Quinazoline derivatives useful as selective HDAC6 inhibitors

Abstract

Provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the variables are defined herein. Also provided herein are pharmaceutical compositions comprising compounds of formula (I), and methods of using the compounds, for example, in the treatment of neuropathic disorders and fibrotic diseases. TIFF2023530788000215.tif26128

Description

[Technical Field]

[0001] Related applications This application claims priority to and benefits of U.S. Provisional Patent Application No. 63 / 036,282, filed on 8 June 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Background of the Invention WO2008040934 (Patent Document 1), WO2008068170 (Patent Document 2), WO2008087514 (Patent Document 3), WO2009026446 (Patent Document 4), WO2009045440 (Patent Document 5), WO2011011186 (Patent Document 6), WO2013154870 (Patent Document 7), U.S. Patent No. 8,188138 (Patent Document 8), U.S. Patent No. 8,058273 (Patent Document 9), U.S. Patent No. 7,803,800 (Patent Document 10), U.S. Patent No. 9,387,209 (Patent Document 11), and U.S. Patent No. 9,155,739 (Patent Document 12) disclose histone deacetylase (HDAC) inhibitors that have antitumor activity and antineurodegenerative activity.

[0003] Histones play crucial roles in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation / deacetylation alters chromatin structure and affects transcription. Histone deacetylase 6 (HDAC6), in contrast to other HDACs, is a cytoplasmic class II histone deacetylase (HDAC) that is specific to non-histone proteins, including α-tubulin. HDAC6 regulates several intracellular processes, including proteolysis, cell motility, and intercellular interactions. HDAC6 has been implicated in regulating mitochondrial transport. Inhibition of HDAC6 may increase α-tubulin acetylation and promote mitochondrial transport in hippocampal neurons.

[0004] Peripheral neuropathy is a heterogeneous group of diseases characterized by a progressive, ascending loss of nerve function originating from the peripheral regions of the extremities. Phenotypic overlap between different types of hereditary and acquired peripheral neuropathies indicates that similar pathophysiological processes are at work. Many downstream pathways in peripheral neurons have been proposed, such as axonal transport, proteolysis, and interaction with Schwann cells, organelle damage, channelopathies, and neuroinflammatory signaling, each of which has an adverse effect on peripheral nerves. Histone deacetylase 6 (HDAC6) plays an important role at the intersection of these convergent pathogenic pathways. The enzymatic deacetylase activity of HDAC6 is upregulated in neurodegenerative disorders and typically results in downstream nerve stress.

[0005] There is a need for novel and improved compounds that act as inhibitors of HDAC6 and as agents for the prevention and treatment of neuropathy-related diseases. The compounds, compositions, and methods described herein are directed towards this goal. [Invention 1001] Compound of formula (I): [[ID=...]] TIFF0007897463000001.tif43128 or a pharmaceutically acceptable salt thereof, in the formula, R 1 However, hydrogen, (C 1-2 )alkyl, or fluoro(C 1-2 ) is alkyl; R 2 However, hydrogen, halogen, or (C 1-3 ) is alkyl; R 3 However, hydrogen, or (C 1-3 ) is alkyl; R 4 However, hydrogen, halogen, (C 1-3 )alkyl, or methoxy, N(C 1-3 )(C 1-3 ) and; R5 However, hydrogen, (C 1-3 ) Alkyl, halogen, or trifluoromethyl; R 6 However, hydrogen, (C 1-3 ) alkyl, halogen; R 7 However, it is hydrogen or halogen; R 8 but is hydrogen, methyl, methoxy, or fluoro; and R 9 However, it is hydrogen or fluoro. A compound of formula (I) or a pharmaceutically acceptable salt thereof. [Invention 1002] R 1 A compound of the present invention 1001, wherein the compound is methyl. [Invention 1003] R 1 A compound of the present invention 1001, wherein the compound is ethyl. [Invention 1004] R 2 A compound of the present invention 1001, wherein the compound is hydrogen. [Invention 1005] R 2 A compound of the present invention 1001, wherein the halogen is... [Invention 1006] R 2 A compound of the present invention 1001, wherein the compound is methyl. [Invention 1007] R 3 A compound of the present invention 1001, wherein the compound is hydrogen. [Invention 1008] R 6 A compound of the present invention 1001, wherein the compound is methyl. [Invention 1009] R 2 A compound of the present invention 1001, wherein isopropyl. [Invention 1010] R 4 A compound of the present invention 1001, wherein the compound is dimethylamino. [Invention 1011] R 6 A compound of the present invention 1001, wherein isopropyl. [Invention 1012] Those of formula (IA): TIFF0007897463000002.tif24128 The compound of the present invention 1001. [Invention 1013] R 2 and R 6 A compound of the present invention 1012, wherein each of the elements is methyl. [Invention 1014] R 2 and R 6 A compound of the present invention 1012, wherein each of these is hydrogen. [Invention 1015] R 1 Compounds of the present invention 1013 or 1014, wherein is ethyl. [Invention 1016] R 8 Compounds of the present invention 1013 or 1014, wherein is fluoro. [Invention 1017] Those of formula (IB): TIFF0007897463000003.tif22128 And in the formula, R 8 A compound of the present invention 1001, wherein the compound is fluoro. [Invention 1018] Compound of formula (II): TIFF0007897463000004.tif36128 or a pharmaceutically acceptable salt thereof, in the formula R 1 However, methyl, ethyl, or fluoro(C) 1-2 ) is alkyl; R 2 However, it is phenyl substituted with 1 to 3 substituents independently selected from the group consisting of phenyl or methyl, ethyl, methoxy, trifluoromethyl, and halogens; R 3 but is hydrogen, methyl, methoxy, or fluoro; and R 4 However, it is hydrogen or fluoro. A compound of formula (II) or a pharmaceutically acceptable salt thereof. [Invention 1019] A compound of the present invention 1001 or 1018, selected from Table 1. [Invention 1020] below: (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-8-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-5-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-(2-methyl-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dichlorophenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(4-bromo-2-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(3,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-diisopropylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-diisopropylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-8-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-8-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-difluorophenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-difluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-N-hydroxyacrylamide, 3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxypropanamide, (E)-3-(3-(2,6-dimethylphenyl)-2,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(3,5-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(3,5-dimethylphenyl)-7-fluoro-2-(1-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(4-bromo-2,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(4-bromo-3-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,3-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-(4-fluoro-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(4-chloro-2-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,4-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(4-bromo-2-fluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2-bromo-4-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-mesityl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(4-bromo-2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methoxy-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-(4-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-8-fluoro-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-3-(2-ethylphenyl)-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-(2-fluoro-6-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-4-oxo-3-(p-tolyl)-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-7-fluoro-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(4-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(2-ethyl-3-(4-ethylphenyl)-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide, and (E)-3-(3-(4-(dimethylamino)phenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide A compound of the present invention 1001 or 1018, selected from the group consisting of the following. [Invention 1021] A pharmaceutical composition comprising a therapeutically effective amount of a selective HDAC6 inhibitor (HDAC6i) of the present invention 1001-1020 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or medium. [Invention 1022] A method for promoting neurite outgrowth in a subject of need, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt of the present invention 1001-1020, and a pharmaceutically acceptable carrier or medium. [Invention 1023] A method for the prevention or treatment of peripheral neuropathy in a subject in need, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt of the present invention 1001-1020, and a pharmaceutically acceptable carrier or medium. [Invention 1024] The method of the present invention 1023, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, or postherpetic neuralgia originating from herpes zoster. [Invention 1025] The method of the present invention 1024, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy. [Invention 1026] The method of the present invention 1025, wherein the chemotherapy is platinum-based chemotherapy, alkaloid-based chemotherapy, or taxane-based chemotherapy. [Invention 1027] A method for enhancing tubulin hyperacetylation of cells in a subject, comprising treating the subject with an effective amount of a selective HDAC6 inhibitor of the present invention 1001-1020 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or medium. [Invention 1028] A method for the prevention or treatment of a subject's fibrosis, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt of the present invention 1001-1020, and a pharmaceutically acceptable carrier or medium. [Invention 1029] The method of the present invention 1028, wherein the fibrosis is pulmonary fibrosis, hepatic fibrosis, or renal fibrosis. [Invention 1030] The method of the present invention 1029, wherein the pulmonary fibrosis is associated with increased expression of IL-1, TNF-α, IL-6, or collagen in the subject. [Invention 1031] The method of the present invention 1029, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis or virus-induced fibrosis. [Invention 1032] A method for reducing the expression of IL-1, TNF-α, IL-6, or collagen in a subject requiring attention, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt of the present invention 1001-1020, and a pharmaceutically acceptable carrier or medium. [Invention 1033] A method for treating or improving a cytokine-induced inflammatory condition in a subject in need, wherein the cytokine comprises IL-1, TNF-α, IL-6, M-CSF, VCAM-1, or MCP-1, and the subject is administered an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt of the present invention 1001-1020, and a pharmaceutically acceptable carrier or medium. [Invention 1034] The method of the present invention 1033, wherein the aforementioned condition is selected from the group consisting of coronavirus-induced pneumonia, acute respiratory distress syndrome, acute pneumonia, pulmonary fibrosis, hepatic fibrosis, and renal fibrosis. [Invention 1035] Use of selective HDAC6 inhibitors of the present invention 1001-1020 in the manufacture of pharmaceuticals for the prevention or treatment of peripheral neuropathy in a target population. [Invention 1036] Use of the present invention 1035, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, or postherpetic neuralgia originating from herpes zoster. [Invention 1037] The use of the present invention 1036, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy. [Invention 1038] Use of selective HDAC6 inhibitors of the present invention 1001-1020 in the manufacture of pharmaceuticals for the prevention or treatment of fibrosis in a target population. [Invention 1039] Use of selective HDAC6 inhibitors 1001-1020 of the present invention in the manufacture of pharmaceuticals for the treatment of acute respiratory distress syndrome, acute pneumonia, pulmonary fibrosis, cornonavirus-induced pneumonia, hepatic fibrosis, and renal fibrosis. [Invention 1040] A method for the prevention or treatment of diabetic neuropathy in a subject, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt of the present invention 1001-1020, and a pharmaceutically acceptable carrier or medium. [Brief explanation of the drawing]

[0006] [Figure 1] This shows neurite outgrowth (percentage compared to control) with HDAC6 inhibitors. [Figure 2] Western blots of acetylated α-tubulin (Ac-α-tub) and actin protein in primary DRG cells 48 hours after treatment with an HDAC6 inhibitor are shown. [Figure 3] This study demonstrates the protective effect of HDAC6 inhibitors in improving cisplatin-induced neurite degeneration. [Figure 4] The following groups show their 50% paw withdrawal threshold (PWT): sham control (no cisplatin treatment, no study drug treatment), media control group (treated with cisplatin and drug media only), compound 2 treatment group, ACY-1215 treatment group, and pregabalin treatment group. [Figure 5] Lung tissue images for compounds 34, 33, 2, and nintedanib, as well as controls, are shown. [Figure 6] The IL-6 concentrations for HDAC6 inhibitors are shown. [Figure 7]This shows the 50% paw stimulus avoidance threshold (PWT) to static mechanical stimulation using the von Fly filament and up-down method. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] WO2008040934 [Patent Document 2] WO2008068170 [Patent Document 3] WO2008087514 [Patent Document 4] WO2009026446 [Patent Document 5] WO2009045440 [Patent Document 6] WO2011011186 [Patent Document 7] WO2013154870 [Patent Document 8] U.S. Patent No. 8188138 [Patent Document 9] U.S. Patent No. 8058273 [Patent Document 10] U.S. Patent No. 7803800 [Patent Document 11] U.S. Patent No. 9387209 [Patent Document 12] U.S. Patent No. 9155739 [Overview of the Initiative]

[0008] In one aspect, the compound provided herein is of formula (I): TIFF0007897463000005.tif33128 or a pharmaceutically acceptable salt thereof, where R 1 is (C 1-2 )alkyl, or fluoro(C 1-2 ) alkyl; R 2 is hydrogen, halogen, or (C 1-3) alkyl; R 3 is hydrogen, or (C 1-3 ) alkyl; R 4 is hydrogen, halogen, (C 1-3 ) alkyl or methoxy, R 5 is hydrogen, (C 1-3 ) Alkyl, halogen, or trifluoromethyl; R 6 is hydrogen, (C 1-3 ) alkyl, halogen; R 7 R is hydrogen or halogen; 8 is hydrogen, methyl, methoxy, or fluoro; and R 9 It is hydrogen or fluoro.

[0009] In some situations, R 1 is methyl. In other contexts, R 1 is ethyl. In some embodiments, R 2 In one embodiment, R is hydrogen, but in another embodiment, 2 is a halogen. In a certain manner, R 2 is methyl. In another embodiment, R 3 is hydrogen. In a further embodiment, R 6 It is methyl.

[0010] In a further stage, the compound is of formula (1A): The filename is TIFF0007897463000006.tif23128.

[0011] In another embodiment, the compound is of formula (1B): TIFF0007897463000007.tif22128, and in the formula, R 8 It is fluoro.

[0012] In some embodiments, the compound is selected from Table 1.

[0013] In one aspect, the compound provided herein is of formula (II): TIFF0007897463000008.tif26128 or a pharmaceutically acceptable salt thereof, where R 1 is methyl, ethyl, or fluoro(C) 1-2 ) alkyl; R 2 R is a phenyl compound substituted with 1 to 3 substituents independently selected from the group consisting of phenyl, methyl, ethyl, methoxy, trifluoromethyl, and halogens; 3 is hydrogen, methyl, methoxy, or fluoro; and R 4 It is hydrogen or fluoro.

[0014] In one aspect, the foregoing provides a pharmaceutical composition comprising a therapeutically effective amount of a selective HDAC6 inhibitor (HDAC6i) of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or medium.

[0015] In some embodiments, a method for the prevention or treatment of chemotherapy-induced peripheral neuropathy in a subject, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt disclosed herein, and a pharmaceutically acceptable carrier or medium. In other embodiments, the chemotherapy is platinum-based, alkaloid-based, or taxane-based chemotherapy.

[0016] A method for enhancing tubulin hyperacetylation of cells in a subject in several aspects, comprising treating the subject with an effective amount of a selective HDAC6 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or medium.

[0017] In another embodiment, a method for the prevention or treatment of fibrosis in a subject, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt disclosed herein, and a pharmaceutically acceptable carrier or medium. In a further embodiment, the fibrosis is pulmonary fibrosis, hepatic fibrosis, or renal fibrosis, and the pulmonary fibrosis is associated with increased IL-6 expression in the subject. In another embodiment, the pulmonary fibrosis is idiopathic pulmonary fibrosis or virus-induced fibrosis.

[0018] A method for reducing IL-6 expression in a subject in which it is needed, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt disclosed herein, and a pharmaceutically acceptable carrier or medium.

[0019] In a further embodiment, a method for treating or improving a cytokine-induced inflammatory condition in a subject in need, wherein the cytokine comprises IL-6, M-CSF, VCAM-1, MCP-1 tPA, MMP-1, MMP9, type I collagen, and type III collagen, and the subject is administered an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt disclosed herein, and a pharmaceutically acceptable carrier or medium. In another embodiment, the condition is selected from the group consisting of pulmonary fibrosis, coronavirus-induced pneumonia, hepatic fibrosis, and renal fibrosis.

[0020] In some embodiments, the use of a selective HDAC6 inhibitor disclosed herein in the manufacture of a pharmaceutical product for the prevention or treatment of chemotherapy-induced peripheral neuropathy in a subject requiring treatment.

[0021] In another embodiment, the use of a selective HDAC6 inhibitor disclosed herein in the manufacture of a pharmaceutical product for the prevention or treatment of fibrosis in a subject requiring it.

[0022] In a further embodiment, the use of the selective HDAC6 inhibitors disclosed herein in the manufacture of pharmaceuticals for the treatment of pulmonary fibrosis, cornonavirus-induced pneumonia, hepatic fibrosis, and renal fibrosis.

[0023] In some embodiments, a method for the prevention or treatment of diabetes-induced neuropathy in a subject, comprising administering to the subject an effective amount of a selective HDAC6 inhibitor or pharmaceutically acceptable salt disclosed herein, and a pharmaceutically acceptable carrier or medium. [Modes for carrying out the invention]

[0024] Detailed description of certain aspects of the invention As generally described herein, the present invention provides compounds designed to act, for example, as histone deacetylase (HDAC) inhibitors, such as HDAC6 inhibitors. In certain embodiments, such compounds are expected to be useful as therapeutic agents for treating diabetic neuropathy, such as diabetic peripheral neuropathy. In other embodiments, such compounds are expected to be useful as therapeutic agents for treating chemotherapy-induced neuropathy, such as chemotherapy-induced peripheral neuropathy.

[0025] definition chemical definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are based on the Periodic Table, CAS edition, Handbook of Chemistry and Physics, 75. th Identification is made according to the ed.'s endpapers, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional group moieties and reactivity, are referred to Thomas Sorrell, *Organic Chemistry*, University Science Books, Sausalito, 1999; Smith and March, *March's Advanced Organic Chemistry*, 5 thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0026] Isomers, such as stereoisomers, can be isolated from a mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0027] "Stereoisomers": It should be understood that compounds having the same molecular formula but differing in the bonding properties or arrangement of their atoms or their spatial arrangement are also called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are incompatible mirror images of each other are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by the Kahn-Prelogue R and S order rule, or by the rotation of the plane of polarization of the molecule, which is designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0028] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). In other words, the "S" isomer of a compound is substantially free of the "R" isomer and is therefore enantiomer-rich of the "R" isomer. The terms "enantiomerically pure" or "pure enantiomer" indicate that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of enantiomers. In a certain manner, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0029] In the compositions provided herein, enantiomers pure compounds may be present together with other active or inactive components. For example, a pharmaceutical composition containing an enantiomers pure R-position / central / carbon compound may, for example, contain about 90% excipients and about 10% enantiomers pure R-compounds. In certain embodiments, the enantiomers pure R-compound in such a composition may, for example, consist of at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound by the total weight of the compound. For example, a pharmaceutical composition containing an enantiomers pure S-compound may, for example, contain about 90% excipients and about 10% of the enantiomers pure S-compound by the total weight of the compound. In certain embodiments, the enantiomers pure S-compound in such a composition may, for example, consist of at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound by the total weight of the compound. In certain embodiments, the active component may be formulated with little or no excipients or carriers.

[0030] The term "diastereomerically pure" indicates that a compound contains a single diastereomer in greater than 75% by weight, greater than 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 91% by weight, greater than 92% by weight, greater than 93% by weight, greater than 94% by weight, greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight, or greater than 99.9% by weight. Methods for determining diastereomer and enantiomer purity are well known in the art. Diastereomer purity can be determined by any analytical method capable of quantitatively distinguishing a compound and its diastereomers, such as high-performance liquid chromatography (HPLC).

[0031] The articles “a” and “an” may be used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an analogue” means one or more analogues.

[0032] When a range of values is recited, it is intended to include each value and sub-range within the range. For example, "C 1-6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.

[0033] The following terms are intended to have the meanings presented along with them and are useful in understanding the description and intended scope of the present invention.

[0034] "Alkyl" refers to a group of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4Alkyl). In some embodiments, alkyl groups have 1 to 3 carbon atoms ("C"). 1-3 Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 Alkyl). In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 2-6 Alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tert-amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and so on. Unless otherwise specified, each example of an alkyl group may be independently substituted, i.e., unsubstituted ("unsubstituted alkyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, alkyl groups are unsubstituted C 1-10 It is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C 1-10 It is alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0035] "Alkylene" refers to an alkyl group that has had two hydrogen atoms removed to provide a divalent group, and may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). For example, exemplary substituted alkylene groups, which are substituted with one or more alkyl(methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-). Where a range or number of carbon atoms is provided for a particular alkylene group, it is understood that this range or number refers to a range or number of carbon atoms in a straight-chain carbon-divalent chain. The alkylene group may be substituted with one or more substituents as described herein, or it may be unsubstituted.

[0036] "Alkenyl" refers to a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 ("Alkenyl"). In certain embodiments, the alkenyl does not contain any triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2-10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkenyl"). In some embodiments, the alkenyl group has 2-3 carbon atoms ("C"). 2-3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (such as 2-butenyl) or terminal (such as 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and others. Further examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), and others. Unless otherwise specified, each example of an alkenyl group may be independently substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2-10 It is an alkenyl. In certain embodiments, the alkenyl group is substituted with C 2-10 It is Alkenil.

[0037] "Alkynyl" refers to a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 ("Alkynyl"). In certain embodiments, the alkynyl group does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2-10 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkynyl"). In some embodiments, the alkynyl group has 2-3 carbon atoms ("C"). 2-3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be internal (such as 2-butynyl) or terminal (such as 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C 2-4This includes alkynyl groups as well as pentynyl (C5), hexynyl (C6), and others. Further examples of alkynyls include heptynyl (C7), octinyl (C8), and others. Unless otherwise specified, each example of an alkynyl group may be independently substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C 2-10 It is an alkynyl group. In certain embodiments, the alkynyl group is substituted with C 2-10 It is alkinyl.

[0038] As used herein, the term “heteroalkyl” means an alkyl group as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain, and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between bonding sites. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC"). 1-10 "Alkyl" refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-9 A heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1-8 A heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1-7 A heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). 1-6A heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1-5 A heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1-4 A heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("hetero C"). 1-3 A heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom ("hetero C"). 1-2 In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 alkyl"). 2-6 The heteroalkyl group is an alkyl group. Unless otherwise specified, each example of a heteroalkyl group is either unsubstituted ("unsubstituted heteroalkyl group") or substituted with one or more substituents ("substituted heteroalkyl group"). In certain embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1-10 It is alkyl. In certain embodiments, heteroalkyl groups are substituted heteroC 1-10 It is alkyl.

[0039] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) that has 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10"Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring of the above definition is fused with one or more carbocykyl or heterocyclyl groups, where the bond group or bond site is on the aryl ring, and in such cases the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Representative aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each example of an aryl group may be independently substituted, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C 6-14 It is aryl. In certain embodiments, the aryl group is substituted C 6-14 It is Ariel.

[0040] In certain embodiments, an aryl group substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0041] Typical examples of substitution aryls include: TIFF0007897463000009.tif20128 is included, and in the formula, R 56 and R 57 One of them may be hydrogen, and R56 and R 57 At least one of them is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR. 58 COR 59 , NR 58 SOR 59 NR 58 SO2R 59 COOalkyl, COOaryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59 Selected from S-alkyl, SOalkyl, SO2alkyl, S-aryl, SOaryl, SO2aryl; or R 56 and R 57 They may together form a 5-8 atom cyclic ring (saturated or unsaturated) which optionally contains one or more heteroatoms selected from N, O, or S. 60 and R 61 These are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl substitution C6~C 10 They are aryl, 5-10 member heteroaryl, or substituted 5-10 member heteroaryl.

[0042] A "condensed aryl" refers to an aryl ring in which two of its ring carbons are shared with a second aryl or heteroaryl ring, or with a carbocykyl or heterocyclyl ring.

[0043] "Heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having a ring carbon atom and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom whose valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocykrill or heterocyclyl groups, where the bond site is on the heteroaryl ring, and in such cases the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which the heteroaryl ring as defined above is fused with one or more aryl groups, where the bond site is on either the aryl or heteroaryl ring, and in such cases the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. One of the rings is a bicyclic heteroaryl group that does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), and the bond site may be on either ring, i.e., on a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0044] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a ring carbon atom provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each example of the heteroaryl group may be independently substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0045] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and prinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0046] Typical examples of heteroaryls include: The formula includes TIFF0007897463000010.tif67128, where each Z is a carbonyl, N, or NR. 65 Selected from O and S; and R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryl compounds.

[0047] A "carbocyrill" or "carbocyclic" is a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3-10 This refers to a non-aromatic cyclic hydrocarbon group having zero heteroatoms ("carbocyryl"). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C"). 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Exemplary C 3-8 The carbocyric group is not limited to the aforementioned C 3-6 This includes carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrielinyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3-10 The carbocyric group is not limited to the aforementioned C 3-8 Carbocyclyl group and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C10 ) and others are included. As shown in the examples above, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or includes condensed, bridged, or spirocyclic systems such as bicyclic systems ("bicyclic carbocyclyl") and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on the carbocyclyl ring, and in such cases the number of carbons continues to specify the number of carbons in the carbocyclic system. Unless otherwise specified, each example of a carbocyclyl group may be independently substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is unsubstituted C 3-10 It is a carbocyclyl. In certain aspects, the carbocyclyl group is substituted with C 3-10 It is carbocyclyl.

[0048] In some aspects, "carbocyrill" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3-8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3-6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms ("C"). 5-6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 This includes cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6This includes cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3-10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3-10 It is a cycloalkyl group.

[0049] A "heterocyclyl" or "heterocyclic" group refers to a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom whose valence is acceptable. A heterocyclyl group can be a monocyclic ("monocyclic heterocyclyl") or a bicyclic system ("bicyclic heterocyclyl"), and can be condensed, bridged, or spirocyclic, and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the bond site is on either the carbocyclyl or heterocyclyl ring, or ring systems in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each example of a heterocyclyl may be independently substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0050] In some embodiments, the heterocyclyl group is a 5-10 member non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 member heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 member non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 member heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 member non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 member heterocyclyl"). In some embodiments, the 5-6 member heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclil has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclil has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxylanyl, and thiorenyl. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidine-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianyl, and dioxanyl. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0052] The "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0053] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero may also apply to any of the aforementioned hydrocarbyl groups, e.g., alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, etc., having 1 to 5 heteroatoms, particularly 1 to 3 heteroatoms.

[0054] "Acyl" is the base, -C(O)R 20 This refers to R 20 This refers to hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl as defined herein. "Alkanoyl" is an acyl group, where R 20 These are groups other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1~C8 alkyl, and -C(O)-(CH2). t (C6~C 10 aryl), -C(O)-(CH2) t(5-10 member heteroaryl), -C(O)-(CH2) t (C3~C 10 Cycloalkyl, and -C(O)-(CH2) t (4- to 10-membered heterocyclines are included, where t is an integer from 0 to 4. In a certain manner, R 21 C1-C8 alkyl groups substituted with halo or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, which are each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0055] "alkoxy" is a base-OR 29 This refers to R 29 These are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted carbocyclyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., those having between 1 and 6 carbon atoms. Furthermore, specific alkoxy groups have between 1 and 4 carbon atoms.

[0056] In a certain manner, R 29 is amino, substituted amino, C6~C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10A group having one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent, selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 member heteroaryl), -O-(CH2) t (C3~C 10 Cycloalkyl, and -O-(CH2) t The group comprises (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary “substituted alkoxy” groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0057] "Amino" refers to the group, -NH2.

[0058] The "oxo group" refers to -C(=O)-.

[0059] "Substituting amino" is defined by the formula -N(R 38 ) refers to the amino group of 2, and here R 38 R is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 38At least one of them is not hydrogen. In a certain embodiment, each R 38 C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxyl; C3-C8 alkenyl substituted with halo or hydroxyl; C3-C8 alkynyl substituted with halo or hydroxyl; or -(CH2) t (C6~C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl, or -(CH2) t Independently selected from (4-10 member heterocyclyls), where t is an integer between 0 and 8, these are either unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups combine to form an alkylene group.

[0060] Examples of "substituted amino" groups include, but are not limited to, -NR 39 -C1~C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3~C 10 Cycloalkyl, and -NR 39 -(CH2) t (4-10 member heterocyclyls are included, where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39'' independently represents H or C1-C8 alkyl; and any alkyl group present may be substituted by a halo, substituted or unsubstituted amino, or hydroxyl; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may be substituted by an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. To avoid ambiguity, the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. A substituted amino includes both monosubstituted and disubstituted amino groups.

[0061] "Carboxylate" refers to the group, -C(O)OH.

[0062] "Cyano" refers to the base, -CN.

[0063] "Halo" or "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I). In certain embodiments, the halo group is either fluoro or chloro.

[0064] "Haloalkyl" refers to an alkyl group in which one alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, and tetrafluoroethyl.

[0065] "Hydroxy" refers to the group, -OH.

[0066] "Nitro" refers to the group, -NO2.

[0067] "Thioketo" refers to the base, which is S.

[0068] Alkyl, alkenyl, alkynyl, carbocyrill, heterocyclyl, aryl, and heteroaryl groups as defined herein may be substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyrill, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl groups). Generally, the term “substituted” means, whether or not it is preceded by the term “optionally,” that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, e.g., a substituent that results in a stable compound after substitution, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a “substituted” group has substituents at one or more substituted positions on the group, and if multiple positions in any given structure are substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of an organic compound, i.e., any substituents described herein that result in the formation of a stable compound. The present invention intends for any and all such combinations to obtain a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have any suitable substituents described herein that satisfy the hydrogen substituent and / or the valence of the heteroatom, resulting in the formation of a stable moiety.

[0069] Exemplary carbon atom substituents include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa -SSR cc -C(=O)Raa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2Raa -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 This includes aryls and 5- to 14-membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, 3, 4, or 5 R dd The groups are independently substituted; or the two geminal hydrogens on the carbon atom are the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb , or =NOR cc It has been replaced by; R aa Each example is independent of C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenil, C 2-10Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5- to 14-membered heteroaryls, or two R aa The groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R bb Each example independently involves hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5- to 14-membered heteroaryls, or two R bbThe groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R cc Each example independently involves hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5- to 14-membered heteroaryls, or two R cc The groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R dd Each example is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NRff )OR ee -OC(=NR ff )R ee -OC(=NR ff )OR ee -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by or two geminal R dd Substituents can combine to form =O or =S. R ee Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, C 6-10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg It is substituted with the base; R ff Each example independently involves hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg It is substituted with the base; and R gg Each example independently represents halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OC. 1-6 Alkyl, -ON(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 Alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2,-NHC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3,-OSi(C 1-6 Alkyl)3-C(=S)N(C 1-6 Alkyl)2, C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, C 6-10 It can be an aryl, a 3-10 member heterocyclyl, a 5-10 member heteroaryl; or two geminal R gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0070] A "counterion" or "anionic counterion" is a negatively charged group bonded to a cationic quaternary amino group to maintain electronic neutrality. Examples of counterions include halide ions (e.g., F - Cl - , Br - , I - ), NO3 - ClO4 - , OH - H2PO4 - HSO4 - These include sulfonate ions (e.g., methanesulfonate ions, trifluoromethanesulfonate ions, p-toluenesulfonate ions, benzenesulfonate ions, 10-camphorsulfonate ions, naphthalene-2-sulfonate ions, naphthalene-1-sulfonic acid-5-sulfonate ions, ethane-1-sulfonic acid-2-sulfonate ions, etc.) and carboxylate ions (e.g., acetate ions, ethaneate ions, propanoate ions, benzoate ions, glycerate ions, lactate ions, tartrate ions, glycolate ions, etc.).

[0071] These and other exemplary substituents are described in more detail in the Detailed Description and the Claims. The present invention is not limited in any way by the above-mentioned exemplary list of substituents.

[0072] Other definitions "Pharmacologically acceptable" means approved or eligible for approval by a federal or state government or a corresponding regulatory authority in a country other than the United States, or listed in the United States Pharmacopeia or any other generally accepted pharmacopoeia for use in animals, particularly humans.

[0073] "Pharmacologically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts are nontoxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or those formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid Acid addition salts formed with organic acids such as phonic acid, 4-methylbicyclo[2.2.2]-octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. Salts further include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. The term "pharmaceutically acceptable cation" refers to an acceptable cation counterion of an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium cations. See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0074] The term "prodrug" is intended to encompass therapeutically inactive compounds that, under physiological conditions, are converted into therapeutically active agents of the present invention. One method for producing a prodrug involves designing a selected portion that, under physiological conditions, is hydrolyzed or cleaved at a targeted in vivo site of action to produce a desired molecule, which then produces its therapeutic effect. In certain embodiments, the prodrug is converted by the activity of the enzyme in question.

[0075] A "tautomer" is an interchangeable form of a particular compound structure, referring to a compound that differs in the substitution of hydrogen atoms and electrons. Thus, the two structures can maintain equilibrium through the transfer of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with either an acid or a base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are similarly formed by acid or base treatment. The tautomer form may be relevant to achieving the optimal chemical reactivity and biological activity of the compound of interest.

[0076] The “subjects” to which the drug is intended to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or non-human animals, such as mammals including primates (e.g., crab-eating macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal.

[0077] In certain embodiments, substituents on an oxygen atom are oxygen protecting groups (also called hydroxyl protecting groups). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, -C(=NRbb )R aa -C(=NR bb )OR aa -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 is included, and here R aa , R bb , and R cc The term is defined as specified herein. Oxygen protecting groups are well known in the art, as seen in Protect Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd This includes details described in the edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0078] Exemplary oxygen-protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0079] In certain embodiments, substituents on a sulfur atom are sulfur protecting groups (also called thiol protecting groups). Sulfur protecting groups are not limited to -R aa , -N(R bb )2, -C(=O)SR aa -C(=O)R aa , -CO2R aa -C(=O)N(R bb)2, -C(=NR bb )R aa -C(=NR bb )OR aa -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 is included, and here R aa , R bb , and R cc The term is defined herein. Sulfur protecting groups are well known in the art, as seen in Protect Groups in Organic Synthesis, TW Greene and PGM Wuts, 3. rd This includes details described in the edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0080] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). The amino protecting group may include, but is not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa -C(=O)N(R cc )2, -S(=O)2R aa -C(=NR cc )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2ORcc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc , C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 The group includes aryl and 5-14 member heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base, and here R aa , R bb , R cc and R dd The term is defined herein. Amino protecting groups are well known in the art, as seen in Protect Groups in Organic Synthesis, TW Greene and PGM Wuts, 3. rd This includes details described in the edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0081] Examples of amino protecting groups include, but are not limited to, amide groups (e.g., -C(=O)R) and formamide. aa ); Carbamate groups including but not limited to 9-fluorenylmethylcarbamate (Fmoc), t-butylcarbamate (BOC), and benzylcarbamate (Cbz) (e.g., -C(=O)OR aa );sulfonamide groups including but not limited to p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM) (e.g., -S(=O)2R aa ) is included.

[0082] Diseases, disorders, and conditions are used interchangeably within this specification.

[0083] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to actions taken while the subject is suffering from a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or that interfere with or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), and also refer to actions taken before the subject begins to suffer from a particular disease, disorder, or condition.

[0084] Generally, the “effective amount” of a compound refers to an amount sufficient to induce a desired biological response, for example, to treat a neurological disorder. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject.

[0085] As used herein, and unless otherwise specified, “therapeutic effective dose” of a compound means an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. The therapeutic effective dose of a compound means the amount of the therapeutic agent that, alone or in combination with other therapeutic methods, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic effective dose” may include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0086] In an alternative embodiment, the present invention intends to administer the compound or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof as a prophylactic agent before a subject begins to develop a particular disease, disorder, or condition. As used herein, and unless otherwise specified, “prophylactic effective dose” of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. The prophylactic effective dose of a compound means the amount of the therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent.

[0087] compound In one aspect, the compound provided herein is of formula (I): TIFF0007897463000011.tif43128 or a pharmaceutically acceptable salt thereof, in the formula R 1 is (C 1-2 )alkyl, or fluoro(C 1-2 ) is alkyl; R 2 is hydrogen, halogen, or (C 1-3 ) is alkyl; R 3 is hydrogen, or (C 1-3 ) is alkyl; R 4 is hydrogen, halogen, or (C 1-3 )alkyl, methoxy or N(C 1-3 )(C 1-3 ) and; R 5 is hydrogen, (C 1-3 ) Alkyl, halogen, or trifluoromethyl; R 6 is hydrogen, (C 1-3 ) alkyl, halogen; R 7 is hydrogen or halogen; R 8is hydrogen, methyl, methoxy, or fluoro; and R 9 It is hydrogen or fluoro.

[0088] In some embodiments, the compound is of formula (1A): The filename is TIFF0007897463000012.tif24128.

[0089] In some embodiments, the compound is of formula (1B): The filename is TIFF0007897463000013.tif22128.

[0090] base R 1 In some embodiments, R 1 is (C 1-2 )alkyl, or fluoro(C 1-2 It is alkyl.

[0091] In some situations, R 1 It is methyl.

[0092] In some situations, R 1 It is ethyl.

[0093] In some situations, R 1 It is hydrogen.

[0094] base R 2 In some embodiments, R 2 is hydrogen, halogen, or (C 1-3 It is alkyl.

[0095] In some embodiments, R 2 It is methyl.

[0096] In some embodiments, R 2 It is ethyl.

[0097] In some embodiments, R 2 It is fluoro.

[0098] In some embodiments, R 2 It is isopropyl.

[0099] base R 3 In some embodiments, R 3 is hydrogen, or (C 1-3 It is alkyl.

[0100] In some embodiments, R 3 It is hydrogen.

[0101] In some embodiments, R 3 It is methyl.

[0102] In some embodiments, R 3 It is ethyl.

[0103] base R 4 In some embodiments, R 4 is hydrogen, halogen, (C 1-3 )alkyl, methoxy, or N(C 1-3 )(C 1-3 )

[0104] In some embodiments, R 4 It is hydrogen.

[0105] In some embodiments, R 4 It is methyl.

[0106] In some embodiments, R 4 It is ethyl.

[0107] In some embodiments, R 4 It is methoxy.

[0108] In some embodiments, R 4 It is dimethylamino.

[0109] In some embodiments, R 4 is fluoro

[0110] In some embodiments, R 4 It is chloroform.

[0111] In some embodiments, R 4 It is Bromo.

[0112] base R 5 In some embodiments, R 5 is hydrogen, (C 1-3 ) It is alkyl, halogen, or trifluoromethyl.

[0113] In some embodiments, R 5 It is hydrogen.

[0114] In some embodiments, R 5 It is methyl.

[0115] In some embodiments, R 5 It is ethyl.

[0116] In some embodiments, R 5 It is trifluoromethyl.

[0117] base R 6 In some embodiments, R 6 is hydrogen, (C 1-3 ) It is an alkyl or halogen.

[0118] In some embodiments, R 6 It is hydrogen.

[0119] In some embodiments, R 6 It is methyl.

[0120] In some embodiments, R 6 It is ethyl.

[0121] In some embodiments, R 6 It is isopropyl.

[0122] base R 7 In some embodiments, R 7 It is hydrogen or a halogen.

[0123] In some embodiments, R 7 It is hydrogen.

[0124] In some embodiments, R 7 It is fluoro.

[0125] base R 8 In some embodiments, R 8 These are hydrogen, methyl, methoxy, or fluoro.

[0126] In some embodiments, R 8 It is hydrogen.

[0127] In some embodiments, R 8 It is methyl.

[0128] In some embodiments, R 8 It is ethyl.

[0129] In some embodiments, R 8 is methoxy.

[0130] In some embodiments, R 8 It is fluoro.

[0131] base R 9 In some embodiments, R 9 It is hydrogen or fluoro.

[0132] In some embodiments, R 9 It is hydrogen.

[0133] In some embodiments, R 9 It is fluoro.

[0134] In some embodiments, the compound is of formula (IA), and R 2 and R 6 Each of these is methyl. In some embodiments, the compound is of formula (IA) and R 2 and R 6 Each of them is methyl, and R 1 is ethyl. In some embodiments, the compound is of formula (IA), and R 2 and R 6 Each of them is methyl, and R 1 is ethyl, and R 8 It is fluoro.

[0135] In some embodiments, the compound is of formula (IA), and R 2 and R 6 Each of these is hydrogen. In some embodiments, the compound is of formula (IA) and R 2 and R 6 Each of them is hydrogen, and R 1 is ethyl. In some embodiments, the compound is of formula (IA), and R 2 and R 6 Each of them is hydrogen, and R 1 is ethyl, and R 8 It is fluoro.

[0136] In some embodiments, the compound is of formula (IA), and R 1 It is ethyl.

[0137] In some embodiments, the compound is of formula (IA), and R 8 It is fluoro.

[0138] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below.

[0139] [Table 1] TIFF0007897463000015.tif234128TIFF0007897463000016.tif239128TIFF0007897463000017.tif235128TIFF0007897463000018.tif83128

[0140] In one aspect, what is provided herein are the compounds described herein. In another aspect, what is provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I) or formula (II)).

[0141] In one aspect, the foregoing provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I) or formula (II)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in a pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0142] Alternative approach In an alternative embodiment, the compounds described herein may include one or more isotopic substitutions. For example, hydrogen 2 H (D, i.e., deuterium) or 3 It could be H (T, i.e., tritium); carbon, for example, 13 C or 14 It could be C; oxygen, for example, 18 It can be O; nitrogen, for example, 15 It can be N, and so can the others. In other embodiments, a specific isotope (for example, 3 H, 13 C, 14 C, 18 O, or 15N) can be at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound.

[0143] Instructions for use and treatment In several aspects, compounds of formula (I) or formula (II) are useful for enhancing tubulin hyperacetylation in cells. The microtubule network is formed by the polymerization of α / β tubulin heterodimers and plays a crucial role in regulating cell morphology, intracellular transport, cell motility, and cell division. α and β tubulin subunits undergo numerous post-translational modifications, including tyrosination, phosphorylation, polyglutamylation, polyglycylation, and acetylation. Tubulin is one of the major acetylated cytoplasmic proteins and a major substrate of the histone deacetylase HDAC6. Inhibition of HDAC6 is known to result in higher levels of tubulin acetylation and enhance mitochondrial movement in hippocampal neurons. Inhibition of HDAC6 is expected to increase mitochondrial transport in neuronal cells and enhance neuronal regeneration.

[0144] In some aspects described herein, for example, compounds of formula (I) or formula (II) are useful for promoting neurite outgrowth and neurite regeneration in the target area. In some aspects disclosed herein, compounds of formula (I) are useful for improving conditions associated with neurite degeneration in the target area.

[0145] In several other aspects, the foregoing discloses methods of using the compounds described herein, for example, compounds of formula (I) or formula (II), as therapeutic agents for the treatment of nerve or neuronal damage.

[0146] In some further contexts, this specification describes methods of using the compounds described herein, for example, compounds of formula (I) or formula (II), which are useful as therapeutic agents for inducing nerve or neuronal regeneration.

[0147] In some aspects disclosed and described herein, for example, compounds of formula (I) or formula (II) are useful as therapeutic agents for treating neurological disorders.

[0148] In some aspects, the compounds described herein, for example, the compounds of formula (I) or formula (II), are useful as therapeutic agents for treating neurological disorders.

[0149] Examples of neuropathic disorders include neuropathic pain, but the criteria can also be applied to diabetic neuropathy, postherpetic neuralgia, postherpetic neuralgia, fibromyalgia, etc. However, neuropathic disorders are not limited to pain, and include various peripheral and central nervous system pains, painful diabetic neuropathy, complex regional pain syndrome, chemotherapy-induced nerve injury, cancer pain, HIV-related sensory neuropathy, HIV-related myelopathy, phantom limb pain, trigeminal neuralgia, postherpetic neuralgia, painful radiculopathy, central post-stroke pain, sciatica, orofacial pain, acute or chronic inflammatory demyelinating polyradiculopathy, alcoholic neuropathy, carpal tunnel syndrome, knuckle pain, trigger finger, iatrogenic nerve injury, nerve injury due to nerve compression or infiltration by tumors, post-irradiation nerve injury, toxic peripheral neuropathy, post-traumatic peripheral nerve injury pain, glossopharyngeal pain These may include neuralgia, autoimmune nerve injury, acute, chronic, or refractory muscle and myofascial pain, post-stroke pain, post-traumatic spinal cord injury pain, pain associated with multiple sclerosis or Parkinson's disease, spinal stenosis or herniated disc pain, so-called lower back pain, pain due to cervical spondylosis or ligamentous osteoarthritis, stomatitis, periarthritis of the shoulder, pain from rheumatoid arthritis or osteoarthritis, nociceptive pain, pain from incisions, abrasions, fractures or contusions, pain from dialysis needle insertion or dialysis during dialysis, senile or neurogenic pruritus, scalp pruritus, atopic dermatitis, restless limb syndrome, numbness in the hands and feet, post-extraction pain, postoperative pain, and pain prevention through preoperative administration.

[0150] In some embodiments, compounds of formula (I) or formula (II) are used to treat peripheral neuropathic pain disorders, including those with systemic (usually symmetrical) distribution and those with local distribution. Peripheral neuropathy includes those associated with diabetes, prediabetes and other metabolic disorders, infections (primarily HIV infection and leprosy), chemotherapy, immune disorders (e.g., Guillain-Barré syndrome) and inflammatory disorders, hereditary neuropathy and channel diseases (such as hereditary erythromelopathy, a disorder in which blood vessels are incidentally blocked, becoming congested and inflamed).

[0151] In some aspects, the compounds described herein, for example, the compounds of formula (I) or formula (II), are useful as therapeutic agents for treating trigeminal neuralgia.

[0152] In some embodiments, compounds of formula (I) or formula (II) may be used to treat diabetic neuropathy, a type of nerve damage that occurs in diabetic patients and can affect as much as 50% of diabetic patients.

[0153] In several aspects, the compounds described herein, for example, compounds of formula (I) or formula (II), are expected to be useful as therapeutic agents for treating chemotherapy-induced peripheral neuropathy (CIPN). Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and widely reported adverse side effects of cancer treatment. The overall incidence of CIPN ranges from 30% to 80% of patients treated for cancer, depending on the chemotherapy regimen and duration of treatment used. The occurrence of CIPN can lead to limitations on chemotherapy doses, delays in additional treatment cycles, and even early termination of treatment. Furthermore, CIPN often persists or even worsens after the completion of chemotherapy, thereby significantly reducing the quality of life for cancer survivors.

[0154] In some aspects, chemotherapy is platinum-based chemotherapy, alkaloid-based chemotherapy, or taxane-based chemotherapy.

[0155] In several aspects disclosed herein, the compounds described herein, for example, the compound of formula (I), are useful for treating or improving conditions associated with acute inflammatory responses in organ tissues. In some embodiments, the compounds are used to treat or improve acute respiratory distress syndrome. In some embodiments described herein, the compounds are used to treat or improve conditions associated with acute pneumonia.

[0156] In some aspects disclosed herein, the compounds described herein, for example, compounds of formula (I) or formula (II), are useful as therapeutic agents for treating inflammation-related diseases. In some embodiments, inflammation-related diseases are associated with cytokine storms.

[0157] In some aspects, the compounds disclosed herein, for example, compounds of formula (I) or formula (II), are useful as therapeutic agents for treating or improving conditions resulting from excessive fibrosis in response to injury associated with an inflammatory response. In some embodiments, the compounds disclosed herein, for example, compounds of formula (I) or formula (II), are useful as therapeutic agents for reducing the expression of collagen, such as type I or type III collagen, in the target area.

[0158] In further embodiments, fibrosis is pulmonary fibrosis, hepatic fibrosis, or renal fibrosis, and in some embodiments, pulmonary fibrosis is associated with increased expression of TNF-α, IL-1, or IL-6. In other embodiments, pulmonary fibrosis is idiopathic pulmonary fibrosis or virus-induced fibrosis. In further embodiments, the use of the selective HDAC6 inhibitors disclosed herein in the manufacture of pharmaceuticals for the treatment of pulmonary fibrosis, hepatic fibrosis, and renal fibrosis.

[0159] In several aspects, the compounds described herein, for example, compounds of formula (I) or formula (II), are useful as therapeutic agents for treating or improving cytokine-induced inflammatory conditions in the target area. Such cytokines may be TNF-α, IL-1, IL-6, M-CSF, MCP-1, MMP-1, and MMP9.

[0160] In several aspects, the compounds described herein, for example, compounds of formula (I) or formula (II), are useful as therapeutic agents for reducing the expression of TNF-α, IL-1, and IL-6 in the target area. [Examples]

[0161] To allow for a more complete understanding of the inventions described herein, the following examples are provided. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope in any way.

[0162] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by routine optimization for those skilled in the art.

[0163] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of appropriate protecting groups for specific functional groups, as well as the appropriate conditions for protection and deprotection, are well known in the art. For example, many protecting groups, as well as their introduction and removal, are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0164] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) grinding, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes provide details regarding the preparation of representative oxysterols listed herein. The compounds provided herein may be prepared from starting materials and reagents known or commercially available to those skilled in the art of organic synthesis. Exemplary chiral columns usable for the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0165] Reported herein 1 1H-NMR (for example, for the region between δ(ppm) approximately 0.5 and 4 ppm) will be understood as an exemplary interpretation (e.g., an exemplary peak integral) of the NMR spectrum of a compound.

[0166] Abbreviations: PE: Petroleum ether; Depositphotos: Ethyl acetate; THF: Tetrahydrofuran; PCC: Pyridinium chlorochromate; TLC: Thin-layer chromatography; PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); AcCl: Acetyl chloride; i-PrMgCl: Isopropyl magnesium chloride; TBSCl: Tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Titanium tetra Isopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: methyl; i-Pr: isopropyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: desmartinperiodinane; EtMgBr: ethylmagnesium bromide; Depositphotos: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl.Py: Pyridine; TBAF: Tetra-n-butylammonium fluoride; THF: Tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylamide; LiOH.H2O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxy D); MeCN: Acetonitrile; NBS: N-bromosuccinimide; Na2SO4: Sodium sulfate; Na2S2O3: Sodium thiosulfate; MeCN: Acetonitrile; MeOH: Methanol; Boc: t-Butoxycarbonyl; MTBE: Methyl tert-butyl ether; K-selectride: Potassium tri-sec-butylborohydride; 9-BBNdimer: 9-Borabicyclo(3.3.1)nonane (dimer); DIPEA: Diisopropylethylamine; DMF: Dimethylformamide; FA: Formic acid; SM: Starting material.

[0167] Example 1: Scheme 1-2 a TIFF0007897463000019.tif49163 a Reagents and conditions: (a)(i) Propionic anhydride, P(OPh)3, 0°C to room temperature, 20 min; (ii) 2,6-difluoroaniline, pyridine, MW 200W, 20 min, 40%; (b) Acrylic acid, Pd(OAc)2, [(t-Bu)3PH]BF4, Cs2CO3, DMF, MW 200W, 25 min, 86%; (c)(i) EDCI HCl, HOBt(ii)NH2OTHP, DMF, room temperature, 23 hours, 66%; (d) TFA, MeOH, 86%

[0168] Example 2: Scheme 1-3 a TIFF0007897463000020.tif57168 aReagents and conditions: (a) NIS, AcOH, 85°C, 4 hours, 96%; (b) (i) Acetyl chloride or propionic anhydride, P(OPh)3, 0°C to room temperature, 20 minutes; (ii) 2,6-difluoroaniline, pyridine, MW 200W, 20 minutes; (c) Pd(OAc)2, PPh3, ethyl acrylate, NaOAc, DMA, MW 250W, 25 minutes; (d) Pd(dba)3, [(t-Bu)3PH]BF4, Me2Zn, THF, MW 115°C, 60 minutes; (e) NaOH, NH2OH, MeOH, 0°C

[0169] Example 3: Scheme 1-4 a TIFF0007897463000021.tif56168 a Reagents and conditions: (a) NIS, AcOH, 85°C, 4 hours, 84%; (b) Propionic anhydride, P(OPh)3, 0°C to room temperature, MW 200W, 20 minutes; (ii) 4-fluoro-2,6-dimethylaniline, pyridine, MW 200W, 20 minutes; (c) Pd(OAc)2, PPh3, ethyl acrylate, NaOAc, DMA, MW 250W, 25 minutes; (d) Pd2(dba)3, [(t-Bu)3PH]BF4, Me2Zn, THF, MW 115°C, 40 minutes; (e) NaOH, NH2OH, MeOH, 0°C to room temperature, 2.5 hours

[0170] Example 4: Scheme 1-5 a TIFF0007897463000022.tif55167 a Reagents and conditions: (a) N-iodosuccinimide, AcOH, 90°C, 4 hours, 94%; (b) (i) Propionic anhydride, P(OPh)3, MW 250W, 25 minutes; (ii) Amine, pyridine, 110°C, MW 250W, 25 minutes, 58%; (c) Pd(OAc)2, PPh3, ethyl acrylate, NaOAc, DMA, MW 250W, 25 minutes, 52%; (d) NaOH, NH2OH, 0°C to room temperature, 70%

[0171] Example 5: Scheme 1-6 a TIFF0007897463000023.tif53170 aReagents and conditions: (a) NIS, AcOH, 85°C, 4 hours, 84%; (b) Propionic anhydride, P(OPh)3, 0°C to room temperature, MW 250W, 20 minutes; (ii) 2,4-Dimethylaniline, Pyridine, MW 250W, 20 minutes, 58%; (c) Pd(OAc)2, PPh3, Methyl acrylate, NaOAc, DMA, MW 250W, 25 minutes, 35%; (d) NaOMe, DMF, MeOH, 80°C, 4 hours, 31%; (e) NaOH, NH2OH, MeOH, 0°C to room temperature, 4 hours, 37%

[0172] Example 6: Scheme 1-7 TIFF0007897463000024.tif59170 a Reagents and conditions: (a) NaBH4, THF, MeOH, room temperature, 4 hours, 40%; (b) (i) Ni(OAc)2 4 H2O, (ii) NaBH4, MeOH, DCM, 0°C, 3.5 hours, 42%; (c) NaOH, NH2OH, room temperature

[0173] Example 7: Scheme 1-8 a TIFF0007897463000025.tif53170 a Reagents and conditions: (i) Propionic anhydride, P(OPh)3, 0°C to room temperature, 20 min; (ii) 2,6-difluoroaniline, pyridine, MW 200W, 20 min, 53%; (b) Selecfluor, DMF, 90°C, 6 hours, 43%; (c) Acrylic acid, Pd(OAc)2, [(t-Bu)3PH]BF4, Cs2CO3, DMF, MW 200W, 25 min, 67%; (c)(i) EDCI HCl, HOBt(ii) NH2OTHP, DMF, room temperature, 18 hours, 88%; (d) TFA, MeOH, 73%

[0174] Example 8: 2-amino-4-fluoro-5-iodobenzoic acid (2a) TIFF0007897463000026.tif20128NIS (30.5 g, 135.37 mmol) was added to a solution of 2-amino-4-fluorobenzoic acid (20.0 g, 128.92 mmol) in AcOH (210 mL) at 90 °C for 4 hours. After cooling to room temperature, the reaction mixture was added to a solution of NaHSO3 (5.2 g, 50.22 mmol) in ice water (1.2 L) to precipitate a brown solid, which was then filtered. The solid was washed with H2O (100 mL) and dried in a vacuum dryer to obtain the product as a brown solid (35.0 g, 97%). Rf = 0.13 (EA / Hex = 1:2) ESIMS(+) m / z 282 [M + H] +

[0175] Example 9: 6-amino-2-fluoro-3-iodobenzoic acid (2b) A mixture of 2-amino-6-fluorobenzoic acid (7 g, 45.12 mmol) and NIS (10.7 g, 47.38 mmol) in AcOH (75 mL) was heated at 95 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was added to ice water (200 mL), and the precipitated solid was filtered. The solid was dried under reduced pressure, and the product was obtained as a brown solid (12.5 g, 98%).

[0176] Example 10: 2-amino-3-fluoro-5-iodobenzoic acid (2c) A mixture of 2-amino-3-fluorobenzoic acid (7.5 g, 48.35 mmol) and NIS (11.42 g, 50.76 mmol) in AcOH (80 mL) was heated at 95 °C for 3.5 hours. After cooling to room temperature, the reaction mixture was added to a solution of NaHSO3 (1.95 g, 18.83 mmol) in ice water (450 mL) and then filtered. The solid was washed with H2O (80 mL) and then redissolved with siRNA (200 mL). The organic layer was washed with a solution of NaCl (100 mL x 2 saturated solutions) and dried over MgSO4. MgSO4 was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude solid. The crude product was washed with DCM to obtain the product as a brown solid (8.9 g, 66%). The filtrate was concentrated and washed again with DCM to obtain the product as a brown solid. (0.3g, 2%) Total (9.2g, 68%) Rf = 0.32 (EA / Hex = 1:2)

[0177] Example 11: 2-amino-4-chloro-5-iodobenzoic acid (2d) A mixture of 2-amino-4-chlorobenzoic acid (5.0 g, 29.24 mmol) and NIS (4.2 g, 30.70 mmol) in AcOH (49 mL) was heated at 90°C for 4.5 hours. After cooling to room temperature, the resulting solution was added to an ice-cold solution of NaHSO3 (1.4 g, 13.45 mmol) in H2O (300 mL) to precipitate the solid. The solid was collected, washed with H2O (100 mL), and dried under reduced pressure to obtain the product as a brown solid (8.3 g, 96%). Rf = 0.4 (EA / Hex = 1 / 2)

[0178] Example 12: 2-amino-5-iodonicotinic acid (66) A slurry solution of 2-aminonicotinic acid (4.0 g, 28.96 mmol) and NIS (6.8 g, 30.41 mmol) in AcOH (48 mL) was stirred at 90°C for 4 hours. The resulting solution was added to H2O (600 mL) to precipitate the product. The slurry solution was filtered, and the filtered solid was further washed with ether (30 mL) to obtain the product as a brown solid (7.2 g, 94%).

[0179] Example 13: 3-(4-bromophenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3b) TIFF0007897463000031.tif20128 A solution of 2a (5.2 g, 18.50 mmol) in pyridine (25 mL) was mixed dropwise with propionic anhydride (3.6 mL, 27.76 mmol) at 0°C and stirred at room temperature for 20 minutes. P(OPh)3 (6.3 mL, 24.06 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 4-bromoaniline (4.8 g, 27.76 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the reaction was stopped by adding 3N HCl (55 mL) to the resulting solution to pH=2, and extracted with EA (100 mL × 2) and H2O (100 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark brown oil. The crude product was purified by precipitation (ether / Hex = 1 / 1) to obtain a brown solid (1.99 g, 23%). The filtrate was concentrated and precipitated again (ether / Hex = 1 / 1) to obtain a brown solid (1.99 g, 23%). Total (4.0 g, 46%). Rf = 0.4 (EA / Hex = 1:3)

[0180] 2-Ethyl-7-fluoro-6-iodo-3-(2-methyl-3-(trifluoromethyl)phenyl)quinazoline-4(3H)-one(3c) TIFF0007897463000032.tif27128 A solution of 2a (3.2 g, 11.40 mmol) in pyridine (15 mL) was added dropwise with propionic anhydride (2.2 mL, 17.12 mmol) at 0°C, and the mixture was stirred at room temperature for 30 minutes. P(OPh)3 (3.9 mL, 14.84 mmol) was added to the resulting solution and the mixture was stimulated at 250 W in a MW for 20 minutes. 2-Methyl-3-(trifluoromethyl)aniline (3.0 g, 17.12 mmol) was added to the reaction mixture and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (50 mL) to pH=2 and extracted with EA (100 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark brown oil. The crude product was purified by flash column (φ4.5×8.5, EA / HEX=1 / 8~1-7) to obtain a yellow oily mixture. Ether (10 mL) and Hex (5 mL) were added to the yellow mixture, and the mixture was left overnight at -20°C to obtain a yellowish solid (2.5 g, 46%). The filtrate was concentrated, Hex (15 mL) was added, and the mixture was left at -20°C for 3 hours to obtain a yellowish solid (0.5 g, 9%). Total (3.0 g, 55%). Rf = 0.63 (EA / Hex = 1:2); ESIMS(+) m / z 477 [M + H] +

[0181] 3-(2,6-dimethylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3d) TIFF0007897463000033.tif21128 A solution of 2a (9.0 g, 32.03 mmol) in pyridine (42 mL) was mixed with propionic anhydride (6.2 mL, 48.05 mmol) and P(OPh)3 (10.9 mL, 41.64 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 2,6-dimethylaniline (5.1 mL, 41.64 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (150 mL) to pH=2 and extracted with DCM (100 mL x 3). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was precipitated with EA (5 mL) and Hex (15 mL), and the mixture was sonicated for 2 minutes to precipitate the product (clear to slurry). Hex (50 mL) was added to the slurry solution during sonication, and the product precipitated as an orange solid (8.9 g, 66%). Rf = 0.48 (EA / Hex = 1:2)

[0182] 3-(3,5-dimethylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3e) TIFF0007897463000034.tif24128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 3,5-dimethylaniline (3.3 mL, 26.69 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (100 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellowish solid. The solid was further washed with EA / Hex (1 / 7 mL) to obtain the product as a clear orange solid (4.0 g, 53%). Rf = 0.53 (EA / Hex = 1:2)

[0183] 3-(4-bromo-2-methylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3f) TIFF0007897463000035.tif20128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C, and the mixture was stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and the mixture was stimulated at 250 W in a MW for 20 minutes. 4-bromo-2-methylaniline (5 g, 26.69 mmol) was added to the reaction mixture and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (100 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellowish-brown oil. The crude product was mixed with EA / Hex (5 / 25 mL) and concentrated to obtain a slurry. The crude product was washed with EA / Hex (5 / 25 mL) to obtain a clear orange solid (4.5 g, 52%). Rf = 0.58 (EA / Hex = 1:2)

[0184] 3-(2,6-diisopropylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one (3g) TIFF0007897463000036.tif30128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 2,6-diisopropylaniline (7.0 mL, 26.69 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the reaction was stopped by adding 3N HCl (68 mL) to the resulting solution to pH=2 and extracted with DCM (100 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an oily slurry. The crude product was washed with EA / Hex (3 / 18 mL) to obtain a white solid (4.3 g, 50%). Rf = 0.5 (EA / Hex = 1:2)

[0185] 3-(2,6-dimethylphenyl)-2-ethyl-8-fluoro-6-iodoquinazoline-4(3H)-one(3m) TIFF0007897463000037.tif24128 A solution of 2c (4.7 g, 16.72 mmol) in pyridine (22 mL) was mixed dropwise with propionic anhydride (3.2 mL, 25.09 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (5.6 mL, 25.09 mmol) was added to the resulting solution and stimulated with a 250 W MW for 20 minutes. 2,6-dimethylaniline (2.7 mL, 21.74 mmol) was added to the reaction mixture and stimulated with a 250 W MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (66 mL) to pH=2 and extracted with DCM (100 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a black oily slurry. The crude product was filtered to obtain a clear orange solid (1.21 g, 17%). The filtrate was purified using a flash column (φ4.5 × 7, EA / Hex = 1 / 7~1-6.5) to obtain a yellow oily product. The oily product was left at -20°C for 0.5 hours to obtain a white solid (2.5 g, 35%). Total (3.7 g, 52%). Rf = 0.6 (EA / Hex = 1:2)

[0186] 3-(4-bromo-2,5-dimethylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3s) TIFF0007897463000038.tif22128 A solution of 2a (5.8 g, 20.60 mmol) in pyridine (27 mL) was mixed with propionic anhydride (4.0 mL, 30.90 mmol) at 0°C and stirred at room temperature for 5 minutes. P(OPh)3 (7 mL, 26.78 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 4-bromo-2,5-dimethylaniline (5.4 g, 26.78 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (70 mL) to pH=2 and extracted with DCM (100 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ4.5×9, EA / Hex=2 / 15~1 / 6) ​​to obtain the product as a brown oil. Hex (50 mL) was added to the oil and sonicated at room temperature for 5 minutes to obtain the product as a white solid (5.3 g, 51%). Total (5.8 g, 50%). Rf = 0.63 (EA / Hex = 1:2); ESIMS(+) m / z 501 [M + H] +

[0187] 3-(4-bromo-3-methylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3t) TIFF0007897463000039.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 4-bromo-3-methylaniline (4.3 g, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (65 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown slurry oil. To the crude product, EA (3 mL), Hex (15 mL), and ether (5 mL) were added, and the mixture was sonicated to precipitate the product as a beige solid (3.3 g, 38%). The filtrate was concentrated and purified using a flash column (φ4 × 8, EA / Hex = 1 / 9~1 / 7) to obtain the product as a yellow oil. The oil was diluted with EA (5 mL) and Hex (50 mL) and left at 0°C for 18 hours to precipitate the product as a white solid (1.2 g, 14%). Total (4.5 g, 52%). Rf = 0.53 (EA / Hex = 1:2)

[0188] 3-(2,3-dimethylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3u) TIFF0007897463000040.tif21128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 2,3-dimethylaniline hydrochloride (3.6 g, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (60 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown slurry oil. The crude product was filtered, the filtrate was concentrated, and the product was purified using a flash column (φ4.5×9, EA / Hex=1 / 9) to obtain a yellow oily substance (4.0g, 53%). Rf = 0.53 (EA / Hex = 1:2); ESIMS(+) m / z 423 [M + H] +

[0189] 3-(2,5-dimethylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3w) TIFF0007897463000041.tif21128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 2,5-dimethylaniline (3 mL, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (63 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ4.5 × 11.5 mm, EA / Hex = 1 / 10 to 1 / 5) to obtain the product as a beige solid (3.2 g, 42%). Rf = 0.58 (EA / Hex = 1:2)

[0190] 3-(2,4-dimethylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3y) TIFF0007897463000042.tif21128 A solution of 2a (4.5 g, 16.01 mmol) in pyridine (21 mL) was mixed with propionic anhydride (3.3 mL, 24.02 mmol) and stirred at room temperature for 10 minutes. P(OPh)3 (5.4 mL, 20.82 mmol) was added to the resulting solution and stimulated at MW 250 W for 20 minutes. 2,4-dimethylaniline (3 mL, 20.82 mmol) was added to the reaction mixture and stimulated at MW 250 W for 20 minutes. After cooling to room temperature, the reaction was stopped by adding 3N HCl (66 mL) to pH=2 and extracted with DCM (75 mL × 2) and H2O (20 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oily substance. This was left overnight at room temperature to obtain the product as orange crystals. The crystals were further washed with EA (3 mL) and Hex (20 mL) to obtain the product (3.5 g, 52%). Rf = 0.63 (EA / Hex = 1:2)

[0191] 3-(2-bromo-4-chlorophenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3z) TIFF0007897463000043.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was added dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C, and the mixture was stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and the mixture was stimulated at 250 W in a MW for 20 minutes. 2-bromo-4-chloroaniline (4.8 g, 23.13 mmol) was added to the reaction mixture and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (60 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a greenish-brown oil. The crude product was purified using a flash column (φ4.5×8, EA / Hex=1 / 10) to obtain a yellow oily product. Hex (50 mL) was added to the oily product, and sonication was performed at room temperature for 2 minutes to precipitate the product as a white solid (3.6 g, 40%). Rf = 0.58 (EA / Hex = 1:2); ESIMS(+) m / z 509 [M + H] +

[0192] 2-Ethyl-7-fluoro-3-(4-fluoro-2-methylphenyl)-6-iodoquinazoline-4(3H)-one(3aa) TIFF0007897463000044.tif20128 A solution of 2a (4.5 g, 16.01 mmol) in pyridine (21 mL) was mixed with propionic anhydride (3.3 mL, 24.02 mmol) and stirred at room temperature for 10 minutes. P(OPh)3 (5.4 mL, 20.82 mmol) was added to the resulting solution and stimulated at 250 W in a MW for 20 minutes. 4-Fluoro-2-methylaniline (2.3 mL, 20.82 mmol) was added to the reaction mixture and stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the reaction was stopped by adding 3N HCl (60 mL) to the resulting solution to pH=2, and extracted with DCM (75 mL × 2) and H2O (50 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark red oil. The crude product was purified using a flash column (φ4×12, EA / Hex = 1 / 10~1 / 9.5) to obtain a yellow oily product. Hex (30 mL) and ether (3 mL) were added to the oily product, and the mixture was left overnight at -20°C to obtain beige crystals (5.8 g, 85%). Rf = 0.65 (EA / Hex = 1:2)

[0193] 3-(4-bromo-2-fluorophenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3ab) TIFF0007897463000045.tif20128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was added dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C, and the mixture was stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and the mixture was stimulated at 250 W in a MW for 20 minutes. 4-bromo-2-fluoroaniline (4.4 g, 23.13 mmol) was added to the reaction mixture and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (65 mL) to pH=2, and extracted with DCM (75 mL × 2) and H2O (50 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ4.5×11, EA / Hex = 1 / 10~1-8) to obtain a yellow oily slurry. Hex (50 mL) was added to the oily slurry, and the mixture was sonicated at room temperature for 2 minutes to precipitate the product as a white solid (4.5 g, 52%). Rf = 0.53 (EA / Hex = 1:2)

[0194] 2-Ethyl-7-fluoro-6-iodo-3-mesitylquinazoline-4(3H)-one(3ad) TIFF0007897463000046.tif21128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated with a MW at 250 W for 20 minutes. 2,4,6-trimethylaniline (3.3 mL, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 2N HCl (110 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified using a flash column (φ4.5 × 10, EA / Hex = 1 / 10~1 / 9) to obtain the product as a yellow oily substance, which was then directly used in the next step (9.2 g, >100%). Rf = 0.6 (EA / Hex = 1:2)

[0195] 3-(4-bromo-2,6-dimethylphenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3ae) TIFF0007897463000047.tif22128 A solution of 2a (8.0 g, 28.47 mmol) in pyridine (38 mL) was mixed with propionic anhydride (5.5 mL, 42.70 mmol) and P(OPh)3 (9.7 mL, 37.01 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 4-bromo-2,6-dimethylaniline (7.4 g, 37.01 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 2N HCl (190 mL) to pH=2 and extracted with DCM (100 mL x 2). The slurry organic layer was filtered, and the filtrate was purified using a flash column (φ5.5 × 8, EA / Hex = 1 / 10~1 / 8) to obtain the product as a yellow oil. Hex (30 mL) was added to the oil, and sonication was performed to precipitate the product as a white solid (1.5 g, 11%). Rf = 0.58 (EA / Hex = 1:2)

[0196] 2-Ethyl-7-fluoro-6-iodo-3-phenylquinazoline-4(3H)-one(3ag) TIFF0007897463000048.tif21128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated with a MW at 250 W for 20 minutes. Aniline (2.1 mL, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (75 mL × 2) and H2O (20 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ4.5 × 10, EA / Hex = 1 / 10~1 / 8) to obtain the product as a beige solid. The solid was washed with Hex (50 mL) to obtain the product as a beige solid (4.1 g, 58%). Rf = 0.5 (EA / Hex = 1:2)

[0197] 2-Ethyl-7-fluoro-6-iodo-3-(4-methoxy-2-methylphenyl)quinazoline-4(3H)-one(3ah) TIFF0007897463000049.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated with a MW at 250 W for 20 minutes. 4-methoxy-2-methylaniline (3 mL, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (100 mL × 2) and H2O (20 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark red oil. The crude product was purified using a flash column (φ4.5 × 10, EA / Hex = 1 / 10 to 1 / 8) to obtain the product as a yellow oil. Hex (50 mL) was added to the oil, and sonication was performed to precipitate the product as a white solid (2.6 g, 34%). Rf = 0.43 (EA / Hex = 1:2)

[0198] 2-Ethyl-8-fluoro-3-(4-fluoro-2-methylphenyl)-6-iodoquinazoline-4(3H)-one(3ai) TIFF0007897463000050.tif27128 A solution of 2c (4.6 g, 16.37 mmol) in pyridine (22 mL) was mixed with propionic anhydride (3.1 mL, 24.55 mmol) and P(OPh)3 (5.5 mL, 21.28 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 4-fluoro-2-methylaniline (2.4 mL, 21.28 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (62 mL) to pH=2 and extracted with DCM (100 mL × 2) and H2O (50 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark red solid. The solid was washed with ether (10 mL) to obtain the product as a pale pink solid (5.2 g, 77%). Rf = 0.58 (EA / Hex = 1:2)

[0199] 3-(2,6-dimethylphenyl)-2-ethyl-6-iodopyrido[2,3-d]pyrimidine-4(3H)-one(67) TIFF0007897463000051.tif21128 A solution of 66 (4.0 g, 15.15 mmol) in pyridine (20 mL) was mixed with propionic anhydride (2.9 mL, 22.73 mmol) and P(OPh)3 (5.1 mL, 19.70 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 2,6-dimethylaniline (2.4 mL, 19.70 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 2N HCl (100 mL) to pH=2 and extracted with DCM (75 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ4.5 × 10, EA / Hex = 1 / 6 to EA / DCM / Hex = 1 / 7 / 12) to obtain the product as yellow crystals. The solid was washed with Hex (20 mL) to obtain the product as white crystals (3.5 g, 58%). Rf = 0.25 (EA / Hex = 1:2)

[0200] 3-(2,6-diisopropylphenyl)-7-fluoro-6-iodo-2-methylquinazoline-4(3H)-one(3h) TIFF0007897463000052.tif27128 To a solution of 2a (7.0 g, 24.91 mmol) in pyridine (33 mL), acetyl chloride (2.7 mL, 37.37 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 10 minutes. P(OPh)3 (8.5 mL, 32.38 mmol) was added to the resulting solution, and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-diisopropylaniline (7.0 mL, 37.37 mmol) was added to the reaction mixture, and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (115 mL) to pH=2, and extracted with EA (100 mL) and DCM (100 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was washed with (EA / ether = 1 / 3) and filtered to obtain an orange solid (4.3 g, 37%). The filtrate was concentrated and precipitated again with EA / ether = 1 / 3 to obtain a brown solid (1.48 g, 13%). Total (5.8 g, 50%). Rf = 0.43 (EA / Hex = 1:2); ESIMS(+) m / z 465 [M + H] +

[0201] 3-(2,6-dichlorophenyl)-7-fluoro-6-iodo-2-methylquinazoline-4(3H)-one(3i) TIFF0007897463000053.tif22128 To a solution of 2a (6.0 g, 21.35 mmol) in pyridine (28 mL), acetyl chloride (2.3 mL, 32.03 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 15 minutes. P(OPh)3 (7 mL, 27.76 mmol) was added to the resulting solution, and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-dichlorolaniline (5.2 g, 32.03 mmol) was added to the reaction mixture, and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (80 mL) to pH=2, and extracted with DCM (75 mL × 3) and H2O (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified using a flash column (φ4.5×8, EA / Hex = 1 / 7~1 / 5) to obtain a yellowish solid (5g, 52%). Rf = 0.35 (EA / Hex = 1:2)

[0202] 3-(2,6-dimethylphenyl)-7-fluoro-6-iodo-2-methylquinazoline-4(3H)-one(3j) TIFF0007897463000054.tif19128 To a solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL), acetyl chloride (1.9 mL, 26.69 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 20 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution, and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-dimethylaniline (3.3 mL, 26.69 mmol) was added to the reaction mixture, and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (80 mL) to pH=2, and extracted with DCM (100 mL × 2), NaCl (saturated 75 mL), and H2O (5 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark oil. Ether / Hex (3 / 3 mL) was added to the crude product and left overnight at below -20°C to obtain a clear orange solid (2.7 g, 37%). The filtrate was further purified using a flash column (φ4.5 × 8, EA / HEX = 1 / 8~1 / 6.5) to obtain the product as a yellow oil. The oil was precipitated with ether / Hex (5 / 5 mL) and left for 2 hours at below -20°C to obtain the product as a white solid (2 g, 28%). Total (4.7 g, 65%) Rf = 0.38 (EA / Hex = 1:2)

[0203] 3-(2,6-dimethylphenyl)-5-fluoro-6-iodo-2-methylquinazoline-4(3H)-one(3k) TIFF0007897463000055.tif19128 To a solution of 2b (5.0 g, 17.79 mmol) in pyridine (24 mL), acetyl chloride (1.9 mL, 26.69 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 20 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution, and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-diisopropylaniline (7.0 mL, 37.37 mmol) was added to the reaction mixture, and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl to pH=2, and extracted with DCM (100 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5×9, EA / HEX=1 / 5~1 / 3) to obtain a yellow solid. The solid was washed with ether (30 mL) to obtain a yellowish solid (2.5 g, 35%). Rf = 0.25 (EA / Hex = 1:2); ESIMS(+) m / z 431 [M + Na] +

[0204] 3-(2,6-dimethylphenyl)-8-fluoro-6-iodo-2-methylquinazoline-4(3H)-one(3l) TIFF0007897463000056.tif24128 To a solution of 2c (4.5 g, 16.01 mmol) in pyridine (21 mL), acetyl chloride (1.7 mL, 24.02 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 10 minutes. P(OPh)3 (5.4 mL, 20.81 mmol) was added to the resulting solution, and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-dimethylaniline (2.6 mL, 20.81 mmol) was added to the reaction mixture, and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (60 mL) to pH=2, and extracted with DCM (100 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. To the crude product, EA (3 mL), ether (20 mL), and Hex (5 mL) were added and concentrated to obtain a clear orange solid. (2.3 g, 35%) The filtrate was purified by column (φ4.5 × 6, EA / Hex = 1 / 7-1-6) to obtain a yellow oily product. Ether (20 mL) was added to the oily substance and left overnight at below -20°C to obtain a white solid (1.9 g, 29%). Total (4.2 g, 64%). Rf = 0.6 (EA / Hex = 1:2)

[0205] 3-(2,6-difluorophenyl)-7-fluoro-6-iodo-2-methylquinazoline-4(3H)-one(3n) TIFF0007897463000057.tif22128 To a solution of 2a (5 g, 17.79 mmol) in pyridine (23 mL), acetyl chloride (1.9 mL, 26.69 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 20 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution, and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-difluoroaniline (2.7 mL, 23.13 mmol) was added to the reaction mixture, and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (60 mL) to pH=2, and extracted with CHCl3 (100 mL × 2) and H2O (5 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oily slurry. The crude product was washed with ether (10 mL) to obtain an orange solid (4.1 g, 56%). The filtrate was purified by flash column (φ4.5 × 7.5, EA / Hex = 1-7) to obtain a white solid (0.9 g, 12%). Total (5.0 g, 68%). Rf = 0.45 (EA / Hex = 1:2)

[0206] 3-(2,6-difluorophenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3o) TIFF0007897463000058.tif28128 A solution of 2a (5 g, 17.79 mmol) in pyridine (23 mL) was mixed dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 2,6-difluoroaniline (2.7 mL, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the reaction was stopped by adding 3N HCl (68 mL) to the resulting solution to pH=2 and extracted with DCM (100 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a black oil. The crude product was purified using a flash column (φ4.5×8, EA / Hex = 1 / 7~1-6) to obtain the product as a yellow oil. Hex (35 mL) was added to the oil, and the mixture was sonicated at room temperature for 1 minute to precipitate the product as a white solid (3.1 g, 40%). Rf = 0.45 (EA / Hex = 1:2)

[0207] 3-(3,5-dimethylphenyl)-7-fluoro-6-iodo-2-methylquinazoline-4(3H)-one(3p) TIFF0007897463000059.tif27128 A mixture of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was mixed with acetyl chloride (1.9 mL, 26.69 mmol) dropwise at 0°C, and the mixture was stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and the mixture was stimulated at 250 W in a MW for 20 minutes. 3,5-dimethylaniline (2.9 mL, 23.13 mmol) was added to the reaction mixture and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (65 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange solid. The crude product was washed with EA / Hex (30 / 10 mL) and sonicated at room temperature for 3 minutes to obtain an orange solid (4.2 g, 58%). Rf = 0.0.5 (EA / Hex = 1:2)

[0208] 7-Chloro-3-(2,6-dimethylphenyl)-6-iodo-2-methylquinazoline-4(3H)-one(3q) TIFF0007897463000060.tif21128 To a mixture of 2d (5.0 g, 16.84 mmol) in pyridine (22 mL), acetyl chloride (1.8 mL, 25.26 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 15 minutes. P(OPh)3 (6 mL, 21.89 mmol) was added to the resulting solution, and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-dimethylaniline (2.7 mL, 21.89 mmol) was added to the reaction mixture, and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (68 mL) to pH=2, and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ4.5×7.5, DCM / Hex=3 / 4~EA / Hex=1 / 4) to obtain the product as a yellow oily substance (>100%). Rf = 0.53 (EA / Hex = 1:2)

[0209] 7-Chloro-3-(2,6-dimethylphenyl)-2-ethyl-6-iodoquinazoline-4(3H)-one(3r) TIFF0007897463000061.tif25128 A mixture of 2d (6.2 g, 20.74 mmol) in pyridine (27 mL) was mixed with propionic anhydride (4 mL, 31.11 mmol) dropwise at 0°C, and the mixture was stirred at room temperature for 10 minutes. P(OPh)3 (7 mL, 26.96 mmol) was added to the resulting solution and the mixture was stimulated at 250 W in a MW for 20 minutes. 2,6-dimethylaniline (3.8 mL, 31.11 mmol) was added to the reaction mixture and the mixture was stimulated at 250 W in a MW for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (70 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark brown oil. The crude product was purified by precipitation (EA / Hex = 1 / 7) to obtain a white solid (3g, 33%). The filtrate was concentrated and purified by flash column (φ4.5×6, EA / Hex = 1 / 8) to obtain a brown solid (0.9g, 10%). Total (3.9g, 43%). Rf = 0.55 (EA / Hex = 1:2)

[0210] (E)-3-(3-(4-bromophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4b) A reaction mixture of 3b (4.0 g, 8.48 mmol), Pd(OAc)2 (0.1 g, 0.43 mmol), PPh3 (0.2 g, 0.85 mmol), NaOAc (1.0 g, 12.71 mmol), and ethyl acrylate (1.4 mL, 12.71 mmol) in DMA (14 mL) was stimulated on a MW 250 W for 20 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with SiO (100 mL × 3) and saturated NaCl (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5 × 10.5, EA / HEX = 1 / 3) to obtain a solid mixture. The solid mixture was further washed with ether (10 mL) to obtain the product as an orange solid (1.26 g, 33%). Rf = 0.6 (EA / Hex = 1:2)

[0211] (E)-3-(2-ethyl-7-fluoro-3-(2-methyl-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4c) A reaction mixture of 3c (3.0 g, 6.30 mmol), Pd(OAc)2 (0.07 g, 0.32 mmol), PPh3 (0.2 g, 0.63 mmol), NaOAc (0.8 g, 9.45 mmol), and ethyl acrylate (1 mL, 9.45 mmol) in DMA (12 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by precipitation (MeOH 40 mL) to obtain the product as a brown solid (1.6 g, 58%). The filtrate was concentrated and precipitated with ether to obtain the product as a yellow solid (0.1g, 4%). Total (1.7g, 61%); Rf = 0.5 (EA / Hex = 1:2); ESIMS(+) m / z 471 [M + Na] +

[0212] (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4d) A reaction mixture of 3d (5.2 g, 12.32 mmol), Pd(OAc)2 (0.1 g, 0.62 mmol), PPh3 (0.3 g, 1.23 mmol), NaOAc (1.5 g, 18.48 mmol), and ethyl acrylate (1.4 mL, 13.55 mmol) in DMA (24 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a brown solid. The crude product was washed with MeOH (50 mL) to obtain the product as a brown solid (3.1 g, 64%). Rf = 0.55 (EA / Hex = 1:2)

[0213] (E)-3-(3-(3,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4e) A reaction mixture of 3e (4.0 g, 9.48 mmol), Pd(OAc)2 (0.1 g, 0.47 mmol), PPh3 (0.3 g, 0.95 mmol), NaOAc (1.2 g, 14.22 mmol), and ethyl acrylate (1 mL, 10.43 mmol) in DMA (19 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark solid. The crude product was washed with MeOH (50 mL x 2) to obtain the product as a brown solid (2.4 g, 64%). Rf = 0.5 (EA / Hex = 1:2)

[0214] (E)-3-(3-(4-bromo-2-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4f) A reaction mixture of 3f (4.1 g, 8.38 mmol), Pd(OAc)2 (0.1 g, 0.42 mmol), PPh3 (0.2 g, 0.84 mmol), NaOAc (1.0 g, 12.56 mmol), and ethyl acrylate (1 mL, 12.56 mmol) in DMA (16 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5 × 8, DCM / Hex=2 / 1) to obtain the product as a brown solid. (2.0g, 52%). Rf = 0.45 (EA / Hex = 1:2)

[0215] (E)-3-(3-(2,6-diisopropylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4g) A reaction mixture of 3 g (4.3 g, 8.97 mmol), Pd(OAc)2 (0.1 g, 0.45 mmol), PPh3 (0.2 g, 0.90 mmol), NaOAc (1.1 g, 13.46 mmol), and ethyl acrylate (1 mL, 9.87 mmol) in DMA (18 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (75 mL x 2), H2O (20 mL), and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark brown solid. The crude product was washed with MeOH (25 mL) and filtered to obtain the product as an orange solid. (2.5g, 62%). Rf = 0.55 (EA / Hex = 1:2)

[0216] (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-8-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4m) A reaction mixture of 3m (3.7g, 8.77 mmol), Pd(OAc)2 (0.1g, 0.43 mmol), PPh3 (0.2g, 0.88 mmol), NaOAc (1.1g, 13.15 mmol), and ethyl acrylate (1.0 mL, 9.64 mmol) in DMA (17 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified using a flash column (φ4.5×8, EA / HEX = 1 / 7~1 / 6) ​​to obtain the product as an orange foamy substance (2.9g, 84%). Rf = 0.4 (EA / Hex = 1:2)

[0217] (E)-3-(3-(4-bromo-2,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4s) A reaction mixture of 3s (4.0 g, 7.98 mmol), Pd(OAc)2 (0.1 g, 0.40 mmol), PPh3 (0.2 g, 0.80 mmol), NaOAc (1.0 g, 11.97 mmol), and ethyl acrylate (0.9 mL, 8.78 mmol) in DMA (16 mL) was stimulated on a MW 250 W for 20 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with DCM (75 mL × 2) and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4 × 8, EA / HEX = 1 / 10~1 / 9) to obtain the product as a yellow oil. Hex (50 mL) was added to the oily substance and sonicated at below room temperature for 2 minutes to precipitate the product as a white solid (1.4 g, 38%). The filtrate was concentrated and washed with MeOH (30 mL) to obtain the product as a yellow solid (0.4 g, 9%). Total (1.8 g, 47%). Rf = 0.55 (EA / Hex = 1:2); ESIMS(+) m / z 474 [M + H]+

[0218] (E)-3-(3-(4-bromo-3-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4t) A reaction mixture of 3t (4.5g, 9.24 mmol), Pd(OAc)2 (0.1g, 0.46 mmol), PPh3 (0.2g, 0.92 mmol), NaOAc (1.1g, 13.86 mmol), and ethyl acrylate (1 mL, 9.24 mmol) in DMA (19 mL) was stimulated with a MW 250 W for 30 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5 × 10, EA / HEX = 1 / 9~1 / 7) to obtain the product as a yellow solid. The solid was washed with Hex (50 mL) to obtain the product as a yellow solid (1.8 g, 42%). Rf = 0.45 (EA / Hex = 1:2)

[0219] (E)-3-(3-(2,3-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4u) A reaction mixture of 3u (4.0g, 9.47 mmol), Pd(OAc)2 (0.1g, 0.47 mmol), PPh3 (0.3g, 0.95 mmol), NaOAc (1.2g, 14.21 mmol), and ethyl acrylate (1 mL, 9.47 mmol) in DMA (19 mL) was stimulated on a MW 250 W for 30 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5 × 8.5, EA / HEX = 1 / 9~1 / 7) to obtain the product as an orange oil. The oily substance was precipitated with Hex (20 mL) and ether (5 mL), and the mixture was sonicated below 0°C to obtain a beige solid product (1.7 g, 46%). Rf = 0.5 (EA / Hex = 1:2)

[0220] (E)-3-(3-(2,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4w) A reaction mixture of 3w (3.2g, 7.53 mmol), Pd(OAc)2 (0.1g, 0.38 mmol), PPh3 (0.2g, 0.75 mmol), NaOAc (0.9g, 11.30 mmol), and ethyl acrylate (0.9mL, 8.28 mmol) in DMA (15mL) was stimulated on a MW 250W for 25 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with DCM (75mL x 2) and saturated NaCl (75mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black slurry oil. The crude product was washed with MeOH (15mL) to obtain the product as a yellowish-brown solid (1.4g, 47%). Rf = 0.5 (EA / Hex = 1:2)

[0221] (E)-3-(3-(2,4-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4y) A reaction mixture of 3y (3.5 g, 8.29 mmol), Pd(OAc)2 (0.1 g, 0.41 mmol), PPh3 (0.2 g, 0.83 mmol), NaOAc (1.0 g, 12.44 mmol), and ethyl acrylate (1.0 mL, 9.12 mmol) in DMA (16 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with DCM (75 mL × 2) and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a brown slurry oil. The crude product was washed with MeOH (30 mL) to obtain the product as a brown solid. The filtrate was concentrated, and the residue was washed with MeOH (20 mL) to obtain the product as a yellow-orange solid (0.8 g, 24%). Total (2.1 g, 65%). Rf = 0.65 (EA / Hex = 1:2)

[0222] (E)-3-(3-(2-bromo-4-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4z) A reaction mixture of 3z (3.6 g, 7.09 mmol), Pd(OAc)2 (79 mg, 0.35 mmol), PPh3 (0.2 g, 0.71 mmol), NaOAc (0.9 g, 10.64 mmol), and ethyl acrylate (0.8 mL, 7.80 mmol) in DMA (10 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with DCM (75 mL × 2) and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a brown oil. The crude product was purified by flash column (φ4.5 × 8, EA / HEX = 1 / 10~1 / 8) to obtain the product as a brown solid (1.3 g, 37%). Rf = 0.68 (EA / Hex = 1:2)

[0223] (E)-3-(2-ethyl-7-fluoro-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4aa) A reaction mixture of 3aa (3.5 g, 8.21 mmol), Pd(OAc)2 (0.1 g, 0.41 mmol), PPh3 (0.2 g, 0.82 mmol), NaOAc (1.0 g, 12.32 mmol), and ethyl acrylate (1.0 mL, 9.03 mmol) in DMA (16 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with DCM (75 mL × 2) and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ3.5×11, EA / HEX=1 / 10~1 / 6~DCM / Hex=1 / 5~1 / 3) to obtain the product as a brown solid (1.5g, 47%). Rf = 0.58 (EA / Hex = 1:2)

[0224] (E)-3-(3-(4-bromo-2-fluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4ab) A reaction mixture of 3ab (4.5 g, 9.25 mmol), Pd(OAc)2 (0.1 g, 0.46 mmol), PPh3 (0.2 g, 0.92 mmol), NaOAc (1.1 g, 13.87 mmol), and ethyl acrylate (1.1 mL, 10.17 mmol) in DMA (19 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with DCM (100 mL x 2) and saturated NaCl (100 mL) and H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5 × 10, EA / HEX = 1 / 10~1 / 8) to obtain the product as a green solid (1.6 g, 38%). Rf = 0.48 (EA / Hex = 1:2); ESIMS(+) m / z 464 [M + H]+

[0225] (E)-3-(2-ethyl-7-fluoro-3-mesityl-4-oxo-3,4-dihydroquinazolin-6-yl) ethyl acrylate (4ad) A reaction mixture of 3ad (5.4g, 12.45 mmol), Pd(OAc)2 (0.1g, 0.62 mmol), PPh3 (0.3g, 1.25 mmol), NaOAc (1.5g, 18.68 mmol), and ethyl acrylate (1.5 mL, 13.70 mmol) in DMA (24 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM (30 mL) and filtered. The filtrate was extracted with DCM (75 mL x 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black solid. The crude product was dissolved in DCM (7.5 mL) and purified by flash column (φ4.5 × 10, EA / HEX = 1 / 10 to 1 / 8) to obtain an orange solid. The solid was washed with Hex (30 mL) to obtain the product as an orange solid (2.3 g, 46%). Rf = 0.5 (EA / Hex = 1:2)

[0226] (E)-3-(3-(4-bromo-2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4ae) A reaction mixture of 3ae (1.5 g, 3.03 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), PPh3 (79 mg, 0.30 mmol), NaOAc (0.4 g, 4.55 mmol), and ethyl acrylate (0.4 mL, 3.34 mmol) in DMA (6 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (50 mL x 2) and saturated NaCl (50 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black solid. The crude product was washed with MeOH (15 mL) (from oily to slurry solution), and the solid was filtered to obtain the product as a brown solid (0.5 g, 35%). Rf = 0.6 (EA / Hex = 1:2)

[0227] (E)-3-(2-ethyl-7-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-yl)acrylic acid (4 ag) A reaction mixture of 3 ag (4.1 g, 10.40 mmol), Pd(OAc)2 (0.1 g, 0.52 mmol), PPh3 (0.3 g, 1.04 mmol), NaOAc (1.3 g, 15.60 mmol), and ethyl acrylate (1.2 mL, 11.44 mmol) in DMA (21 mL) was stimulated on a MW 250 W for 30 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified using a flash column (φ4×11, EA / HEX = 1 / 10~1 / 7.5) to obtain a clear orange solid (2.5g, 65%). Rf = 0.38 (EA / Hex = 1:2)

[0228] (E)-3-(2-ethyl-7-fluoro-3-(4-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4ah) A reaction mixture of 3ah (2.6 g, 6.00 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), PPh3 (0.2 g, 0.60 mmol), NaOAc (0.7 g, 9.00 mmol), and ethyl acrylate (0.7 mL, 6.60 mmol) in DMA (12 mL) was stimulated with a MW 250 W for 30 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (50 mL × 2) and saturated NaCl (50 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified by flash column (φ4 × 9, EA / HEX = 1 / 10~1 / 6) ​​to obtain the product as a brown oil. EA (2 mL), Hex (5 mL), and ether (1.5 mL) were added to the oily substance, and the mixture was sonicated to precipitate the product as a brown solid (1.7 g, 69%). Rf = 0.35 (EA / Hex = 1:2)

[0229] (E)-3-(2-ethyl-8-fluoro-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4ai) A reaction mixture of 3ai (5.2 g, 12.57 mmol), Pd(OAc)2 (0.1 g, 0.63 mmol), PPh3 (0.3 g, 1.26 mmol), NaOAc (1.6 g, 18.85 mmol), and ethyl acrylate (1.5 mL, 13.82 mmol) in DMA (24 mL) was stimulated on a MW 250 W for 30 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified using a flash column (φ4.5 × 10, EA / HEX = 1 / 10 to 1 / 8) to obtain a yellow solid product (3.0 g, 60%). Rf = 0.43 (EA / Hex = 1:2)

[0230] (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-yl)ethyl acrylate (68) A reaction mixture of 67 (3.5 g, 8.66 mmol), Pd(OAc)2 (0.1 g, 0.43 mmol), PPh3 (0.2 g, 0.87 mmol), NaOAc (1.1 g, 12.99 mmol), and ethyl acrylate (1.0 mL, 9.52 mmol) in DMA (17 mL) was stimulated with a MW 250 W for 30 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified by flash column (φ4 × 9, EA / HEX = 1 / 6~1 / 3) to obtain the product as a clear orange solid. (1.7g, 52%). Rf = 0.43 (EA / Hex = 1:1)

[0231] 3-(3,5-dimethylphenyl)-7-fluoro-2-(1-fluoroethyl)-6-iodoquinazoline-4(3H)-one(4v) A mixture of 3v (4.0 g, 9.47 mmol) and selecfluro (5.0 g, 14.21 mmol) in 40 mL of DMF was heated at 90°C for 6 hours. The resulting solution was concentrated and H2O (75 mL) was added. The reaction solution was extracted using DCM (75 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified by flash column (φ4.5 × 9, EA / DCM / Hex = 13 / 130 / 400~7 / 70 / 200) to obtain the product as a yellow solid (1.71 g, 43%). Rf = 0.55 (EA / Hex = 1:20)

[0232] (E)-3-(3-(2,6-diisopropylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4h) A reaction mixture of 3h (2.3g, 4.96 mmol), Pd(OAc)2 (0.06g, 0.25 mmol), PPh3 (0.1g, 0.50 mmol), NaOAc (0.6g, 7.43 mmol), and ethyl acrylate (1 mL, 7.43 mmol) in DMA (8.5 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL), siRNA (100 mL), and saturated NaCl (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. MeOH (40 mL) was added to the crude product to precipitate a brown solid, and the solid was further washed with H2O to obtain the brown solid product (1.5 g, 69%). The filtrate was concentrated and precipitated again to obtain the reddish-brown solid product (0.2 g, 11%). Total (1.7 g, 80%); Rf = 0.43 (EA / Hex = 1:2)

[0233] (E)-3-(3-(2,6-dichlorophenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4i) A reaction mixture of 3i (5.0 g, 11.16 mmol), Pd(OAc)2 (0.13 g, 0.56 mmol), PPh3 (0.3 g, 1.12 mmol), NaOAc (1.4 g, 16.74 mmol), and ethyl acrylate (2 mL, 16.74 mmol) in DMA (22 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. MeOH (40 mL) was added to the crude product, and the product precipitated as a brown solid (3.0 g, 63%). Rf = 0.3 (EA / Hex = 1:2)

[0234] (E)-3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4j) A reaction mixture of 3j (4.7g, 11.52 mmol), Pd(OAc)2 (0.13g, 0.58 mmol), PPh3 (0.3g, 1.15 mmol), NaOAc (1.4g, 17.28 mmol), and ethyl acrylate (1.4mL, 12.67 mmol) in DMA (23mL) was stimulated on a MW 250W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (75mL x 2), H2O (10mL), and saturated NaCl (75mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. MeOH (40 mL) and EA (5 mL) were added to the crude product, and the solid precipitated as a brown solid (1.7 g, 39%). The filtrate was further purified using a flash column (φ4.5 × 8, EA / HEX = 1 / 8~1 / 6) ​​to obtain the product as a yellow solid (2.0 g, 46%). Total (3.7 g, 84%); Rf = 0.5 (EA / Hex = 1:2); ESIMS(+) m / z 403 [M + Na] +

[0235] (E)-3-(3-(2,6-dimethylphenyl)-5-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4k) A reaction mixture of 3k (2.5g, 6.13 mmol), Pd(OAc)2 (0.07g, 0.31 mmol), PPh3 (0.2g, 0.61 mmol), NaOAc (0.8g, 9.20 mmol), and ethyl acrylate (1 mL, 9.20 mmol) in DMA (30 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was concentrated and extracted with siRNA (75 mL × 2), H2O (50 mL), and saturated NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5×8, EA / HEX=1 / 7~1 / 4) to obtain the product as a yellow foam (1.2g, 53%); Rf = 0.23 (EA / Hex = 1:2); ESIMS(+) m / z 403 [M + Na] +

[0236] (E)-3-(3-(2,6-dimethylphenyl)-8-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4L) A reaction mixture of 3 L (4.2 g, 10.29 mmol), Pd(OAc)2 (0.11 g, 0.51 mmol), PPh3 (0.3 g, 1.03 mmol), NaOAc (1.3 g, 15.44 mmol), and ethyl acrylate (1.2 mL, 11.32 mmol) in DMA (21 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM (50 mL) and filtered. The filtrate was extracted with DCM (75 mL x 2), H2O (20 mL), and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified using a flash column (φ4.5×8, EA / HEX = 1 / 7~1 / 5) to obtain the product as a yellow foam (3.6g, 83%). Rf = 0.3 (EA / Hex = 1:2)

[0237] (E)-3-(3-(2,6-difluorophenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4n) A reaction mixture of 3n (5 g, 12.02 mmol), Pd(OAc)2 (0.13 g, 0.60 mmol), PPh3 (0.3 g, 1.20 mmol), NaOAc (1.5 g, 18.03 mmol), and ethyl acrylate (1.4 mL, 13.22 mmol) in DMA (24 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM (30 mL) and filtered. The filtrate was extracted with DCM (75 mL x 2), H2O (10 mL), and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black solid. The crude product was dissolved in DCM (7.5 mL) and purified by flash column (φ4.5 × 8, DCM / Hex = 1 / 2 ~ EA / HEX = 1 / 7 ~ 1 / 2) to obtain the product as a white solid (2.7 g, 59%). Rf = 0.3 (EA / Hex = 1:2)

[0238] (E)-3-(3-(2,6-difluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)acrylic acid (40) A mixture of 3o (3.1g, 7.09 mmol), Pd(OAc)2 (0.1g, 0.57 mmol), [(t-Bu)3PH]BF4 (0.2g, 0.57 mmol), acrylic acid (1 mL, 14.18 mmol), and Cs2CO3 (3.5g, 10.64 mmol) in DMF (25 mL) was stimulated with a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with EA (75 mL) and NaHCO3 (saturated) (75 mL x 3). The aqueous layer was acidified to pH=2 with 3N HCl (57 mL) in an ice bath (some solid precipitated). The resulting solution was filtered, and the filtered solid was dried under reduced pressure to obtain the product as a pale pink solid. (2.3g, 86%). Rf = 0.2 (MeOH / DCM = 1 / 10)

[0239] (E)-3-(3-(3,5-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4p) A reaction mixture of 3p (4.1 g, 10.04 mmol), Pd(OAc)2 (0.1 g, 0.50 mmol), PPh3 (0.3 g, 1.04 mmol), NaOAc (1.2 g, 15.07 mmol), and ethyl acrylate (1.2 mL, 11.05 mmol) in DMA (20 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (75 mL x 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black solid. The solid was washed with MeOH (50 mL) to obtain the product as a dark red solid. (2.3g, 60%);Rf = 0.25 (EA / Hex = 1:2)

[0240] (E)-3-(7-chloro-3-(2,6-dimethylphenyl)-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4q) A reaction mixture of 3q (5.7g, 13.47 mmol), Pd(OAc)2 (0.2g, 0.67 mmol), PPh3 (0.4g, 1.35 mmol), NaOAc (1.7g, 20.21 mmol), and ethyl acrylate (1.6mL, 14.82 mmol) in DMA (25 mL) was stimulated on a MW 250W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (100 mL x 2) and saturated NaCl (100 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified using a flash column (φ4.5×8, DCM / Hex=2 / 3~EA / Hex=1 / 4) to obtain an orange oily substance. Hex (40 mL) was added to the oily substance, and the mixture was sonicated at room temperature for 1 minute to precipitate the product as a white solid. (0.8 g, 15% in two steps); Rf = 0.48 (EA / Hex = 1:2)

[0241] (E)-3-(7-chloro-3-(2,6-dimethylphenyl)-2-ethyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4r) A reaction mixture of 3r (3.0 g, 7.47 mmol), Pd(OAc)2 (0.1 g, 0.37 mmol), PPh3 (0.2 g, 0.75 mmol), NaOAc (1.0 g, 11.21 mmol), and ethyl acrylate (1 mL, 8.22 mmol) in DMA (15 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM and filtered. The filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5 × 8, EA / Hex=1 / 7) to obtain an orange solid. The solid was further washed with ether (30 mL) to obtain the product in Orand solid form (1.7 g, 55%). Rf = 0.48 (EA / Hex = 1:2)

[0242] Example 14: (E)-3-(2-ethyl-7-fluoro-3-(2-methyl-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5c, compound 4) To a slurry solution of NaOH (0.3 g, 7.14 mmol) in NH2OH (2 M / MeOH, 27 mL), 4c (1.7 g, 3.57 mmol) was added at 0°C and stirred for 0.5 hours. The reaction solution was stirred further at room temperature for 1.5 hours, then stirred at 30°C for 1 hour. To the resulting solution, 2N HCl was added to stop the reaction to pH=2, and the solution was stirred at room temperature for 10 minutes. The slurry solution was extracted with DCM (75 mL × 2) and H2O (75 mL). The organic layer of the slurry was separated and concentrated. The residue was purified by flash column (φ3.5 × 8, MeOH / DCM = 1 / 80~1 / 50) to obtain a mixture fraction. The mixture was further purified by washing with MeOH / EA = 1 / 5 mL to obtain the product as a yellowish solid (0.2 g, 10%). TIFF0007897463000095.tif33156

[0243] Example 15: (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5d, compound 2) TIFF0007897463000096.tif21128 To a slurry solution of NaOH (0.8 g, 20.28 mmol) in NH2OH (76 mL), 4d (4.0 g, 10.14 mmol) was added at room temperature and the mixture was stirred for 1.5 hours. To the resulting solution, 2N HCl (25 mL) was added to stop the reaction by bringing the pH to 2, and the mixture was extracted with CHCl3 (100 mL × 2) and H2O (100 mL). The organic layer was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a flash column (φ5.5 × 9, MeOH / CHCl3 = 1 / 40~1 / 20) to obtain the product as an orange solid. The solid was dissolved in MeOH (5 mL), CHCl3 (5 mL), and DCM (20 mL), and concentrated until 5 mL of solvent remained. EA (3 mL) was added to the residue and sonicated to precipitate the product (from clear to slurry). Hex (20 mL) was added to the slurry solution during sonication and precipitated the product as a beige solid (1.98 g, 51%). TIFF0007897463000097.tif26154

[0244] Example 16: (E)-3-(3-(3,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5e, compound 7) TIFF0007897463000098.tif24128 To a slurry solution of NaOH (0.5 g, 12.18 mmol) in NH2OH (45 mL), 4e (2.4 g, 6.08 mmol) was added at 0°C and stirred for 1.5 hours. The resulting solution was warmed to room temperature and stirred for a further 2.5 hours. The reaction solution was extracted with DCM (100 mL), H2O (100 mL), and DCM (100 mL + 2N HCl 18 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oily substance. The crude product was purified by flash column (φ4.5 × 6, MeOH / DCM = 1 / 30~1 / 20) to obtain the product as an orange solid. The solid was further washed with EA (25 mL) to obtain the product as a clear orange solid. (0.7g, 30%). TIFF0007897463000099.tif27158

[0245] Example 17: (E)-3-(3-(4-bromo-2-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5f, compound 6) TIFF0007897463000100.tif20128 To a slurry solution of NaOH (0.3 g, 7.25 mmol) in NH2OH (27 mL), 4f (1.7 g, 3.62 mmol) was added at 0°C and stirred for 10 minutes. The resulting solution was warmed to room temperature and stirred for a further 1.5 hours. The reaction solution was extracted with DCM (100 mL), H2O (100 mL), and DCM (100 mL + 2N HCl 9 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ3.5 × 8, MeOH / CHCl3 = 1 / 30~1 / 25) to obtain the product as an orange-red oil. The oil was precipitated with EA / ether (4 / 3 mL) to obtain the product as an orange solid. (0.3g, 16%). TIFF0007897463000101.tif27156

[0246] Example 18: (E)-3-(3-(2,6-diisopropylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5g, compound 8) TIFF0007897463000102.tif30128 To a slurry solution of NaOH (0.5 g, 11.24 mmol) in NH2OH (42 mL), 4 g (2.5 g, 5.62 mmol) was added and the mixture was stirred at room temperature for a further 1.5 hours. To the reaction solution, a solution of NaOH (0.1 g, 2.81 mmol) in NH2OH (10 mL) was added and the mixture was stirred at room temperature for 0.5 hours. The resulting solution was extracted with DCM (100 mL), NaCl (100 mL saturated), and CHCl3 (100 mL + 12 mL 2N HCl). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ4.5×8, MeOH / CHCl3=1 / 50) to obtain a mixed product. The mixture was further purified by flash column (φ3.5×7, EA / Hex=1 / 1~2 / 1) to obtain a white to yellowish foamy product. The foamy product was washed with ether / Hex (1.5 / 1mL) to obtain a white solid product (0.2g, 9%). TIFF0007897463000103.tif34159

[0247] Example 19: (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-8-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5m, compound 11) TIFF0007897463000104.tif24128 To a slurry solution of NaOH (0.6 g, 14.71 mmol) in NH2OH (55 mL), 4 m (2.9 g, 7.36 mmol) was added at 0°C for 0.5 hours, and then stirred at room temperature for 1 hour. The resulting solution was stopped with 2N HCl (20 mL), and extracted with CHCl3 (100 mL × 2), H2O (100 mL), and NaCl (50 mL saturated). The organic layer was concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was diluted with EA (20 mL) and sonicated at room temperature for 2 minutes to precipitate the product as a beige solid. The solid was further washed with EA (20 mL) to obtain the product as a beige solid (2.0 g, 70%). TIFF0007897463000105.tif27156

[0248] Example 20: (E)-3-(3-(4-bromo-2,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5s, compound 20) TIFF0007897463000106.tif22128 To a slurry solution of NaOH (0.2 g, 6.00 mmol) in NH2OH (23 mL), 4s (1.4 g, 3.00 mmol) was added at 0°C and stirred for 3 hours. The resulting solution (slurry to clear) was stopped by adding 2N HCl (5.5 mL) to pH=7, and extracted with DCM (60 mL × 2) and H2O (60 mL). The emulsifier solution was filtered, and the filtrate was concentrated to obtain the crude product as a yellow oil. The crude product was combined with the filtered solid and dissolved in MeOH (30 mL) and DCM (10 mL). The crude product was purified by flash column (φ4 × 8, MeOH / DCM = 1 / 50 to 1 / 30) to obtain the product as a clear orange oil. The oily substance was diluted with DCM (1 mL) and EA (3 mL), and precipitated by dropwise addition of Hex (20 mL) under sonication, resulting in a clear orange solid precipitate (0.6 g, 45%). TIFF0007897463000107.tif27159

[0249] Example 21: (E)-3-(3-(4-bromo-3-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5t, compound 21) TIFF0007897463000108.tif22128 To a slurry solution of NaOH (0.3 g, 6.53 mmol) in NH2OH (25 mL), 4 t (1.5 g, 3.27 mmol) was added at 0°C and stirred at 30°C for 5 hours. The resulting solution was stopped by adding 2N HCl (17 mL) to pH=7, and extracted with DCM (75 mL) and H2O (75 mL). The emulsifier solution was filtered, and the organic layer of the filtrate was recovered. The aqueous layer was further extracted with DCM (75 mL). The organic layers were combined and concentrated to obtain the crude product as a yellow solid. The crude product was purified by flash column (φ4 × 9, MeOH / DCM = 1 / 60~1 / 30) to obtain the product as an orange oil. The oily substance was diluted with MeOH (1 drop), DCM (2 mL), and EA (2 mL), and precipitated by adding Hex (30 mL) dropwise under sonication, resulting in a white solid precipitate (0.2 g, 10%). TIFF0007897463000109.tif34158

[0250] Example 22: (E)-3-(3-(2,3-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5u, compound 22) TIFF0007897463000110.tif21128 To a slurry solution of NaOH (0.3 g, 7.61 mmol) in NH2OH (29 mL), 4 μg (1.5 g, 3.80 mmol) was added at 0°C and stirred at room temperature for 1 hour. The resulting solution was stopped by adding 2N HCl (9.5 mL) to pH=7, and extracted with DCM (75 mL × 2), H2O (30 mL), and NaCl (20 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a clear orange oil. The crude product was purified by flash column (φ4 × 9, MeOH / DCM = 1 / 50~1 / 35) to obtain the product as a clear orange oil. The oily substance was diluted with MeOH (3 mL) and DCM (5 mL), and precipitated by dropwise addition of Hex (50 mL) under sonication, yielding a white solid product (0.8 g, 57%). TIFF0007897463000111.tif34159

[0251] Example 23: (E)-3-(3-(2,5-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compound 23, 5w) TIFF0007897463000112.tif21128 To a slurry solution of NaOH (0.3 g, 7.10 mmol) in NH2OH (27 mL), 4 w (1.4 g, 3.55 mmol) was added at 0°C and stirred at 30°C for 2 hours. The resulting solution was stopped by adding 2N HCl (14 mL) to pH=7, and extracted with DCM (75 mL × 2) and H2O (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as an orange-brown oil. The crude product was purified by flash column (φ4.5 × 8, MeOH / DCM = 1 / 50~1 / 25) to obtain the product as an orange oil. The oil was diluted with MeOH (1 mL), and EA (3 mL) was added over 2 minutes under sonication to precipitate the product as a clear orange solid. (0.3g, 22%). TIFF0007897463000113.tif34159

[0252] Example 24: (E)-3-(3-(2,4-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compound 27, 5y) TIFF0007897463000114.tif21128 To a slurry solution of NaOH (0.4 g, 10.65 mmol) in NH2OH (40 mL), 4y (2.1 g, 5.32 mmol) was added at 0°C and stirred at room temperature for 1.5 hours. The resulting solution was stopped by adding 2N HCl (15 mL) to pH=7 and extracted with DCM (70 mL × 3) and H2O (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a greenish-brown oil. The crude product was purified by flash column (φ4 × 11, MeOH / DCM = 1 / 50~1 / 30) to obtain the product as an orange oil. The oil was diluted with MeOH (1 mL), DCM (3 mL), and ether (5 mL). The solution was concentrated until a solid appeared on the wall. The slurry solution was sonicated, and Hex (5 mL) was added to precipitate the product as a clear orange solid (1.2 g, 57%). TIFF0007897463000115.tif33154

[0253] Example 25: (E)-3-(3-(2-bromo-4-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compound 29, 5z) TIFF0007897463000116.tif25128 To a slurry solution of NaOH (0.3 g, 7.21 mmol) in NH2OH (27 mL), 4z (1.7 g, 3.61 mmol) was added at 0°C and the mixture was stirred at room temperature for 1.5 hours. The resulting orange-red solution was stopped by adding 2N HCl (11 mL) to pH=7 (from orange-red to yellow), and extracted with DCM (100 mL × 2) and H2O (100 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ3.5 × 11, MeOH / DCM = 1 / 50~1 / 33) to obtain the product as an orange oil. The oil was diluted with EA (2 mL) and DCM (1 mL) and sonicated until the product precipitated. The precipitated solid was dissolved in MeOH (1 mL) and DCM (3 mL), and then concentrated. The residue was diluted with EA (3 mL) and Hex (1 mL), and sonicated until the product precipitated as a white solid (0.1 g, 8%). TIFF0007897463000117.tif27159

[0254] Example 26: (E)-3-(3-(4-chloro-2-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl) ethyl acrylate (5ac) TIFF0007897463000118.tif22128 A reaction mixture of 4z (0.9g, 1.88 mmol), Pd2(dba)3 (37mg, 0.04 mmol), and [(t-Bu)3PH]BF4 (43mg, 0.15 mmol) in THF (4mL) was mixed with Me2Zn (3.5mL, 1.2M / toluene) and stimulated with MW [mode: standard, 200W, run time: 30 min, retention time: 55 min]. The resulting solution was filtered, and the filtrate was extracted with DCM (70mL x 2) and H2O (70mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified by flash column (φ3.5×15, EA / HEX=1 / 10~1 / 8) to obtain the product as a yellow solid (0.5g, 59%). Rf = 0.43 (EA / Hex = 1:5);ESIMS(+) m / z 415 [M+H] +

[0255] Example 27: (E)-3-(3-(4-chloro-2-methylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compounds 25, 6ac) TIFF0007897463000119.tif22128 To a slurry solution of NaOH (0.1 g, 2.36 mmol) in NH2OH (9 mL), 5ac (0.5 g, 1.18 mmol) was added at 0°C and stirred at room temperature for 7 hours (starting material still remained). The resulting solution was stopped by adding 1N HCl (10 mL) to pH=7 and extracted with DCM (40 mL × 3) and H2O (40 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ3.5 × 11, MeOH / DCM = 1 / 50~1 / 30) to obtain the product as an orange oil. The oil was diluted with MeOH (1 drop), DCM (3 mL), EA (3 mL), and Hex (10 mL) to obtain the product as a beige solid. The solid was dissolved in MeOH (0.5 mL) and DCM (1 mL), and left overnight at room temperature to obtain the product as white crystals (28 mg, compound 25-1). After filtration, some crystals were observed in the filtrate (50 mg, compound 25-2). Total (78 mg, 16%). TIFF0007897463000120.tif26158

[0256] Example 28: (E)-3-(2-ethyl-7-fluoro-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compound 26, 5aa) TIFF0007897463000121.tif20128 To a slurry solution of NaOH (0.3 g, 7.53 mmol) in NH2OH (26 mL), 4aa (1.5 g, 3.77 mmol) was added at 0°C and stirred at room temperature for 2.5 hours. The resulting yellow solution was stopped by adding 2N HCl (14 mL) to pH=7, and extracted with DCM (80 mL × 3) and H2O (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. (Some white suspended solids were observed in the aqueous layer). The crude product was purified by flash column (φ3.5 × 12, MeOH / DCM = 1 / 30~1 / 25) to obtain the product as an orange oil. The oily substance was diluted with DCM (1 mL) and EA (2 mL), and precipitated with Hex (20 mL) to obtain a clear orange solid product (0.8 g, 53%). TIFF0007897463000122.tif34158

[0257] Example 29: (E)-3-(3-(4-bromo-2-fluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compounds 28, 5ab) TIFF0007897463000123.tif20128 A slurry solution of NaOH (0.3 g, 6.91 mmol) in NH2OH (26 mL) was mixed with 4ab (1.6 g, 3.45 mmol) and stirred at 0°C for 2.5 hours. The resulting yellow slurry solution was stopped by adding 2N HCl (12 mL) to pH=7, and extracted with DCM (75 mL × 2) and H2O (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange-yellow oily substance. (Some white suspended solids were observed in the aqueous layer). The crude product was purified by flash column (φ3.5 × 8.5, MeOH / DCM = 1 / 50~1 / 30) to obtain the product as a beige solid (46 mg, 9%). The starting material was recovered (recovered: 1.1 g, 69%). TIFF0007897463000124.tif26158

[0258] Example 30: (E)-3-(2-ethyl-7-fluoro-3-mesityl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compound 30, 5ad) TIFF0007897463000125.tif21128 To a slurry solution of NaOH (0.5 g, 11.46 mmol) in NH2OH (43 mL), 4ad (2.3 g, 5.73 mmol) was added at 0°C and the mixture was stirred at room temperature for 1 hour. The resulting solution was stopped by adding 2N HCl (21 mL) to pH=7, and extracted with DCM (75 mL × 2) and NaCl (saturated 75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oily substance. The crude product was purified by flash column (φ4 × 9, MeOH / DCM = 1 / 60~1 / 30) to obtain the product as a clear orange solid. The solid was dissolved in MeOH (2 mL) and DCM (10 mL) and concentrated until 1 mL of solvent remained. EA (3 mL) and Hex (5 mL) were added to the residue, and the mixture was sonicated until the product precipitated. Hex (10 mL) was added to the slurry solution, and the product was obtained as a clear orange solid (1.5 g, 66%). TIFF0007897463000126.tif27157

[0259] Example 31: (E)-3-(3-(4-bromo-2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compound 31, 5ae) TIFF0007897463000127.tif22128 To a slurry solution of NaOH (0.1 g, 2.96 mmol) in NH2OH (11 mL), 4ae (0.7 g, 1.48 mmol) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The resulting solution was stopped by adding 1N HCl to pH=7 and extracted with DCM (50 mL × 2) and NaCl (saturated 50 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ3.5 × 9, MeOH / DCM = 1 / 50~1 / 35) to obtain the product as an orange oil. MeOH (2 mL) and DCM (10 mL) were added to the oil and concentrated until 1 mL of solvent remained. EA (1.5 mL) and Hex (5 mL) were added to the residue and sonicated for 5 minutes. The solution was left at room temperature for 10 minutes to precipitate the product. The slurry solution was sonicated, and Hex (10 mL) was added to obtain the product as a clear orange solid (0.2 g, 35%). TIFF0007897463000128.tif26155

[0260] Example 32: (E)-3-(2-ethyl-7-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5 ag, compound 33) TIFF0007897463000129.tif21128 To a slurry solution of NaOH (0.3 g, 6.55 mmol) in NH2OH (25 mL), 4 ah (1.2 g, 3.28 mmol) was added at 0°C and stirred under the same conditions for 40 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour. The reaction was stopped by adding 1N HCl (12 mL) to the resulting solution to pH=7, and extracted with a solution of DCM (100 mL × 2), mixed MeOH (10 mL × 2), and NaCl (saturated 75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ4.5 × 8, MeOH / DCM = 1 / 50~1 / 20) to obtain the product as a clear orange oil. The oily substance was diluted with MeOH (1 mL) and DCM (5 mL), and concentrated until 1 mL of solvent remained. EA (3 mL) was added to the residue, and the mixture was sonicated to precipitate the product (from clear to slurry). Hex (10 mL) was added to the slurry solution, and the mixture was sonicated for 2 minutes to obtain the product as a clear orange solid (0.4 g, 35%). TIFF0007897463000130.tif27160

[0261] Example 33: (E)-3-(2-ethyl-7-fluoro-3-(4-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5ah, compound 34) TIFF0007897463000131.tif22128 To a slurry solution of NaOH (0.3 g, 8.28 mmol) in NH2OH (31 mL), 4 ah (1.7 g, 4.14 mmol) was added at 0°C and stirred at room temperature for 1 hour. The resulting solution was stopped by adding 2N HCl (12 mL) to pH=7, and extracted with DCM (100 mL × 2) and NaCl (saturated 100 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ4.5 × 9, MeOH / DCM = 1 / 50~1 / 25) to obtain the product as an orange oil. The oil was diluted with MeOH (1 mL) and DCM (5 mL) and concentrated until 1 mL of solvent remained. EA (3 mL) was added to the residue and sonicated at 0°C to precipitate the product (from clear to slurry). Hex (10 mL) was added to the slurry solution and filtered to obtain the product as an orange solid (1.2 g, 70%). TIFF0007897463000132.tif34158

[0262] Example 34: (E)-3-(2-ethyl-8-fluoro-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5ai, compound 35) TIFF0007897463000133.tif27128 To a slurry solution of NaOH (0.6 g, 15.06 mmol) in NH2OH (56 mL), 4ai (3.0 g, 7.53 mmol) was added at 0°C and the mixture was stirred at room temperature for 2.5 hours. The resulting solution was stopped by adding 2N HCl (24 mL) to pH=7, and extracted with DCM (100 mL), CHCl3 (200 mL), and NaCl (100 mL saturated). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ4.5 × 10, MeOH / DCM = 1 / 40~1 / 20) to obtain the product as an orange oil. The oil was diluted with EA (5 mL), DCM (3 mL), and MeOH (1 mL) and sonicated for 2 minutes. The resulting solution was left at room temperature for 1 minute (from clear to slurry), and then sonicated for 2 minutes to precipitate the product as a clear, colored solid (1.5 g, 51%). TIFF0007897463000134.tif34160

[0263] Example 35: (E)-3-(3-(3,5-dimethylphenyl)-7-fluoro-2-(1-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acrylic acid (5v) A mixture of 4v (1.7g, 3.88 mmol), Pd(OAc)2 (70mg, 0.31 mmol), [(t-Bu)3PH]BF4 (90mg, 0.31 mmol), acrylic acid (0.5mL, 7.77 mmol), and Cs2CO3 (1.9g, 5.83 mmol) in DMF (14 mL) was stimulated with a MW 200W for 25 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (50 mL) and NaHCO3 (saturated) (75 mL). However, this showed severe emulsification. The mixture solution was concentrated below 60°C and separated. The organic layer was recovered and further extracted with NaHCO3 (50 mL). The aqueous layers were combined and acidified to pH=2 with 3N HCl in an ice bath (some solid precipitated). The resulting solution was filtered, and the filtered solid was dried under reduced pressure to obtain the product as a yellow solid (1.0 g, 67%). Rf = 0.04 (EA / HEX = 1 / 2)

[0264] (E)-3-(3-(3,5-dimethylphenyl)-7-fluoro-2-(1-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide(6v) TIFF0007897463000136.tif29128 A mixture of 5v (1.0g, 2.60 mmol), EDCI HCl (1.0g, 5.20 mmol), and HOBt (0.5g, 3.90 mmol) in DMF (5 mL) was mixed with TEA (0.7 mL, 5.20 mmol) and stirred at room temperature for 1.5 hours. Further EDCI (0.5g, 2.60 mmol) was added to the reaction solution and stirred for another hour. NH2OTHP (0.3g, 2.86 mmol) was added to the resulting solution and stirred at room temperature for 16 hours. Et3N (0.02 mL, 0.17 mmol) was added to the resulting mixture and stirred at room temperature for 16 hours. The resulting solution was concentrated and extracted with DCM (75 mL × 2) and H2O (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oily substance. The crude product was purified by flash column chromatography (φ4.5×9.5, EA / Hex=2 / 5~3 / 2) to obtain the product as a yellow foam (1.1g, 88%). Rf = 0.78 (MeOH / DCM = 1 / 10)

[0265] Example 36: (E)-3-(3-(3,5-dimethylphenyl)-7-fluoro-2-(1-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (7v, compound 19) To a mixture solution of 6v (1.1 g, 2.28 mmol) in MeOH (38 mL), TFA (0.5 mL, 6.83 mmol) was added and the mixture was stirred at 70°C for 2.5 hours. The resulting solution was extracted with DCM (50 mL × 2) and H2O (50 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified by flash column (φ4 × 8, MeOH / DCM = 1 / 60~1 / 30) to obtain the product as an orange solid. The solid was washed with Hex (50 mL) to obtain the product as a clear orange solid (0.7 g, 73%). TIFF0007897463000138.tif34159

[0266] Example 37: (E)-3-(3-(2,6-diisopropylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5h, compound 9) TIFF0007897463000139.tif27128 To a slurry solution of NaOH (0.3 g, 7.91 mmol) in NH2OH (2 M / MeOH, 30 mL), 1.7 g (3.96 mmol) was added at 0°C and stirred for 0.5 hours (no reaction). The slurry solution was warmed to room temperature and stirred for 0.5 hours (slow reaction). The reaction solution was warmed to 30°C and stirred for 1 hour (the starting materials were not finished, but by-products were increasing), and then 2N HCl was added to pH=2 to stop the reaction. The mixed solution was concentrated and extracted with DCM (100 mL x 2), H2O (100 mL) and NaCl (30 mL saturated). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark oily substance. The crude product was purified using a flash column (φ4.5×8.5, MeOH / DCM=1 / 80~1 / 40) to obtain a clear orange solid (0.9g, 53%). TIFF0007897463000140.tif27157

[0267] Example 38: (E)-3-(3-(2,6-dichlorophenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5i, compound 5) TIFF0007897463000141.tif22128 To a slurry solution of NaOH (0.6 g, 14.10 mmol) in NH2OH (53 mL), 4i (3.0 g, 7.05 mmol) was added at room temperature and the mixture was stirred for 0.5 hours. The resulting solution was stopped by adding 2N HCl (33 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oily substance. The crude product was purified by flash column (φ4.5 × 8.5, MeOH / DCM = 1 / 70~1 / 30) to obtain the product as an orange solid. The solid was further washed with MeOH / EA = 8.5 / 1.5 mL to obtain the product as an orange solid (0.9 g, 31%). TIFF0007897463000142.tif26158

[0268] Example 39: (E)-3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5j, compound 1) TIFF0007897463000143.tif19128 To a slurry solution of NaOH (0.4 g, 9.04 mmol) in NH2OH (2 M / MeOH, 34 mL), 4 J (1.7 g, 4.52 mmol) was added at 0°C and stirred for 1 hour. The reaction solution was further warmed to room temperature for 30 minutes. To the resulting solution, 3N HCl (19.5 mL) was added to pH=2 to stop the reaction, and the mixture was stirred at room temperature for 10 minutes. The mixture solution was concentrated, and H2O (50 mL) and DCM (50 mL) were added over 1 minute under sonication. The organic layer was separated and concentrated (slurry) to obtain the crude product. The crude product was washed with EA (5 mL) to obtain the product as a clear orange solid (0.5 g, 28%). The aqueous layer was extracted with DCM (30 mL), which showed some slurry solid. The solid was filtered and further washed with EA (20 mL) and MeOH (1 mL) solutions to obtain the product as a clear orange solid (0.8 g, 46%). Total (1.2 g, 74%) TIFF0007897463000144.tif27157

[0269] Example 40: (E)-3-(3-(2,6-dimethylphenyl)-5-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5k, compound 3) TIFF0007897463000145.tif19128 To a slurry solution of NaOH (0.2 g, 6.10 mmol) in NH2OH (2 M / MeOH, 23 mL), 4 K (1.2 g, 3.05 mmol) was added at room temperature and the mixture was stirred for 0.5 hours. The resulting solution was stopped by adding 2 N HCl (17 mL) to pH=2, and extracted with DCM (75 mL), H2O (50 mL), and NaCl (20 mL saturated). The slurry solution was filtered, and the filtered solid was washed with ether to obtain the product as a yellow solid. The crude product was further washed with EA / MeOH=5 / 1 mL to obtain the product as a yellowish solid (0.3, 24%). TIFF0007897463000146.tif26159

[0270] Example 41: (E)-3-(3-(2,6-dimethylphenyl)-8-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5L, compound 10) TIFF0007897463000147.tif24128 To a slurry solution of NaOH (0.7 g, 16.84 mmol) in NH2OH (63 mL), 4 L (3.2 g, 8.41 mmol) was added at 0°C for 0.5 hours. The resulting yellow solution was extracted with CHCl3 (250 mL × 2), NaCl (saturated 200 mL), and 2N HCl (26 mL) (from yellow to colorless). The organic layer was concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ4.5 × 8, MeOH / CHCl3 = 1 / 70~1 / 5), the pure fraction was recovered and concentrated to obtain a colorless oil. The oil was diluted with EA (5 mL) and precipitated with Hex (50 mL) to obtain the product as a white solid (1.2 g, 39%). The mixture fraction was collected and concentrated to obtain a reddish-orange oil. The oil was diluted with EA (10 mL) and sonicated at room temperature for 4 minutes to obtain the product as a beige solid (0.8 g, 24%). Total (1.9 g, 63%) TIFF0007897463000148.tif27155

[0271] Example 42: (E)-3-(3-(2,6-difluorophenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5n, compound 12) TIFF0007897463000149.tif22128 To a slurry solution of NaOH (0.4 g, 8.96 mmol) in NH2OH (34 mL), 4n (1.7 g, 4.48 mmol) was added at 0°C for 0.5 hours, and then stirred at room temperature for 1 hour. The resulting yellow solution was stopped with 2N HCl (10 mL) and extracted with DCM (100 mL), H2O (100 mL), and NaCl (50 mL saturated), but showed severe emulsification. The combined organic and emulsified layers were concentrated until 20 mL of the solution remained. Ether (10 mL) and Hex (10 mL) were added to the residue and sonicated for 1 minute. The jelly-like solution was filtered, and the filtrate was purified by flash column (φ3.5 × 7, MeOH / DCM = 1 / 15) to obtain the product as a reddish-orange oil. The oily substance was precipitated with Hex (30 mL), and the product was obtained as a reddish-orange solid (49 mg, 3%). TIFF0007897463000150.tif27159

[0272] Example 43: (E)-3-(3-(2,6-difluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (50) A mixture of 4o (2.9 g, 6.09 mmol), EDCI HCl (1.8 g, 9.14 mmol), HOBt (1.1 g, 7.92 mmol), and Et3N (2.5 mL, 18.28 mmol) in DMF (12 mL) was stirred at room temperature for 1 hour. NH2OTHP (0.8 g, 6.70 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for a further 4.5 hours. The resulting solution was extracted with DCM (100 mL × 2) and H2O (100 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ4.5 × 8, EA / Hex = 1 / 5~1 / 4.5) to obtain the product as a yellow oil. The oily substance was precipitated with EA (5 mL) and Hex (10 mL) to obtain the product as a white solid (1.9 g, 66%). Rf = 0.53 (MeOH / DCM = 1 / 10)

[0273] Example 44: (E)-3-(3-(3,5-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5p, compound 18) TIFF0007897463000152.tif27128 To a slurry solution of NaOH (0.5 g, 12.09 mmol) in NH2OH (46 mL), 4p (2.3 g, 6.05 mmol) was added at 0°C and stirred for 3.5 hours. The resulting solution was stopped by adding 2N HCl (15 mL) to pH=7 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a brown oily substance. The crude product was purified by flash column (φ4.5 × 8, MeOH / DCM = 1 / 70~1 / 25) to obtain the product as an orange-red solid. EA (5 mL) was added to the solid and precipitated with Hex (20 mL) to obtain the product as an orange-red solid (0.9 g, 41%). TIFF0007897463000153.tif26154

[0274] Example 45: (E)-3-(3-(2,6-dimethylphenyl)-2,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (5q) To a mixture of 4q (0.8g, 1.91 mmol), pd(dba)3 (35mg, 0.04 mmol), and [(t-Bu)3PH]BF4 (44mg, 0.15 mmol) in THF (4 mL), Me2Zn (3.2 mL, 3.82 mmol, 1.2 M / toluene) was added, and the mixture was stimulated with a MW 250W for 30 minutes [mode: standard, temperature = 120, run time = 30 min, retention time = 30 min, open container]. After cooling to room temperature, the resulting solution was filtered, H2O (75 mL) was added to the filtrate, and it was extracted with DCM (75 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as an orange oil. The crude product was purified using a flash column (φ3.5 × 7) to obtain the product as a yellow solid (0.3 g, 35%). Rf = 0.25 (EA / Hex = 1:2); ESIMS(+) m / z 377 [M+H] +

[0275] (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (5r) A mixture of 4r (1.5g, 3.65 mmol), pd(dba)3 (64mg, 0.07 mmol), and [(t-Bu)3PH]BF4 (84mg, 0.29 mmol) in THF (9mL) was mixed with Me2Zn (6.1mL, 7.30 mmol, 1.2M / toluene), stimulated with MW 250W for 30 minutes [mode: standard, temperature=120, run time=30 min, retention time=30 min, open container], cooled to room temperature, filtered the resulting solution, added H2O (75mL) to the filtrate, and extracted with DCM (75mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ4.5×7.5, EA / Hex=1 / 10~1 / 7) to obtain the product as a white solid (0.7g, 50%). Rf = 0.43 (EA / Hex = 1:2); ESIMS(+) m / z 391 [M+H] +

[0276] Example 46: (E)-3-(3-(2,6-difluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (6o, compound 13) To a mixture solution of 5o (1.9 g, 4.01 mmol) in MeOH (66 mL), TFA (0.9 mL, 12.04 mmol) was added and the mixture was stirred at 70°C for 2 hours. The resulting solution was extracted with DCM (150 mL × 2) and H2O (100 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified by flash column (φ4.5 × 6, MeOH / DCM = 1 / 50~1 / 40) to obtain the product as a white solid (1.4 g, 86%). TIFF0007897463000157.tif34157

[0277] Example 47: (E)-3-(3-(2,6-dimethylphenyl)-2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (6q, compound 16) TIFF0007897463000158.tif21128 To a slurry solution of NaOH (53 mg, 1.33 mmol) in NH2OH (5 mL), 5 q (0.3 g, 0.66 mmol) was added at 0°C and stirred for 2 hours. The resulting solution was stopped by adding 1N HCl (10 mL) to pH=7, and extracted with DCM (75 mL × 2) and MeOH (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as an orange oil. The crude product was purified by flash column (φ3.5 × 8, MeOH / DCM = 1 / 60~1 / 25) to obtain the product as an orange solid (0.2 g, 69%). TIFF0007897463000159.tif27159

[0278] Example 48: 3-(2,6-dibromo-4-fluorophenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3x) TIFF0007897463000160.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (24 mL) was mixed dropwise with propionic anhydride (3.4 mL, 26.69 mmol) at 0°C and stirred at room temperature for 10 minutes. P(OPh)3 (6 mL, 23.13 mmol) was added to the resulting solution and stimulated with a MW at 250 W for 20 minutes. 2,6-dibromo-4-fluoroaniline (6.2 g, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. After cooling to room temperature, the resulting solution was stopped by adding 3N HCl (72 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ4.5×9, EA / Hex=1 / 10) to obtain a yellow oily product. The oily product was diluted with Hex (70 mL) and sonicated in an ice bath to precipitate the product as a white solid (3.8 g, 38%). Rf = 0.58 (EA / Hex = 1:2)

[0279] (E)-3-(3-(2,6-dibromo-4-fluorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4x) A reaction mixture of 3x (3.8g, 6.67mmol), Pd(OAc)2 (74mg, 0.33mmol), PPh3 (0.2g, 0.67mmol), NaOAc (0.8g, 10.00mmol), and ethyl acrylate (0.8mL, 7.33mmol) in DMA (9mL) was stimulated on a MW 250W for 20 minutes. After cooling to room temperature, the resulting solution was filtered and extracted with DCM (75mL x 2) and saturated NaCl (75mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark oil. The crude product was purified by flash column (φ4.5×9, EA / HEX=1 / 9.5) to obtain the product as a yellow solid. The solid was washed with Hex (10 mL) to obtain the product as a yellow solid (0.6 g, 17%). Rf = 0.58 (EA / Hex = 1:2); ESIMS(+) m / z 543 [M+H] +

[0280] (E)-3-(2-ethyl-7-fluoro-3-(4-fluoro-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (5x) A mixture of 4x (0.8g, 1.37 mmol), Pd2(dba)3 (27mg, 0.03 mmol), and [(t-Bu)3PH]BF4 (32mg, 0.11 mmol) in THF (3 mL) was mixed with Me2Zn (4.6 mL, 1.2 M / toluene) and stimulated with MW [mode: standard, 200 W, run time: 30 min, retention time: 55 min]. The resulting solution was filtered, and the filtrate was extracted with DCM (50 mL × 2) and H2O (50 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ3.5 × 12, EA / HEX = 1 / 10 ~ 1 / 7.5) to obtain the product as a yellow solid. (0.4g, 73%). Rf = 0.35 (EA / Hex = 1:5);ESIMS(+) m / z 413 [M+H] +

[0281] Example 49: (E)-3-(2-ethyl-7-fluoro-3-(4-fluoro-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compound 24, 6x) TIFF0007897463000163.tif22128 To a slurry solution of NaOH (0.1 g, 2.09 mmol) in NH2OH (8 mL), 5x (0.4 g, 1.04 mmol) was added at 0°C and stirred at room temperature for 2.5 hours. The resulting solution was stopped by adding 1N HCl (8 mL) to pH=7, and extracted with DCM (50 mL × 3) and H2O (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as an orange oil. The crude product was purified by flash column (φ2.5 × 8, MeOH / DCM = 1 / 50~1 / 35) to obtain the product as a clear orange solid. The oily substance was diluted with DCM (3 mL) and MeOH (1 drop), and Hex (20 mL) was added over 2 minutes under sonication to precipitate the product as a white solid. The solid was dissolved in MeOH (3 mL) and DCM (1 mL), and recrystallized to obtain the product (80 mg, 19%). TIFF0007897463000164.tif27160

[0282] Example 50: (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (6r, compound 17) TIFF0007897463000165.tif25128 To a slurry solution of NaOH (0.2 g, 3.64 mmol) in NH2OH (13 mL), 5r (0.7 g, 1.82 mmol) was added at 0°C and the mixture was stirred for 3.5 hours. To the resulting solution, 1N HCl (9 mL) was added to pH=7 (from yellow to colorless slurry) to stop the reaction. H2O (30 mL) was added to the slurry solution and filtered. The filtered solid was dissolved in MeOH (50 mL), and the filtrate was extracted with DCM (50 mL x 2) and MeOH (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ3.5×7, MeOH / DCM=1 / 100~1 / 30) to obtain the product as an orange solid (0.5g, 78%). TIFF0007897463000166.tif27159

[0283] Example 51: (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)methyl acrylate (3af) A reaction mixture of 3d (2.5 g, 5.92 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), PPh3 (0.2 g, 0.59 mmol), NaOAc (0.7 g, 8.89 mmol), and ethyl acrylate (0.6 mL, 6.52 mmol) in DMA (12 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (75 mL x 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. EA (5 mL) was added to the oil, and the product precipitated as a brown solid. The (0.7g, 32%) filtrate was purified by flash column (φ3.5×10, EA / Hex = 1 / 10~1 / 6) ​​to obtain a beige solid. The solid was washed with Hex (10mL) to obtain the product as a beige solid (70mg, 3%). Total (0.8g, 35%); Rf = 0.6 (EA / Hex = 1:2)

[0284] (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methoxy-4-oxo-3,4-dihydroquinazoline-6-yl)methyl acrylate (4af) A mixture of 3af (0.8g, 2.08 mmol) and NaOMe (0.3g, 6.23 mmol) in MeOH (2 mL) and DMF (0.7 mL) was heated at 80°C for 5 hours. The resulting solution was stopped with H2O and extracted with DCM (50 mL × 2). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oil. The oil was purified by flash column (φ3.5 × 10, EA / Hex = 1 / 6~1 / 3.5) to obtain a beige solid (0.3 g, 31%). Rf = 0.25 (EA / Hex = 1:2)

[0285] Example 52: (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methoxy-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide (compound 32, 5af) TIFF0007897463000169.tif21128 To a slurry solution of NaOH (0.5 g, 12.18 mmol) in NH2OH (45 mL), 4af (0.23 g, 0.64 mmol) was added at 0°C and stirred for 10 minutes. The reaction solution was warmed to room temperature and stirred for a further 1.5 hours. To the resulting solution, NH2OH (2.5 mL) was added and stirred for a further 2.5 hours. The reaction was stopped by adding 1N HCl (6.5 mL) to the reaction solution until the pH was 7 (from yellow to colorless), and extracted with DCM (25 mL x 2) and H2O (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ2.5×8, MeOH / DCM = 1 / 50~1 / 30) to obtain a white solid. The solid was dissolved in DCM (5 mL) and MeOH (1 mL), and then concentrated until 1.5 mL of solvent remained. EA (1 mL) was added to the residue, and the solution was sonicated until it became a slurry. Hex (15 mL) was added to the slurry solution, and it was left to stand at 0°C to obtain a white solid (0.1 g, 37%). TIFF0007897463000170.tif33159

[0286] Example 53: (E)-3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinazoline-6-yl)ethyl acrylate (61) A mixture of TIFF0007897463000171.tif241284j (1.2g, 3.05 mmol) and NaBH4 (0.2g, 6.10 mmol) was mixed with THF (10 mL) and MeOH (2.5 mL) (pale blue to dark yellow, effervescent), and stirred at room temperature for 4 hours. H2O (50 mL) was added to the resulting greenish-brown solution and extracted with DCM (50 mL × 3). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ4.5 × 8, EA / DCM / Hex = 10 / 9 / 1~2 / 1 / 1) to obtain the product as a beige solid. (0.5g, 40%); Rf = 0.2 (EA / Hex = 1:2); ESIMS(+) m / z 381 [M - H] -

[0287] Example 54: (E)-3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-N-hydroxyacrylamide (62, compound 14) TIFF0007897463000172.tif24128 To a slurry solution of NaOH (0.1 g, 2.46 mmol) in NH2OH (10 mL), 61 (0.5 g, 1.23 mmol) was added at room temperature over 3 hours (the starting material was not completed). NH2OH (2 mL) was added to the resulting solution and the mixture was stirred for a further 0.5 hours. The reaction solution was stopped with 2N HCl (10 mL) and extracted with DCM (70 mL × 2), H2O (70 mL) and NaCl (saturated 10 mL). The organic layer was concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ3.5 × 7, MeOH / DCM = 1 / 50~1 / 40) to obtain the product as a yellow solid (0.1 g, 29%). TIFF0007897463000173.tif33160

[0288] Example 55: 3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)propanoate ethyl(63) A mixture of TIFF0007897463000174.tif221284j (1.2g, 3.05 mmol) and nickel acetate tetrahydrate (0.2g, 0.89 mmol) was mixed with DCM (12 mL) and MeOH (15 mL) and stirred at 0°C for 5 minutes. NaBH4 (0.2g, 5.32 mmol) was added to the resulting solution at 0°C and stirred under the same conditions for 2 hours (the starting materials were not completed). NaBH4 (0.1g, 1.85 mmol) was further added to the reaction solution and stirred for 0.5 hours. The resulting solution was stopped with H2O (60 mL) and filtered. The filtrate was extracted with DCM (75 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ3.5 × 10, EA / Hex = 1 / 5) to obtain a yellow oily product. Hex (10 mL) was added to the oily product to precipitate it, and the mixture was left at -20°C for 4 hours to obtain an orange solid. (0.6 g, 42%); Rf = 0.25 (EA / Hex = 1:2); ESIMS(+) m / z 383 [M+H] +

[0289] Example 56: 3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxypropanamide (64, compound 15) To a slurry solution of NaOH (0.1 g, 2.98 mmol) in NH2OH (11 mL), 63 (0.6 g, 1.49 mmol) was added over 1 hour at 0°C. The resulting solution was stopped with 1N HCl (11 mL) and extracted with DCM (35 mL × 2) and H2O (10 mL). The organic layer was concentrated under reduced pressure to obtain the crude product as a yellow oily substance. The crude product was purified by flash column (φ3.5 × 7, MeOH / DCM = 1 / 30) to obtain the product as a white viscous solid. The solid was dissolved in EA (5 mL) and precipitated with Hex (20 mL) to obtain a white solid (0.5 g, 91%). TIFF0007897463000176.tif34159

[0290] Example 57: 2-Ethyl-3-(2-ethylphenyl)-7-fluoro-6-iodoquinazoline-4(3H)-one(3an) TIFF0007897463000177.tif27128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (22 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 2-ethylaniline (3 mL, 23.13 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ4.5×9, EA / HEX=1 / 9) to obtain a beige solid. The solid was washed with EA (2 mL) and Hex (20 mL) to obtain a white solid (2.6 g, 34%). Rf = 0.55 (EA / Hex = 1:2)

[0291] (E)-3-(2-ethyl-3-(2-ethylphenyl)-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4an) A reaction mixture of 3an (2.6 g, 6.11 mmol), Pd(OAc)2 (70 mg, 0.31 mmol), PPh3 (0.2 g, 0.61 mmol), NaOAc (0.8 g, 9.17 mmol), and ethyl acrylate (0.7 mL, 6.72 mmol) in DMA (12 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM (30 mL) and filtered. The filtrate was extracted with DCM (50 mL x 2) and saturated NaCl (50 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified using a flash column (φ3.5×8, EA / HEX = 1 / 9~1 / 8) to obtain the product as a brown oil. Hex (30 mL) was added to the oil and sonicated for 30 seconds, causing the product to precipitate as a brown solid (1.4 g, 59%). Rf = 0.55 (EA / Hex = 1:2)

[0292] Example 58: (E)-3-(2-ethyl-3-(2-ethylphenyl)-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5an, compound 36) TIFF0007897463000179.tif27128 To a slurry solution of NaOH (0.3 g, 7.25 mmol) in NH2OH (27 mL), 4an (1.4 g, 3.63 mmol) was added at 0°C and the mixture was stirred at room temperature for 1.5 hours. The resulting solution was stopped by adding 1N HCl (20 mL) to pH=7, and extracted with DCM (75 mL × 2) and H2O (50 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified by flash column (φ3.5 × 8, MeOH / DCM = 1 / 50~1 / 40) to obtain the product as an orange oil. The oil was dissolved in EA (3 mL), and Hex (10 mL) was added during sonication to precipitate the product as a clear orange solid (0.7 g, 51%). TIFF0007897463000180.tif34156

[0293] Example 59: 2-Ethyl-7-fluoro-3-(4-fluorophenyl)-6-iodoquinazoline-4(3H)-one(3ak) TIFF0007897463000181.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 4-fluoroaniline (2.2 mL, 23.13 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (65 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ4.5×9, EA / HEX=1 / 9) to obtain a slurry solution. The residue was washed with Hex (10 mL) to obtain the product as a clear orange solid (3.8 g, 52%). Rf = 0.63 (EA / Hex = 1:2)

[0294] 2-Ethyl-7-fluoro-6-iodo-3-(p-tolyl)quinazoline-4(3H)-one(3al) TIFF0007897463000182.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 4-methylaniline hydrochloride (3.3 g, 23.13 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified using a flash column (φ4.5×9, EA / HEX=1 / 9~1 / 8~EA / DCM / Hex=1 / 7 / 7) to obtain a slurry solution. The slurry solution was filtered to obtain the product as a white solid (2.8g, 39%). Rf = 0.55 (EA / Hex = 1:2)

[0295] 2-Ethyl-7-fluoro-6-iodo-3-(4-methoxyphenyl)quinazoline-4(3H)-one(3am) TIFF0007897463000183.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (22 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 4-methoxyaniline (2.9 g, 23.13 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (65 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a black oil. The crude product was purified using a flash column (φ4.5×9, EA / HEX=1 / 9~DCM / Hex=1 / 1) to obtain a yellow solid. The solid was washed with Hex (50 mL) to obtain a white solid (3.3 g, 43%). Rf = 0.38 (EA / Hex = 1:2)

[0296] 2-Ethyl-7-fluoro-3-(2-fluoro-6-methylphenyl)-6-iodoquinazoline-4(3H)-one(3an) TIFF0007897463000184.tif21128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (22 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated with a MW at 250 W for 20 minutes. 2-Fluoro-6-methyl (2.9 g, 23.13 mmol) was added to the reaction mixture and stimulated with a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (75 mL x 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a brown oil. The crude product was purified using a flash column (φ4.5×9, EA / HEX = 1 / 9~1 / 8) to obtain a yellow oily product. The oily substance was left to stand overnight to obtain beige crystals. Hex (15 mL) was added to the mixture solution and left at 0°C for 2 hours to precipitate the product as a white solid (3.0 g, 40%). Rf = 0.55 (EA / Hex = 1:2)

[0297] 2-Ethyl-3-(4-ethylphenyl)-7-fluoro-6-iodoquinazoline-4(3H)-one(3ao) TIFF0007897463000185.tif21128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 4-ethylaniline (2.9 mL, 23.13 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product in a brown slurry solution. To the resulting residue, EA (1 mL), Hex (3 mL), and ether (5 mL) were added, and the product was precipitated as a beige solid (3.5 g, 47%). Rf = 0.68 (EA / Hex = 1:2)

[0298] 3-(4-chlorophenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3ap) TIFF0007897463000186.tif22128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 2-ethylaniline (3 mL, 23.13 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified using a flash column (φ4.5×9, EA / HEX = 1 / 9~1 / 8) to obtain a yellow oily product. Hex (5 mL) was added to the oily product and sonicated to obtain a white solid (3.2 g, 42%). Rf = 0.55 (EA / Hex = 1:2)

[0299] (E)-3-(2-ethyl-7-fluoro-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4ak) A reaction mixture of 3ak (3.8g, 9.22 mmol), Pd(OAc)2 (0.1g, 0.46 mmol), PPh3 (0.2g, 0.92 mmol), NaOAc (1.1g, 13.83 mmol), and ethyl acrylate (1.1 mL, 10.14 mmol) in DMA (18 mL) was stimulated with a MW 250 W for 25 minutes. The resulting solution was filtered, and the filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified by flash column (φ4 × 8, EA / HEX = 1 / 8~1 / 7) to obtain a brown liquid. Hex (15 mL) was added to the residue and sonicated, causing the product to precipitate as a beige solid (2.0 g, 56%). Rf = 0.4 (EA / Hex = 1:2)

[0300] (E)-3-(2-ethyl-7-fluoro-4-oxo-3-(p-tolyl)-3,4-dihydroquinazolin-6-yl) ethyl acrylate (4al) A reaction mixture of 3al (2.8g, 6.86 mmol), Pd(OAc)2 (76mg, 0.34 mmol), PPh3 (0.2g, 0.69 mmol), NaOAc (0.8g, 10.29 mmol), and ethyl acrylate (0.8mL, 7.55 mmol) in DMA (12mL) was stimulated on a MW 250W for 25 minutes. The resulting solution was filtered, and the filtrate was extracted with DCM (75mL × 2) and saturated NaCl (saturated 75mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified by flash column (φ4×9, EA / HEX=1 / 9~1 / 7) to obtain the product as a grayish-white solid (1.6g, 61%). Rf = 0.48 (EA / Hex = 1:2)

[0301] (E)-3-(2-ethyl-7-fluoro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4am) A reaction mixture of 3am (3.2g, 7.54 mmol), Pd(OAc)2 (85mg, 0.38 mmol), PPh3 (0.2g, 0.75 mmol), NaOAc (0.9g, 11.32 mmol), and ethyl acrylate (0.9mL, 8.30 mmol) in DMA (15mL) was stimulated on a MW 250W for 25 minutes. The resulting solution was filtered, and the filtrate was extracted with DCM (75mL × 2) and saturated NaCl (saturated 75mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified by flash column (φ3.5 × 9, EA / HEX=1 / 10~DCM / Hex=2 / 1) to obtain the product as a yellow solid. The solid was washed with ether (5 mL) to obtain the product as a yellow solid (1.4 g, 47%). Rf = 0.33 (EA / Hex = 1:2)

[0302] (E)-3-(2-ethyl-7-fluoro-3-(2-fluoro-6-methylphenyl)-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4an) A reaction mixture of 3an (3.0 g, 7.04 mmol), Pd(OAc)2 (79 mg, 0.35 mmol), PPh3 (0.2 g, 0.70 mmol), NaOAc (0.9 g, 10.56 mmol), and ethyl acrylate (0.8 mL, 7.74 mmol) in DMA (14 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was diluted with DCM (30 mL) and filtered. The filtrate was extracted with DCM (70 mL x 2) and saturated NaCl (70 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified using a flash column (φ3.5×8, EA / HEX = 1 / 8~1 / 7) to obtain the product as a brown oil. Hex (3 mL) was added to the oil and sonicated for 30 seconds, causing the product to precipitate as an orange solid (1.4 g, 50%). Rf = 0.5 (EA / Hex = 1:2)

[0303] (E)-3-(2-ethyl-3-(4-ethylphenyl)-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4ao) A reaction mixture of 3ao (3.1 g, 7.34 mmol), Pd(OAc)2 (83 mg, 0.37 mmol), PPh3 (0.2 g, 0.73 mmol), NaOAc (0.9 g, 11.01 mmol), and ethyl acrylate (0.9 mL, 8.08 mmol) in DMA (15 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified by flash column (φ4 × 8, EA / HEX = 1 / 8 ~ 1 / 7.5) to obtain the product as a yellow slurry solution. Hex (20 mL) was added to the solution, and the product precipitated as a yellow solid (1.3 g, 45%). Rf = 0.65 (EA / Hex = 1:2)

[0304] (E)-3-(3-(4-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl) ethyl acrylate (4ap) A reaction mixture of 3ap (3.2g, 6.11 mmol), Pd(OAc)2 (83 mg, 0.37 mmol), PPh3 (0.2g, 0.75 mmol), NaOAc (0.9g, 11.21 mmol), and ethyl acrylate (0.9 mL, 8.22 mmol) in DMA (15 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black oil. The crude product was purified by precipitation (EA / Hex = 3 / 2 mL) to obtain the product as an orange solid (1.8 g, 59%). Rf = 0.4 (EA / Hex = 1:2)

[0305] Example 60: (E)-3-(2-ethyl-7-fluoro-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5ak, compound 40) TIFF0007897463000193.tif22128 To a slurry solution of NaOH (0.4 g, 10.40 mmol) in NH2OH (39 mL), 4ak (2.0 g, 5.20 mmol) was added at 0°C and the mixture was stirred at room temperature for 1.5 hours. The resulting solution was stopped by adding 1N HCl (27 mL) to pH=7, and extracted with CHCl3 (75 mL) and NaCl (saturated 75 mL). The slurry solution was filtered, and the organic layer was separated. The aqueous layer was extracted with CHCl3 (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified by flash column (φ4 × 10, MeOH / DCM = 1 / 40~1 / 30) to obtain the product as a white solid. The solid was dissolved in MeOH (1 mL) and DCM (5 mL) and concentrated until 1.5 mL of solvent remained. EA (1 mL) was added to the residue and sonicated to precipitate the product (from clear to slurry). Hex (10 mL) was added to the slurry solution and filtered to obtain the product as a white solid (0.5 g, 23%). TIFF0007897463000194.tif27157

[0306] Example 61: (E)-3-(2-ethyl-7-fluoro-4-oxo-3-(p-tolyl)-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5al, compound 39) TIFF0007897463000195.tif22128 To a slurry solution of NaOH (0.3 g, 8.30 mmol) in NH2OH (31 mL), 4 Al (1.6 g, 4.15 mmol) was added at 0°C and the mixture was stirred at room temperature for 1 hour. The resulting solution was stopped by adding 1 N HCl (20 mL) to pH=7, and extracted with DCM (75 mL) and NaCl (saturated 75 mL). The slurry solution was filtered, and the organic layer was separated. The aqueous layer was extracted with DCM (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a yellow oil. The crude product was purified by flash column (φ3.5 × 9, MeOH / DCM = 1 / 40~1 / 30) to obtain the product as a clear orange oil. The solid was diluted with MeOH (1 mL) and DCM (2 mL), and EA (2 mL) was added during sonication to precipitate the product (from clear to slurry). Hex (5 mL) was added to the slurry solution to obtain the product as a clear orange to white solid (0.5 g, 31%). TIFF0007897463000196.tif27160

[0307] Example 61: (E)-3-(2-ethyl-7-fluoro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5am, compound 38) TIFF0007897463000197.tif22128 To a slurry solution of NaOH (0.3 g, 7.06 mmol) in NH2OH (26 mL), 4 am (1.4 g, 3.53 mmol) was added at 0°C and stirred at room temperature for 1 hour. The resulting solution was stopped by adding 1 N HCl (20 mL) to pH=7, and extracted with CHCl3 (75 mL) and NaCl (saturated 75 mL). The slurry solution was filtered, and the organic layer was separated. The aqueous layer was extracted with CHCl3 (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product. The crude product was purified by flash column (φ4 × 8, MeOH / DCM = 1 / 40~1 / 35) to obtain the product as a clear orange oil. The oil was diluted with MeOH (1 mL) and DCM (5 mL) and concentrated until 1 mL of solvent remained. During sonication, EA (2 mL) was added to the residue to precipitate the product (from clear to slurry). Hex (10 mL) was added to the slurry solution to precipitate the product as a clear orang solid (0.5 g, 38%). TIFF0007897463000198.tif34158

[0308] Example 62: (E)-3-(2-ethyl-7-fluoro-3-(2-fluoro-6-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5an, compound 37) TIFF0007897463000199.tif22128 To a slurry solution of NaOH (0.3 g, 7.03 mmol) in NH2OH (26 mL), 4AN (1.4 g, 3.51 mmol) was added at 0°C and the mixture was stirred at room temperature for 30 minutes. The resulting solution was stopped by adding 1N HCl (18 mL) to pH=7, and extracted with CHCl3 (75 mL), DCM (75 mL), and NaCl (saturated 75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oily substance. The crude product was purified by flash column (φ3.5 × 9, MeOH / DCM = 1 / 40~1 / 35) to obtain the product as a clear orange to white solid. The solid was dissolved in MeOH (1 mL) and DCM (3 mL) and concentrated until 1 mL of solvent remained. During sonication, EA (1 mL) was added to the residue to precipitate the product (from clear to slurry). Hex (20 mL) was added to the slurry solution to precipitate the product as a clear orange to white solid (1.0 g, 76%). TIFF0007897463000200.tif27159

[0309] Example 63: (E)-3-(2-ethyl-3-(4-ethylphenyl)-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5ao, compound 42) TIFF0007897463000201.tif22128 To a slurry solution of NaOH (0.3 g, 6.59 mmol) in NH2OH (25 mL), 4ao (1.3 g, 3.30 mmol) was added at 0°C and stirred at room temperature for 2.5 hours. The resulting solution was stopped by adding 1N HCl (20 mL) to pH=7 and extracted with DCM (75 mL) and H2O (50 mL). The slurry solution was filtered and the aqueous layer was extracted with DCM (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ4 × 8, MeOH / DCM = 1 / 50~1 / 30) to obtain the product as an orange solid. The solid was dissolved in MeOH (1 mL) and DCM (5 mL) and concentrated until 1 mL of solvent remained. EA (2 mL) was added to the residue and sonicated. Hex (10 mL) was added to the slurry solution and the product was precipitated as a beige solid (0.4 g, 30%). TIFF0007897463000202.tif34155

[0310] Example 64: (E)-3-(3-(4-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (5ap, compound 41) TIFF0007897463000203.tif22128 To a slurry solution of NaOH (0.4 g, 8.88 mmol) in NH2OH (33 mL), 4ap (1.8 g, 4.44 mmol) was added at 0°C and stirred at room temperature for 3.5 hours. The resulting solution was stopped by adding 1N HCl (20 mL) to pH=7, and extracted with CHCl3 (75 mL) and NaCl (saturated 75 mL). The slurry solution was filtered, and the organic layer was separated. The aqueous layer was extracted with CHCl3 (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ4 × 9, MeOH / DCM = 1 / 40~1 / 35) to obtain the product as a clear orange oil. The oil was diluted with DCM (5 mL) and concentrated until 2 mL of solvent remained. During sonication, EA (1 mL) was added to the residue to precipitate the product (from clear to slurry). Hex (10 mL) was added to the slurry solution to precipitate the product as a clear orange solid (0.2 g, 9%). TIFF0007897463000204.tif26157

[0311] Example 65: 3-(4-(dimethylamino)phenyl)-2-ethyl-7-fluoro-6-iodoquinazoline-4(3H)-one(3aq) TIFF0007897463000205.tif27128 A solution of 2a (5.0 g, 17.79 mmol) in pyridine (23 mL) was mixed with propionic anhydride (3.4 mL, 26.69 mmol) and P(OPh)3 (6.0 mL, 23.13 mmol) and stirred at room temperature for 10 minutes. The resulting solution was stimulated in a MW at 250 W for 20 minutes. 4-n,n-dimethylaminoaniline (2.9 mL, 23.13 mmol) was added to the reaction mixture and stimulated in a MW at 250 W for 20 minutes. The resulting solution was stopped by adding 3N HCl (68 mL) to pH=2 and extracted with DCM (75 mL × 2). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as a dark blue slurry solution. To the resulting residue, EA (1 mL), Hex (3 mL), and ether (5 mL) were added, and the product was precipitated as a deep blue solid (4.0 g, 51%). Rf = 0.38 (EA / Hex = 1:2)

[0312] (E)-3-(3-(4-(dimethylamino)phenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)ethyl acrylate (4aq) A reaction mixture of 3aq (4.0 g, 9.15 mmol), Pd(OAc)2 (0.1 g, 0.46 mmol), PPh3 (0.2 g, 0.91 mmol), NaOAc (1.1 g, 13.72 mmol), and ethyl acrylate (1.0 mL, 10.06 mmol) in DMA (18 mL) was stimulated on a MW 250 W for 25 minutes. After cooling to room temperature, the resulting solution was filtered, and the filtrate was extracted with DCM (75 mL × 2) and saturated NaCl (75 mL saturated). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a black solid. The solid was washed with MeOH (30 mL) to obtain the product as a greenish-brown solid (2.5 g, 66%). Rf = 0.35 (EA / Hex = 1:2)

[0313] Example 66: (E)-3-(3-(4-(dimethylamino)phenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide (5aq, compound 43) TIFF0007897463000207.tif27128 To a slurry solution of NaOH (0.5 g, 12.21 mmol) in NH2OH (46 mL), 4 aq (2.5 g, 6.11 mmol) was added at 0°C and stirred at room temperature for 5 hours. The reaction was stopped by adding 2N HCl (25 mL) to the resulting solution to pH=7, and extracted with [M (75 mL + MeOH 5 mL) × 2) and H2O (75 mL). The slurry solution was filtered, and the aqueous layer was extracted with DCM (75 mL). The organic layer was dried over MgSO4 and concentrated to obtain the crude product as an orange oil. The crude product was purified by flash column (φ4 × 8, MeOH / DCM = 1 / 50~1 / 30) to obtain the product as an orange solid. The solid was dissolved in MeOH (1 mL) and DCM (5 mL), and concentrated until 1 mL of solvent remained. EA (2 mL) was added to the residue, and it was sonicated. Hex (10 mL) was added to the slurry solution, and the product was precipitated as a beige solid (0.4 g, 30%). TIFF0007897463000208.tif34155

[0314] Example 67: 7-Fluoro-6-iodo-2-methyl-3-(o-tolyl)quinazoline-4(3H)-one(42e) TIFF0007897463000209.tif16128 A mixture of 2-amino-4-fluoro-5-iodobenzoic acid (3.00 g, 10.7 mmol) in pyridine (10 mL) was mixed with triphenyl phosphite (3.5 mL, 12.8 mmol) and acetyl chloride (1.2 mL, 16.0 mmol), and the mixture was stirred at room temperature for 15 minutes. Then, 2-methylaniline hydrochloride (2.35 g, 16.0 mmol) was added to the mixture, and the mixture was irradiated with microwaves (200 W) for 10 minutes under reflux. The mixture was partitioned between toluene (140 mL) and water (100 mL). The aqueous layer was extracted with toluene (100 mL x 2), and the combined organic layer was dried over MgSO4, evaporated, and precipitated. The precipitate was collected and dried under reduced pressure to obtain 42e (3.17 g, 75%) as an off-white solid. f = 0.46 (siRNA / hexane=1 / 2); ESIMS(-) m / z 393.4.

[0315] Example 68: (E)-3-(7-fluoro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazolin-6-yl)acrylic acid Acrylic acid (0.28 mL, 4.06 mmol) was added to a mixture of 42e (1.60 g, 4.06 mmol), Pd(OAc)2 (36 mg, 0.162 mmol), [(t-Bu)3PH]BF4 (94 mg, 0.325 mmol), and Cs2CO3 (1.32 g, 4.04 mmol) in DMF (20 mL). The reaction mixture was treated according to general procedure A to obtain crude (E)-3-(7-fluoro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazolin-6-yl)acrylic acid product (928 mg, 67%) as a red solid. ESIMS(-) m / z 337.2 [M - H] - .

[0316] Example 69: (E)-3-(7-fluoro-2-methyl-4-oxo-3- (o-trill) -3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (compounds 44, 43e) A mixture of (E)-3-(7-fluoro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazolin-6-yl)acrylic acid (650 mg, 1.92 mmol), EDCI (552 mg, 2.88 mmol), and HOBt (259 mg, 1.92 mmol) in 10 mL of DMF was stirred at room temperature for 30 minutes. Then, NH2OTHP (252 mg, 2.11 mmol) was added to the mixture, and the mixture was stirred at room temperature for a further 1.5 hours. The mixture was added to 60 mL of water and allowed to precipitate. The precipitate was filtered and purified by column chromatography (silica gel: φ2.0 × 11 cm; elution by MeOH / CH2Cl2 = 0 / 100 to 1 / 99 gradient). The desired fraction was collected, evaporated, and dried under reduced pressure to obtain the O-THP compound (542 mg, 65%) as a red solid. To the solution of the O-THP compound (542 mg, 1.24 mmol) in MeOH (10 mL), TFA (10 mL, 129 mmol) was added. The reaction mixture was stirred at 55°C for 18 hours. The solvent was evaporated, and the residue was partitioned between siRNA (30 mL) and water (30 mL). The aqueous layer was extracted with siRNA (30 mL × 3). The combined organic layers were dried over MgSO4, evaporated, and purified by column chromatography (silica gel: φ2.0 × 11 cm; elution by a gradient of MeOH / CH2Cl2 = 1 / 99 to 3 / 97). The desired fraction was collected, evaporated, and dried under reduced pressure to obtain compound (COMPUND) 44 (192 mg, 44%) as a pale yellow solid. TIFF0007897463000212.tif27155

[0317] Example 70: HDAC6 selective inhibitors showed neuroprotective effects in paclitaxel-induced neuropathy by promoting neurite outgrowth. To investigate the effects of HDAC6 inhibitors on neuronal protection and regeneration, we tested the recovery of dorsal root ganglion (DRG) cells after paclitaxel injury. Dorsal root ganglia were excised from 7-week-old female C57BL / 6J mice and incubated for 24 hours with 0.1 μM and 1 μM concentrations of HDAC6 inhibitors (compounds: compound 33, compound 34, or compound 2) or 100 ng / ml of nerve growth factor BDNF (positive control), followed by incubation with 0.1 μM paclitaxel for 24 hours. Paclitaxel-treated DRG neurons showed a 55% reduction in neurite outgrowth, but pretreatment with HDAC6 inhibitors significantly rescued neurite outgrowth induced by paclitaxel injury (Figure 1). Furthermore, the neuroprotective effect of HDAC6 inhibitors was consistent with hyperacetylation of tubulin (Figure 2).

[0318] Figure 1 shows that HDAC6 inhibitors demonstrated a significant neuroprotective effect against paclitaxel-induced injury in a DRG neurite outgrowth model. Neurites were stained with βIII-tubulin.

[0319] Figure 2 shows Western blots of acetylated α-tubulin (Ac-α-tub) and actin protein in primary DRG cells 48 hours after HDAC6 inhibitor treatment.

[0320] Example 71: HDAC6 selective inhibitors showed protective effects against cisplatin-induced neurite degeneration. The protective effect of HDAC6 inhibitors was investigated using rat DRG cells. DRG cells were treated with 0.5 mM cisplatin for 48 hours, either with 0.3 μM compound 2 or ACY1215, or without compound 2 or ACY1215. Neurite area and bleb number (cell apoptosis) per image were calculated, and their ratios between the test groups were compared, as shown in Figure 3. DRG cells treated with HDAC6 inhibitors showed a significantly lower degree of neurite degeneration (p<0.05).

[0321] Figure 3 shows the protective effect of HDAC6 inhibitors on the improvement of cisplatin-induced neurite degeneration.

[0322] Example 72: Compound 2 reverses cisplatin-induced neuropathy, but ACY1215 does not. To understand whether compound 2 exerts neuroprotective activity in cisplatin-induced neuropathy, a foot-stimulus avoidance mouse model was used. The 50% foot-stimulus avoidance threshold (PWT) for static mechanical stimuli was assessed using the von Frye filament and up-down method, following the procedure described by Chaplan (1994). Mechanical allodynia, the sensation of pain caused by harmless stimuli such as light touch, was assessed weekly (days 7, 14, 21, 28, 36, and 42) using the manual von Frye test. Animals indicated sensation by withdrawing their feet. The minimum force that caused foot avoidance was considered the reflex threshold.

[0323] Balb / c mice weighing approximately 25±2 grams were administered cisplatin intraperitoneally at a dose of 1.5 mg / kg for 5 consecutive days (cumulative dose of 7.5 mg / kg), followed by a 5-day recovery period. The cisplatin administration cycle was repeated to reach a cumulative dose of 15 mg / kg, inducing neurological impairment. The test compounds, compound 2 and ACY1215, were administered orally once daily for 2 weeks (excluding weekends) from day 16 to day 29. Pregabalin, a drug known to provide transient analgesia, was administered at a dose of 15 mg / kg before each von Frey stimulation test to serve as a positive control.

[0324] Cisplatin-treated (control) animals showed a significant decrease in the mean escape threshold on day 14 compared to sham control animals (p<0.001). Pregabalin administered 1 hour prior to the von Frye stimulation test increased the escape threshold compared to cisplatin control animals that did not receive pregabalin pretreatment. Compound 2 treatment significantly increased the mean escape threshold compared to cisplatin control animals, indicating that compound 2 reversed the cisplatin-induced neuropathic state in the animals. In addition, compound 2 exhibited superior activity distinct from ACY-1215; compound 2, as a highly selective HDAC6 inhibitor, promotes neuropathic recovery more effectively than less selective HDAC6 inhibitors.

[0325] Figure 4 shows the 50% foot stimulus avoidance threshold (PWT) for the following groups: sham control group (no cisplatin treatment, no test drug treatment), media control group (treated with cisplatin and drug media only), compound 2 treatment group, ACY-1215 treatment group, and pregabalin treatment group.

[0326] Example 73: Prevention and treatment of pulmonary fibrosis The activity of compounds 2 and 33 in the prevention and / or treatment of pulmonary fibrosis was investigated using a bleomycin-induced pulmonary fibrosis model, which includes inactivated bleomycin hydrolase, increased oxidative stress, and increased inflammatory cytokines. In the prevention model, mice were intratracheally administered bleomycin 1 hour before the first oral dose of 30 mg / kg of the test compound. The treatment was continued for 21 consecutive days, and the mice were sacrificed. Histological changes in lung tissue were analyzed by H&E staining to assess the degree of pulmonary fibrosis.

[0327] Treatment with compound 2 and compound 33 significantly reduced the incidence of pulmonary fibrosis in animals (Figure 5) and the presence of IL-6, a pro-inflammatory cytokine associated with pulmonary fibrosis, in bronchoalveolar lavage fluid (BALF) (Figure 6). In summary, compound 2 and compound 33 were shown to prevent pulmonary fibrosis after lung injury and to suppress IL-6 expression in lung tissue.

[0328] In addition, compounds 2 and 33, which are HDAC6 inhibitors, were tested for their effect in aiding the recovery of animals from lung injury and post-injury pulmonary fibrosis. HDAC6 inhibitors show protective effects in inflammatory pneumonia and pulmonary fibrosis.

[0329] Figure 5 shows that compounds 2 and 33 reduced pulmonary fibrosis.

[0330] Figure 6 shows that compounds 2 and 33 suppressed IL-6 levels in BALF.

[0331] Example 74: Cytokine profiles in response to HDAC6 inhibitor treatment in fibrous diseases HDAC6 inhibitor compounds were tested on the commercially available BioMAP platform for cytokine profiles associated with tissue damage. The BioMAP fibrosis panel included three stimulated systems to model TGFβ and TNFα-driven myofibroblast differentiation during chronic inflammation and wound healing in different tissue settings. Renal fibrosis associated with end-stage renal failure was captured in the REMyoF system, consisting of a co-culture of renal proximal tubular epithelial cells and adult fibroblasts. Interstitial lung diseases, including pulmonary fibrosis such as idiopathic pulmonary fibrosis (IPF), were modeled in the SAEMyoF system by co-culturing small airway epithelial cells and adult fibroblasts. Both co-culture systems modeled paracrine interactions between myofibroblasts and proximal epithelial cells, while the effect on fibroblasts alone was investigated using the monoculture MyoF system. Signature BioMAP profiles reflecting changes in protein biomarker readout within each system were generated for each test compound. The readouts of biomarkers selected for therapeutic and biological relevance predicted disease outcomes or specific drug effects, and their clinical efficacy was validated using known agents. Each readout was quantitatively measured by an immunoassay method that detects proteins (e.g., ELISA).

[0332] BioMap readouts showed that compound 2 suppressed inflammation-related activity (decreased M-CSF, VCAM-1, sIL-6, MCP-1; increased I-TAC), myofibroblast activation-related activity (decreased αSMA, N-cadherin), fibrosis-related matrix activity (decreased TIMP-1, MMP-1, type I collagen, type III collagen, MMP-9), and tissue remodeling / wound healing activity (decreased EGFR, tPA, uPA, bFGF, sVEGF). Compound 33 also suppressed inflammation-related activity (decreased M-CSF, sIL-6, MCP-1; regulation of IP-10, I-TAC), myofibroblast activation-related activity (decreased αSMA, E-cadherin, N-cadherin), fibrosis-related matrix activity (decreased type III collagen, MMP-9; increased type IV collagen; regulation of MMP-1, type I collagen), and tissue remodeling / wound healing activity (decreased EGFR, tPA, uPA; regulation of sVEGF). Furthermore, it was compared to nintedanib, a treatment method approved for idiopathic pulmonary fibrosis and which has shown beneficial effects in treating hepatic fibrosis (Wollin et al 2020) and renal fibrosis (Liu et al 2017) in animal models. Both compound 2 and compound 33 showed remarkable activity in reducing cytokines known to mechanistically contribute to the pathogenesis of pulmonary fibrosis, renal fibrosis, and hepatic fibrosis, including TNF-α, IL-1, IL-6, MMP-9, VEGF, and type I collagen.

[0333] In summary, HDAC6 inhibitors, such as compounds 2 and 33, are effective in suppressing inflammatory responses and may be used to treat or improve cytokine-induced tissue damage. By modulating levels of inflammatory cytokines, HDAC6 inhibitors may be effective in treating fibrotic diseases such as idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, renal fibrosis, and hepatic fibrosis.

[0334] Example 75: The compounds in Table II exhibit high selectivity for HDAC6 inhibition. The activity of HDAC1 and HDAC6 was measured using an acetylated AMC-labeled peptide substrate (RHKKAc), a fluorescent peptide derived from p53 residues 379-382. The proteins included in the assay were as follows: (1) Human HDAC1 (GenBank accession number NM_004964): full length with C-terminal GST tag, MW=79.9kDa, expressed in Sf9 cells by a baculovirus expression system; (2) Human HDAC6 (GenBank accession number BC069243): full length with N-terminal GST tag, MW=159kDa, expressed in Sf9 cells by a baculovirus expression system.

[0335] The compounds in Table II exhibit high selectivity for HDAC6 inhibition and excellent pharmacological properties.

[0336] [Table II]

[0337] Example 76: Compound 2 reduced paclitaxel-induced peripheral neuropathy. Chemotherapy-induced peripheral neuropathy was induced in male Sprague-Dawley (SD) rats weighing 320 ± 30 grams by intraperitoneal administration of paclitaxel at a dose of 6 mg / kg for 5 consecutive days, with a cumulative total dose of 30 mg / kg.

[0338] Compound 2 or the medium was administered orally once daily for two weeks during weekdays (days 8-12 and 15-19). Mechanical allodynia was assessed weekly by manual VonFlye test. Animals were given 20-30 minutes to adapt before the test. A series of eight VonFlye monofilaments with logarithmically increasing hardness [3.61 (0.4g), 3.84 (0.6g), 4.08 (1.0g), 4.31 (2.0g), 4.56 (4.0g), 4.93 (8.0g), 5.18 (15.0g), and (26.0g)] were manually pressed onto the foot. The manual VonFlye monofilament was applied vertically from under the mesh bed to the center of the plantar surface with enough force to cause slight buckling of the foot, and held for approximately 6-8 seconds. A rapid withdrawal of the foot was considered a positive response; however, walking was considered an ambiguous response, in which case the stimulus was reapplied. The 50% foot stimulus avoidance threshold (PWT) to static mechanical stimuli was assessed using the von Fley filament and up-down method.

[0339] Fonfrey's data are presented as mean ± SEM (standard error of the mean). The treatment group was compared to the paclitaxel control group using Student's t-test. A p-value < 0.05 is considered statistically significant.

[0340] Paclitaxel-treated animals showed a significant reduction in the mean escape force threshold, starting from day 7, compared to sham controls: 6.22 ± 1.6 g (medication group) vs. 25.18 ± 0.49 g (sham control group).

[0341] Treatment with pregabalin, a positive control for transient analgesia, administered at a dose level of 15 mg / kg one hour prior to the vonfly stimulation test, resulted in a significant increase in the mean escape force threshold of treated animals, starting on day 14 of the study (media group, 8.22 ± 2.5 g vs. pregabalin group, 24.1 ± 3.45 g) and continuing to day 21 (media group, 7.75 ± 1.4 g vs. pregabalin group, 26 ± 0 g), compared to the media.

[0342] Animals treated with compound 2 showed a significant increase in the mean escape force threshold compared to the medium from day 14 of the study. Compound 2-related analgesia was maintained for at least two weeks after discontinuation of the drug, but pregabalin did not show efficacy (Figure 7).

[0343] Compound 2 at 15 and 30 mg / kg, starting from day 14 of the study, significantly reduced the susceptibility of treated animals to mechanical stimuli, and the effect persisted for at least 14 days after discontinuation of administration. The prolonged duration of analgesic activity suggests that neurons recovered after treatment with compound 2.

[0344] Figure 7 shows the 50% paw stimulus avoidance threshold (PWT) to static mechanical stimulation using the von Frye filament and up-down method.

[0345] Equivalents and range In the claims, articles such as “a,” “an,” and “the” may mean one or more unless otherwise stated or evident from the context. Claims or statements containing “or” between one or more members of a group are considered satisfied unless otherwise stated or evident from the context if one, multiple, or all of the group members are present, used, or otherwise related in a given product or process. The present invention includes embodiments in which exactly one member of a group is present, used, or otherwise related in a given product or process. The present invention includes embodiments in which multiple, or all, of the group members are present, used, or otherwise related in a given product or process.

[0346] Furthermore, the present invention encompasses all variations, combinations, and reorderings in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in other claims dependent on the same basic claim. Where elements are presented as a list, for example in Markush group form, each subgroup of the elements is also disclosed, and any element may be removed from the group. In general, where the present invention or aspects of the present invention are referred to as including certain elements and / or features, it should be understood that certain aspects of the present invention or aspects of the present invention consist of or are essentially derived from such elements and / or features. For the sake of simplification, these aspects are not specifically shown in this specification in these terms. It should also be noted that the terms “including” and “containing” are intended to be open and allow for the inclusion of additional elements or stages. Where a scope is indicated, an endpoint is included. Furthermore, unless otherwise stated or otherwise evident from the context and the understanding of those skilled in the art, values ​​expressed as ranges may, unless the context clearly indicates otherwise, assume any specific value or subrange within the ranges described in different embodiments of the invention, up to one-tenth of the lower limit unit of the range.

[0347] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any of the incorporated references and this specification, this specification shall prevail. In addition, any particular aspect of the Invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Such aspects may be excluded even if the exclusion is not expressly indicated herein, as they are considered to be known to those skilled in the art. Any particular aspect of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0348] Those skilled in the art will be able to recognize or confirm many equivalents of the specific embodiments described herein by means of routine experiments alone. The scope of the embodiments described herein is not limited to the foregoing, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this description without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, in the formula, R 1 However, hydrogen, (C 1-2 )alkyl, or fluoro(C 1-2 ) is alkyl; R 2 However, it is methyl; R 3 However, it is hydrogen; R 4 However, it is hydrogen; R 5 However, it is hydrogen; R 6 However, it is methyl; R 7 is hydrogen or halogen; R 8 but is methyl, methoxy, or fluoro; and R 9 However, it is hydrogen or fluoro. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. R 1 The compound according to claim 1, wherein is methyl.

3. R 1 The compound according to claim 1, wherein is ethyl.

4. Those of formula (IA): The compound according to claim 1.

5. R 1 The compound according to claim 4, wherein is ethyl.

6. R 8 The compound according to claim 4, wherein is fluoro.

7. Those of formula (IB): And in the formula, R 8 The compound according to claim 1, wherein is fluoro.

8. below: A compound according to claim 1, selected from the group consisting of the following.

9. below: (E)-3-(3-(2,6-dimethylphenyl)-7-fluoro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-2,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide, (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide, and (E)-3-(3-(2,6-dimethylphenyl)-2-ethyl-7-methoxy-4-oxo-3,4-dihydroquinazoline-6-yl)-N-hydroxyacrylamide, A compound according to claim 1, selected from the group consisting of the following.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or medium.

11. A pharmaceutical composition for promoting neurite outgrowth in a subject requiring it, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier or medium.

12. A pharmaceutical composition for the prevention or treatment of peripheral neuropathy in a subject requiring it, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier or medium.

13. The pharmaceutical composition according to claim 12, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, or postherpetic neuralgia derived from herpes zoster.

14. The pharmaceutical composition according to claim 13, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy.

15. The pharmaceutical composition according to claim 14, wherein the chemotherapy is a platinum-based chemotherapy, an alkaloid-based chemotherapy, or a taxane-based chemotherapy.

16. A pharmaceutical composition for enhancing tubulin hyperacetylation of cells in a subject, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or medium.

17. A pharmaceutical composition for the prevention or treatment of a target fibrosis, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier or medium.

18. The pharmaceutical composition according to claim 17, wherein the fibrosis is pulmonary fibrosis, hepatic fibrosis, or renal fibrosis.

19. The pharmaceutical composition according to claim 18, wherein the pulmonary fibrosis is associated with increased expression of IL-1, TNF-α, IL-6, or collagen in the subject.

20. The pharmaceutical composition according to claim 18, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis or virus-induced fibrosis.

21. A pharmaceutical composition that reduces the expression of IL-1, TNF-α, IL-6, or collagen in a subject that requires it, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier or medium.

22. A pharmaceutical composition for treating or improving a cytokine-induced inflammatory condition in a subject in need thereof, wherein the cytokine comprises IL-1, TNF-α, IL-6, M-CSF, VCAM-1, or MCP-1, and comprises a therapeutically effective amount of any one of the compounds or pharmaceutically acceptable salts described in claims 1 to 9, and a pharmaceutically acceptable carrier or medium.

23. The pharmaceutical composition according to claim 22, wherein the aforementioned condition is selected from the group consisting of coronavirus-induced pneumonia, acute respiratory distress syndrome, acute pneumonia, pulmonary fibrosis, hepatic fibrosis, and renal fibrosis.

24. Use of the compound according to any one of claims 1 to 9 in the manufacture of a pharmaceutical product for the prevention or treatment of peripheral neuropathy in a subject that requires it.

25. The use according to claim 24, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, or postherpetic neuralgia originating from herpes zoster.

26. The use according to claim 25, wherein the peripheral neuropathy is chemotherapy-induced peripheral neuropathy.

27. Use of the compound according to any one of claims 1 to 9 in the manufacture of a pharmaceutical for the prevention or treatment of fibrosis in a subject that requires it.

28. Use of a compound according to any one of claims 1 to 9 in the manufacture of a pharmaceutical product for the treatment of acute respiratory distress syndrome, acute pneumonia, pulmonary fibrosis, cornonavirus-induced pneumonia, hepatic fibrosis, and renal fibrosis.

29. A pharmaceutical composition for the prevention or treatment of diabetic neuropathy in a subject, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier or medium.

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