Small molecule bromodomain inhibitors and their uses

Abstract

The present invention relates to compounds that bind to or otherwise modulate the activity of bromodomain-containing proteins, processes for preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds to treat a wide variety of conditions and disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 838,083, filed April 24, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to compounds that inhibit the binding of bromodomain-containing proteins to acetylated proteins, processes for preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds to treat a wide variety of medical conditions, diseases, or disorders. [Background technology]

[0003] Epigenetic chromatin remodeling is a central mechanism for regulating gene expression. Pharmacological regulation of epigenetic changes represents a new mode of therapeutic intervention against cancer and inflammation. Emerging evidence suggests that such epigenetic regulation may also provide therapeutic avenues for the treatment of obesity, as well as metabolic, cardiovascular, neurodegenerative, psychiatric, and infectious diseases.

[0004] Eukaryotic genomes are in turn organized into basic packaging units called nucleosomes, which consist of a double-stranded DNA helix of approximately 147 base pairs wrapped around a histone octamer, each of which consists of two H2A, H2B, H3, and H4 protein subunits. Nucleosomes further condense into chromatin structures that can exist in a relatively loose state of euchromatin, or in a tightly condensed heterochromatin structure. The transition from heterochromatin to euchromatin allows for the transcription of genes, although not all of the genes in the euchromatin structure are transcribed. This transition from heterochromatin to euchromatin is controlled by post-translational modifications of histone proteins, including acetylation of lysine residues in H3 / H4 proteins. Histone acetylation is catalyzed by histone acetyltransferases (HATs) and results in an open euchromatin structure that allows for the transcription of genes, including tumor suppressor genes. Conversely, histone deacetylation leads to the repression of such genes, an activity that is catalyzed by histone deacetylases (HDACs). Inhibition of histone deacetylases is one mode of cancer treatment, and the histone deacetylase inhibitor vorinostat (Zolinza®) has been shown to be an effective drug for cutaneous T-cell lymphoma in humans.

[0005] Histone acetylation is also regulated by bromodomain-containing proteins. Bromodomains are roughly 110 amino acid long evolutionarily conserved bundles of four alpha helices that bind to acetyl-lysine residues of acetylated proteins. These domains are present in several chromatin-associated proteins, including HATs. Bromodomains were first identified as novel structural motifs in the brahma protein, a regulator of homeotic genes in Drosophila, but are also found in human and yeast proteins, either as single copies or as consecutively repeated domains, and are thought to confer specificity for the complex pattern of epigenetic modifications, also known as the histone code (Cell. 1992 Feb 7;68(3):561-72; J. Biomol. Screen. 2011 Dec;16(10):1170-85). The human genome encodes approximately 50 bromodomain-containing proteins (Bioinformatics. 2004 Jun 12;20(9):1416-27), some of which may be involved in the pathogenesis of cancer, inflammation, obesity, metabolic, cardiovascular, neurodegenerative, psychiatric, and infectious diseases (Med. Chem. Commun. 2012 Jan 4 3(2):123-134, Curr. Opin. Drug Discov. Devel. 2009 Sep;12(5):659-65, Discov. Med. 2010 Dec;10(55):489-99, FEBS Lett. 2010 Aug 4;584(15):3260-8, J. Virol. 2006 Sep;80(18):8909-19, J Virol. 2005 Jul;79(14):8920-32, Curr.Opin.Pharmacol.2008 Feb;8(1):57-64). Thus, inhibition and / or modulation of bromodomain-containing proteins may present a new mode of pharmacological intervention for such diseases. Of the approximately 50 bromodomain-containing proteins encoded by the human genome, the BET proteins represent a small protein family that includes BRD2, BRD3, BRD4, and BRDT.BET proteins contain two tandem bromodomains followed by a specific terminal (ET) domain for protein-protein interactions in the carboxy-terminal region (J. Biol Chem. 2007 May 4;282(18):13141-5). BET proteins are thought to function by binding to acetylated nucleosomes, opening chromatin structure and / or promoting transcription initiation (Front. Biosci. 2001 Aug 1;6:D1008-18).

[0006] Previously, it was clearly shown that inhibition of BRD4, either by BRD4-specific RNAi or by a small molecule BET inhibitor (JQ1), induces repression of the MYC oncogene (Nature 2011 Aug 3;478(7370):524-8). This indirect suppression of MYC gene expression as a secondary effect of BRD4 inhibition constitutes the central mechanism of action exerted by BET inhibitors.

[0007] Inhibition of BET proteins has been shown to be an effective mode of intervention in rodent models of human NUT midline carcinoma, multiple myeloma, Burkitt lymphoma, and acute myeloid leukemia by suppressing expression of the MYC gene (Nature 2010 Dec23,468(7327):1067-73, Cell.2011 Sep 16;146(6):904-1, Proc.Nat.l Acad.Sci.US A.2011 Oct 4;108(40):16669-74), as well as the MYCN gene (Cancer Discov.2013 Mar:3(3)308-23). ​​MYC and homologous genes are some of the most overexpressed genes in human cancers, however, to date there are no pharmaceutical compounds that directly antagonize the activity of the proteins encoded by the MYC and homologous genes, due in part to the lack of effective drug binding sites. Thus, there is a need for a means to indirectly suppress the expression of MYC and homologous genes by inhibiting the bromodomains of BET proteins, which would provide an effective mode of treatment for various diseases, disorders, or medical conditions, including various cancers.

[0008] In addition to being bromodomain-containing proteins, CBP and p300 are two paralogous histone acetyltransferases (HATs) that have additional functions as transcriptional coactivators. CBP and p300 interact with over 400 proteins through their multiple protein interaction domains, which contain bromodomains adjacent to the HAT catalytic domain, thereby playing important roles in various physiological and pathological processes (Cell Mol Life Sci. 2013 Nov; 70(21): 3989-4008, Chem Rev. 2015 Mar 25; 115(6): 2419-52).

[0009] CBP and p300 are now recognized as therapeutic targets for various types of cancer. For example, small molecules targeting the bromodomain of CBP / p300 have been shown to be effective in experimental models of leukemia (Cancer Res. 2015 Dec 1;75(23):5106-5119), while HAT catalytic inhibitors have shown efficacy in experimental models of prostate cancer (Nature. 2017 Oct 5,550(7674):128-132).

[0010] Importantly, CBP and p300 have been shown to constitute a paralogous target pair suitable for synthetic lethality, where inactivating mutations in one gene sensitize cancer cells to drugs that target the product of the second gene due to pathway interdependence (Cancer Discov. 2016 Apr;6(4):430-45). This particular type of synthetic lethality, termed "paralog targeting," is expected to be applicable to a broad range of cancer types that harbor loss-of-function mutations in the CBP or p300 genes. For example, mutations in the CBP and p300 genes were found in 33.3% and 8.8% of follicular lymphoma cases, 13.3% of marginal zone B-cell lymphoma cases, 28.6% and 26.8% of cutaneous squamous cell carcinoma cases, 8.0% and 7.2% of endometrial carcinoma cases, and 7.7% and 8.3% of small cell lung carcinoma cases, respectively (Cold Spring Harb Perspect Med. 2017 Mar 1;7(3).pii:a026534, Cancer Discov. 2016 Apr;6(4):430-45).

[0011] In addition, bromodomain inhibition of CBP / p300 was shown to suppress expression of the IRF4 gene, a transcription factor known to control expression of the MYC oncogene, resulting in growth inhibition of multiple myeloma cells (Elife.2016 Jan 5;5.pii:e10483). Thus, inhibition of CBP / p300 by small molecules may be one potential mode of cancer therapy, regardless of the mutational status of the CBP or p300 genes.

[0012] Accumulating evidence indicating the importance of CBP and p300 in tumorigenesis, along with previous indications of the efficacy of BET inhibitors in clinical studies, collectively indicate that multi-bromodomain inhibitors that simultaneously target BET / CBP / p300 proteins may confer superior efficacy over simple BET inhibitors while preventing the development of drug resistance, particularly in cancers harboring mutations in the CBP or p300 genes. Summary of the Invention

[0013] The present invention relates in particular to compounds of formula (I): [ka] and tautomers, optical isomers, or stereoisomers thereof, or pharma- ceutically acceptable salts thereof, wherein: X is O, NH, NC(O)C 1-3 Alkyl, [ka] or NS(O)Me, A, [ka] and E, [ka] and R 1 is H, halogen, or Me; n is 0, 1, 2, or 3; The compound is provided wherein Q is: [ka]

[0014] In one embodiment, the present invention provides a compound of formula (II): [ka] and pharma- ceutically acceptable salts thereof.

[0015] wherein the X, E, Q, and A substituents are as defined in formula (I).

[0016] Preferably, X is O, NC(O)Me, or NS(O). 2 Even more preferably, X is O.

[0017] Preferably, A is [ka] It is.

[0018] Preferably, E is [ka] and R 1 is H, F, Cl, and n is 0, 1, 2, or 3.

[0019] Even more preferably, E is [ka] and R 1 are H, F, and Cl.

[0020] Preferably, Q is [ka] Even more preferably, Q is [ka] It is.

[0021] Even more preferably, the compound of formula (I) is selected from the group consisting of: [ka]

[0022] In one embodiment, the compound of formula (I) is one of the following: [ka]

[0023] In one embodiment, the compound of formula (I) is none of the following: [ka]

[0024] In another embodiment, the present invention provides a compound of formula (III): [ka] or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: A, [ka] and R 1 is H or a halogen.

[0025] In one embodiment, the present invention provides a compound of formula (IIIa): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 and the A substituent is as defined in formula (III). [Brief description of the drawings]

[0026] For a fuller understanding of the nature, objects, and advantages of the present disclosure, reference should be made to the following detailed description read in conjunction with the following drawings, in which like reference numerals indicate like elements and in which:

[0027] [Figure 1] (A) and (B) show the tumor volume and tumor weight in mice resulting from Kasumi-1 xenografts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Certain of the compounds described herein may contain one or more chiral centers (including, for example, the compound species of the examples unless otherwise indicated by the chemical name) or may be capable of existing as multiple stereoisomers. The scope of the present disclosure includes mixtures of stereoisomers, as well as purified enantiomers, or mixtures enriched in enantiomers and / or diastereomers. In some embodiments, the compounds provided herein exist as (S)-enantiomers. In some embodiments, the compounds provided herein exist as (R)-enantiomers. Also included within the scope of the present disclosure are the individual stereoisomers of the compounds represented by formula I, as well as any fully or partially equilibrated mixtures thereof. The present disclosure also includes the individual stereoisomers of the compounds represented by the above formula as a mixture with its isomers in which one or more chiral centers are inverted.

[0029] In some embodiments, the compounds of the present invention are provided as pharmaceutically acceptable salts, including non-toxic salts of the compounds described herein.Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate and ascorbate; salts containing acidic amino acids such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt and N,N'-dibenzylethylenediamine salt; and salts containing basic amino acids such as lysine salt and arginine salt.

[0030] The salt provided may be hydrated or solvated in some cases.The present invention includes the salt or solvate of the compound described herein, including combinations thereof such as solvates of salt.The compounds of the present disclosure may exist in solvated, for example hydrated or ethanol complexed, as well as non-solvated form, and the present invention encompasses all such forms.The salt of the present disclosure may be a pharmaceutically acceptable salt.

[0031] The compounds provided herein or their pharma- ceutically acceptable salts may crystallize in two or more forms, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of this disclosure. Polymorphism can generally occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as X-ray diffraction patterns, solubility, and melting point.

[0032] Although it is possible to administer the compounds of the present disclosure in the form of bulk active chemicals, it is preferred to administer the compounds in the form of pharmaceutical compositions or formulations.Therefore, pharmaceutical compositions are provided that include one or more compounds of formula I and / or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0033] A further embodiment of the invention provides a process for preparing a pharmaceutical composition comprising an admixture of one or more compounds of formula I and / or pharma-ceutically acceptable salts thereof with one or more pharma-ceutically acceptable carriers, diluents, or excipients.

[0034] In some embodiments, compounds are provided that bind to or otherwise regulate the acetylated protein that binds to bromodomain-containing proteins.Such compounds include at least one compound selected from formula I provided herein.Exemplary compounds include, but are not limited to, the compounds previously described by name or structure.

[0035] In some embodiments, compounds are provided for use in the treatment or prevention of a disease or condition mediated by inhibiting the binding of a bromodomain-containing protein to an acetylated protein.In some embodiments, compounds are provided for use in the treatment of a disease or condition mediated by inhibiting the binding of a bromodomain-containing protein to an acetylated protein.

[0036] In some embodiments, methods are provided for treating or preventing a disease comprising administering a compound provided herein to inhibit activity of a bromodomain-containing protein.

[0037] In some embodiments, a method is provided for treating or preventing a disease comprising administering a compound provided herein to inhibit the activity of a bromodomain-containing protein by inhibiting binding to an acetylated protein. In some embodiments, the method is a method of treating a disease comprising administering a compound provided herein to inhibit the activity of a bromodomain-containing protein by inhibiting binding to an acetylated protein.

[0038] In some embodiments, the use of a compound or a salt thereof for preparing a pharmaceutical composition for the treatment or prevention of a disease or condition mediated by inhibiting a bromodomain-containing protein by inhibiting binding to an acetylated protein is provided. In some embodiments, the use of a compound or a salt thereof for preparing a pharmaceutical composition for the treatment of a disease or condition mediated by inhibiting a bromodomain-containing protein by inhibiting binding to an acetylated protein is provided. In some embodiments, the acetylated protein is an acetylated histone.

[0039] In some embodiments, the acetylated protein is an acetylated histone that is involved in the regulation or dysregulation of gene expression.

[0040] The compounds of the present invention, their pharma- ceutically acceptable salts and pharmaceutical compositions thereof can be used to treat or prevent a wide variety of conditions or disorders. In some embodiments, the compounds of the present invention, their pharma- ceutically acceptable salts and pharmaceutical compositions thereof can be used to treat a wide variety of conditions or disorders.

[0041] In some embodiments, the disease is selected from cancer, fibrosis, inflammation, or an inflammatory disorder.

[0042] In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from human NUT midline carcinoma, multiple myeloma, Burkitt lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, and prostate cancer. In some embodiments, the cancer is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and acute lymphocytic leukemia. In some embodiments, the cancer is associated with human T-cell leukemia virus type 1 (HTLV-1), including adult T-cell leukemia / lymphoma (ATLL) or HTLV-1-associated myelopathy / tropical spastic paralysis (HAM / TSP).

[0043] In some embodiments, the disease is fibrosis. In some embodiments, the fibrosis is selected from pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), renal fibrosis, intestinal fibrosis, hepatic fibrosis, and liver cirrhosis. In some embodiments, the disease is idiopathic pulmonary fibrosis (IPF). IPF is a devastating orphan lung disease that robs patients of their lung function. This loss of breathing ability results in a mortality rate of over 50% within 2-3 years of diagnosis. This prognosis is further worse in patients with moderate to severe disease, which progresses rapidly and there is no available treatment.

[0044] In some embodiments, the disease is inflammation or an inflammatory disorder. In some embodiments, the inflammation or an inflammatory disorder is selected from allergy, asthma, autoimmune disease, celiac disease, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejection, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, sinusitis, active hepatitis, atherosclerosis, periodontitis, juvenile rheumatoid arthritis, cystic fibrosis lung disease, Guillain-Barre syndrome, Graves' ophthalmopathy, and non-alcoholic steatohepatitis (NASH). In some embodiments, the disease is inflammation. In some embodiments, the disease is an inflammatory disorder.

[0045] In some embodiments, the disease is inflammation and / or fibrosis associated with acute radiation exposure. In some embodiments, the disease is inflammation associated with acute radiation exposure. In some embodiments, the disease is fibrosis associated with acute radiation exposure. In some embodiments, the disease is inflammation and fibrosis associated with acute radiation exposure. In some embodiments, the disease is inflammation and / or fibrosis associated with acute radiation exposure and the patient has been identified as having been exposed to abnormally high levels of radiation (e.g., a victim of a nuclear accident).

[0046] In some embodiments, the methods provided herein are methods of treating a disease. In some embodiments, the methods provided herein are methods of preventing a disease.

[0047] The manner in which the compound described herein or its pharmaceutical composition can be administered can vary. In some embodiments, the compound can be administered orally. The preferred pharmaceutical composition can be formulated for oral administration in the form of tablets, capsules, caplets, syrups, solutions, and suspensions. Such oral formulations can be provided in modified release dosage forms, such as sustained release tablet and capsule formulations. The pharmaceutical composition can also be administered via parenteral administration / injection, i.e., intravenous, intramuscular, subcutaneous, intraperitoneal, intraarterial, intrathecal, and intracerebroventricular. Intravenous administration is the preferred method of injection. Suitable carriers for injection are well known to those skilled in the art and include 5% dextrose solution, saline, and phosphate buffered saline.

[0048] Pharmaceutical compositions can also be administered using other means, for example, rectal administration. Formulations useful for rectal administration, such as suppositories, are well known to those of skill in the art.

[0049] The compounds may also be administered by inhalation delivery or other direct application to the affected tissue, for example in the form of oral pulmonary or intranasal inhalation delivery or nebulized inhalation delivery, including formulations for aerosol administration via a nebulizer, dry powder inhalation (DPI), pressurized metered dose inhaler (MDI), etc., as well as by methods using a nebulizer, DPI, MDI, etc., by administering the compounds discussed herein with a nebulizer, DPI, or MDI, etc., as well as by the dosing regimens discussed in US2015 / 0044288 and AU2018206852 (which claim priority to US61 / 675,286, US61 / 756,983, and US61 / 824,818), the contents of which are incorporated herein by reference in their entireties. The compounds may also be administered topically, such as in lotion form, transdermally, such as using a transdermal patch (e.g., by using technology commercially available from Novartis and Alza Corporation), by powder injection, or by buccal, sublingual, or intranasal absorption. Pharmaceutical compositions may be formulated in unit dosage form, or in multiple or subunit doses.

[0050] The administration of the pharmaceutical composition described herein can be intermittent, or gradual, continuous, constant or controlled rate.The pharmaceutical composition can be administered to a subject, and the time of day and the number of times per day that the pharmaceutical composition is administered can be varied.

[0051] A further object of the present disclosure is a kit comprising a composition containing at least one compound disclosed herein for the treatment and prevention of a disease or a pathological condition associated with a disease. The composition of the kit may comprise at least one carrier, at least one binder, at least one diluent, at least one excipient, at least one other therapeutic agent, or a mixture thereof.

[0052] The compounds provided herein may also be used to prepare a medicament for the treatment or prevention of a disease or condition characterized by a bromodomain-containing protein binding to an acetylated protein and altering normal gene expression. In some embodiments, the compounds provided herein may be used to prepare a medicament for the treatment of a disease or condition characterized by a bromodomain-containing protein binding to an acetylated protein and altering normal gene expression. Also provided are methods for the treatment, prevention, delay of onset, or delay of progression of a disorder mediated by an acetylated protein involved in the regulation or dysregulation of gene expression in a subject in need of such treatment. The methods involve administering to a subject a therapeutically effective amount of a compound provided herein, including a salt of a compound provided herein, or a pharmaceutical composition comprising such a compound.

[0053] In some embodiments, methods for treating, preventing, delaying the onset, or delaying the progression of a disorder mediated by acetylated proteins involved in the regulation or dysregulation of gene expression in a subject in need of such treatment include administration of at least one compound provided herein, including but not limited to compounds provided according to Formula I, Formula II, Formula III, and Formula III(a).

[0054] The compounds provided herein alone or in pharmaceutical compositions may be used in the treatment of a variety of disorders and conditions, and therefore may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prevention of those disorders or conditions. Thus, in some embodiments, the present disclosure includes administering the compounds of the present disclosure in combination with other therapeutic compounds. Such combinations of pharma- ceutical active agents may be administered together or separately, and when administered separately, administration may be performed simultaneously or sequentially in any order. The amounts and relative administration timing of the compounds or agents will be selected to achieve the desired therapeutic effect. Concomitant administration of the compounds of the present disclosure with other therapeutic agents may be combined by simultaneous administration: (1) in a single pharmaceutical composition containing two or more compounds, or (2) in separate pharmaceutical compositions, each containing one of the compounds. Alternatively, the combination may be administered separately in a sequential manner, with one therapeutic agent being administered first and the other being administered second. Such sequential administration may be closely spaced apart or spaced apart in the administration interval.

[0055] In some embodiments, the disclosure includes combination therapy comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of the disclosure and one or more other therapies, including chemotherapy, radiation therapy, gene therapy, or immunotherapy.

[0056] It is contemplated, and therefore within the scope of the present invention, that any feature described above may be combined with any other feature described above. It is also contemplated, and therefore within the scope of the present invention, that a negative disclaimer may be added to exclude any compound or remove any feature.

[0057] As used herein, the term "halogen" refers to fluoro, chloro, bromo, or iodo.

[0058] As used herein, the terms "effective amount," "therapeutic amount," and "effective dose" refer to an amount of a compound of the present disclosure sufficient to induce a desired pharmacological or therapeutic effect, thus resulting in effective prevention or treatment of a disorder. Treatment of a disorder may be manifested by delaying or preventing the onset or progression of the disorder, as well as the onset or progression of symptoms associated with the disorder. Treatment of a disorder may also be manifested by a reduction or elimination of symptoms, reversal of the progression of the disorder, as well as any other contribution to the health of the patient. An effective dose may vary depending on factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.

[0059] As used herein, the term "pharmaceutical acceptable" refers to a carrier, diluent, excipient, or salt form of a compound of the present disclosure that is compatible with other ingredients in the formulation of a pharmaceutical composition.

[0060] As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure, optionally mixed with one or more pharma- ceutically acceptable carriers, diluents, or excipients. Pharmaceutical compositions preferably exhibit a degree of stability to environmental conditions that makes them suitable for manufacturing and commercialization purposes.

[0061] As used herein, "treating" means administering a compound or pharmaceutical composition of the present disclosure to a subject to improve, reduce, or alleviate the symptoms of a disease. As used herein, "treating" or "treating" describes the management and care of a subject with the goal of eradicating a disease, condition, or disorder, and includes administering a compound disclosed herein, or a pharma-ceutically acceptable salt, to reduce symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. As used herein, "preventing" means administering a compound disclosed herein to a subject, a pharmaceutical composition, to prevent the onset of a disease or to delay the onset of a disease. The term "treating" can also include the treatment of a cell in vitro or an animal model.

[0062] As used herein, a "subject" refers to any warm-blooded animal, ie, a mammal, including a rodent (eg, a mouse or rat), dog, primate, lemur, or human.

[0063] Additional methods and materials can be found, for example, in U.S. Patent Publication No. 2018 / 0305344, the disclosure of which is incorporated by reference in its entirety. EXAMPLES

[0064] Exemplary compounds of formula (I) and corresponding assay data are provided below. [Table 1] [Table 1-2]

[0065] Synthetic Procedures for Examples 1-15. General Methods: All air or moisture sensitive reactions were performed under a positive pressure of nitrogen using oven-dried glassware. Chemical reagents and anhydrous solvents were obtained from commercial sources and used as received. Prepurification was performed on a Waters semi-preparative HPLC. The column used was a Phenomenex Luna C18 (5 micron, 30×75 mm) with a flow rate of 45 mL / min. The mobile phase consisted of acetonitrile and water, each containing 0.1% trifluoroacetic acid. A gradient of 10% to 50% acetonitrile over 8 minutes was used during purification. Partial collection occurred by UV detection (220 nm). Analytical analysis of purity was determined by two different methods, denoted as Final QC Methods 1 and 2. Method 1: Analysis was performed on an Agilent 1290 Infinity Series HPLC. UHPLC long gradient of 4% to 100% equivalent acetonitrile (with 0.05% trifluoroacetic acid) in water over 3 minutes, with a run time of 4.5 minutes at a flow rate of 0.8 mL / min. A Phenomenex Luna C18 column (3 microns, 3×75 mm) was used at a temperature of 50° C. Method 2: Analysis was performed on an Agilent 1260 using a 7 minute gradient of 4% to 100% acetonitrile in water (with 0.05% trifluoroacetic acid) with a run time of 8 minutes at a flow rate of 1 mL / min (with 0.025% trifluoroacetic acid). A Phenomenex Luna C18 column (3 microns, 3×75 mm) was used at a temperature of 50° C. Purity measurements were performed using an Agilent Diode Array Detector for both Method 1 and Method 2. Mass measurements were performed using an Agilent 6130 mass spectrometer with electrospray ionization in positive mode. All of the analogs for the assay had a purity of >95% based on both analytical methods. 1 H spectra were recorded. High resolution mass spectra were recorded on an Agilent 6210 time-of-flight LC / MS system.

[0066] Example 1. (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.1) [ka] Step 1: Synthesis of (S)-4-(6-bromo-2-chloroquinazolin-4-yl)-3-phenylmorpholine To a mixture of 6-bromo-2,4-dichloroquinazoline (8.34 g, 30 mmol) and (S)-3-phenylmorpholine (5.14 g, 31.5 mmol) in THF (50 ml) was added triethylamine (4.55 g, 45.0 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc / H 2 The organic layer was dried (Na 2 SO 4 ) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 20-50% EtOAc / Hexane as the eluent to give (S)-4-(6-bromo-2-chloroquinazolin-4-yl)-3-phenylmorpholine (8.8 g, 21.74 mmol, 72.5% yield). LC-MS (Method 1):t R =3.70 min, m / z(M+H) + =406.

[0067] Step 2. Synthesis of (S)-5-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one In a two-neck flask, add (S)-4-(6-bromo-2-chloroquinazolin-4-yl)-3-phenylmorpholine (1619 mg, 4 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1096 mg, 4.40 mmol), PdCl 2 (dppf)-CH 2 Cl 2The adduct (327 mg, 0.400 mmol) and potassium carbonate (1824 mg, 13.20 mmol) were added. The air was removed and N 2 (3 times). Then 1,4-dioxane (12 mL) / water (6 mL) was added and heated at 70° C. for 1.5 h. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with EtOAc (10 mL×2). The combined organic layers were dried (Na 2 SO 4 ), filtered. After removing the solvent, the mixture was diluted with 0–5–10% MeOH / CH 2 Cl 2 The product was purified by silica gel chromatography using as the eluent (S)-5-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (1505 mg, 3.37 mmol, 84% yield). 1 H NMR (400MHz, DMSO-d 6 )δ8.01(dd,J=8.8,1.9Hz,1H),7.84(d,J=2.6Hz,1H),7.75(d,J=1.9Hz,1H),7.73(d,J= 8.8Hz,1H),7.59(d,J=7.7Hz,2H),7.45(t,J=7.6Hz,2H),7.35(t,J=7.3Hz,1H),7.14(s ,1H),5.63(s,1H),4.45(d,J=13.3Hz,1H),4.39-4.27(m,1H),3.97-3.90(m,2H),3.72( td,J=10.9,2.4Hz,1H),3.63(t,J=12.0Hz,1H),3.41(s,3H),1.91(s,3H);LC-MS(Method 1):t R= 3.34 minutes, m / z(M+H) + =447.

[0068] Step 3. Synthesis of (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-1,3-dimethylipyridin-2(1H)-one (Cpd.1) A microwave tube was charged with (S)-5-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (1500 mg, 3.36 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (1340 mg, 5.03 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (274 mg, 0.336 mmol), and K 2 CO 3 (2087 mg, 15.10 mmol) was added. Air was removed and N 2 (3 times). Then 1,4-dioxane (12 mL) / water (6 mL) was added and heated at 90° C. for 1.5 h. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with EtOAc (2 mL×2). The combined organic layers were dried (Na 2 SO 4 ), filtered through PL-thiol MP resin, then eluted with EtOAc / MeOH. After removing the solvent, the eluents were 0–10% MeOH / EtOAc, and 0–10% MeOH / CH 2 Cl 2 The product was purified by silica gel chromatography using a second column using hexanes to give (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (1293 mg, 2.348 mmol, 70.0% yield). 1 H NMR (400MHz, DMSO-d 6)δ8.24(s,1H),7.98-7.93(m,3H),7.90(d,J=2.0Hz,1H),7.76(d,J=8.8Hz,1H),7. 57(d,J=7.6Hz,2H),7.41(d,J=2.4Hz,1H),7.34(t,J=7.6Hz,2H),7.22(t,J=7.4Hz ,1H),5.34(t,J=4.5Hz,1H),4.74(s,1H),4.05(s,2H),4.14-3.96(m,3H),3.93-3. 83(m,2H),3.78-3.66(m,1H),3.46(s,3H),1.98(s,3H),1.07(s,6H);LC-MS(Method 2):t R= 4.25 minutes, m / z(M+H) + =551.

[0069] Example 2. (S)-4-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Cpd.2) [ka] Step 1. Synthesis of (S)-4-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one In a two-neck flask, (S)-4-(6-bromo-2-chloroquinazolin-4-yl)-3-phenylmorpholine (2.428 g, 6 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (2.83 g, 6.60 mmol), PdCl 2 (dppf)-CH 2 Cl 2 The adduct (0.49 g, 0.60 mmol), and potassium carbonate (2.74 g, 19.80 mmol) were added. Air was removed and N 2(3 times). Then 1,4-dioxane (24 ml) / water (10 ml) was added and heated at 70° C. for 1.5 h. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with EtOAc (10 mL×2). The combined organic layers were dried (Na 2 SO 4 After removal of the solvent, the product was purified by silica gel chromatography using 20-90% EtOAc / Hexanes as the eluent to give (S)-4-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (3.412 g, 5.45 mmol, 91% yield). 1 H NMR (400MHz, DMSO-d 6 )δ7.94(dd,J=8.6,1.8Hz,1H),7.91-7.86(m,3H),7.82(s,1H),7.80(d,J=8.7Hz,1H),7.5 2(d,J=7.7Hz,2H),7.48(s,1H),7.44-7.33(m,4H),7.27(t,J=7.3Hz,1H),6.51(d,J=3.5Hz ,1H),5.66(s,1H),4.44-4.31(m,2H),3.91(dd,J=12.3,3.7Hz,1H),3.88-3.81(m,1H),3.7 2(td,J=11.0,2.5Hz,1H),3.59(t,J=12.4Hz,1H),3.37(s,3H),2.36(s,3H);LC-MS(Method 1):t R= 3.67 minutes, m / z(M+H) + =626.

[0070] Step 2. Synthesis of (S)-4-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one A microwave tube was charged with (S)-4-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (3412 mg, 5.45 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (1741 mg, 6.54 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (445 mg, 0.545 mmol), and K 2 CO 3 (2712 mg, 19.62 mmol) was added. Air was removed and N 2 (3 times). Then 1,4-dioxane (20 ml) / water (10 ml) was added and heated at 90° C. for 1.5 h. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with EtOAc (2 mL×2). The combined organic layers were dried (Na 2 SO 4 ), filtered through PL-Thiol MP resin and then eluted with EtOAc / MeOH. After removal of the solvent, the product was purified by silica gel chromatography using 0-10% MeOH / EtOAc as eluent to give (S)-4-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (3111 mg, 4.26 mmol, 78% yield). 1 H NMR (400MHz, DMSO-d 6)δ8.25(s,1H),7.99-7.94(m,3H),7.92(d,J=8.2Hz,2H),7.88(dd,J=8.6,1.8Hz,1H),7.82(d ,J=8.7Hz,1H),7.59(s,1H),7.52(d,J=7.6Hz,2H),7.42(d,J=8.1Hz,2H),7.28(t,J=7.6Hz,2H ),7.17(t,J=7.4Hz,1H),6.61(d,J=3.5Hz,1H),5.35(t,J=4.5Hz,1H),4.73(s,1H),4.06(s,2H) ),4.11-3.81(m,5H),3.78-3.66(m,1H),3.43(s,3H),2.37(s,3H),1.07(s,6H);LC-MS(Method 1):t R= 3.08 minutes, m / z(M+H) + =730.

[0071] Step 3. Synthesis of (S)-4-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Cpd.2) To a solution of (S)-4-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (3111 mg, 4.26 mmol) in THF (22 mL), was added NaOH (水溶液)(1M, 21.3 mmol, 21.3 mL, 5 equiv.) was added. The mixture was sealed and then heated to 75° C. for 36 h (complete and no by-product). The layers were separated and the aqueous layer was extracted with EtOAc (5 mL×5). The combined organics were dried, filtered and concentrated. After removal of the solvent, the product was purified by silica gel chromatography using 0-5-10% MeOH / EtOAc as eluent to give (S)-4-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (2026 mg, 3.52 mmol, 83% yield). 1 H NMR (400MHz, DMSO-d 6 )δ12.16(s,1H),8.24(s,1H),8.10(d,J=2.0Hz,1H),8.00(dd,J=8.8,1.9Hz,1H),7.96(s,1H) ,7.83(d,J=8.7Hz,1H),7.52(d,J=7.6Hz,2H),7.39(s,1H),7.31(d,J=2.6Hz,1H),7.26(t,J=7 .6Hz,2H),7.15(t,J=7.4Hz,1H),6.39(t,J=2.2Hz,1H),5.32(t,J=4.7Hz,1H),4.73(s,1H),4 .06(s,2H),4.03(d,J=5.7Hz,1H),3.97-3.68(m,5H),3.54(s,3H),1.07(s,6H);LC-MS(Method 2):t R= 4.18 minutes, m / z (M+H) + =576.

[0072] Example 3. (S)-5-(4-(3-cyclopropylmorpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.3) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-cyclopropylmorpholine following a similar procedure as described in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ8.25(s,1H),8.05(d,J=2.6Hz,1H),8.01(s,1H),7.94(dd,J=8.8,1.9Hz,1H),7.87( d,J=2.0Hz,1H),7.78(d,J=2.5Hz,1H),7.75(d,J=8.7Hz,1H),4.73(s,1H),4.06(s,2H) ),3.98-3.83(m,6H),3.72-3.58(m,1H),3.52(s,3H),2.09(s,3H),1.62-1.58(m,1H), 1.07(s,6H),0.49-0.36(m,1H),0.36-0.23(m,2H),-0.21--0.25(m,1H);LC-MS(Method 2):t R =4.00min, m / z(M+H) + =515.

[0073] Example 4. (S)-4-(4-(3-cyclopropylmorpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Cpd.4) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-cyclopropylmorpholine following a similar procedure as described in Example 2. 1 H NMR (400MHz, DMSO-d 6)δ12.19(s,1H),8.27(s,1H),8.02(s,1H),7.99(d,J=1.9Hz,1H),7.95(dd,J=8.7,1.8Hz, 1H),7.80(d,J=8.6Hz,1H),7.49(s,1H),7.38(t,J=2.6Hz,1H),6.42(t,J=2.2Hz,1H),4.7 4(s,1H),4.07(s,2H),3.99-3.80(m,6H),3.70-3.60(m,1H),3.58(s,3H),1.61-1.59(m,1 LC-MS (Method 2): t R= 3.99 minutes, m / z (M+H) + =540.

[0074] Example 5. (S)-4-(4-(3-(4-fluorophenyl)morpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Cpd.5) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-(4-fluorophenyl)morpholine following a similar procedure as described in Example 2. 1 H NMR (400MHz, DMSO-d 6)δ12.17(s,1H),8.24(d,J=2.9Hz,1H),8.11(d,J=2.5Hz,1H),8.00(dt,J=8.7,2.6Hz,1H),7.97(d,J =2.9Hz,1H),7.83(dd,J=8.7,2.9Hz,1H),7.57-7.53(m,2H),7.44(d,J=2.9Hz,1H),7.32(q,J=2.9Hz ,1H),7.07(td,J=8.8,2.9Hz,2H),6.40-6.38(m,1H),5.28(p,J=3.3Hz,1H),4.74(d,J=2.9Hz,1H),4 .06(d,J=2.9Hz,2H),4.05-3.89(m,4H),3.77-3.74(m,2H),3.56(s,3H),1.08(s,6H);LC-MS(Method 2):t R= 4.20 minutes, m / z (M+H) + =594.

[0075] Example 6. (S)-5-(4-(3-(4-fluorophenyl)morpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.6) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-(4-fluorophenyl)morpholine following a similar procedure as described in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ8.23(s,1H),8.02-7.94(m,3H),7.91(d,J=2.0Hz,1H),7.77(d,J=8.7Hz,1H ),7.60(dd,J=8.5,5.5Hz,2H),7.48(s,1H),7.14(t,J=8.7Hz,2H),5.30(t,J=4 .7Hz,1H),4.73(s,1H),4.06(s,2H),4.03-3.99(m,2H),3.93-3.84(m,3H),3.7 9-3.69(m,1H),3.48(s,3H),2.01(s,3H),1.07(d,J=2.9Hz,6H);LC-MS(Method 2):t R=4.24 minutes, m / z(M+H) + =569.

[0076] Example 7. (R)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-(thiophen-2-yl)morpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.7) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (R)-3-(thiophen-2-yl)morpholine following a similar procedure as described in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ8.29(s,1H),8.03(s,1H),8.02-7.91(m,3H),7.79(d,J=8.7Hz,1H),7.57(d,J=2.9Hz,1H),7.48-7.40( m,1H),7.18(d,J=3.5Hz,1H),7.01(dd,J=5.1,3.5Hz,1H),5.81(s,1H),4.73(s,1H),4.19(dd,J=11.9,2. 5Hz,1H),4.13(d,J=13.4Hz,1H),4.06(s,2H),4.02(dd,J=12.0,3.2Hz,1H),3.97(d,J=11.2Hz,1H),3.89 -3.76(m,1H),3.66(ddd,J=13.9,10.6,3.3Hz,1H),3.48(s,3H),2.02(s,3H),1.07(s,6H);LC-MS(Method 2):t R= 4.00 minutes, m / z(M+H) + =557.

[0077] Example 8. (S)-5-(4-(3-cyclobutylmorpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.8) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-cyclobutylmorpholine following a similar procedure as described in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ8.26(s,1H),8.04(d,J=2.6Hz,1H),8.02(s,1H),7.93(dd,J=8.8,2.1Hz,1H),7.89(d,J= 2.1Hz,1H),7.80-7.76(m,1H),7.74(d,J=8.8Hz,1H),4.73(s,1H),4.60(d,J=10.5Hz,1H),4 .07(s,2H),3.87-3.72(m,5H),3.53(s,3H),3.22-3.15(m,1H),2.09(s,3H),1.97-1.96(m,1 H),1.78-1.68(m,3H),1.57(d,J=6.9Hz,1H),1.31-1.16(m,2H),1.08(s,6H);LC-MS(Method 2):t R= 3.97 minutes, m / z(M+H) + =529.

[0078] Example 9. (S)-5-(4-(3-(4-cyclophenyl)morpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.9) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-(4-chlorophenyl)morpholine following a similar procedure as described in Example 1. 1 H NMR (400MHz, DMSO-d 6)δ8.23(s,1H),8.02-7.93(m,3H),7.90(d,J=2.2Hz,1H),7.77(d,J=8.8Hz,1H) ,7.59(d,J=8.1Hz,2H),7.49(s,1H),7.37(d,J=8.5Hz,2H),5.29(t,J=4.8Hz,1 H),4.73(s,1H),4.06(s,2H),4.01(q,J=4.9,3.8Hz,2H),3.97-3.81(m,3H),3. 80-3.68(m,1H),3.48(s,3H),2.02(s,3H),1.07(d,J=3.3Hz,6H);LC-MS(Method 2):t R= 4.54 minutes, m / z(M+H) + =585.

[0079] Example 10. 5-(4-((S)-3-cyclohexylmorpholino)-2-((S)-2-(hydroxymethyl)morpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.10) [ka] The starting material, (S)-5-(2-chloro-4-(3-cyclohexylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one, was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-cyclohexylmorpholine following a similar procedure as described in Example 1.

[0080] A microwave tube was charged with (S)-5-(2-chloro-4-(3-cyclohexylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (453 mg, 1 mmol) and (S)-morpholin-2-ylmethanol, HCl (461 mg, 3.00 mmol), followed by the addition of EtOH (2 ml) and Hunig's base (0.873 ml, 5.00 mmol). The tube was sealed and heated at 90° C. overnight. After cooling to room temperature, the mixture was concentrated to remove most of the EtOH. Then, EtOAc / H 2HO (5 mL / 5 mL) was added. The organic layer was dried (NaSO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 0-5-10% MeOH / EtOAc as eluent to give 5-(4-((S)-3-cyclohexylmorpholino)-2-((S)-2-(hydroxymethyl)morpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (349 mg, 0.654 mmol, 65.4% yield). 1 H NMR (400MHz, DMSO-d 6 )δ7.90(d,J=2.7Hz,1H),7.74-7.71(m,2H),7.67(dd,J=2.7,1.3Hz,1H),7.44-7.37(m,1H),4.77(t,J=5.5Hz,1H) ,4.59(d,J=13.0Hz,1H),4.44(d,J=13.1Hz,1H),4.28(d,J=10.3Hz,1H),4.00(t,J=11.4Hz,2H),3.94-3.85(m,1H) ),3.84-3.70(m,2H),3.61(dd,J=11.9,2.8Hz,1H),3.51(s,3H),3.55-3.34(m,5H),3.00-2.82(m,1H),2.67(dd,J LC-MS (Method 2): t R= 4.30 minutes, m / z(M+H) + =534.

[0081] Example 11. 5-(2-((S)-2-(hydroxymethyl)morpholino)-4-((S)-3-phenylmorpholino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.11) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-phenylmorpholine following a similar procedure as described in Example 10. 1 H NMR (400MHz, DMSO-d6 )δ7.86(d,J=2.7Hz,1H),7.80-7.78(m,2H),7.49(d,J=7.3Hz,2H),7.45-7.39(m,2H),7.32(t,J=7.5H z,2H),7.26-7.19(m,1H),5.10(t,J=5.0Hz,1H),4.78(t,J=5.7Hz,1H),4.53(d,J=12.9Hz,1H),4.40( d,J=13.2Hz,1H),4.04-3.92(m,2H),3.95-3.83(m,3H),3.78-3.62(m,2H),3.46(s,3H),3.55-3.34(m ,3H),3.26(s,1H),2.80(t,J=12.3Hz,1H),2.64(dd,J=13.1,10.5Hz,1H),2.00(s,3H);LC-MS(Method 2):t R= 3.93 minutes, m / z(M+H) + =528.

[0082] Example 12. (S)-5-(4-(3-cyclohexylmorpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Cpd.12) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-cyclohexylmorpholine following a similar procedure as described in Example 1. 1 H NMR (400MHz, DMSO-d 6)δ8.24(s,1H),8.01(d,J=2.7Hz,1H),8.00(s,1H),7.91(dd,J=8.7,2.0Hz,1H),7.86(d,J=2.1Hz,1H),7. 75-7.72(m,2H),4.73(s,1H),4.51(d,J=10.5Hz,1H),4.12-4.08(m,4H),3.93-3.78(m,2H),3.68(dd,J=1 1.9,2.8Hz,1H),3.53(s,3H),3.57-3.46(m,1H),2.27-2.19(m,1H),2.10(s,3H),1.89(d,J=12 .7Hz,1H),1.79-1.70(m,2H),1.59-1.56(m,2H),1.08(s,6H),1.31-0.71(m,5H);LC-MS(Method 2):t R= 4.43 minutes, m / z(M+H) + =557.

[0083] Example 13. 4-(4-((S)-3-cyclohexylmorpholino)-2-((S)-2-(hydroxymethyl)morpholino)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Cpd.13) [ka] The starting material (S)-4-(2-chloro-4-(3-cyclohexylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-cyclohexylmorpholine according to the same procedure described in Example 1. The title compound was prepared from (S)-4-(2-chloro-4-(3-cyclohexylmorpholino)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and (S)-morpholin-2-ylmethanol, HCl according to the same procedure described in Example 10 and Example 2. 1 H NMR (400MHz, DMSO-d 6)δ12.14(s,1H),7.83(d,J=2.1Hz,1H),7.74(dd,J=8.7,1.9Hz,1H),7.46(d,J=8.7Hz,1H),7.39-7.32(m,2H),6.37(t,J= 2.4Hz,1H),4.77(t,J=5.5Hz,1H),4.61(d,J=12.9Hz,1H),4.46(d,J=13.1Hz,1H),4.25(d,J=10.3Hz,1H),4.00(t,J=12. 4Hz,2H),3.94-3.86(m,1H),3.79(dd,J=10.9,3.2Hz,1H),3.73-3.59(m,2H),3.57(s,3H),3.54-3.34(m,5H),2.92(td,J LC-MS (Method 2): t R =4.15 minutes, m / z(M+H) + =559.

[0084] Example 14. (S)-4-(4-(3-cyclohexylmorpholino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Cpd.14) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-cyclohexylmorpholine following a similar procedure as described in Example 2. 1 H NMR (400MHz, DMSO-d 6)δ12.19(s,1H),8.27(s,1H),8.02(s,1H),7.99(d,J=2.1Hz,1H),7.93(dd,J=8.7,2.0Hz,1H),7.79( d,J=8.5Hz,1H),7.47(d,J=1.9Hz,1H),7.38(t,J=2.7Hz,1H),6.42(t,J=2.5Hz,1H),4.73(d,J=1.4H z,1H),4.47(d,J=10.3Hz,1H),4.12-4.08(m,4H),3.87-3.64(m,3H),3.59(s,3H),3.52(dt,J=12.6, 6.6Hz,1H),2.22(d,J=10.7Hz,1H),1.95-1.49(m,5H),1.09(s,6H),1.32-0.68(m,5H);LC-MS(Method 2):t R= 4.42 minutes, m / z(M+H) + =582.

[0085] Example 15. 4-(4-((S)-3-(4-fluorophenyl)morpholino)-2-((S)-2-(hydroxymethyl)morpholino)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Cpd.15) [ka] The title compound was prepared from 6-bromo-2,4-dichloroquinazoline and (S)-3-(4-fluorophenyl)morpholine following a similar procedure as described in Example 13. 1 H NMR (400MHz, DMSO- <d 6)δ12.13(s,1H),7.99(d,J=2.2Hz,1H),7.82(dd,J=8.7,2.0Hz,1H),7.53-7.42(m,3H), 7.36(s,1H),7.32(t,J=2.8Hz,1H),7.07(t,J=8.8Hz,2H),6.37(t,J=2.4Hz,1H),5.03(t ,J=5.3Hz,1H),4.80(t,J=5.8Hz,1H),4.53(d,J=13.0Hz,1H),4.40(d,J=13.2Hz,1H),3 .92-3.86(m,5H),3.72(dt,J=13.5,4.0Hz,1H),3.56(s,3H),3.54-3.41(m,4H),3.26(br s,1H),2.80(t,J=12.7Hz,1H),2.65(dd,J=13.1,10.5Hz,1H);LC-MS(Method 2):t R= 4.00 minutes, m / z(M+H) + =571.

[0086] Example 16. BROMOSCAN assay. Competitive ligand binding assays for the bromodomains of BET family proteins, CBP, and p300 proteins were performed at Eurofins DicoverX Corporation (San Diego, CA) using the BROMOscan® service.

[0087] Briefly, T7 phages displaying tandem bromodomains of BET family proteins, CBP, and p300, were grown in parallel in 24-well blocks in E. coli hosts derived from the BL21 strain. E. coli were infected with T7 phages and incubated with shaking at 32 °C until lysis (90–150 min). Lysates were then centrifuged (5,000 × g) and filtered (0.2 μm) to remove cellular debris. To generate affinity resins for the assay, streptavidin-coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 min at room temperature. Ligated beads were blocked with excess biotin and washed with SEA BLOCK Blocking Buffer (Thermo Fisher, Rockford, IL), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific phage binding. Binding reactions were assembled by combining DNA-tagged proteins, coordinated affinity beads, and test compounds in 1x binding buffer (17% Seablock, 0.33x PBS, 0.04% Tween20, 0.02% BSA, 0.004% sodium azide, 7.4mM DTT). Test compounds were prepared as 1000x stocks in DMSO and subsequently diluted to ensure a final DMSO concentration of 0.1%. The assay plate was incubated for 1 hour at room temperature with shaking, and the affinity beads were washed with wash buffer (1xPBS, 0.05% Tween20). The beads were then resuspended in elution buffer (1xPBS, 0.05% Tween20, 2μm non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. The DNA-tagged protein concentration in the eluate was then measured by qPCR. Using 3-fold serial dilutions across 11 compound concentrations ranging from 0 µM to 10 µM, d The value was obtained. d Values ​​were calculated using a standard dose-response curve, using the Hill equation with a slope of -1. Curves were fitted using a nonlinear least-squares fit with the Levenberg-Marquardt algorithm.

[0088] Example 17. AlphaScreen Assay Utilizing full-length recombinant human BRD4 (NCBI reference sequence: NM_058243) corresponding to amino acid positions 2-1362 including an N-terminal His tag (Reaction Biology, Catalog No. RD-21-153) expressed in Sf9 insect cells, and histone H4 peptide (1-21) containing acetylated lysine residues at positions 5, 8, 12, and 16 as ligand, the AlphaScreen® assay, a fluorescence resonance energy transfer (FRET) based assay, was performed at Reaction Biology (Malvern, PA) following the manufacturer's protocol (PerkinElmer, Waltham, MA). Briefly, BRD4 and test compounds were pre-incubated for 30 min at room temperature in 50 mM HEPES, pH 7.5, 100 mM NaCI, 0.05% CHAPS, 0.1% BSA over 11 compound concentrations ranging from 0 μM to 20 μM obtained in 3-fold serial dilutions. H4 ligand peptide was then added and the mixture was incubated for an additional 30 min at room temperature. Streptavidin-coated donor beads and Ni acceptor beads were then added and the mixture was incubated for an additional 60 min. Fluorescence measurements (Ex / Em=680 / 520-620 nm) were taken and the data was fitted to a Hill equation with a variable slope to determine the IC 50 Got the value.

[0089] Example 18. MV4-11 Assay. Cell lines: MV4-11 cell line was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured in RPMI 1640 (Invitrogen 11879020) culture medium supplemented with 10% fetal bovine serum and 100 units / mL penicillin, 100 pg / mL streptomycin at 37 °C and 5% CO. 2 The plates were maintained in a humidified air incubator at 95%.

[0090] Cytotoxicity Assay: MV4-11 cells were cultured as described above and seeded into 1536-well white solid tissue culture plates in 5 μL of RPMI 1640 (Invitrogen 11879020) culture medium supplemented with 10% fetal bovine serum and 100 units / mL penicillin, 100 μg / mL streptomycin using a Multidrop Combi peristaltic dispenser (ThermoFisher, Waltham, MA) at a density of 500 cells / well. 23 nL of compound in DMSO was transferred to the 1536-well assay plate using a 1536-well pintool dispenser fitted with 20 nL pins (Wako Automation, San Diego, CA). After 72 h incubation at 37°C, 2.5 μL of CellTiter-Glo (Promega) was dispensed into each well using a BioRAPTR FRD dispenser (Beckman Coulter, Brea, CA). Plates were incubated at room temperature for 10 min, transferred to a ViewLux microplate imager (PerkinElmer, Waltham, MA) and ATP-coupled luminescence was measured using a 1 s exposure.

[0091] Example 19. Kasumi-1 assay. Cell viability assay: A cell viability assay was performed using the acute myeloid leukemia cell line Kasumi-1 (ATCC® CRL-2724™) (ATCC, Manassas, VA) to determine the GI, which is the compound concentration that produces 50% growth inhibition. 50 Briefly, cells were seeded in 96-well flat-bottom cell culture plates at a density of 30,000 cells per well (MV-4-11) or 10,000 cells per well (Kasumi-1) in RPMI supplemented with 10% fetal bovine serum and L-glutamine, penicillin, and streptomycin. Cells were incubated at 37 °C for 24 h in 5% CO 2Cells were maintained at 4°C and then exposed to a given compound at either 11 or 21 concentrations ranging from 0 to 20 μM in a volume of 150 μL in the presence of 0.2% dimethylsulfoxide (the solvent used in the serial dilution of compounds). Exposure was maintained for approximately 72 hours and cell viability was measured using CellTiter-Blue® (Promega, Madison, Wl) according to the manufacturer's instructions. A four-parameter dose-response model in GraphPad Prism (La Jolla, CA) was used to calculate the G1 50 values ​​were calculated. [Table 2] [Table 3]

[0092] Example 20. Mouse Kasumi-1 xenograft study. Kasumi-1 xenograft studies were performed by HD Biosciences (Shanghai, China) at their AAALAC-accredited facility. All animal study procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of HD Biosciences. Kasumi-1 cell suspensions (1 × 10 7 Kasumi-1 human leukemia tumor models were established in female CB-17 SICD mice by subcutaneous injection of 0.2 mL / 0.2 mL of 1:1 DPBS and BD Matrigel into the right flank. Tumors were grown to a size of 100–150 mm. 3Mice were allowed to grow to 100 mg / kg / day and randomly divided into 6 groups (8 animals / group) with similar mean tumor volumes and body weights. Compounds were formulated as solutions in 30% solutol in water and pH was adjusted in situ with 1.05 equivalents of HCl (0.1N HCl (aq)), while the reference compound I-BET762 was formulated with 2% DMSO + 98% (20% HP-β-CD in water). Compounds were administered to mice once a day via oral gavage and tumor measurements were taken daily for the following 4 weeks. Tumor volumes were monitored and measured twice weekly. Animals were then sacrificed at the end of the study and tumor weights were obtained (Figure 1).

[0093] Other embodiments Although the present invention has been described with its detailed description, it should be understood that the foregoing description is intended to illustrate, and not to limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. It should be understood by those skilled in the art to which the present invention pertains that any of the features described herein with respect to any particular aspect and / or embodiment of the present invention can be combined with any one or more of the other features of any other aspect and / or embodiment of the present invention described herein, with appropriate modifications to ensure compatibility of the combination. Such combinations are considered to be part of the invention contemplated by this disclosure.

Claims

1. A compound of formula (I) 【Chemical C1】 During the ceremony, X is O, NH, NC(O)C1-3 alkyl, 【Chemical C2】 or NS(O)Me, A, 【Chemical C3】 and E. 【Chemical C4】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C5】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

2. A compound of formula (I) 【Chemical C6】 During the ceremony, X is O, NH, NC(O)C1-3 alkyl, 【Chemical C7】 or NS(O)Me, A, 【C8】 and E. 【Chemical C9】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【C10】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

3. A compound of formula (I) 【Chemical C11】 During the ceremony, X is O, NC(O)Me, or NS(O)Me; A is 【Chemical C12】 and E. 【Chemical C13】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C14】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

4. A compound of formula (I) 【Chemical C15】 During the ceremony, X is O, NC(O)Me, or NS(O)Me; A is 【Chemical C16】 and E. 【C17】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【C18】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

5. A compound of formula (II) 【Chemical C19】 During the ceremony, X is O, NH, NC(O)C1-3 alkyl, 【Chemical C20】 or NS(O)Me, A, 【Chemical C21】 or 【Chemical C22】 and E. 【Chemical C23】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C24】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

6. A compound of formula (II) 【Chemical C25】 During the ceremony, X is O, NH, NC(O)C1-3 alkyl, 【Chemical C26】 or NS(O)Me, A, 【Chemical C27】 and E. 【Chemical C28】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C29】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

7. A compound of formula (II) 【Chemical C30】 During the ceremony, X is O, NH, NC(O)C1-3 alkyl, 【Chemical C31】 or NS(O)Me, A, 【Chemical C32】 and E. 【Chemical C33】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C34】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

8. A compound of formula (II) 【Chemical C35】 During the ceremony, X is O, NC(O)Me, or NS(O)Me; A, 【Chemical C36】 and E. 【C37】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C38】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

9. A compound of formula (II) 【C39】 During the ceremony, X is O, NC(O)Me, or NS(O)Me; A is 【Chemical C40】 and E. 【Chemical C41】 R1 is H, halogen, or Me; n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C42】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

10. A compound of formula (II) 【Chemical C43】 During the ceremony, X is O, NC(O)Me, or NS(O)Me; A is 【Chemical C44】 and E. 【C45】 R1 is H, F, Cl, and n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C46】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

11. A compound of formula (II) 【C47】 During the ceremony, X is O, NC(O)Me, or NS(O)Me; A is 【C48】 and E is 【C49】 R1 is H, F, Cl, and n is 0, 1, 2, or 3; Q is one of the following: 【C50】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

12. A compound of formula (II) 【Chemical C51】 During the ceremony, X is O, A, 【Chemical C52】 and E is 【Chemical C53】 R1 is H, F, Cl, and n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C54】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

13. A compound of formula (II) 【Chemical C55】 During the ceremony, X is O and A is 【Chemical C56】 and E is 【Chemical C57】 R1 is H, F, Cl, and n is 0, 1, 2, or 3; Q is one of the following: 【Chemical C58】 and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

14. A compound selected from the group consisting of: 【Chemical C59】 。

15. 15. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease by inhibiting the activity of a bromodomain-containing protein.

16. 15. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease by inhibiting the activity of a bromodomain of a BET family protein.

17. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease by inhibiting the activity of the bromodomain of CBP / p300 protein.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

19. 1. A pharmaceutical composition for treating or preventing a disease in a subject in need thereof, comprising: The pharmaceutical composition is a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to claim 18; The pharmaceutical composition, wherein the disease is selected from the group consisting of cancer, fibrosis, inflammation, and inflammatory disorders.

20. 20. The pharmaceutical composition of claim 19, wherein the disease is cancer.

21. 21. The pharmaceutical composition of claim 20, wherein the cancer is selected from the group consisting of human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, and prostate cancer.

22. 21. The pharmaceutical composition of claim 20, wherein the cancer is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and acute lymphocytic leukemia.

23. 21. The pharmaceutical composition of claim 20, wherein the cancer is selected from the group consisting of adult T-cell leukemia / lymphoma (ATLL), mixed lineage leukemia (MLL), and human T-cell leukemia virus type 1 (HTLV-1), including HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM / TSP).

24. 20. The pharmaceutical composition of claim 19, wherein the disease is fibrosis.

25. 25. The pharmaceutical composition of claim 24, wherein the fibrosis is selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, intestinal fibrosis, hepatic fibrosis, and liver cirrhosis.

26. 20. The pharmaceutical composition of claim 19, wherein the disease is inflammation or an inflammatory disorder.

27. 27. The pharmaceutical composition of claim 26, wherein the inflammation or inflammatory disorder is selected from the group consisting of allergies, asthma, autoimmune diseases, celiac disease, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejection, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, sinusitis, active hepatitis, atherosclerosis, periodontitis, juvenile rheumatoid arthritis, cystic fibrosis lung disease, Guillain-Barre syndrome, Graves' ophthalmopathy, and nonalcoholic steatohepatitis (NASH).

28. 20. Use of a compound according to any one of claims 1 to 14, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for treating or preventing inflammation in a subject in need thereof.

29. Use of a therapeutically effective amount of a compound according to any one of claims 1 to 14, a pharma- ceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to claim 18, in the preparation of a medicament for treating or preventing fibrosis in a subject in need thereof.

30. 20. Use of a therapeutically effective amount of a compound according to any one of claims 1 to 14, a pharma- ceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to claim 18, in the preparation of a medicament for treating or preventing idiopathic pulmonary fibrosis in a subject in need thereof.

31. The use according to any one of claims 15 to 17 and 28 to 30, wherein the medicament is a medicament for treating a disease.

32. The use according to any one of claims 15 to 17 and 28 to 30, wherein the medicament is a medicament for preventing a disease.

33. 20. The pharmaceutical composition of claim 19, wherein the subject is a human subject.

34. A compound of formula (I) 【Chemical C60】 In the formula, X is O; A, 【Chemical C61】 and E 【Chemical C62】 R1 is H, F, Cl, and n is 0, 1, 2, or 3; Q, 【Chemical C63】 That is, and / or a tautomer, optical isomer, or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

35. Use of at least one compound according to any one of claims 1 to 14 or of a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating or preventing a disease.

36. 36. The use of claim 35, wherein the disease is selected from the group consisting of cancer, fibrosis, inflammation, and inflammatory disorders.

37. A compound according to any one of claims 1 to 14 for use in the treatment or prevention of a disease in a human subject in need thereof.

38. 38. The compound of claim 37, wherein the disease is selected from the group consisting of cancer, fibrosis, inflammation, and inflammatory disorders.

39. 20. The composition of claim 18 for use as a medicament.

40. 20. The pharmaceutical composition of claim 18, suitable for intravenous administration.

41. 20. The pharmaceutical composition of claim 18 suitable for oral administration.

42. 20. The pharmaceutical composition of claim 18, suitable for parenteral administration.

43. 20. The pharmaceutical composition of claim 19, wherein the disease is idiopathic pulmonary fibrosis.

44. 44. The pharmaceutical composition of claim 43, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered by inhaled delivery or other direct application to the affected tissue.

45. 44. The pharmaceutical composition of claim 43, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered in the form of oral pulmonary or intranasal inhalation delivery.

46. 20. The pharmaceutical composition of claim 19, suitable for aerosol administration.

47. 44. The pharmaceutical composition of claim 43, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered in the form of a nebulized inhalant.

48. 44. The pharmaceutical composition of claim 43, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered using a nebulizer, a dry powder inhaler (DPI), or a metered dose inhaler (MDI).

49. 47. The pharmaceutical composition of claim 46, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered using a nebulizer, a dry powder inhaler (DPI), or a metered dose inhaler (MDI).

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