound as a white solid (17.8 mg, yield 39%). LCMS[M+1] = 442.1. 1 H NMR (400 MHz, methanol-d4) δ 8.05 (d, J = 1.7 Hz, 1H), 7.93 (dd, J = 1.7, 8.4 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.11 (br d, J = 11.4 Hz, 1H), 6.25 (s, 1H), 4.71 (br d, J = 13.1 Hz, 1H), 4.08 (br d, J = 13.6 Hz, 1H), 3.52 - 3.38 (m, 1H), 3.29 - 3.21 (m, 1H), 2.74 (br t, J = 12.0 Hz, 1H), 2.16 (s, 3H), 2.14 - 1.95 (m, 2H), 1.92 - 1.77 (m, 2H).

[0266]

[0271] Example 96

[0267] [ka]

[0268]

[0272] 3-(6-(4-acetylpiperazine-1-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-chlorobenzonitrile

[0273] The precursor of the title compound, tert-butyl 4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)piperazine-1-carboxylate, was prepared according to Scheme 1, using tert-butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate as the starting material.

[0269]

[0274] Step 1, 4-chloro-3-(5,7-difluoro-4-oxo-6-(piperazine-1-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0275] To a solution of tert-butyl 4-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)piperazine-1-carboxylate (83 mg, 166 μmol, 1.0 equivalent) in HCl / dioxane (2.5 mL), the mixture was stirred at 20°C for 1 hour. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase: 5-40% acetonitrile in water (0.04% HCl)) to obtain the title compound as a yellow solid (46.6 mg, yield 66%). LCMS[M+1] = 401.1. 1 H NMR (400 MHz, methanol-d4) δ 8.12 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 2.0, 8.4 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 1.8, 11.2 Hz, 1H), 6.68 (s, 1H), 3.59 - 3.53 (m, 4H), 3.44 - 3.37 (m, 4H).

[0270]

[0276] Step 2, 3-(6-(4-acetylpiperazine-1-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-chlorobenzonitrile:

[0277] To a solution of 4-chloro-3-(5,7-difluoro-4-oxo-6-(piperazin-1-yl)-1,4-dihydroquinoline-2-yl)benzonitrile (30 mg, 74.8 μmol, 1.0 equivalent) in DCM (1.5 mL), triethylamine (31 μL, 225 μmol, 3.0 equivalents) and acetic anhydride (6.3 μL, 67 μmol, 0.9 equivalents) were added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: 10-50% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a yellow solid (17.2 mg, yield 50%). LCMS[M+1] = 443.1. 1 H NMR (400 MHz, methanol-d4) δ 8.05 (d, J = 2.0 Hz, 1H), 7.95 - 7.91 (m, 1H), 7.85 - 7.81 (m, 1H), 7.14 (dd, J = 1.8, 11.6 Hz, 1H), 6.27 (s, 1H), 3.72 (td, J = 5.2, 19.0 Hz, 4H), 3.29 - 3.18 (m, 4H), 2.16 (s, 3H).

[0271]

[0278] Example 97

[0272] [ka]

[0273]

[0279] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(1H-pyrazole-3-yl)-1,4-dihydroquinoline-2-yl)benzonitrile

[0280] Step 1, 1-(6-amino-2,4-difluoro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)phenyl)ethane-1-one:

[0281] To a solution of 1-(6-amino-2,4-difluoro-3-iodophenyl)ethane-1-one (350 mg, 1.2 mmol, 1 equivalent) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (492 mg, 1.8 mmol, 1.5 equivalents) in DME (7 mL) / EtOH (7 mL) / H2O (1.4 mL), Na2CO3 (375 mg, 3.5 mmol, 3 equivalents) and Pd(PPh3)2Cl2 (82.7 mg, 118 μmol, 0.1 equivalent) were added. The mixture was stirred under N2 conditions with microwave irradiation at 80°C for 1 hour. The reaction product was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 × 35 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: 20-50% acetonitrile in water (+ 10 mM NH₄HCO₃)) to obtain the title compound as a white solid (200 mg, yield 53%). 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (br s, 2H), 7.63 (d, J = 1.8 Hz, 1H), 6.62 - 6.48 (m, 1H), 6.39 (d, J = 1.8 Hz, 1H), 5.11 (br d, J = 8.8 Hz, 1H), 3.90 - 3.72 (m, 1H), 3.55 - 3.38 (m, 1H), 2.53 (br s, 3H), 2.30 - 2.19 (m, 1H), 2.01 - 1.90 (m, 1H), 1.84 - 1.73 (m, 1H), 1.70 - 1.55 (m, 1H), 1.54 - 1.41 (m, 2H).

[0274]

[0282] Step 2, N-(2-acetyl-4-(1-(2-chloro-5-cyanobenzoyl)-1H-pyrazole-3-yl)-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide:

[0283] To a solution of 1-(6-amino-2,4-difluoro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)phenyl)ethane-1-one (180 mg, 560 μmol, 1.0 equivalent) in THF (5 mL), NaH (67.2 mg, 1.7 mmol, 3.0 equivalents; 60% dispersion in oil) at 0°C was added. Next, 2-chloro-5-cyanobenzoyl chloride (336 mg, 1.7 mmol, 3.0 equivalents) was added to the reaction mixture, and the mixture was stirred under N2 at 20°C for 16 hours. The residue was slowly poured into water (10 mL). The aqueous solution was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a white solid (160 mg, 51% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.80 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.13 - 8.08 (m, 1H), 8.04 (dd, J = 2.0, 8.4 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.54 (br d, J = 10.6 Hz, 1H), 7.08 (br s, 1H), 2.54 (d, J = 3.8 Hz, 3H).

[0275]

[0284] Step 3, N-(2-acetyl-3,5-difluoro-4-(1H-pyrazole-3-yl)phenyl)-2-chloro-5-cyanobenzamide:

[0285] To a solution of N-[2-acetyl-4-[1-(2-chloro-5-cyanobenzoyl)pyrazole-3-yl]-3,5-difluorophenyl]-2-chloro-5-cyano-benzamide (160 mg, 284 μmol, 1.0 equivalent) in MeOH (3 mL), K2CO3 (79 mg, 567 μmol, 2.0 equivalent) was added. The mixture was stirred at 20°C for 1 hour. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (33% to 100% ethyl acetate in petroleum ether) to obtain the title compound as a white solid (80 mg, yield 70%). 1 H NMR (400 MHz, DMSO-d6) δ 13.27 (br s, 1H), 11.21 - 11.04 (m, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.09 - 8.04 (m, 1H), 7.92 (s, 1H), 7.89 - 7.84 (m, 1H), 7.54 (br d, J = 11.4 Hz, 1H), 6.59 (br s, 1H), 2.59 (br d, J = 3.8 Hz, 3H).

[0276]

[0286] Step 4, 4-chloro-3-(5,7-difluoro-4-oxo-6-(1H-pyrazole-3-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0287] To a solution of N-(2-acetyl-3,5-difluoro-4-(1H-pyrazole-3-yl)phenyl)-2-chloro-5-cyanobenzamide (50 mg, 125 μmol, 1.0 equivalent) in dioxane (1.5 mL), NaOH (49.9 mg, 1.3 mmol, 10 equivalents) was added. The mixture was stirred at 110 °C for 1 hour. The pH of the reaction mixture was adjusted to 6-7 with 1 M aqueous HCl. The mixture was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (3 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: 10-40% acetonitrile in water (+10 mM NH4HCO3)). The product was then further purified by preparative TLC (10:1 dichloromethane:methanol). The isolated product was then pulverized with MTBE (3 mL) to obtain the title compound as an off-white solid (2.8 mg, yield 5.9%). LCMS[M+1] = 383.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.35 - 13.14 (m, 1H), 12.27 - 12.16 (m, 1H), 8.25 (br s, 1H), 8.08 (br dd, J = 1.6, 8.4 Hz, 1H), 7.93 (br d, J = 8.6 Hz, 1H), 7.89 - 7.77 (m, 1H), 7.24 (br d, J = 10.4 Hz, 1H), 6.58 (br s, 1H), 6.09 (br s, 1H).

[0277]

[0288] Example 98

[0278] [ka]

[0279]

[0289] 4-Chloro-3-(5,7-difluoro-4-oxo-6-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0290] To a solution of 4-chloro-3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile (200 mg, 452 μmol, 1.0 equivalent) and 2-oxa-6-azaspiro[3.3]heptane oxalate (86 mg, 452 μmol, 1.0 equivalent) in DMF (4 mL), Cs2CO3 (736 mg, 2.3 mmol, 5 equivalents), (5-diphenylphosphanyl-9,9-dimethyl-xanthene-4-yl)-diphenylphosphan (52 mg, 90 μmol, 0.2 equivalents) and Pd2dba3 (41.4 mg, 45 μmol, 0.1 equivalents) were added. The mixture was stirred under N2 at 120 °C for 1 hour. The residue was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5um; mobile phase: 10-50% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a yellow solid (31.2 mg, yield 16%). LCMS[M+1] = 414.0. 1 H NMR (400 MHz, DMSO-d6) δ = 12.00 - 11.75 (m, 1H), 8.21 (s, 1H), 8.07 (br d, J = 7.6 Hz, 1H), 7.91 (br d, J = 8.4 Hz, 1H), 7.06 (br d, J = 12.8 Hz, 1H), 5.93 (s, 1H), 4.73 (s, 4H), 4.33 (br s, 4H).

[0280]

[0291] Example 99

[0281] [ka]

[0282]

[0292] 4-Chloro-3-(5,7-difluoro-6-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile

[0293] Step 1, tert-butyl 6-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:

[0294] This compound was prepared using N,N-dimethylazetidine-3-amine-dihydrochloride as a starting material, in the same manner as in Example 98. 1 H NMR (400 MHz, methanol-d4) δ 8.01 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 1.8, 8.4 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.42 - 7.33 (m, 1H), 7.07 (br d, J = 13.0 Hz, 1H), 6.18 (br s, 1H), 4.37 (br s, 4H), 4.11 (s, 4H), 1.45 (s, 9H).

[0283]

[0295] Step 2, 4-chloro-3-(5,7-difluoro-4-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1,4-dihydroquinoline-2-yl)benzonitrile:

[0296] A solution of tert-butyl 6-(2-(2-chloro-5-cyanophenyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 195 μmol, 1.0 equivalent) in TFA (0.6 mL) and DCM (2 mL) was stirred under N2 at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: 1-40% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a yellow solid (27 mg, yield 34%). 1H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.84 - 7.77 (m, 1H), 7.10 (dd, J = 1.8, 13.2 Hz, 1H), 6.23 (s, 1H), 4.45 (t, J = 2.4 Hz, 4H), 4.27 (s, 4H).

[0284]

[0297] Step 3, 4-chloro-3-(5,7-difluoro-6-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0298] To a solution of 4-chloro-3-(5,7-difluoro-4-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1,4-dihydroquinoline-2-yl)benzonitrile (19 mg, 46 μmol, 1.0 equivalent) in MeOH (0.5 mL), NaBH(OAc)3 (29.2 mg, 138 μmol, 3.0 equivalents), acetic acid (7.9 μL, 138 μmol, 3 equivalents), and formaldehyde (10.3 μL, 138 μmol, 3.0 equivalents; 37% in water) at 20°C were added under N2 conditions. The mixture was stirred at 20°C for 4 hours. The solution was directly purified by preparative HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: 1-40% acetonitrile in water (+0.2% formic acid)) to obtain the title compound as a yellow solid (4.1 mg, yield 20%). LCMS[M+1] = 427.0. 1 H NMR (400 MHz, methanol-d4) δ 8.53 (br s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.90 (dd, J = 1.8, 8.4 Hz, 1H), 7.86 - 7.74 (m, 1H), 7.09 (br d, J = 12.8 Hz, 1H), 6.21 (s, 1H), 4.43 (br s, 4H), 4.19 (s, 4H), 2.80 (s, 3H).

[0299] The compounds in Table 8 were prepared using the same procedure as described in Example 98.

[0285] [Table 8]

[0286]

[0300] Example 104

[0287] [ka]

[0288]

[0301] (S)-4-chloro-3-(5,7-difluoro-6-(3-methoxypyrrolidine-1-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0302] Scheme 6, Step 1, (S)-1-(3-bromo-2,6-difluoro-4-nitrophenyl)-3-methoxypyrrolidine:

[0303] Diisopropylethylamine (5.44 mL, 31.3 mmol, 4 equivalents) was added to a solution of 2-bromo-3,4,5-trifluoro-1-nitrobenzene (2 g, 7.81 mmol, 1.0 equivalent) and (S)-3-methoxypyrrolidine hydrochloride (1.18 g, 8.59 mmol, 1.1 equivalent) in DMF (12 mL). The mixture was stirred at 55°C for 5 hours. The residue was poured into water (30 mL). The aqueous phase was extracted with MTBE (2 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow solid (2.6 g, 98% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.73 (dd, J = 1.8, 14.2 Hz, 1H), 4.04 (tt, J = 2.0, 4.2 Hz, 1H), 4.01 - 3.88 (m, 2H), 3.76 - 3.66 (m, 2H), 3.37 (s, 3H), 2.16 (ddt, J = 2.0, 4.4, 8.6 Hz, 1H), 2.00 - 1.89 (m, 1H).

[0289]

[0304] Scheme 6, Step 2, (S)-2-bromo-3,5-difluoro-4-(3-methoxypyrrolidine-1-yl)aniline:

[0305] To a solution of (S)-1-(3-bromo-2,6-difluoro-4-nitrophenyl)-3-methoxypyrrolidine (2.5 g, 7.42 mmol, 1 equivalent) in EtOH (16 mL) and water (4 mL), iron(0) (2.07 g, 37.1 mmol, 5.0 equivalents) and NH4Cl (1.98 g, 37.1 mmol, 5.0 equivalents) were added. The mixture was stirred at 80°C for 20 minutes. The suspension was filtered through a Celite pad, and the filter cake was washed with ethyl acetate (2 × 50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (15:1~5:1 petroleum ether:ethyl acetate) to obtain the title compound as a brown solid (1.8 g, yield 79%). 1 ¹H NMR (400 MHz, chloroform-d): δ 6.32 (dd, J = 2.0, 13.0 Hz, 1H), 4.17 - 3.89 (m, 3H), 3.53 - 3.41 (m, 2H), 3.35 (s, 3H), 3.31 - 3.20 (m, 2H), 2.18 - 2.05 (m, 1H), 1.99 (ddd, J = 3.8, 8.2, 12.4 Hz, 1H).

[0290]

[0306] Scheme 6, Step 3, (S)-1-(6-amino-2,4-difluoro-3-(3-methoxypyrrolidine-1-yl)phenyl)ethane-1-one:

[0307] Pd(PPh3)4 (677 mg, 586 μmol, 0.1 equivalent) was added to a solution of (S)-2-bromo-3,5-difluoro-4-(3-methoxypyrrolidine-1-yl)aniline (1.8 g, 5.86 mmol, 1.0 equivalent) and tributyl(1-ethoxyvinyl) stannan (2.97 mL, 8.79 mmol, 1.5 equivalent) in toluene (27 mL). The mixture was stirred at 120 °C for 16 hours. The mixture was added to an aqueous solution of KF (30 mL) and stirred for 1 hour. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain (S)-2-(1-ethoxyvinyl)-3,5-difluoro-4-(3-methoxypyrrolidine-1-yl)aniline (1.5 g, crude) as a brown solid.

[0291]

[0308] (S)-2-(1-ethoxyvinyl)-3,5-difluoro-4-(3-methoxypyrrolidine-1-yl)aniline (1.2 g, 4.02 mmol, 1 equivalent) was treated with HCl (10 mL; 4 M in dioxane) and stirred at 20°C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (20:1~5:1 petroleum ether:ethyl acetate) to obtain the title compound as a white solid (400 mg, yield 37%). 1 H NMR (400 MHz, chloroform-d) δ 6.30 - 6.00 (m, 3H), 4.06 (td, J = 3.0, 6.2 Hz, 1H), 3.49 - 3.39 (m, 2H), 3.39 - 3.34 (m, 3H), 3.30 - 3.16 (m, 2H), 2.58 (d, J = 8.8 Hz, 3H), 2.14 (td, J = 6.8, 13.6 Hz, 1H), 2.00 (ddd, J = 3.8, 8.2, 12.4 Hz, 1H).

[0292]

[0309] Scheme 6, Step 3, (S)-N-(2-acetyl-3,5-difluoro-4-(3-methoxypyrrolidine-1-yl)phenyl)-2-chloro-5-cyanobenzamide:

[0310] To a solution of (S)-1-(6-amino-2,4-difluoro-3-(3-methoxypyrrolidine-1-yl)phenyl)ethane-1-one (120 mg, 444 μmol, 1.0 equivalent) in isopropyl acetate (1.8 mL), 2-chloro-5-cyanobenzoyl chloride (98 mg, 488 μmol, 1.1 equivalents) was added. The mixture was stirred under N2 at 80°C for 2 hours. The mixture was cooled to 20°C. The residue was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was ground with MTBE (3 mL) to obtain the title compound as a yellow solid (80 mg, yield 42%). 1 H NMR (400 MHz, chloroform-d) δ = 11.62 (s, 1H), 8.45 - 8.26 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.73 - 7.67 (m, 1H), 7.65 - 7.57 (m, 1H), 4.13 - 4.01 (m, 1H), 3.78 - 3.67 (m, 2H), 3.45 (br d, J = 9.2 Hz, 2H), 3.39 (s, 3H), 2.65 (d, J = 8.8 Hz, 3H), 2.12 - 2.02 (m, 2H).

[0293]

[0311] Scheme 6, Step 4, (S)-4-chloro-3-(5,7-difluoro-6-(3-methoxypyrrolidine-1-yl)-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile:

[0312] To a solution of (S)-N-(2-acetyl-3,5-difluoro-4-(3-methoxypyrrolidine-1-yl)phenyl)-2-chloro-5-cyanobenzamide (80 mg, 184 μmol, 1.0 equivalent) in dioxane (1.2 mL), LiOH (6.6 mg, 277 μmol, 1.5 equivalents) was added. The mixture was stirred under N2 at 110 °C for 16 hours. The pH of the mixture was adjusted to 4-5 with HCl aqueous solution (1 M). The mixture was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was pulverized with acetonitrile (1 mL) to obtain the title compound as a white solid (36.6 mg, yield 47%). LCMS[M+1] = 416.0. 1 H NMR (400 MHz, methanol-d4) δ 8.03 (d, J = 2.0 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.85 - 7.77 (m, 1H), 7.09 (br d, J = 12.2 Hz, 1H), 6.21 (br s, 1H), 4.10 (td, J = 2.4, 5.2 Hz, 1H), 3.84 - 3.68 (m, 2H), 3.53 - 3.43 (m, 2H), 3.40 - 3.35 (m, 3H), 2.15 - 2.02 (m, 2H).

[0294]

[0313] The compounds in Table 9 were prepared according to Scheme 6, using the same procedure as described in Example 104.

[0295] [Table 9-1]

[0296] [Table 9-2]

[0297] [Table 9-3]

[0298] [Table 9-4]

[0299]

[0314] Examples 118 and 119

[0300] [ka]

[0301]

[0315] 4-Chloro-3-(3,5,7-trifluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile and 4-Chloro-3-(3-chloro-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile (60 mg, 189 μmol, 1.0 equivalent) and Selectfluor (67.1 mg, 189 μmol, 1 equivalent) were dissolved in DMA (1.5 mL), and the solution was placed in a microwave tube. The tube was sealed and heated by microwave irradiation at 150 °C for 0.5 hours. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30mm×3um; mobile phase: 35-50% acetonitrile in water (+0.2% formic acid)) to obtain 4-chloro-3-(3,5,7-trifluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile (10.4 mg, yield 17%) and 4-chloro-3-(3-chloro-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)benzonitrile (2.7 mg, yield 3.7%) as brown solids. Example 118, LCMS:[M+H](C 16 The calculated value for H6ClF3N2O is m / z 335.0, while the measured value using LCMS is also m / z 335.0. 1H NMR (400 MHz, methanol-d4) δ 8.14 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 2.0, 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.10 (br d, J = 9.4 Hz, 1H), 7.01 (ddd, J = 2.2, 9.4, 11.8 Hz, 1H). Example 119, LCMS: [M+H](C 16 The calculated value for H6Cl2F2N2O is m / z 351.0, while the measured value using LCMS is m / z 350.9. 1 H NMR (400 MHz, methanol-d4) δ 8.08 (d, J = 1.8 Hz, 1H), 7.98 (dd, J = 2.0, 8.6 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.10 - 6.98 (m, 2H).

[0302] Biochemical and cellular assays

[0316] PPARγ-NCOR1 recruitment assay:

[0317] Efficacy of the compound (EC 50The maximum degree of NCOR1 recruitment to PPARG was evaluated by a TR-FRET binding assay that measures the association of biotinylated NCOR1 ID2 peptide (biotin-GHSFADPASNLGLEDIIRKALMG-amide) to the PPARG / RXRA LBD heterodimer. Specifically, 20 microliters of TR-FRET master mix consisting of 25 mM MOPS pH 7.4, 25 mM KCl, 1 mM EDTA, 0.01% BSA, 0.01% Tween-20, and 1 mM TCEP, containing 2 nM WT PPARG LBD (expressed in 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), is mixed with the compound (0.3% fc) in 60 nL DMSO. Ten-point dose response titrations of DMSO(v / v) were added to a 384-well plate containing two sets of DMSO(v / v) solutions. The mixture was incubated for 3 hours and read using an EnVision plate reader (Perkin Elmer) with an Ex / Em 615 / 665. Efficacy (EC) 50 To determine the degree of NCOR1 recruitment, the TR-FRET ratio was normalized in the CDD Vault to the mean ratio in the DMSO control well (0%) and to the mean maximum ratio of the positive control compound (T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide); defined as 100%) and analyzed using the Levenberg-Marquardt algorithm.

[0303]

[0318] PPARγ-MED1 blockade assay:

[0319] The efficacy of the compound (IC 50The maximum degree of MED1 repulsion towards PPARG was evaluated by a TR-FRET binding assay that measures the association of biotinylated MED1 LxxLL peptide (biotin-VSSMAGNTKNHPMLMNLLKDNPAQ-amide) to the PPARG / RXRA LBD heterodimer. Specifically, 20 microliters of TR-FRET master mix consisting of 25 mM MOPS pH 7.4, 25 mM KCl, 1 mM EDTA, 0.01% BSA, 0.01% Tween-20, and 1 mM TCEP, containing 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), is mixed with the compound in 60 nL DMSO (0.3% DMSO). Ten reaction doses of fc(v / v) were added in double 384-well plates. The mixture was incubated for 3 hours and read using an EnVision plate reader (Perkin Elmer) with an Ex / Em 615 / 665. The efficacy of the MED1 repulsion (IC) was assessed. 50 To determine the degree of the positive control compound (GW9662 (2-chloro-5-nitrobenzanilide); defined as 100%), the TR-FRET ratio was normalized to the mean ratio in the DMSO control well (0%) in the CDD Vault and to the mean minimum ratio, and analyzed using the Levenberg-Marquardt algorithm.

[0304]

[0320] Bladder cancer pharmacodynamic assay

[0321] Cells 5637 (PPARG-amplified) and HT1197 (RXRA S427F mutant) were used to evaluate the regulation of PPARG target genes using quantitative PCR. After treating the cells with a PPARG reverse agonist for 24 hours, the expression of the housekeeping gene TBP (IDT, catalog no. Hs.PT 58v.39858774) was used for normalized expression across samples, and the expression of FABP4 (IDT, catalog no. Hs.PT 58.20106818) and ANGPTL4 (IDT, catalog no. Hs.PT 58.25480012) was analyzed. Quantitative PCR was performed using the ABI QuantStudio 7 Flex reaction system. Data were analyzed against a DMSO control using the comparative Ct method (ΔΔCt) and reported.

[0305] Table 10

[0322] Regarding the PPARG-NCOR recruitment assay, EC 50 The following ranges were represented: A: <10nM, B: 10~100nM, C: 100~1,000nM, D: 1,000~10,000nM, E: >10,000nM. The percentage of NCOR recruitment was represented as follows: A: >100% (> control compound, T907), B: <100% (< control compound, T907).

[0306]

[0323] Regarding the PPARG-MED1 recruitment assay, EC 50 The following ranges were represented: A: <10 nM, B: 10~100 nM, C: 100~1,000 nM, D: 1,000~10,000 nM, E: >10,000 nM. The percentage of MED1 blockade was represented as follows: A: >100% (> control compound, GW9662), B: <100% (< control compound, GW9662).

[0307]

[0324] Regarding the 5637 cell assay, EC 50The following ranges are used: A: <10 nM, B: 10~100 nM, C: 100~1,000 nM, D: 1,000~10,000 nM, E: >10,000 nM, ND: Undetermined. The percentage of inhibition of FABP4 and PPARG target genes at a compound concentration of 100 nM is expressed as a percentage of the DMSO-controlled experiment.

[0308]

[0325] Regarding the HT1197 cell assay, EC 50 The following ranges are used: A: <10 nM, B: 10~100 nM, C: 100~1,000 nM, D: 1,000~10,000 nM, E: >10,000 nM, ND: Undetermined. The percentage of inhibition of ANGPTL4 and PPARG target genes at a compound concentration of 100 nM is expressed as a percentage of the DMSO-controlled experiment.

[0309] [Table 10-1]

[0310] [Table 10-2]

[0311] [Table 10-3]

[0312]

[0326] Although many embodiments have been described, it is clear that our basic examples can be modified to provide other embodiments utilizing the compounds and methods of the present invention. Therefore, it should be understood that the scope of the invention is defined by the scope of the appended claims, rather than by the specific embodiments shown as examples.

[0313]

[0327] All references cited throughout this application (including references to documents, granted patents, published patent applications, and concurrently pending patent applications) are explicitly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are given the meanings commonly known to those skilled in the art.

Claims

1. Equation I 【Chemistry 1】 Compounds or pharmaceutically acceptable salts thereof (In the formula, R １ is hydrogen, halo, (C １ ~C ４ ) Alkyl or hydroxyl, R ２ It is a halo, R ３ It is cyano or nitro, R ４ is hydrogen, halo, (C １ -C ４ -C １ -C ４ -alkoxy or hydroxyl, R ５ Hello, hello (C １ ~C ４ ) Alkyl or cyano, R ６ Hello, hello (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkyl or cyano, R ７ Hello, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) Alkoxy, -(C １ ~C ４ ) alkyl OR ａ , - (C １ ~C ４ ) Alkyl C(O)R ａ , - (C １ ~C ４ ) Alkyl C(O)OR ａ , -C(O)NR ａ R ｂ , - (C １ ~C ４ ) Alkyl C(O)NR ａ R ｂ , -C(O)R ａ , -C(O)OR ａ , -NR ａ R ｂ , - (C １ ~C ４ ) Alkyl NR ａ R ｂ , -C(O)NR ａ SO ３ H, -NR ａ C(O)R ｂ , -NR ａ C(O)OR ｂ , -NR ａ C(S)OR ｂ , -NR ｃ C(O)N ａ R ｂ , -NR ｃ C(S)NR ａ R ｂ , -NR ｃ S(O) ２ NR ａ R ｂ , -C(S)R ａ , -S(O) ２ R ａ , -S(O)R ａ , -C(S)OR ａ , -C(S)NR ａ R ｂ , -NR ａ C(S)R ｂ , -SR ａ , phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl, and each of the phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl is optionally and independently R ８ Substituted with 1 to 3 groups selected from, R ８ is 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 0]~C ４ alkylOR ｄ 4]-(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)NRS ｄ O 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 , R ｅ and R ｆ Each is independently hydrogen or (C １ ~C ４ ) is alkyl, (q and r are each independently either 0 or 1).

2. Compound is formula II 【Chemistry 2】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ A compound according to claim 1 or 2, wherein the compound is chlorous acid, or a pharmaceutically acceptable salt thereof.

4. R ３ A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is cyano.

5. R １ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, fluoro, hydroxyl, or methyl.

6. R １ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, fluoro, or chloro.

7. R １ A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

8. R ５ A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein is halo or cyano.

9. R ５ A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

10. R ５ A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein is chloro or fluoro.

11. R ５ A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro.

12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein q is 1.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein r is 1.

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein r is 0.

15. R ６ A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

16. R ６ A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro.

17. R ７ But, hello, hello (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, -(C １ ~C ４ ) alkyl OR ａ , -C(O)NR ａ R ｂ , phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl, wherein each of the phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl may, and independently, ８ A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, substituted with one to three groups selected from the above.

18. R ７ But, hello, hello (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, -(C １ ~C ４ ) alkyl OR ａ , -C(O)NR ａ R ｂ , phenyl, pyridinyl, pyrazolyl and oxetanyl, and each of the phenyl, pyridinyl, pyrazolyl and oxetanyl may and independently be R ８ A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, substituted with one to three groups selected from the above.

19. R ７ But, hello, hello (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, -(C １ ~C ４ ) alkyl OR ａ , - (C １ ~C ４ ) Alkyl C(O)NR ａ R ｂ , - (C １ ~C ４ ) Alkyl C(O)OR ａ , -C(O)NR ａ R ｂ , phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl, wherein each of the phenyl, 4-6 membered heterocyclil and 5-7 membered heteroaryl may, and independently, ８ A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, substituted with one to three groups selected from the above.

20. R ７ But, hello, hello (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, -(C １ ~C ４ ) Alkyl C(O)NR ａ R ｂ , - (C １ ~C ４ ) alkyl OR ａ , - (C １ ~C ４ ) Alkyl C(O)OR ａ , -C(O)NR ａ R ｂ , azetidinil, phenyl, pyridinil, piperazinil, piperidinil, pyridinil, pyrazolyl, tetrahydropyridinil, pyrrolidinil, pyrazinil, dihydropyridazinil, pyridazinil, imadazolyl, dihydropyridinil, dihydropyrimidinil, pyrimidinil, and oxetanil, and each of the above azetidinil, phenyl, pyridinil, piperazinil, piperidinil, pyridinil, pyrazolyl, tetrahydropyridinil, pyrrolidinil, pyrazinil, dihydropyridazinil, pyridazinil, imadazolyl, dihydropyridinil, dihydropyrimidinil, pyrimidinil, and oxetanil may and independently, ８ A compound according to any one of claims 1 to 16 and 19 or a pharmaceutically acceptable salt thereof, substituted with one to three groups selected from the above.

21. R ８ But, hello, (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, -(C １ ~C ４ ) alkyl OR ｄ , - (C １ ~C ４ ) Alkyl NR ｄ R ｅ , - (C １ ~C ４ ) Alkyl C(O)OR ｄ , Hello (C １ ~C ４ ) Alkyl, -C(O)OR ｄ , - (C １ ~C ４ ) Alkyl C(O)NR ｄ R ｅ , -C(O)NR ｄ R ｅ , oxo, cyano, -C(O)R ｄ , -NR ｄ R ｅ , and -S(O) ２ R ｄ A compound according to any one of claims 1 to 20, selected from the above, or a pharmaceutically acceptable salt thereof.

22. R ８ But, hello, (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, selected from alkoxy, oxo, and cyano.

23. R ８ ga halo (C １ ~C ４ A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

24. Structural formula: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 [Chemistry 3-4] [Transformation 3-5] 【Chemistry 3-6】 【Chemistry 3-7】 【Transformation 3-8】 【Chemistry 3-9】 【Chemistry 3-10】 【Chemistry 3-11】 【Chemistry 3-12】 【Chemistry 3-13】 【Chemistry 3-14】 【Chemistry 3-15】 【Chemistry 3-16】 【Chemistry 3-17】 【Chemistry 3-18】 【Chemistry 3-19】 The compound, or any pharmaceutically acceptable salt of the above.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25 for treating cancer that is responsive to PPAR suppression in the target.

27. The pharmaceutical composition according to claim 26, wherein the cancer is selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial carcinoma, skin cancer, melanoma, colon cancer, kidney cancer, brain cancer, and hematopoietic cancer.

28. The pharmaceutical composition according to claim 26 or 27, wherein the cancer is bladder cancer.

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