Isoxazole hydroxamic acid as a histone deacetylase 6 inhibitor

Abstract

To provide methods of treating diseases.SOLUTION: The present disclosure provides compounds represented by Formula (I) and pharmaceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, where X and n are defined as described in the specification. The present disclosure also provides compounds of Formula (I) used to treat diseases and conditions, e.g., cancer, in which inhibition of HDAC provides a benefit. In one aspect, the present disclosure provides compounds having any one of Formulas I-V below, and pharmaceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, collectively referred to as "Compounds of the Disclosure". The Compounds of the Disclosure are histone deacetylase inhibitors.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Statement on the Rights of the Government This invention was made with government support under authorization number 5R01NS079183 granted by the National Institutes of Health (NIH). The U.S. Government reserves certain rights in this invention.

[0002] Technical field This disclosure relates to isoxazole-substituted hydroxamic acid HDAC inhibitors (HDACIs), pharmaceutical compositions comprising HDACIs, and methods for treating diseases and conditions, such as cancer, in which inhibition of HDACs is beneficial. [Background technology]

[0003] Background of the Invention Covalent post-translational modifications (PTMs) of epigenomic proteins contribute to their biological roles, acting as carriers of epigenetic information from one cell generation to the next. Epigenetics, meaning the highest or highest level of genetics, refers to external modifications to DNA and associated histones that "turn on" or "turn off" genes. These modifications do not alter the DNA sequence, but instead influence how cells "decode" genes. PTMs play a crucial role in regulating protein function, transcription, DNA replication, and DNA damage repair.

[0004] The main events surrounding epigenetic regulation are concentrated in three modes of action: writers, readers, and erasers. Writers are responsible for affixing various PTM markers to histones, including acetylation catalyzed by histone acetyltransferases (HATs). Readers refer to proteins that recognize and bind to these PTM markers, thereby mediating their action, and erasers include various enzymes such as histone deacetylases (HDACs) that catalyze the removal of these markers. In the case of acetylated histone lysine residues, HDACs are responsible for catalyzing the hydrolysis of the acetyl marker to yield an unsubstituted lysine residue. The HDAC family currently consists of 18 enzymes, which are classified into four subgroups according to their homology to the yeast family. HDAC1, 2, 3, and 8 (classified as Class I HDACs according to their homology to yeast Rpd3) are characterized by ubiquitous expression and localization to the nucleus. Class II HDACs exhibit tissue-specific expression and a shuttle between the nucleus and cytoplasm. These enzymes homologous to yeast Hda1 are subdivided into Class IIa (HDAC4, 5, 7, and 9) and Class IIb (HDAC6 and 10). HDAC11, the sole member of the Class IV subfamily, exhibits similarity between the catalytic domains of both Class I and Class II enzymes. Class I, II, and IV HDACs use Zn as a cofactor for deacetylation activity. 2+ These require nicotinamide adenine dinucleotide and are also referred to as conventional HDACs. Sirtuins 1-7 form class III HDACs, with their activity depending on nicotinamide adenine dinucleotide.

[0005] The pharmacological manipulation of enzymes involved in the regulation of protein PTMs, particularly those linked to highly specific PTM markers, holds great potential for a better understanding of cellular function. The discovery of selective small molecule modulators of these enzymes is likely to provide chemical means to better understand the role of these PTMs at the cellular level, and similarly, could lead to modifiers for important diseases. In the field of HDACs, it is possible to block deacetylase enzymes. Numerous compounds exist, and some have paved the way for market entry into cancer treatment. However, the vast majority of these HDACIs are not very selective to isoforms. Many HDACIs inhibit an entire class of HDAC enzymes, rather than just one, and are therefore classified as pan-selective. Among the various HDAC isoforms that appear to be promising therapeutic targets for treating cancer and certain human diseases such as certain CNS disorders, HDAC6 has emerged as a particularly attractive target, given, among other things, that HDAC6 knockout animals remain viable. While HDAC6 does not have an obvious role in the PTM of histone proteins, it is rather involved in regulating the acetylation state of α-tubulin, HSP-90, cortactin, HSF-1, and other protein targets. The enzyme also plays a role in the recognition and clearance of misfolded polyubiquitinated proteins from cells to aggresome formation. HDACCI is disclosed in WO2017 / 040564. There is a continuing need for novel agents, such as small molecules, to treat and / or prevent cancer and other diseases in response to HDAC inhibition. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2017 / 040564 [Overview of the project] [Means for solving the problem]

[0007] Summary of the Invention In one embodiment, the present disclosure provides compounds having any one of the following formulas I to V, collectively referred to as the "Compounds of the Disclosure," as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. The Compounds of the Disclosure are histone deacetylase inhibitors.

[0008] In one embodiment, the present disclosure provides compounds having any one of the following formulas VI to X, collectively referred to as “Intermediates of the Disclosure.” The Intermediates of the Disclosure are synthetic intermediates that can be used to prepare histone deacetylase inhibitors having formulas I to V.

[0009] In another aspect, the Disclosure provides a method for treating diseases and conditions in which inhibition of HDACs would be beneficial, such as cancer, neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, or autoimmune diseases, comprising the step of administering a therapeutically effective amount of the compound of the Disclosure to an individual, such as a human patient in need.

[0010] In another aspect, the Disclosure provides a method for treating diseases and conditions such as cancer, neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases, comprising the step of administering a therapeutically effective amount of the compound of the Disclosure to an individual in need thereof.

[0011] In another embodiment, the present disclosure provides a method for increasing the sensitivity of cancer cells to radiotherapy and / or chemotherapy, comprising the step of administering a therapeutically effective amount of the compound of the present disclosure to an individual in need thereof.

[0012] In another aspect, the Disclosure provides the use of the Compounds of the Disclosure in combination with other drugs and / or therapeutic methods.

[0013] In another aspect, the Disclosure provides compounds of the Disclosure that exhibit selectivity to certain HDAC isozymes, such as HDAC6, rather than to other HDAC isozymes.

[0014] In another aspect, the Disclosure provides compounds of the Disclosure for use in the treatment of a particular disease or condition, such as cancer, neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases.

[0015] In another aspect, the Disclosure provides the use of the compounds of the Disclosure for manufacturing pharmaceuticals for treating a disease or condition of interest, such as cancer, neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases.

[0016] In another embodiment, the Disclosure provides packaged compositions comprising the Compounds of the Disclosure and, optionally, a second therapeutic agent useful for treating the disease or condition of interest, as well as kits comprising a package insert containing instructions for use in treating diseases or conditions such as cancer, neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases.

[0017] In another aspect, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0018] Additional embodiments and advantages of the present disclosure are described in part in the following description and may arise from the description or be taught by the practice of the present disclosure. These embodiments and advantages will be recognized and achieved in particular by the elements and combinations pointed out in the appended claims.

[0019] It should be understood that both the above summary and the following detailed description are illustrative and descriptive only and do not limit the claimed invention. [Brief explanation of the drawing]

[0020] [Figure 1]Figure 1 shows examples of immunoblots demonstrating the activity of SS-01-100 in the WM164 human melanoma cell line, in and out of the presence of IFNg.

[0021] [Figure 2] Figure 2 shows examples of immunoblots demonstrating the activity of SS-01-100 in the WM164 human melanoma cell line, in and out of the presence of IL-6.

[0022] [Figure 3] Figure 3 shows an example of an immunoblot demonstrating SS-02-08 activity in the WM164 human melanoma cell line.

[0023] [Figure 4] Figure 4 is a line graph showing the HDAC activity of SS-1-100 in the WM164 cancer cell line.

[0024] [Figure 5] Figure 5 is a line graph showing the cytotoxicity of SS-1-100 in the WM164 cancer cell line.

[0025] [Figure 6] Figure 6 is a line graph showing the HDAC activity of SS-2-08 in the WM164 cancer cell line.

[0026] [Figure 7] Figure 7 is a line graph showing the cytotoxicity of SS-2-08 in the WM164 cancer cell line.

[0027] [Figure 8] Figure 8 is a line graph showing that SS-2-08 induces low cytotoxicity in various cancer cell lines.

[0028] [Figure 9] Figure 9 is a line graph showing that SS-2-08 has HDAC activity in various cancer cell lines.

[0029] [Figure 10] Figure 10 includes two line graphs showing the activity (cell death rate and HDAC inhibition rate) of SS-2-08 in the PC3 human prostate cell line compared to Nexturastat A and Tuvastatin A.

[0030] [Figure 11] Figure 11 includes two line graphs showing the activity (cell death rate and HDAC inhibition rate) of SS-2-08 in 5637 human bladder cells compared to nextulastat A and tubastatin A.

[0031] [Figure 12] Figure 12 includes two line graphs showing the activity (cell death rate and HDAC inhibition rate) of SS-2-08 in T24 human bladder cells compared to nextulastat A and tuberstatin A.

[0032] [Figure 13] Figure 13 includes two line graphs showing the activity (cell death rate and HDAC inhibition rate) of SS-2-08 in SM1 mouse melanoma cells compared to nextulastat A and tubastatin A.

[0033] [Figure 14] Figure 14 is a line graph showing the apoptotic activity of SS-2-08, nextulastat A, tuberstatin A, and LBH589 in melanoma cells.

[0034] [Figure 15] Figure 15 is a line graph showing the survival rates of SS-2-08, nextulastat A, tubastatin A, and LBH589 in melanoma cells.

[0035] [Figure 16]Figure 16 is a line graph showing the cytotoxicity of SS-2-08, nextulastat A, tubastatin A, and LBH589 in melanoma cells.

[0036] [Figure 17] Figure 17 is a graph showing that SS-2-08 reduces tumor growth in vivo in a syngeneic SM1 mouse melanoma model.

[0037] [Figure 18] Figure 18 shows the results of the tubulin acetylation test in the HEK293 cell line. The blot on the left is acetyl-tubulin, and the blot on the right (inverted) is GAPDH. The first lane of each blot is HEK-293 cells treated with tubastatin A (10 μM) for 24 hours. The second lane of each blot is the same cells treated with a vehicle. The next lanes are SS-1-100 and SS-2-08 with increasing concentrations from 10 nM to 10 μM. In the SS-2-08 blot, a 10 μM dose is applied in double succession. [Modes for carrying out the invention]

[0038] Detailed description of the invention In one embodiment, the present disclosure relates to HDACI having formula I: [ka] The formula also provides pharmaceutically acceptable salts, solvates and prodrugs thereof (wherein, X is as follows: [ka] Selected from the group consisting of, R 1 It is selected from the group consisting of hydrogen and C1-4 alkyl groups, R2 is selected from the group consisting of C6-C14 aryl and aralkyl compounds, which are substituted as needed. R3 is selected from the group consisting of optionally substituted C6 to C14 aryl, optionally substituted 5- to 14-membered heteroaryl and -C(=O)NR d R e , R 4a , R 4b , R 4e and R 4f are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b , -C(=O)NR a R b , -C(=O)R c , C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 haloalkyl and haloalkoxy, R 4c and R 4d are each independently selected from the group consisting of hydrogen and C 1~4 alkyl, or R 4c and R 4d together with the carbon atom to which they are bonded form -C(=O)-, R 5a , R 5b , R 5c and R 5d are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b , -C(=O)NR a R b , -C(=O)R c , C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 haloalkyl and haloalkoxy, Z is selected from the group consisting of -O-, -N(R 8 )- and -C(=O)-, or Z is absent, R8 is hydrogen, C 1~4 Alkyl, substituted C as needed 3~6 Cycloalkyl, C6-C as needed. 14 Selected from the group consisting of aryls, aralkyls, and 5-14 member heteroaryls and heteroaralkyls which are substituted as needed, m is 0, 1, or 2. n is 1, 2, 3, 4, 5, or 6. [ka] This represents a single bond or a double bond. R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, substituted C as needed 3~6 Cycloalkyl, C6-C as needed. 14 They are independently selected from the group consisting of aryls and 5- to 14-membered heteroaryls which are substituted as needed, or R a and R b These, together with the nitrogen atoms to which they are bonded, form 3- to 12-membered heterocycloids, which are substituted as needed. R d and R e These, together with the nitrogen atoms to which they are bonded, form 3- to 12-membered heterocycloids, which are substituted as needed. R c C 1~4 (It is alkyl.)

[0039] In another embodiment, the disclosure provides HDACI having formula I, as well as pharmaceutically acceptable salts, solvates and prodrugs thereof, provided that Z is absent, R 3 This is a biring or triring C 10~14 Aryls, 9-14 member bicyclic or tricyclic heteroaryls, or -C(=O)NR d R e This is conditional on the following:

[0040] In one embodiment, the present disclosure provides that X is X-1, X-2, X-3 or X-4, Z is -O-, R 1 is selected from the group consisting of hydrogen and C 1~4 alkyl, R 2 is optionally substituted C6 to C 14 aryl, R 3 is selected from the group consisting of optionally substituted C6 to C 14 aryl and optionally substituted 5- to 14-membered heteroaryl, R 4a and R 4b are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b , -C(=O)NR a R b , -C(=O)R c , C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 haloalkyl and haloalkoxy, R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1~4 alkyl, R 5a , R 5b , R 5c and R 5d are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b , -C(=O)NR a R b , -C(=O)R c , C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6are each independently selected from the group consisting of haloalkyl and haloalkoxy, R a and R b are each independently selected from the group consisting of hydrogen and C 1~6 alkyl, or R a and R b , together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclo, R c is C 1~4 alkyl, an HDACI having formula I, and a pharmaceutically acceptable salt, solvate and prodrug thereof are provided.

[0041] In another embodiment, the present disclosure provides an HDACI having formula I wherein X is X-1, and a pharmaceutically acceptable salt, solvate, for example, hydrate, and prodrug thereof. In another embodiment, R 1 is hydrogen. In another embodiment, R 2 is optionally substituted phenyl. In another embodiment, R 2 is optionally substituted 1-naphthyl. In another embodiment, R 2 is optionally substituted 2-naphthyl. In another embodiment, R 2 is aralkyl.

[0042] In another embodiment, the present disclosure provides an HDACI having formula I wherein X is X-2, and a pharmaceutically acceptable salt, solvate, for example, hydrate, and prodrug thereof are provided. In another embodiment, Z is -O-. In another embodiment, Z is -N(R 8 )-. In another embodiment, Z is -C(=O)-. In another embodiment, R 3 is optionally substituted C6-C 14 aryl. In another embodiment, R 3 is optionally substituted 5- to 14-membered heteroaryl. In another embodiment, R 3 is -C(=O)NRd R e In another embodiment, Z does not exist, and R 3 This is a biring or triring C 10~14 Aryls, 9-14 member bicyclic or tricyclic heteroaryls, or -C(=O)NR d R e That is the case.

[0043] In another embodiment, the disclosure provides HDACI having formula I, where X is X-3, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof.

[0044] In another embodiment, the disclosure provides HDACI having formula I, where X is X-4, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof.

[0045] In another embodiment, the disclosure provides HDACI having formula I, where X is X-5, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof.

[0046] In another embodiment, the present disclosure relates to HDACI having formula II: [ka] Furthermore, the formula provides pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof, in which, R 6a , R 6b , R 6c , R 6d and R 6e These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6Haloalkyl, haloalkoxy, and substituted C as needed. 3~6 Each is independently selected from the group consisting of cycloalkyls, optionally substituted phenyls, optionally substituted 5- or 6-membered heteroaryls, and optionally substituted 5- or 6-membered heterocyclos. R a and R b is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclo. R c C 1~4 It is alkyl, n is 1, 2, or 3.

[0047] In another embodiment, the disclosure is R 6a , R 6b , R 6c , R 6d and R 6e However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 The present invention provides HDACIs having formula II, each independently selected from the group consisting of haloalkyls, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. In another embodiment, R 6a , R 6b , R 6c , R 6d and R 6e These are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Each is independently selected from the group consisting of alkoxys.

[0048] In another embodiment, the disclosure provides HDACI having formula II, where n is 1, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0049] In another embodiment, the present disclosure relates to HDACI having formula III: [ka] Furthermore, the pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof are provided. During the ceremony, R 7a , R 7b , R 7c , R 7d and R 7e These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~6 Each is independently selected from the group consisting of cycloalkyls, optionally substituted phenyls, optionally substituted 5- or 6-membered heteroaryls, and optionally substituted 5- or 6-membered heterocyclos. R a and R b is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclo. R c C 1~4 It is alkyl, n is 1, 2, or 3.

[0050] In another embodiment, the disclosure is R 7a , R 7b , R 7c , R 7d and R 7e However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 The present invention provides HDACIs having formula III, each independently selected from the group consisting of haloalkyls, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. In another embodiment, R 7a , R 7b , R 7c , R 7d and R 7e These are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Each is independently selected from the group consisting of alkoxys.

[0051] In another embodiment, the disclosure provides HDACI having formula III, where n is 1, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0052] In another embodiment, the present disclosure relates to HDACI having formula IV: [ka] Furthermore, the pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof are provided. During the ceremony, R 4a and R 4b These are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Independently selected from the group consisting of alkoxys, R 4c and R 4d It is independently selected from the group consisting of hydrogen and methyl, m is either 0 or 1. n is 1, 2, or 3. [ka] This represents a single bond or a double bond.

[0053] In another embodiment, the present disclosure is made when m is 0, [ka] The present invention provides HDACI having formula IV, which represents a double bond, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof.

[0054] In another embodiment, the present disclosure is that m is 1, [ka] The present invention provides HDACI having formula IV, which represents a single bond, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof.

[0055] In another embodiment, the disclosure provides HDACI having formula IV, where n is 1, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0056] In another embodiment, the present disclosure relates to HDACI having formula V: [ka] Furthermore, the pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof are provided. During the ceremony, R 5a and R 5c These are hydrogen, halogen, cyano, and C1~4 Alkyl and C 1~4 Independently selected from the group consisting of alkoxys, n is 1, 2, or 3.

[0057] In another embodiment, the disclosure provides HDACI having formula V, where n is 1, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0058] In another embodiment, the compounds of the present disclosure are one or more of the compounds having formula I of Table 1, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0059] In another embodiment, the Disclosure provides a pharmaceutical composition comprising the compounds of the Disclosure and a pharmaceutically acceptable carrier.

[0060] In another embodiment, the Disclosure provides compounds of the Disclosure for use in the therapeutic treatment of, for example, cancer, inflammation, traumatic brain injury, neurodegenerative disorders, neurological diseases, peripheral neuropathy, stroke, hypertension, autoimmune diseases, inflammatory diseases, and malaria. In another embodiment, the Disclosure provides compounds of the Disclosure for use in the therapeutic treatment of cancer.

[0061] In another embodiment, the present disclosure provides compounds of the present disclosure that increase the sensitivity of cancer cells to the cytotoxic effects of radiotherapy and / or chemotherapy.

[0062] In another embodiment, the Disclosure provides a compound of the Disclosure that selectively inhibits HDAC6 more than other HDAC isozymes.

[0063] In another embodiment, the Disclosure provides the use of the compounds of the Disclosure for manufacturing pharmaceuticals to treat a disease or condition of interest, such as cancer, neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases.

[0064] In another embodiment, the Disclosure provides a packaged composition comprising the compounds of the Disclosure and, optionally, a second therapeutic agent useful for treating the disease or condition of interest, as well as a kit comprising a package insert containing instructions for use in treating diseases or conditions such as cancer, neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases.

[0065] In another embodiment, the present disclosure provides synthetic intermediates that can be used to prepare histone deacetylase inhibitors having formulas I to V.

[0066] In another embodiment, the present disclosure relates to a compound having formula VI: [ka] Provided, During the ceremony, X is selected from the group consisting of X-1, X-2, X-3, X-4, and X-5 (as defined in relation to Equation I), R 1 is hydrogen and C 1~4 Selected from the group consisting of alkyl groups, R 2 C6~C are substituted as needed. 14 Selected from the group consisting of aryl and aralkyl, R 3 C6~C are substituted as needed. 14 Aryls, 5- to 14-membered heteroaryls and -C(=O)NRs as needed. d R e Selected from the group consisting of , R 4a , R 4b , R 4e and R 4f These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, R 4c and R 4d is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R 4c and R 4d These, together with the carbon atoms to which they are bonded, form -C(=O)-, R 5a , R 5b , R 5c and R 5d These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NRa R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, Z is -O-, -N(R 8 Selected from the group consisting of )- and -C(=O)-, Z does not exist. R 8 is hydrogen, C 1~4 Alkyl, substituted C as needed 3~6 Cycloalkyl, C6-C as needed. 14 Selected from the group consisting of aryls, aralkyls, and 5-14 member heteroaryls and heteroaralkyls which are substituted as needed, R 9 C 1~4 It is alkyl, m is 0, 1, or 2. n is 1, 2, 3, 4, 5, or 6. [ka] This represents a single bond or a double bond. R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, substituted C as needed 3~6 Cycloalkyl, C6-C as needed. 14 They are independently selected from the group consisting of aryls and 5- to 14-membered heteroaryls which are substituted as needed, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 12-membered heterocyclone which is substituted as needed, or R d and R eThese, together with the nitrogen atoms to which they are bonded, form 3- to 12-membered heterocycloids, which are substituted as needed. R c C 1~4 It is alkyl.

[0067] In another embodiment, the present disclosure provides a compound having formula VI, wherein Z is absent, and R 3 This is a biring or triring C 10~14 Aryls, 9-14 member bicyclic or tricyclic heteroaryls, or -C(=O)NR d R e This is conditional on the following:

[0068] In one embodiment, the Disclosure is that X is X-1, X-2, X-3, or X-4, Z is -O-, R 1 However, hydrogen and C 1~4 Selected from the group consisting of alkyl groups, R 2 However, C6~C is substituted as needed. 14 It is Ariel, R 3 However, C6~C is substituted as needed. 14 Selected from the group consisting of aryls and 5- to 14-membered heteroaryls which are substituted as needed, R 4a and R 4b However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, R 4c and R 4d However, hydrogen and C 1~4Independently selected from the group consisting of alkyls, R 5a , R 5b , R 5c and R 5d However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, R a and R b However, hydrogen and C 1~6 Independently selected from the group consisting of alkyls, or R a and R b However, these, together with the nitrogen atom to which they are bonded, form a 3-7 member heterocyclo. R c However, C 1~4 It is alkyl. The present invention provides compounds having formula VI, as well as pharmaceutically acceptable salts, solvates, and prodrugs thereof.

[0069] In another embodiment, the disclosure provides a compound having formula VI, where X is X-1. In another embodiment, R 1 is hydrogen. In another embodiment, R 2 R is a phenyl compound that is substituted as needed. In another embodiment, R 2 R is 1-naphthyl, which is substituted as needed. In another embodiment, R 2 R is 2-naphthyl, which is substituted as needed. In another embodiment, R 2 It is Aralkir.

[0070] In another embodiment, the disclosure provides a compound having formula VI, where X is X-2. In another embodiment, Z is -O-. In another embodiment, Z is -N(R 8 )-. In another embodiment, Z is -C(=O)-. In another embodiment, R 3 C6~C are substituted as needed. 14 It is an arrow. In another embodiment, R 3 R is a 5- to 14-membered heteroaryl that is substituted as needed. In another embodiment, R 3 is -C(=O)NR d R e In another embodiment, Z does not exist, and R 3 This is a biring or triring C 10~14 Aryls, 9-14 member bicyclic or tricyclic heteroaryls, or -C(=O)NR d R e That is the case.

[0071] In another embodiment, the disclosure provides a compound having formula VI, wherein X is X-3.

[0072] In another embodiment, the disclosure provides a compound having formula VI, wherein X is X-4.

[0073] In another embodiment, the disclosure provides a compound having formula VI, wherein X is X-5.

[0074] In another embodiment, the present disclosure relates to a compound having formula VII: [ka] Provided, During the ceremony, R 6a , R 6b , R 6c , R 6d and R 6e These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b-C(=O)R c , C 1~6 Al Kill, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~6 Each is independently selected from the group consisting of cycloalkyls, optionally substituted phenyls, optionally substituted 5- or 6-membered heteroaryls, and optionally substituted 5- or 6-membered heterocyclos. R a and R b is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclo. R c C 1~4 It is alkyl, n is 1, 2, or 3. R 9 C 1~4 It is alkyl.

[0075] In another embodiment, the disclosure is R 6a , R 6b , R 6c , R 6d and R 6e However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 The present invention provides compounds having formula VII, each independently selected from the group consisting of haloalkyls. In another embodiment, R 6a , R 6b , R 6c , R 6d and R 6eThese are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Each is independently selected from the group consisting of alkoxys.

[0076] In another embodiment, the disclosure provides a compound having formula VII, where n is 1. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0077] In another embodiment, the present disclosure relates to a compound having formula VIII: [ka] Provided, During the ceremony, R 7a , R 7b , R 7c , R 7d and R 7e These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~6 Each is independently selected from the group consisting of cycloalkyls, optionally substituted phenyls, optionally substituted 5- or 6-membered heteroaryls, and optionally substituted 5- or 6-membered heterocyclos. R a and R b is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclo. R c C 1~4It is alkyl, n is 1, 2, or 3. R 9 C 1~4 It is alkyl.

[0078] In another embodiment, the disclosure is R 7a , R 7b , R 7c , R 7d and R 7e However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b ,- C(=O)R c , C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 The present invention provides compounds having formula VIII, each independently selected from the group consisting of haloalkyls. In another embodiment, R 7a , R 7b , R 7c , R 7d and R 7e These are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Each is independently selected from the group consisting of alkoxys.

[0079] In another embodiment, the disclosure provides a compound having formula VIII, where n is 1. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0080] In another embodiment, the present disclosure relates to a compound having formula IX: [ka] Provided, During the ceremony, R 4a and R 4b These are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Independently selected from the group consisting of alkoxys, R4c and R 4d It is independently selected from the group consisting of hydrogen and methyl, m is either 0 or 1. n is 1, 2, or 3. [ka] This represents a single bond or a double bond. R 9 C 1~4 It is alkyl.

[0081] In another embodiment, the present disclosure is made when m is 0, [ka] This provides a compound having formula IX, which represents a double bond.

[0082] In another embodiment, the present disclosure is that m is 1, [ka] However, it provides a compound having formula IX that represents a single bond.

[0083] In another embodiment, the disclosure provides a compound having formula IX, where n is 1. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0084] In another embodiment, the present disclosure relates to a compound having formula X: [ka] Provided, During the ceremony, R 5a and R 5c These are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Independently selected from the group consisting of alkoxys, n is 1, 2, or 3. R 9 C 1~4 It is alkyl.

[0085] In another embodiment, the disclosure provides a compound having formula X, where n is 1. In another embodiment, n is 2. In yet another embodiment, n is 3.

[0086] In another embodiment, the disclosure is R 9 The present invention provides a compound having one of the formulas VI to X, which is -CH2CH3.

[0087] In another embodiment, the intermediate of the present disclosure is one or more compounds having formula VI in Table 1A. [Table 1A-1] [Table 1A-2] [Table 1A-3] [Table 1A-4] [Table 1A-5] [Table 1A-6] [Table 1A-7]

[0088] In another embodiment, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0089] In another embodiment, the present disclosure provides a method for preparing a compound having formula I, comprising the steps of (1) contacting a compound having formula VI with NH2OH in the presence of a solvent, and optionally (2) isolating the compound having formula I.

[0090] In another embodiment, the present disclosure provides a method for preparing a compound having formula II, comprising the steps of (1) contacting a compound having formula VII with NH2OH in the presence of a solvent, and optionally (2) isolating the compound having formula II.

[0091] In another embodiment, the present disclosure provides a method for preparing a compound having formula III, comprising the steps of (1) contacting a compound having formula VIII with NH2OH in the presence of a solvent, and optionally (2) isolating the compound having formula III.

[0092] In another embodiment, the present disclosure provides a method for producing a compound having formula IV, comprising the steps of (1) contacting a compound having formula IX with NH2OH in the presence of a solvent, and optionally (2) isolating the compound having formula IV.

[0093] In another embodiment, the present disclosure provides a method for preparing a compound having formula X, comprising the steps of (1) contacting a compound having formula X with NH2OH in the presence of a solvent, and optionally (2) isolating the compound having formula X.

[0094] In another embodiment, the disclosure provides a method for preparing a compound having any one of formulas V to X, wherein the step of contacting with NH2OH is carried out in the presence of a base. In one embodiment, the base is NaOH.

[0095] In another embodiment, the disclosure provides a method for producing a compound having any one of formulas V to X, wherein the step of contacting with NH2OH is carried out at a temperature of about 20°C or less. In one embodiment, the temperature is about 0°C.

[0096] In another embodiment, the present disclosure provides a method for preparing a compound having any one of formulas V to X, wherein the solvent comprises water, methanol, or tetrahydrofuran (THF), or a mixture thereof.

[0097] In this disclosure, the terms “halo” or “halogen,” used either by themselves or as part of another group, refer to -Cl, -F, -Br, or -I. In one embodiment, the halo is -Cl or -F. In one embodiment, the halo is -Cl.

[0098] In this disclosure, the term “nitro,” used either by itself or as part of another group, refers to -NO2.

[0099] In this disclosure, the term "cyano," used either by itself or as part of another base, refers to -CN.

[0100] In this disclosure, the term "hydroxy" as used by itself or as part of another group refers to -OH.

[0101] In this disclosure, the term “alkyl” as used by itself or as part of another group means an unsubstituted linear or branched aliphatic hydrocarbon containing 1 to 12 carbon atoms, i.e., C 1~12 Alkyl, or unsubstituted linear or branched aliphatic hydrocarbons containing a specified number of carbon atoms, such as C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, C such as methyl, ethyl, propyl or isopropyl 1~3 This refers to alkyl. In one embodiment, alkyl is C 1~10 It is alkyl. In another embodiment, the alkyl is C 1~6 It is alkyl. In another embodiment, the alkyl is C 1~4 It is alkyl. In another embodiment, the alkyl is a linear C 1~10 It is alkyl. In another embodiment, the alkyl is a branched chain C 3~10 It is alkyl. In another embodiment, the alkyl is a linear C 1~6It is alkyl. In another embodiment, the alkyl is a branched chain C 3~6 It is alkyl. In another embodiment, the alkyl is a linear C 1~4 It is alkyl. In another embodiment, the alkyl is a branched chain C 3~4 It is alkyl. In another embodiment, the alkyl is a linear or branched C 3~4 It is alkyl. Non-restrictive exemplary C 1~10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. (Non-limiting, exemplary C) 1~4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl.

[0102] In this disclosure, the term “cycloalkyl” as used by itself or as part of another group refers to a group consisting of 3 to 12 carbon atoms (i.e., C 3~12 Cycloalkyl, or specified number of carbon atoms This refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having C 3~8 Selected from cycloalkyl groups. In another embodiment, the cycloalkyl group is C 3~6 Selected from cycloalkyl groups. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and cyclopentenyl.

[0103] In this disclosure, the term "optionally substituted cycloalkyl" as used by itself or as part of another group means that the cycloalkyl as defined above is unsubstituted or has a halogen, hydroxyl, nitro, cyano, -SCH3, -SCF3, -NRa R b -C(O)NR a R b -C(=O)CH3, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, substituted C as needed 3~8 This means that the molecule is substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules, optionally substituted aryl molecules, optionally substituted heteroaryl molecules, and optionally substituted heterocyclo molecules. In one embodiment, the optionally substituted cycloalkyl molecule is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl molecule is substituted with one substituent.

[0104] In this disclosure, the term “alkenyl,” used by itself or as part of another group, refers to an alkyl group as defined above, containing one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2~6 Selected from alkenyl groups. In another embodiment, the alkenyl group is C 2~4 Selected from alkenyl groups. Non-restrictive exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0105] In this disclosure, the term “alkynyl,” used by itself or as part of another group, refers to an alkyl group as defined above, containing one to three carbon-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2~6 Selected from alkynyl groups. In another embodiment, the alkynyl group is C 2~4 Selected from alkynyl groups. Non-restrictive exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0106] In this disclosure, the term “haloalkyl,” used by itself or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two, or three fluorine and / or chlorine atoms. In another embodiment, the haloalkyl group is C 1~6 It is a haloalkyl group. In another embodiment, the haloalkyl group is C 1~4 These are haloalkyl groups. Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0107] In this disclosure, the term “alkoxy,” as used by itself or as part of another group, refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl group bonded to a terminal oxygen atom. In one embodiment, the alkoxy group is C 1~4 Arco Selected from xy groups. In another embodiment, the alkoxy group is C 1~6 Selected from alkoxy groups. In another embodiment, the alkoxy group is bonded to a terminal oxygen atom C 1~4 Alkyl compounds are selected from, for example, methoxy, ethoxy, and tert-butoxy.

[0108] In this disclosure, the term “haloalkoxy,” used either by itself or as part of another group, refers to a C bonded to a terminal oxygen atom. 1~4 This refers to haloalkyl groups. Non-restrictive, exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0109] In this disclosure, the term “aryl,” as used by itself or as part of another group, means a monocyclic, bicyclic, or tricyclic aromatic ring system having 6 to 14 carbon atoms, i.e., C6-C 14 This refers to aryl groups. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), 1-naphthyl, phenanthryl, anthrasyl, indenyl, azlenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is selected from phenyl, 1-naphthyl, or 2-naphthyl. In one embodiment, the aryl is a bicyclic or tricyclic C 10 ~C 14 It is an aromatic ring system.

[0110] In this disclosure, the term “aryl as needed” as used herein, either by itself or as part of another group, means that the aryl as defined above is either unsubstituted or has a halogen, hydroxyl, nitro, cyano, -SCH3, -SCF3, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~12 Cycloalkyl, C6-C as needed. 14 Aryls, 5-14 member heteroaryls as needed, and 3-14 member heterocyclo(R) as needed. a and R b is hydrogen and C 1~6 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3-12 member heterocyclo, R c C 1~4This means that the molecule is substituted with 1 to 5 substituents independently selected from the group consisting of alkyl groups.

[0111] In one embodiment, the optionally substituted aryl is optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In yet another embodiment, the optionally substituted phenyl has one substituent. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl, 3,4-di-chlorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The term "aryl as needed" is intended to include groups having optionally substituted condensed cycloalkyl groups and optionally substituted condensed heterocyclo rings. Non-limiting examples include: [ka] It includes.

[0112] In this disclosure, the term “heteroaryl” refers to monocyclic, bicyclic, and tricyclic aromatic ring systems having 5 to 14 ring atoms, i.e., 5 to 14-membered heteroaryls, in which at least one carbon atom of one of the rings is replaced by a heteroatom independently selected from the group consisting of oxygen, nitrogen, and sulfur. In one embodiment, the heteroaryl contains one, two, three, or four heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In yet another embodiment, the heteroaryl has one heteroatom. Non-restrictive exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazonyl, clomenyl, xanthenyl, 2H-pyrrolyl, pyrrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, isoindolyl, 3H-indolyl, indolyl, i This includes dazolyl, prinyl, isoquinolyl, quinolyl, phthalazinyl, naphthilidinyl, sinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthiazolyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenadinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, flazanil, and phenoxadinyl.In one embodiment, the heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrole-2-yl and 1H-pyrrole-3-yl), imidazolyl (e.g., 2H-imidazole-2-yl and 2H-imidazole-4-yl), pyrazolyl (e.g., 1H-pyrazole-3-yl, 1H-pyrazole-4-yl and 1H-pyrazole-5-yl), pyridyl (e.g., pyridine-2-yl, pyridine-3-yl and pyridine-4-yl), pyrimidinyl (e.g., pyrimidine-2-yl) The following are selected from pyrimidine-4-yl and pyrimidine-5-yl), thiazolyl (e.g., thiazole-2-yl, thiazole-4-yl, and thiazole-5-yl), isothiazolyl (e.g., isothiazole-3-yl, isothiazole-4-yl, and isothiazole-5-yl), oxazolyl (e.g., oxazole-2-yl, oxazole-4-yl, and oxazole-5-yl), isoxazolyl (e.g., isoxazole-3-yl, isoxazole-4-yl, and isoxazole-5-yl), and indazolyl (e.g., 1H-indazole-3-yl). The term "heteroaryl" is also intended to include possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0113] In one embodiment, the heteroaryl is a five-membered or six-membered heteroaryl. In one embodiment, the heteroaryl is a five-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having five ring atoms, in which case at least one carbon atom of the ring is replaced by a heteroatom independently selected from nitrogen, oxygen, and sulfur. Non-limiting exemplary five-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl.

[0114] In another embodiment, the heteroaryl is a six-membered heteroaryl, for example, a monocyclic aromatic ring system having six ring atoms, in which case at least one carbon atom of the ring is replaced by a nitrogen atom. Non-limiting exemplary six-membered heteroaryl The reel group includes pyridyl, pyrazinyl, pyrimidinyl, and pyridadinyl.

[0115] In another embodiment, a heteroaryl is a 9- to 14-membered bicyclic aromatic ring system in which at least one carbon atom of one of the rings is replaced by a heteroatom independently selected from the group consisting of oxygen, nitrogen, and sulfur. Non-limiting exemplary 9- to 14-membered bicyclic aromatic ring systems include: [ka] It includes.

[0116] In this disclosure, the term “heteroaryl, as may be substituted” as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or has a halogen, hydroxyl, nitro, cyano, -SCH3, -SCF3, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~12 Cycloalkyl, C6-C as needed. 14 Aryls, 5-14 member heteroaryls as needed, and 3-14 member heterocyclo(R) as needed. a and R b is hydrogen and C 1~6 Independently selected from the group consisting of alkyls, or R a and R bThese, together with the nitrogen atom to which they are bonded, form a 3-12 member heterocyclo, R c C 1~4 This means that the heteroaryl is substituted with 1 to 4 substituents independently selected from the group consisting of alkyl groups. In one embodiment, the heteroaryl, which is optionally substituted, has one substituent. Either of the available carbon or nitrogen atoms can be substituted.

[0117] In this disclosure, the terms “heterocyclic” or “heterocyclo,” used by themselves or as part of another group, refer to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups having 3 to 14 ring members, i.e., 3 to 14 membered heterocyclos, in which at least one carbon atom of one of the rings is replaced by a heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, sulfoxides and sulfones, and / or nitrogen atoms, and these atoms may be oxidized or quaternized. The term “heterocyclo” is intended to include groups in which the ring –CH2– is replaced by –C(=O)–, such as cyclic ureido groups like 2-imidazolidinone, and cyclic amide groups like β-lactam, γ-lactam, δ-lactam, ε-lactam, and piperazine-2-one. The term “heterocyclo” is also intended to include groups having a fused aryl group which may be substituted as needed, such as indolinyl. In one embodiment, the heterocyclo group is selected from a five-membered or six-membered cyclic group containing one ring and one or two oxygen and / or nitrogen atoms. The heterocyclo may be optionally linked to the rest of the molecule via either of the available carbon or nitrogen atoms. Non-limiting exemplary heterocyclo groups include dioxanyl, tetrahydropyranyl, 2-oxopyrrolidine-3-yl, piperazine-2-one, piperazine-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

[0118] In this disclosure, the term “heterocyclo, optionally substituted” as used by itself or as part of another group means that the heterocyclo defined above is either unsubstituted or substituted with halogen, hydroxyl, nitro, cyano, -SCH3, -SCF3, -NR a R b , -C (=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~12 Cycloalkyl, C6-C as needed. 14 Aryls, 5-14 member heteroaryls as needed, and 3-14 member heterocyclo(R) as needed. a and R b is hydrogen and C 1~6 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3-12 member heterocyclo, R c C 1~4 This means that the molecule is substituted with 1 to 4 substituents independently selected from the group consisting of alkyl groups.

[0119] In this disclosure, the term “aralkyl,” used by itself or as part of another group, refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the optionally substituted aralkyl group is a C group substituted with one optionally substituted aryl group. 1~4It is alkyl. In one embodiment, the aralkyl group is a C1 or C2 alkyl group substituted with one optionally substituted aryl group. In one embodiment, the aralkyl group is a C1 or C2 alkyl group substituted with one optionally substituted phenyl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh2, -CH2(4-F-Ph), -CH2(4-Me-Ph), -CH2(4-CF3-Ph), and -CH(4-F-Ph)2.

[0120] In this disclosure, the term “heteroaralkyl,” used by itself or as part of another group, refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. In one embodiment, the heteroaralkyl group is a C group substituted with one optionally substituted heteroaryl group. 1~4 It is alkyl. In one embodiment, the aralkyl group is a C1 or C2 alkyl group substituted with one heteroaryl group, which may be substituted as needed. In one embodiment, the heteroaralkyl group is a C1 or C2 alkyl group substituted with one heteroaryl group, which may be substituted as needed. Non-limiting exemplary heteroaralkyl groups are as follows: [ka] Includes.

[0121] The term "contact" as is commonly used in the art generally refers to bringing together, for example, reacting, a reactant, a reagent, a solvent, a catalyst, and a reactive group in such a way that a desired chemical or physical transformation can be achieved through interactions at the molecular level. In some embodiments, this contact involves two reactants or reagents, where one reactant / reagent is used in an amount of one equivalent or more than one equivalent relative to the other reactant / reagent. The contact step of the method of this disclosure can be carried out over a time and under conditions suitable for preparing the desired product. Unless otherwise specified, the reactants, reagents, solvents, catalysts, and reactive groups can be added individually, simultaneously, or separately, and / or in any order. They can be added in the presence or absence of heat, and, if necessary, under an inert atmosphere.

[0122] The term "disease or condition in which inhibition of HDACs is beneficial" means that the action of HDACs and / or HDACs is beneficial to such diseases or conditions, or HDAC inhibitors (e.g., TSA, pivaloyloxymethylbutane (AN-9; Pivanex), FK-228 (depsipeptide), PXD-101, NVP-LAQ824, SAHA, MS) This relates to conditions that are important or necessary for the onset, progression, or manifestation of diseases or conditions known to be treated by -275 and / or MGCD0103, etc. Examples of such conditions include, but are not limited to, cancer, psoriasis, fibroproliferative disorders (e.g., hepatic fibrosis), smooth muscle proliferative disorders (e.g., atherosclerosis, restenosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar degeneration, Rett syndrome), peripheral neuropathy (Charcot-Marie-Tooth disease, giant axonal degeneration (GAN)), inflammatory diseases (e.g., osteoarthritis, rheumatoid arthritis, colitis), and angiogenesis. This includes diseases (e.g., cancer, rheumatoid arthritis, psoriasis, diabetic retinopathy), hematopoietic disorders (e.g., anemia, sickle cell disease, thalassemia), fungal infections, parasitic infections (e.g., malaria, trypanosomiasis, helminthiasis, protozoan infections), bacterial infections, viral infections, and conditions treatable by immunomodulation (e.g., multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma, allergic rhinitis, inflammatory bowel disease; and for the improvement of transplantation of transplanted organs). Those skilled in the art can easily determine whether a compound can treat a disease or condition mediated by HDAC against any particular cell type by an assay that can be conveniently used, for example, to evaluate the activity of a particular compound.

[0123] The term “second therapeutic agent” means a therapeutic agent different from the compounds of this disclosure that is known to treat the disease or condition of interest. For example, if cancer is the disease or condition of interest, the second therapeutic agent may be a known chemotherapeutic agent such as Taxol or radiation.

[0124] The term "HDAC" refers to a family of enzymes that remove an acetyl group from the ε-amino group of a lysine residue at the N-terminus of a protein, such as a histone. HDACs can include human HDACs, including HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. HDACs can also originate from protozoan or fungal sources.

[0125] The terms “to treat,” “to treat,” and “treatment” refer to eliminating, reducing, alleviating, reversing, and / or improving a disease or disorder and / or symptoms associated therewith. Treatment of a disease or condition does not require, nor exclude, the complete elimination of the disease, condition or symptoms associated therewith, including treatment of acute or chronic signs, symptoms, and / or dysfunction. As used herein, the terms “to treat,” “to treat,” and “treatment” may include “preventive treatment” in subjects who do not have a disease or condition but are at risk of recurrence, or are prone to recurrence, of such disease or condition, or of a previously controlled disease or condition; therefore, “treatment” also includes prevention of relapse or prevention of relapse. The terms “to treat” and their synonyms refer to the administration of a therapeutically effective amount of the compounds of this disclosure to an individual, e.g., a mammalian patient, including, but not limited to, humans and veterinary animals, who require such treatment. Treatment can be symptomatically directed, for example, to suppress symptoms. Treatment can be short-term, moderate-term, or long-term, for example, within the context of maintenance therapy.

[0126] The terms “therapeutic effective dose” or “effective dose,” as used herein, refer to the amount of an active ingredient sufficient to effectively deliver, when administered, the active ingredient to an individual, e.g., a human patient in need, for the treatment of the condition or disease of interest. In the case of cancer or other proliferative disorders, a therapeutic effective dose of an agent reduces (i.e., to some extent delays, and preferably stops) the growth of undesirable cells, reduces the number of cancer cells, shrinks tumor size, and reduces cancer cell size. It may prevent (i.e., delay, and preferably halt) the invasion of tumor cells into peripheral organs, inhibit (i.e., delay, and preferably halt) tumor metastasis, inhibit tumor growth to some extent, reduce HDAC signaling in target cells, and / or alleviate to some extent one or more cancer-related symptoms. The administered compound or composition may be cell division-arresting and / or cytotoxic to the extent that it inhibits growth and / or kills existing cancer cells.

[0127] The terms “simultaneous administration,” “combined administration,” “concurrent administration,” and similar phrases mean administering two or more drugs simultaneously to the subject being treated. “Simultaneously” means that each drug is administered at different time points, in any order, either simultaneously or sequentially. However, if they are not administered simultaneously, it means that they can be administered to the individual in a timely and sufficiently close sequence to achieve the desired therapeutic effect and act synergistically. For example, the compounds of this disclosure may be administered simultaneously or sequentially at different time points in any order. The compounds of this disclosure and the second therapeutic agent may be administered individually in any suitable form and by any preferred route. If the compounds of this disclosure and the second therapeutic agent are not administered simultaneously, it is understood that they may be administered in any order to the subject requiring them. For example, the compounds of the present disclosure can be administered to an individual in need before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or concurrently with or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) the administration of a treatment modality of a second therapeutic agent (e.g., radiotherapy). In various embodiments, the compounds of the present disclosure and the second therapeutic agent are administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, 11 to 12 hours, 24 hours or less, or 48 hours or less.In one embodiment, the components of the combination therapy are administered at intervals of 1 minute to 24 hours.

[0128] In the context describing this disclosure (particularly in the context of the claims), the use of the terms “a,” “an,” “the,” and similar referents should be interpreted as both singular and plural unless otherwise specified. Enumerations of value ranges in this specification serve merely as abbreviations to refer individually to each of the individual values ​​that fall within that range, unless otherwise specifically indicated herein, and each individual value and subrange is incorporated herein as if it were individually cited. Any examples or illustrative phrases presented herein (e.g., “etc.” and “like”) are intended to better illustrate this disclosure and not to limit its scope, unless otherwise asserted. No phrase in this specification should be interpreted as indicating any non-claimed element essential to the practice of this disclosure.

[0129] The term "approximately" as used herein includes ±10% of the number of citations. Therefore, "approximately 10" means 9 to 11.

[0130] The prodrugs of the compounds of this disclosure are also included in this disclosure. / or prodrug techniques, in which the compound is derivatized into a form suitable for administration and then released as a drug in vivo, have been successfully used and are well established for transiently (e.g., bioreversibly) modifying the physicochemical properties of a compound (H. Bundgaard, ed., "Design"). "of Prodrugs," Elsevier, Amsterdam, (1985); RB Silverman, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, San Diego, Chapter 8 (1992); KM Hillgren et al., Med. Res. Rev., Vol. 15, p. 83. (See 1995). Certain prodrugs of HDAC inhibitors are discussed in WO2008 / 055068.

[0131] The compounds of this disclosure may exist as salts. As used herein, the term “pharmaceutically acceptable salt” refers to a salt or zwitterionic form of the compound. Salts of the compound may be prepared during or separately from the final isolation and purification of the compound by reacting the compound with an acid having a suitable cation. A pharmaceutically acceptable salt of the compound may be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of acids that can be used to form a pharmaceutically acceptable salt include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as oxalic acid, maleic acid, succinic acid, tartaric acid, and citric acid. Non-limiting examples of salts of the compounds disclosed herein include, but are not limited to, hydrochloride, hydrobromide, hydroiodic acid, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipine, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, and pivalic acid. This includes salts, propionates, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates, p-toluenesulfonates, undecanoates, lactates, citrates, tartrates, glucons, methanesulfonates, ethane disulfonates, benzenesulfonates, and p-toluenesulfonates. Furthermore, the available amino groups present in the compounds of this disclosure can be quaternized by chlorides, bromides, and methyl iodides, ethyl, propyl, and butyl; dimethyl sulfate, diethyl, dibutyl, and diamyl; chlorides, bromides, and decyl iodides, lauryl, myristyl, and stearyl; and benzyl bromide and phenethyl bromide. When the compounds of this disclosure appear herein, it is intended to include the compounds of this disclosure and their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[0132] The compounds of this disclosure may also be conjugated or linked to auxiliary portions that enhance the beneficial properties of the compounds in therapeutic use. Such conjugates may enhance the delivery of the compound to a specific anatomical site or region of interest (e.g., a tumor), enable sustained therapeutic concentrations of the compound in target cells, modify the pharmacokinetic and pharmacodynamic properties of the compound, and / or improve the therapeutic index or safety profile of the compound. Suitable auxiliary portions include, for example, amino acids, oligopeptides or polypeptides, antibodies such as monoclonal antibodies and other engineered antibodies; and native or synthetic ligands to receptors in target cells or tissues. Other suitable adjuvants include fatty acid or lipid portions that promote the in vivo distribution and / or uptake of the compound by target cells (see, for example, Bradley et al., Clin. Cancer Res. (2001) Vol. 7: pp. 3229).

[0133] The compounds disclosed herein inhibit HDACs and are useful in treating a variety of diseases and conditions. In particular, the compounds disclosed herein are useful in diseases or conditions where HDAC inhibition is beneficial, such as cancer. It is used in methods for treating neurological disorders, neurodegenerative conditions, peripheral neuropathy, autoimmune diseases, inflammatory diseases and conditions, stroke, hypertension, traumatic brain injury, autism, and malaria. The method comprises the step of administering a therapeutically effective amount of the compound of this disclosure to an individual in need.

[0134] The method also comprises the step of administering a second therapeutic agent to an individual in addition to the compounds of the present disclosure. The second therapeutic agent is selected from drugs and adjuvants known to be useful in treating the disease or condition that the individual is suffering from, such as drugs such as chemotherapeutic agents and / or radiation known to be useful in treating certain cancers.

[0135] The compounds of this disclosure were evaluated for their activity in HDAC6 and their selectivity for HDAC6 compared to HDAC1. Selective HDAC6 inhibitors are associated with a variety of disease conditions, including, but not limited to, arthritis, autoimmune disorders, inflammatory disorders, cancer, neurological disorders (such as Rett syndrome), peripheral neuropathy (such as CMT), stroke, hypertension, and diseases caused by or resulting from oxidative stress. Similarly, selective HDAC6 inhibitors, when administered in combination with rapamycin, extended the lifespan of mice with kidney xenografts. This model was used to evaluate the immunosuppressive properties of the compounds and to serve as a model for transplant rejection. Furthermore, selective HDAC6 inhibitors evoke neuroprotection in a rat model of primary cortical neurons under oxidative stress. These studies identified selective HDAC6 inhibitors as non-toxic neuroprotective agents.

[0136] The compounds disclosed herein are selective HDAC6 agents that possess drug-like physicochemical properties.

[0137] Accordingly, in one embodiment, the present disclosure provides a method for treating an individual suffering from a disease or condition, for example, a disease or condition in which inhibition of HDACs would be beneficial, the method comprising the step of administering a therapeutically effective amount of a compound of the present disclosure to the individual in need.

[0138] The methods of this disclosure can be carried out by administering the compounds of this disclosure either as a neat compound or as part of a pharmaceutical composition. Administration of the pharmaceutical composition or the compounds of this disclosure alone can be done during or after the onset of the disease or condition of interest. Typically, the pharmaceutical compositions are sterile and do not contain any toxic, carcinogenic, or mutagenic compounds that would likely cause adverse reactions upon administration.

[0139] In some embodiments, the compounds of the Disclosure may be administered together with a second therapeutic agent useful for treating a disease or condition in which inhibition of HDACs is beneficial. The second therapeutic agent is different from the compounds of the Disclosure. The compounds of the Disclosure and the second therapeutic agent may be administered simultaneously or sequentially. Furthermore, the compounds of the Disclosure and the second therapeutic agent may be administered in a single composition or in two separate compositions. The compounds of the Disclosure and the second therapeutic agent may be administered simultaneously or sequentially to achieve the desired effect.

[0140] The second therapeutic agent is administered in an amount that achieves the desired therapeutic effect. The effective dose ranges for each of the second therapeutic agents are known in the art, and the second therapeutic agent is administered to individuals in need within these established ranges.

[0141] Accordingly, the present disclosure provides compositions and methods for using the compounds of the present disclosure, and optionally a second therapeutic agent, in treating diseases or conditions in which inhibition of HDACs is beneficial.

[0142] The disclosure also provides pharmaceutical compositions comprising the compounds of the disclosure and, if necessary, a second therapeutic agent, which are useful for treating diseases and conditions in which inhibition of HDACs is beneficial.

[0143] Further provided are kits containing, individually or together packaged, the compounds of the present disclosure and, optionally, a second therapeutic agent, as well as package inserts with instructions for using these activators, which are useful for treating diseases and conditions in which inhibition of HDACs would be beneficial.

[0144] The compounds of this disclosure and the second therapeutic agent may be administered together as a single unit dose or individually as multiple unit doses, in which case the compounds of this disclosure may be administered before the second therapeutic agent or vice versa. One or more doses of the compounds of this disclosure and / or one or more doses of the second therapeutic agent may be administered. Accordingly, the compounds of this disclosure may be used in combination with one or more second therapeutic agents, for example, anticancer agents, but not limited to the following.

[0145] Within the scope of the meaning of this disclosure, the terms “disease” or “condition” generally mean a disturbance and / or abnormality that is considered a pathological condition or pathological function, which may manifest in the form of specific signs, symptoms and / or dysfunctions. As demonstrated below, the compounds of this disclosure are HDAC inhibitors and can be used to treat diseases and conditions for which inhibition of HDACs would be beneficial, such as cancer, neurological disorders, neurodegenerative conditions, traumatic brain injury, stroke, inflammation, autoimmune diseases and autism.

[0146] In one embodiment, the Disclosure provides a method for treating cancer, including killing cancer cells or neoplasms, inhibiting the growth of cancer cells or neoplasms, inhibiting the replication of cancer cells or neoplasms, or improving their symptoms, comprising the step of administering to a subject in need a sufficient amount of the compound of the Disclosure, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof. Furthermore, it should be noted that the selective compounds of the Disclosure may promote cancer cell death by reactivation of the immune system through a mechanism involving the PDI receptor. The compounds of the Disclosure may be used alone as anticancer agents or in combination with other anticancer treatments, e.g., radiation, chemotherapy and surgery.

[0147] In another embodiment, the present disclosure provides a method for increasing the sensitivity of cancer cells to the cytotoxic effects of radiotherapy and / or chemotherapy, comprising the step of contacting the cells with the compounds of the present disclosure, as well as pharmaceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof, in an amount sufficient to increase the sensitivity of the cells to the cytotoxic effects of radiotherapy and / or chemotherapy.

[0148] In further embodiments, the present disclosure provides a method for treating cancer, comprising the steps of (a) administering a certain amount of a compound of the present disclosure to an individual in need, and (b) administering a certain amount of radiotherapy, chemotherapy, or both to the individual. Each dose is effective in treating cancer. In another embodiment, the doses are effective together in treating cancer.

[0149] Therefore, this combination therapy of the present disclosure can be used in various settings for the treatment of various cancers. In specific embodiments, the individual requiring treatment has previously received treatment for cancer. Such prior treatments include, but are not limited to, prior chemotherapy, radiotherapy, surgery, or immunotherapy such as cancer vaccines.

[0150] In another embodiment, the cancer to be treated has demonstrated sensitivity to radiotherapy and / or chemotherapy, or is known to respond to radiotherapy and / or chemotherapy. These cancers include, but are not limited to, non-Hodgkin lymphoma, Hodgkin's disease, Ewing's sarcoma, testicular cancer, prostate cancer, ovarian cancer, bladder cancer, laryngeal cancer, cervical cancer, nasopharyngeal cancer, breast cancer, colon cancer, pancreatic cancer, head and neck cancer, esophageal cancer, rectal cancer, small cell lung cancer, non-small cell lung cancer, brain tumors, or other CNS neoplasms.

[0151] In yet another embodiment, the cancer being treated is known to have demonstrated resistance to or be refractory to radiotherapy and / or chemotherapy. Cancer is refractory to treatment if at least a significant portion of the cancer cells does not die or their cell division is not inhibited in response to treatment. Such a determination can be made either in vivo or in vitro by any method known in the art to assay the effectiveness of treatment on cancer cells, using the art-acceptable meaning of “refractory” in this context. In a specific embodiment, cancer is refractory if the number of cancer cells does not decrease significantly or increases.

[0152] Other cancers that can be treated with the compounds and methods of this disclosure include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synoviomas, Mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cavity cancer, laryngeal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminomastoma, fetal cancer, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, glioma, pleomorphic Cancers and metastases selected from the group consisting of solid tumors including glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma; but not limited to, acute lymphoblastic leukemia, acute B-cell lymphoblastic leukemia, acute T-cell lymphoblastic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastoma This includes, but is not limited to, leukemias: myelomonocytic leukemia, acute nonlymphocytic leukemia, acute anaplastic leukemia, myclocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and multiple myeloma; acute and chronic leukemias: hematological infectious cancers including lymphoblastic myeloid and myeloid leukemia; lymphomas: Hodgkin's disease and non-Hodgkin lymphoma; multiple myeloma; Waldenström macroglobulinemia; heavy chain diseases; and polycythemia vera.

[0153] The compounds of this disclosure may also be administered to prevent progression to neoplasms or malignant conditions, including, but not limited to, the cancers listed above. Such prophylactic use has indications for known conditions or conditions suspected of being precursors to neoplasm formation or cancer, in particular, conditions in which hyperplasia, dysplasia, or non-neoplastic cell growth consisting mostly of particularly malformations is suspected (see Robbins and Angell, 1976, Basic Pathology, 2nd edition, WB Saunders Co., Philadelphia, pp. 68-79, for a review of such abnormal growth conditions). Hyperplasia is a form of controlled cell proliferation involving an increase in the number of cells in a tissue or organ without significant alteration of structure or function. For example, endometrial hyperplasia often progresses to endometrial cancer, and precancerous colon polyps often transform into cancerous lesions. Dysplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell is replaced by another type of adult cell. Dysplasia can occur in epithelial cells or connective tissue cells. Typical dysplasia involves somewhat impaired metaplasia of the epithelium. Dysplasia is often a precursor to cancer and is mainly found in epithelium. Dysplasia is non-neoplastic, involving a loss of individual cell homogeneity and cellular structural adaptability. This is the most detrimental form of cell growth. Dysplasia cells often have abnormally large, deep, and infiltrating nuclei and exhibit polymorphism. Dysplasia characteristically occurs where chronic irritation or inflammation is present, and is often found in the cervix, airways, oral cavity, and gallbladder.

[0154] As an alternative, or in addition to the presence of abnormal cell growth characterized as hyperplasia, dysplasia, or malformation, the presence of one or more features of a transformed or malignant phenotype, as demonstrated in vivo or in vitro by cell samples derived from the subject, may indicate the desirability of prophylactic / therapeutic administration of the compositions of this disclosure. Such features of a transformed phenotype include, for example, morphological changes, loosening of basal layer binding, loss of contact inhibition, loss of scaffolding dependence, protease release, increased glucose transport, decreased serum requirements, expression of fetal antigens, and disappearance of 250,000 daltons of cell surface proteins.

[0155] In specific embodiments, leukoplakia, hyperplastic or dysplastic lesions with benign epithelial features, Bowen's disease, and carcinoma in situ are preneoplastic lesions that demonstrate the appropriateness of prophylactic intervention.

[0156] In another embodiment, fibrocystic diseases (cystic hyperplasia, breast malformations, and especially glandular diseases (benign epithelial hyperplasia)) demonstrate the appropriateness of prophylactic intervention.

[0157] The prophylactic use of the compounds and methods disclosed herein is also applicable to several viral infections that may lead to cancer. For example, human papillomavirus can lead to cervical cancer (see, e.g., Hernandez-Avila et al., Archives of Medical Research (1997) 28: pp. 265-271), and Epstein-Barr virus (EBV) can lead to lymphoma (see, e.g., Herrmann et al., J Pathol (2003) 199 See Volume (No. 2): pp. 140-145), hepatitis B or hepatitis C virus may lead to liver cancer (see, for example, El-Serag, J Clin Gastroenterol (2002) Vol. 35 (No. 5 Supplement 2): pp. S72-S78), human T-cell leukemia virus (HTLV)-I may lead to T-cell leukemia (see, for example, Mortreux et al., Leukemia (2003) Vol. 17 (No. 1): pp. 26-38), human herpesvirus-8 infection may lead to Kaposi's sarcoma (see, for example, Kadow et al., Curr Opin Investig Drugs (2002) Vol. 3 (No. 11): pp. 1574-1579), and human immunodeficiency virus (HIV) infection is a contributing factor to cancer development as a result of immunodeficiency (see, for example, Dal Maso See also Lancet Oncol (2003), Vol. 4 (No. 2): pp. 110-119.

[0158] In other embodiments, subjects exhibiting one or more of the following predispositions to malignancy may be treated by administration of the compounds of the Disclosure and by the methods of the Disclosure: chromosomal translocations associated with malignancy (e.g., Philadelphia chromosome in the case of chronic myeloid leukemia, t(14;18) in follicular lymphoma, etc.), familial polyposis or Gardner syndrome (a possible precursor of colon cancer), benign monoclonal gammopathy (a possible precursor of multiple myeloma), cancer or precancerous disease exhibiting a Mendelian (genetic) inheritance pattern. First-degree kinship to a person with the disease (e.g., familial polyposis of the colon, Gardens syndrome, hereditary exostosoma, polyendocrine neoplasia, medullary thyroid carcinoma and pheochromocytoma with amyloid production, Peutz-Jeghers syndrome, von Recklinghausen neurofibromatosis, retinoblastoma, carotid bulb tumor, cutaneous black carcinoma, intraocular black carcinoma, xeroderma pigmentosum, ataxia with telangiectasia, Chediak-Higashi syndrome, albinism, Fanconi aplastic anemia and Bloom syndrome; Robbins and Angel , 1976, Basic Pathology, 2nd edition, WB Saunders Co., Philadelphia, 11 See pages 2-113, etc., and exposure to carcinogens (e.g., smoking, and inhalation or contact with certain chemicals).

[0159] In another specific embodiment, the compounds and methods of the Disclosure are used to treat breast cancer, colon cancer, and It is administered to humans to prevent the progression of ovarian cancer or cervical cancer.

[0160] In one embodiment, the present disclosure provides a method for treating cancer, comprising the steps of (a) administering a certain amount of a compound of the present disclosure to an individual in need, and (b) performing one or more additional anti-cancer treatment modalities on the individual, including, but not limited to, radiotherapy, chemotherapy, surgery, or immunotherapy such as a cancer vaccine. In one embodiment, the step of performing step (a) is before the performance of step (b). In another embodiment, the step of performing step (a) is after the performance of step (b). In yet another embodiment, the step of performing step (a) is simultaneous with the performance of step (b).

[0161] In one embodiment, the additional anti-cancer treatment modality is radiotherapy and / or chemotherapy. In another embodiment, the additional anti-cancer treatment modality is surgery.

[0162] In yet another embodiment, the additional anti-cancer treatment modality is immunotherapy, such as cancer vaccines.

[0163] In one embodiment, the compounds of the disclosed herein are administered adjunct to additional anti-cancer treatment modalities.

[0164] In another embodiment, the additional anti-cancer treatment modality is radiotherapy. Any radiotherapy protocol can be used in the method of this disclosure, depending on the type of cancer being treated. Embodiments of this disclosure use the following electromagnetic radiation: gamma rays (10 -20 ~10 -13 m), X-ray radiation (10 -12 ~10-9 m) Ultraviolet light (10nm~400nm), visible light (400nm~700nm), infrared light (700nm~1mm), and microwave radiation (1mm~30cm) are used.

[0165] For example, but not limited to, X-ray radiation can be used. In particular, high-energy ultra-high-pressure radiation (radiation with energies higher than 1 MeV) can be used for deep tumors, and electron beam and normal-voltage X-ray radiation can be used for skin cancer. Gamma-ray emitting radioactive isotopes, such as radium, cobalt, and other elemental radioactive isotopes, can also be administered. Illustrative radiotherapy protocols useful in this disclosure include, but are not limited to, stereotactic methods in which multiple sources of low-dose radiation are simultaneously focused onto a tissue volume from multiple angles; “internal radiotherapy” such as close-range radiotherapy, brachytherapy, and brachytherapy, including the placement of radioactive implants directly into tumors or other target tissues; intraoperative irradiation in which high doses of external radiation are directed to target tissues exposed during surgery; and particle beam radiotherapy, including the use of fast elementary particles to treat local cancers.

[0166] Numerous cancer treatment protocols currently utilize radiosensitizers activated by electromagnetic radiation, such as X-rays. Examples of X-ray activated radiosensitizers include, but are not limited to, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU1069, SR4233, EO9, RB6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FUdR), hydroxyurea, cisplatin, and their therapeutically effective analogs and derivatives.

[0167] Photodynamic therapy (PDT) for cancer uses visible light as a radioactivator for photosensitizers. Examples of photodynamic radiosensitizers include, but are not limited to, hematoporphyrin derivatives, PHOTOFRIN®, benzoporphyrin derivatives, NPe6, and tin ethioporphyrin. Rufiline (SnET2), pheoborbide-a, bacteriochloro This includes fil-a, naphthalocyanine, phthalocyanine, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof.

[0168] In addition to the compounds of this disclosure, radiosensitizers may be administered in combination with one or more compounds in a therapeutically effective amount, such compounds including, but not limited to, compounds that promote the uptake of the radiosensitizer into target cells, therapeutic agents to target tissues, compounds that control the flow of nutrients and / or oxygen, chemotherapeutic agents that act on tumors with or without additional radiation, or other therapeutically effective compounds for treating cancer or other diseases. Examples of additional therapeutic agents that may be used with radiosensitizers include, but are not limited to, 5-fluorouracil (5-FU), leucovorin, oxygen, carbogens, red blood cell transfusions, perfluorocarbons (e.g., FLUOSOLW®-DA), 2,3-DPG, BW12C, calcium channel blockers, pentoxifylline, anti-angiogenic compounds, hydralazine, and L-BSO.

[0169] In one embodiment, the compounds of the present disclosure are administered before the administration of radiotherapy and / or chemotherapy.

[0170] In another embodiment, the compounds of the present disclosure are administered adjunct to radiotherapy and / or chemotherapy.

[0171] The compounds and additional treatment modalities of this disclosure can act additively or synergistically (i.e., the combination of the compounds and additional anticancer treatment modalities is more effective than the additive effect of each when administered alone). Synergistic combinations make it possible to use lower doses of the compounds and / or additional treatment modalities of this disclosure, and / or administer them less frequently, in patients with cancer. The availability of lower doses of the compounds and / or additional treatment modalities of this disclosure, and / or administering them less frequently, can reduce the toxicity associated with administration of the compounds and / or additional treatment modalities of this disclosure in cancer treatment without reducing their efficacy. Furthermore, the synergistic effect can lead to improved efficacy in cancer treatment and / or a reduction in adverse effects or undesirable side effects associated with the administration of the compounds and / or additional anticancer treatment modalities of this disclosure as monotherapy.

[0172] In one embodiment, the compounds of the Disclosure can act synergistically with radiotherapy when such HDACIs are administered at doses typically used when used alone for cancer treatment. In another embodiment, the compounds of the Disclosure can act synergistically with radiotherapy when such HDACIs are administered at doses less than typically used when used as monotherapy for cancer treatment.

[0173] In one embodiment, radiotherapy can act synergistically with the compounds of the Disclosure when administered at doses typically used when radiotherapy is used as monotherapy for cancer treatment. In another embodiment, radiotherapy can act synergistically with the compounds of the Disclosure when administered at doses less than those typically used when radiotherapy is used as monotherapy for cancer treatment.

[0174] The efficacy of the compounds of this disclosure as HDAC inhibitors for sensitizing cancer cells to the effects of radiotherapy has been demonstrated in vitro and / or in vitro using techniques known in the art. This can be determined by assessing post-treatment survival in vivo. In one embodiment, Since the determination is made in vitro, exponentially growing cells can be exposed to known doses of radiation, and cell viability is monitored. Irradiated cells are cultured in plates for approximately 14 to 21 days, and the colonies are stained. The viability is calculated by dividing the number of colonies by the plate culture rate of non-irradiated cells. A survival curve is generated by graphing the viability on a logarithmic scale against the absorbed dose on a uniform scale. The survival curve generally shows an exponential decrease in the rate of surviving cells at higher radiation doses after the initial shoulder region where the dose is below the lethal dose. When used in combination therapies according to this disclosure, similar protocols can be used for the chemical agents.

[0175] The inherent radiosensitivity of tumor cells, as well as environmental influences such as hypoxia and host immunity, can be further evaluated through in vivo studies. Growth retardation assays are commonly used. This assay measures the time interval required for a radiation-exposed tumor to regrow to a specific volume. The dose required to control approximately 50% of tumors is TCD. 50 Determined by assay.

[0176] In vivo assay systems typically utilize transplantable solid tumor systems in the experimental subject. Radiation survival parameters for normal tissue and tumors can be assayed in vivo using methods known in this art.

[0177] This disclosure provides a method for treating cancer, in conjunction with recognized methods such as surgery, radiotherapy, and chemotherapy, including, for example, chemistry-based pseudo-radiotherapy, by administering an effective amount of the compound of this disclosure, thereby achieving a synergistic enhancement of the effectiveness of the recognized treatment. The effectiveness of the treatment can be measured in clinical studies or in model systems such as tumor models in mouse or cell culture sensitivity assays.

[0178] This disclosure provides combination therapies that result in improved efficacy and / or reduced toxicity. Accordingly, in one embodiment, this disclosure relates to the use of the compounds of this disclosure as radiosensitizers in conjunction with radiotherapy.

[0179] Where the combination therapy of the Disclosure includes the step of administering the compound of the Disclosure together with one or more additional anticancer agents, the compound of the Disclosure and the additional anticancer agents may be administered to the individual simultaneously or sequentially. The agents may also be administered cyclically. A cyclical treatment includes administering one or more anticancer agents for a period of time, then administering one or more different anticancer agents for a period of time, and repeating this sequential administration, i.e., this cycle, in order to reduce the development of resistance to one or more anticancer agents administered, to avoid or reduce the side effects of one or more anticancer agents administered, and / or to improve the efficacy of the treatment.

[0180] Additional anticancer drugs may be administered over a series of sessions. One or a combination of the additional anticancer drugs listed below may be administered.

[0181] This disclosure includes a method for treating cancer, comprising the step of administering to an individual in need of such treatment a compound of the Disclosure and one or more additional anticancer agents, or pharmaceutically acceptable salts thereof. The compounds of the Disclosure and the additional anticancer agents may act additively or synergistically. Suitable anticancer agents include, but are not limited to, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mereaptopurine, thioguanine, hydroxyurea, cyclophosphamide, ifosfamide, nitrosourea, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campateein, bleomycin, and doxorubicin. This includes syn, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil (5-FU), taxanes (such as docetaxel and paclitaxel), leucovorin, levamisol, irinotecan, estramustine, etoposide, nitrogen mustard, BCNU, nitrosourea (such as carmustine and lomustine), platinum complexes (such as cisplatin, carboplatin, and oxaliplatin), imatinib mesylate, hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tilphostine derivatives, herbimycin A, genistein, erbustatin, and lavendastine A.

[0182] In one embodiment, the anticancer agent is not limited to alkylating agents, nitrogen mustard, cyclophosphamide, trophosphamide, chlorambucil, nitrosourea, carmustine (BCNU), lomustine (CCNU), alkyl sulfonates, busulfan, treosulfan, triazine, plant alkaloids, vinca alkaloids (vineristine, vinblastine, vindesine, vinorelbine), taxoids, DNA topoisomerase inhibitor, epipodophilin ), 9-aminocamptothecin, camptothecin, cristatol, mitomycin, mitomycin C, antimetabolite, antifolate, DHFR inhibitor, trimethrexate, IMP dehydrogenase inhibitor, mycophenolic acid, thiazophrine, ribavirin, EICAR, ribonucleotide reductase inhibitor, hydroxyurea, deferoxamine, pyrimidine analog, uracil analog, phloxuridine, doxifluridine, lacitrexed, cytosine analog, cytarabine (ara C) Cytosine arabinoside, fludarabine, purine analogs, mercaptopurine, thioguanine, DNA antimetabolites, 3-HP, 2'-deoxy-5-fluorouridine, 5-HP, alpha-TGDR, aphydicolinglycinate, ara-C, 5-aza-2'-deoxycytidine, beta-TGDR, cyclocytidine, guanazole (inosine glycodialdehyde), macbesin II, pyrazolomidazole, hormone therapy, receptor antagonists, anti-estrogens, tamoxifen, raloxifene, megestrol, LHRH agonists, goserelin, leuprolide acetate, antiandrogens, flutamide, bicalutamide, retinoids / deltoids, cis-retinoic acid, vitamin A derivatives, Total trans retinoic acid (ATRA-IV), vitamin D3 analog, EL1089, CB1093, ICH1060, photodynamic therapy, vertoporfin, B PD-MA, phthalocyanine, photosensitizer Pc4, demethoxy-hypocrelin A (2BA-2-DMHA), cytokine, interferon-α, interferon-I3, interferon-Y, tumor necrosis factor, angiogenesis inhibitor, angiostatin (plasminogen fragment), angiogenesis-inhibiting antithrombin UI, angiozyme, ABT-627, Bay12-9566, benefin, bevacizumab, BMS-275291, cartilage-derived inhibitor (CDI), CAI, CD59 complement fragment, CEP-7055, Co l3, Combretastatin A-4, Endostatin (Collagen XVIII Fragment), Fibronectin Fragment, Gro-Beta, Halofuginone, Heparinase, Heparin Hexasaccharide Fragment, HMV833, Human Chorionic Gonadotropin (hCG), IM-862, Interferon-Inducing Protein (IP-10), Interleukin-12, Kringle 5 (Plasminogen Fragment), Marimast, Metalloproteinase Inhibitor (UMP), 2-Methoxyestradiol, MMI270 (CGS27023A), MoAb IMC-I C11, Neovastat, NM-3, Panzem, P1-88, Placental Ribonuclease Inhibitor, Plasminogen Activator Inhibitor, Platelet Factor-4 (PF4), Prinomast, Prolactin 161 (D fragment), Proliferin-related Protein (PRP), PTK787 / ZK222594, Retinoid, Solimast, Squalamine, SS3304, SU5416, SU6668, SU11248, Tetrahydrocortisol-S, Tetrathiomolybdate, Thalidomide, Thrombospondin-1 (TSP-1), TNP-470, Transforming Growth Factor-Beta (TGF-11), Vasculostatin, Vasostatin Vasostatin (calreticulin fragment), ZD6126, ZD6474, farnesyltransferase inhibitor (FTI), bisphosphonate, antimitotic agent, allocolchicine, halichondrin B, colchicine, colchicine derivatives, dolstatin 10, mytansine, lyzoxin, thiocolchicine Tritylcysteine, isoprenylation inhibitors, dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium ion, cell cycle inhibitors, staurosporine, actinomycin, actinomycin D, dactinomycin, bleomycin, bleomycin A2, bleomycin B2, peplomycin, anthracycline, adriamycin, epirubicin, pirarubicin, zolubicin, mitoxantrone, MDR inhibitors, Verapamil, Ca 2+ The drug may be selected from the group consisting of ATPase inhibitors and thapsigargin.

[0183] Other anticancer agents that may be used in this disclosure include, but are not limited to, asbicin; acralubicin; acodazole hydrochloride; acronin; adzelesin; aldesleukin; altretamine; arnbomycin; amethantrone acetate; aminoglutethimide; amsacrin; anastrozole; anthramycin; and as Paraginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batymast; Benzodepa; Bicalutamide; Bisanthren hydrochloride; Bisnafidomesylate; Bizelcsin; Bleomycin sulfate; Brequinal sodium; B Lopirimin; busulfan; kakutinomycin; carsterone; calasemide; carbetimer; carmustine; carbicin hydrochloride; carzeresin; sedefingol; chlorambucil; ciloremycin; cisplatin; cladribine; cristatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexorlunarnaplatin; dezaguanine; dezaguanine Mesylate; Diadiquan; Docetaxel; Doxorubicin hydrochloride; Doroxifene; Doroxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflomitine hydrochloride; Elsamitolucin; Enloplatin; Empromate; Epipropidine; Epirubicin hydrochloride; Elbrozol; Esolubicin hydrochloride; Estramustine; Estramustine sodium phosphate; Etanidazole; Phosphate Etoposide acid; Etoprine; Fadrozol hydrochloride; Fazarabine; Fenretinide; Furoxuridine; Fludarabine phosphate; Fluorouracil; Fluorocitabine; Fosquidone; Fostoliesin sodium; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Ilmofosin; Interleukin II (including recombinant interleukin II or rIL2), Interferon Alpha-2a; Interferon Alpha-2b; Interferon Alpha-nl; Interferon Alpha-n3; Interferon Beta-Ia; Interferon Gamma-Ib; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Rialozol hydrochloride; Lometrexol sodium; Lomustine; Rosoxantrone hydrochloride; Masopropyl; Mytansin; Mecchlorethamine hydrochloride ); Megestrol acetate; Melengestrol acetate; Melphalan; Menogalyl; Mercaptopurine; Methotrexate sodium; Metoprin; Metsuredepa; Mitindomide; Mitocalcin; Mitochromin; Mitodiline; Mitomarcin; Mitomycin; Mitusper; Mitotan; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogaramycin; Ormaplatin; Oxythran; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfarnide; Pipobro Man; Piposulfan; Pyroxantrone hydrochloride; Plicamycin; Promethane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofrine; Ribopurine; Logretimide; Safingol; . Safinol hydrochloride; Semustine; Simtrazene; Sparfosate sodium; Sparsornycin; Spirogermanium hydrochloride; Spirogermanium Lomustine; Spiroplatin; Streptonigrin; Streptozocin; Slofenull; Talisomycin; Tecogalan sodium; Tegafur; Teroxantrone hydrochloride; Temoporfin; Teroxylone; Testolactone; Thiamipurine; Thioguanine; Thiotepa; Thiazofulin; Tirapazamin; Toremifene citrate; Trestron acetate; Trisilibine phosphate; Trimethrexate; Trimethrexate glucuronide; Triptorelin; Tubrozol hydrochloride; Uracil mustard; Uredepa; Bupreotide; Be Luteporfln; vinblastine sulfate; vincristine sulfate; vin This includes desine; vindesine sulfate; vinepidine sulfate; vingricinate sulfate; vin leukosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozolc; zeniplatin; dinostatin; and zolubicin hydrochloride.

[0184] Further anticancer drugs that may be used in this disclosure include, but are not limited to, 17-AAG; 20-epi-1,25-dihydroxyvitamin D3; 5-ethinyluracil; abiraterone; acralubicin; acylfluben; adesipenolic acid; adzelesin; aldesleukin; ALL TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; and Musaclin; Anagrelide; Anastrozole; Andrografolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-dorsal morphology Anti-dorsalizing morphogenetic protein 1; anti-androgen, prostate cancer; anti-estrogen; antineoplaston; antisense oligonucleotide; aphydicolinglycine salt; apoptosis gene modulator; apoptosis regulator; aprinic acid; araCDP DL PTBA; arginine deaminase; asulacrine; atamestan; atrimustin; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivative; valanol; batimastat; BCR-ABL antagonist; benzochlorin; benzoyl staurosporine; beta-lactam derivative; beta-aretin; beta-clarnycin B; betulinic acid; bFGF inhibitor; bicalutamide; bis-antre n; bisaziridinylsperrnine; bisnafide; bistratene A; bizeresin; bortezomib; breflate; bro Pyrimine; Budotitan; Butionine sulfoximine; Calcipotriol; Carphostin C; Camptothecin derivatives; Canariapox IL-2; Carboxamide aminotriazole; Carboxarnidotriazole; CaRest M3; CARN700; cartilage-derived inhibitors; carzeresin; casein kinase inhibitors; castanospermine; cecropin B; cetrorelix; chlorine; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogs; conagenin; crambesidine 816; crisnator; cryptophycin 8; cryptophycin A derivatives; crasin A; cyclopentaneseraquinones; cycloplatam; cypemycin; cytarabine ocphosphate; cytolytic factors; cytostatin; dacliximab; decitabine; dehydrodydemnin B; deslorerin; dexamethasone; dexphosphamide; dexrazoxane; dexverapamil; diaziquan; didemnin B; Zidox; Diethylnorspermine; Dihydro-5-azacitidine; Dihydrotaxol-9; Dioxamycin; Diphenylspiromustine; Docetaxel; Docosanol; Dracetron; Doxyfluridine; Doroxifen; Dronabinol; Duocalmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflomitin; Elemene; Emitefur; Epirubicin; Epristeride; Estramustine analog; Estrogen agonist; Estrogen antagonist; Etanidazole; Etoposide phosphate; Exemestane; Fadrozol; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopyridol; Frezelastine; Fluasterone; Fludarabine; Fluorodaunoruniein hydrochloride hydrochloride; holphenimex; formestan; fostoliesin; fotemus Chin; Gadolinium texaphylline; Gallium nitrate; Gallocitabine; Ganirelix; Gelatinase inhibitors; Glutathione inhibitors; Hepsulfame; Helegulin; Hexamethylene bisacetamide; Hypericin; Ibandronate; Idarubicin; Idoxifen; Idramanton; Irmofosin; Ilomastam; Imidazoacridone; Imiquimod; Immunostimulating peptides; Insulin-like growth factor 1 receptor inhibitors; Interferon agonists; Interferon; Interleukin; Yobenguan; Iododoxorubien; Ipomeanol 4; Iloproct; Irsogladine; Isobengazole; Isohomohalichondrin B; Itasetron; Jasplakinolide; Kahala Lido F; Larnellarin N triacetate; Lanreotide; Reinamycin; Renograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitor; Leukocyte alpha interferon; Leuprolid + estrogen + progestin; Leuprorelin; Levamysol; Rialozol; Linear polyamine analog; Lipophilic disaccharide peptide; Lipophilic platinum complex; Lysoclinamide 7; Lovaplatin; Rombrisin; Lometrexol; Ronidamin; Loxoxantrone; Lovastatin; Loxolibine; Lulutotecan; Lutetium texaphylline; Li Zofilin; cell-lysing peptide; meitansine; mannostatin A; marimastat; masopropyl; maspin; matrilysin inhibitor; matrix metalloproteinase inhibitor; menogalyl; melbaron; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatch double-stranded RNA; mitogwazone; mitractol; mitomycin analog; mitonafide; mitotoxin fibroblast growth factor saporin; mitoxantrone; mophalotene; morglamostim; Monoclonal antibodies, human chorionic gonadotropins; monophosphoryl lipid A + Myobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitors; multitumor suppressor 1-based therapeutic agents; mustard anticancer agents; micaperoxide B; Mycobacterium cell wall extract; myriapolon; N-acetyldinaline; N-substituted benzamide; nafarelin; nagresti; naloxone + pentazocine; napabin; naphterpine; naltograstim; nedaplatin; nemorubicin; neridronate; neutral endopeptidase; nilutamide; nisamycin; monoacid Nitrogen modulators; nitrogen oxide antioxidants; nitrulline; O6 benzylguanine; octreotide; oxenon; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; parauamine; palmitoyl rhizoxin; pamidronic acid; panaxytriol; panomiphene; parabactin; pazeriptin; pegaspargase; perdesin;Pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perphosphamide; periryl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; pyritrexime; placetin A; placetin B; plasminogen activator inhibitors; platinum complexes; platinum complexes; platinum triamine complexes; porfimer sodium; porphyromycin; prednisone; acridone; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purpurin; pyrazol Acridine (pyrazoloaeridine); pyridoxylated hemoglobin polyoxyethylene conjugate; RAF antagonist; larcitrexed; ramosetron; RAS farnesyl protein transferase inhibitor; RAS inhibitor; RASGAP inhibitor; demethyl retelliptin; rhenium Re186 etidronate; rhizoxin; ribozyme; RH retinamide; logretimide; rohitzkin; romulutide; lokinimex; rubiginone BI; ruboxyl; safingol; saintopine; SarCNU; sarcophytol A; salglamostim; Sdi1 mimetics; semustin; aging-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen-binding protein; ;Schizophyllan;Sobzoxane;Borocapteit sodium;Sodium phenylacetate;Sorberol;Somatomedin-binding protein;Sonelmin;Sparfosinic acid;Spicamycin D;Spiromustin;Suprenopentin;Spongistatin 1;Squalamine;Stem cell inhibitor;Stem cell division inhibitor;Stipiamid;Stromelicin inhibitor;Sulfinosine;Overactive vasoactive intestinal peptide antagonist;Surazsta;Suramin;Swainsonin;Synthetic glycosaminoglycan;Talimustin; Tamoxifen methiozide; tauromustine; tazarotene; tecogalan sodium; tegafur; telrapyrilium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; talibrastin; thiocholalin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid-stimulating hormone; ethyl etioplurinz; tirapazamine; titanocened dichloride (titanocene) This includes bichloride; topsentin; toremifene; pluripotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; trisilibine; trimethrexate; triptrelin; tropisetron; tulosteride; tyrosine kinase inhibitors; tilphostine derivatives; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitors; urokinase receptor antagonists; vapreotide; variolin B; vectors, erythrocyte gene therapy; veraresol; veramine; verdin derivatives; verteporfin; vinorelbine; vinxaltin; vitaxin; borozol; zanoterone; zeniplatin; zirascorb; and dinostatin stimulamers.

[0185] A further aspect of the disclosure is that the compounds of the Disclosure may be administered in combination with chemical agents that are understood to mimic the effects of radiotherapy and / or function by direct contact with DNA. Agents used in combination with the compounds of the Disclosure to treat cancer include, but are not limited to, cis-diaminedichloroplatinum(II) (cisplatin), doxorubicin, 5-fluorouracil, taxol, and topoisomerase inhibitors (such as etoposide, teniposide, irinotecan, and topotecan).

[0186] Furthermore, the Disclosure provides a method for treating cancer using the compounds of the Disclosure as an alternative to chemotherapy or radiotherapy alone, where the toxicity of chemotherapy or radiotherapy has been found, or may be found, to be too high, for example, resulting in unacceptable or unbearable side effects for the subject being treated. The subject being treated may, as necessary, be treated with another anti-cancer treatment modality such as chemotherapy, surgery, or immunotherapy, depending on which treatment is found to be acceptable or tolerable.

[0187] The compounds of this disclosure may also be used in vitro or ex vivo for the treatment of certain cancers, including, but not limited to, leukemia and lymphoma, such treatments including autologous stem cell transplantation. This may include a multi-step approach in which the subject's autologous hematopoietic stem cells are collected, all cancer cells are removed from them, the subject is then administered an amount of the compounds of this disclosure effective in eradicating the subject's remaining bone marrow cell population, and then the stem cell graft is injected back into the subject. Bone marrow function is then restored, and supportive care is provided while the subject is recovering.

[0188] The present method for treating cancer may further comprise the administration of the compounds of the present disclosure and additional therapeutic agents, or pharmaceutically acceptable salts or hydrates thereof. In one embodiment, a composition comprising the compounds of the present disclosure is administered concurrently with the administration of one or more additional therapeutic agents, which may be part of the same composition or present in a different composition from the composition comprising the compounds of the present disclosure. In another embodiment, the compounds of the present disclosure are administered before or after the administration of another therapeutic agent.

[0189] In this method of treating cancer, other therapeutic agents may be antiemetics. Suitable antiemetics include: This includes, but is not limited to, metoclopromide, domperidone, prochlorperazine, prorunetazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizaprid, azasetron, benzquinamide, vietautin, bromoprid, buclidine, clevopride, cyclidine, dimenhydrinate, diphenidol, drasetron, meclizine, metalatal, metopimazine, nabilone, oxyperundyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, and tropisetron.

[0190] In one embodiment, the antiemetic is granisetron or ondansetron. In another embodiment, the other therapeutic agent may be a hematopoietic colony-stimulating factor. Suitable hematopoietic colony-stimulating factors include, but are not limited to, filgrastim, sargrarnostim, morglamostin, and epoietin alfa.

[0191] In yet another embodiment, the other therapeutic agent may be an opioid or non-opioid analgesic. Suitable opioid analgesics include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, methopone, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermid, anilelysine, etheptadine, pimidine, betaprozine, diphenoxylate, fentanyl, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazosin, pentazosin, cyclazosin, methadone, isomethadone, and propoxyfene. Suitable non-opioid analgesics include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofenac, diflucinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamete, mefenamic acid, nabumetone, naproxen, piroxicam, and sulindac. It includes.

[0192] In yet another embodiment, the other therapeutic agent may be an anxiolytic. Suitable anxiolytics include, but are not limited to, buspirone and benzodiazepines such as diazepam, lorazepam, oxapam, clorazepate, clonazepam, chlordiazepoxide, and alprazolam.

[0193] In addition to treating cancer and sensitizing cancer cells to the cytotoxic effects of radiotherapy and chemotherapy, the compounds of this disclosure are used in methods for treating diseases, conditions, and central nervous system injuries such as neurological disorders, neurodegenerative disorders, and traumatic brain injury (TBI). In one embodiment, HDACI, a compound of this disclosure having formula I, can cross the blood-brain barrier and inhibit HDACs in the brain of an individual.

[0194] The compounds of this disclosure also provide therapeutic benefits in models of peripheral neuropathy, such as CMT. HDAC6 inhibitors have been found to cross the blood-neuronal barrier and rescue phenotypes observed in transgenic mice exhibiting symptoms of distal hereditary motor neuropathy. Administration of HDAC6 inhibitors to symptomatic mice increased acetylated α-tubulin levels, restored proper mitochondrial movement and axonal transport, and increased myocardial regeneration. Other peripheral neuropathy includes, but is not limited to, giant axonal degeneration, as well as various forms of mononeuropathy, polyneuropathy, autonomic neuropathy, and neuritis.

[0195] The compounds of the disclosed herein are administered by an effective amount of the compounds of the disclosed herein to treat a neurological disorder, or by an effective amount of the compounds of the disclosed herein to treat a neurological disorder. This is useful for treating neurological disorders. Neurological disorders that can be treated include, but are not limited to, Huntington's disease, lupus, schizophrenia, multiple sclerosis, muscular dystrophy, pallidoluysian atrophy (DRRLA), spinal and bulbar muscular atrophy (SBMA), and subtle spinocerebellar ataxia (SCA1, SCA2, SCA3 / MJD (Machado-Joseph disease), SCA6 and SCA7), drug-induced movement disorders, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, Pick's disease, and Alzheimer's disease. This includes Mars disease, Lewy body dementia, corticobasal degeneration, dystonia, myoclonus, Tourette syndrome, tremor, chorea, non-hiding limb syndrome, Parkinson's disease, Parkinsonian syndromes, anxiety disorders, depression, mental illness, bipolar disorder, Friedreich's ataxia, fragile X syndrome, spinal muscular dystrophy, Rett syndrome, Rubinstein-Taybe syndrome, Wilson's disease, multiple infarcts, CMT, GAN, and other peripheral neuropathy.

[0196] In one embodiment, the neurological disorder being treated is Huntington's disease, Parkinson's disease, Alzheimer's disease, spinal muscular atrophy, lupus, or schizophrenia.

[0197] Charcot-Marie-Tooth disease (CMT) is one of the most common hereditary neurological disorders in the United States, affecting approximately 1 in 2,500 people. CMT affects both motor and sensory neurons, sometimes resulting in foot drop and a chicken-like gait with frequent elevation or depression. Mutations in the small heat shock protein 27 (HSPB1) cause axonal CMT or distal motor neuropathy (distal HMN). Expression of mutant HSPB1 leads to decreased acetylated α-tubulin levels, inducing severe axonal transport impairment. Pharmacological inhibition of histone deacetylase 6 (HDAC6)-induced α-tubulin deacetylation, induced by HDAC6i (tubastatin A), corrects the axonal transport deficit induced by HSPB1 mutations and rescues the CMT phenotype in symptomatic mutant HSPB1 mice. The pathogenic role of α-tubulin deacetylation has been demonstrated in the mutant HSPB1-induced neuropathy, offering promising prospects for HDAC6 inhibitors as a therapeutic strategy for hereditary axonal degeneration. The compounds disclosed herein exhibit potent HDAC6 isoform inhibition, high HDAC6 selectivity, and excellent α-tubulin acetylation in various cell lines.

[0198] Therefore, in another embodiment, the neurological disorder is Charcot-Marie-Tooth disease.

[0199] The compounds of this disclosure may also be used in conjunction with a second therapeutic agent in methods of treating conditions, diseases, or injuries to the CNS. Such second therapeutic agents are drugs known in the art for treating specific conditions, diseases, or injuries, for example, but not limited to, lithium in the treatment of mood disorders, estradiol benzoate and nicotinamide in the treatment of Huntington's disease.

[0200] The compounds disclosed herein are also useful in the treatment of TBI. Traumatic brain injury (TBI) is a serious and complex injury that affects approximately 1.4 million people annually in the United States. TBI is associated with a wide range of symptoms and impairments, including risk factors for developing neurodegenerative disorders such as Alzheimer's disease.

[0201] TBI results in several lesions, including axonal injury, cell death, contusions, and inflammation. The inflammatory cascade is characterized by pro-inflammatory cytokines and microglial activation, which can exacerbate other lesions. While the role of inflammation in TBI is well established, there are currently no effective anti-inflammatory therapies available to treat TBI.

[0202] Several known HDAC inhibitors are used to treat acute and chronic neurodegenerative injuries and diseases, such as It has been shown to be protective in various cell and animal models of Alzheimer's disease, ischemic stroke, multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Recent studies in experimental pediatric TBI have reported that a decrease in hippocampal CA3 histone H3 acetylation persists for several hours to several days after injury. These changes contribute to the demonstrated upstream excitotoxicity and stress cascade associated with TBI. HDACI has also been reported to have anti-inflammatory effects acting by acetylating non-histone proteins. 4-dimethylamino-N-[5-(2-mercaptoacetylamino)pentyl]benzamide (DMA-PB), a selective HDAC6 inhibitor, has been found to increase histone H3 acetylation and reduce the microglial inflammatory response after traumatic brain injury in rats. This demonstrates that HDACIs can be used as therapeutic agents to inhibit neuroinflammation associated with TBI.

[0203] Therefore, the compounds of this disclosure are also useful in the treatment of inflammation and stroke, as well as in the treatment of autism and autism spectrum disorder. The compounds of this disclosure can further be used to treat parasitic infections (e.g., malaria, toxoplasmosis, trypanosomiasis, helminthiasis, protozoal infections) (Andrews et al. Int. J. Parasitol. 2000, 3 (See Volume 0 (Issue 6), pages 761-768).

[0204] In certain embodiments, the compounds of the Disclosure may be used to treat malaria. The compounds of the Disclosure may be co-administered with antimalarial compounds selected from the group consisting of arylamino alcohols, cincona alkaloids, 4-aminoquinolines, type 1 or type 2 folate synthesis inhibitors, 8-aminoquinolines, antimicrobial agents, peroxides, naphthoquinone derivatives, and iron chelators. Antimalarial compounds include, but are not limited to, quinines, quinidines, mefloquines, halfantrines, chloroquines, and amodiaquines. , proguanil, chloroproguanil, pyrimethamine, primakine The antimalarial compound may be 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]quinoline succinate (WR238,605), tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolone, artem ether, areether, artesunate, arteric acid, atovaquone, and deferrioxamine. In one embodiment, the antimalarial compound is chloroquine.

[0205] The compounds of this disclosure can also be used as imaging agents. In particular, by supplying radiolabeled, isotope-labeled, or fluorescently labeled HDACI, these labeled compounds can image HDACs, HDAC-expressing tissues, and tumors. The labeled compounds of this disclosure can also be used to image patients suffering from cancer or other HDAC-mediated diseases, such as stroke, by administering an effective amount of the labeled compound or a composition containing the labeled compound. In one embodiment, the labeled HDACI can emit positron emission tomography and is suitable for use in positron emission tomography (PET). Typically, the labeled compounds of this disclosure are used to identify tissues or target regions that express HDACs at high concentrations. The degree of accumulation of labeled HDACI can be quantified using known methods for quantifying radioactive emission. Furthermore, the labeled HDACI may contain a fluorophore or a similar reporter capable of tracking the migration of specific HDAC isoforms or organelles in vitro.

[0206] Compounds of the present disclosure useful for imaging methods contain one or more radioisotopes capable of emitting one or more forms of radiation suitable for detection by any standard radiation apparatus such as PET, SPECT, gamma cameras, MRI, and similar devices. The isotopes include tritium ( 3 H) and carbon ( 11 The HDACI of this disclosure also contains, Fluorine for imaging methods ( 18 F) and iodine ( 123 It may contain isotopes of I). Typically, the labeled compounds of this disclosure are 11 C marker, that is 11 A C-methyl group-containing alkyl group, or 18 F, 123 I, 125 I, 131 It contains alkyl groups substituted with I or a combination thereof.

[0207] The fluorescently labeled compounds of this disclosure may also be used in the imaging methods of this disclosure. Such compounds may have a FITC, a carbocyamine moiety, or other fluorophores that enable the visualization of HDAC proteins in vitro.

[0208] The labeled compounds and methods of use of this disclosure may be used in vivo, particularly with respect to humans, using bodily fluids and cell samples, as well as for in vitro applications such as diagnostic and research applications. Imaging methods are discussed in WO03 / 060523. Typically, the method involves contacting cells or tissues with the radiolabeled, isotope-labeled, fluorescently labeled, or tagged (such as biotin tagging) compound of this disclosure, and the visualization method used, i.e., radiographic image, which is sufficient to yield about 1 to about 30 mCi of the radiolabeled compound. Depending on the quantity, the process includes the step of producing a radiographic image, a fluorescence image, or a similar image type.

[0209] The imaging method includes the use of a labeled compound of the present disclosure that is capable of producing a target-to-background ratio of radiant intensity of at least 2:1, or a ratio of radiant intensity between the target and background of approximately 5:1, approximately 10:1, or approximately 15:1.

[0210] In some methods, the labeled compounds of the Disclosure are rapidly eliminated from the body's tissues, avoiding prolonged exposure to radiation from the radiolabeled compounds administered to the individual. In some embodiments, the labeled compounds of the Disclosure are eliminated from the body in less than about 24 hours. In some embodiments, the labeled compounds of the Disclosure are eliminated from the body in less than about 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 90 minutes, or 60 minutes. In some embodiments, the labeled compounds of the Disclosure are eliminated in about 60 minutes to about 120 minutes.

[0211] In addition to isotope-labeled and fluorescently labeled derivatives, the disclosure also embodies the use of derivatives containing tags (such as biotin) for identifying biomolecules associated with the HDAC isoform of interest for diagnostic, therapeutic, or research purposes.

[0212] The compounds disclosed herein are also useful in the treatment of autoimmune diseases and inflammation. The compounds disclosed herein are particularly useful in overcoming graft rejection and transplant rejection, as well as in the treatment of arthritis forms.

[0213] Despite the success of the latest transplantation programs, the nephrotoxicity, cardiovascular disease, diabetes, and hyperlipidemia associated with current treatment regimens, as well as the emergence of malignancies after transplantation and graft loss due to chronic rejection, are driving efforts to achieve long-term allograft function associated with minimal immunosuppression. Similarly, there is an increasing incidence of inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis. Animal studies have shown that T regulatory cells (Tregs) expressing Foxp3, a member of the forkhead transcription family, are important for limiting autoreactive and alloreactive immunity. Furthermore, Tregs can be adopted into naive hosts after induction by co-stimulus blockade, immunosuppression, or other strategies to realize therapeutic benefits. However, clinical trials have been unsuccessful in generating enough Tregs to maintain their repressive function after transfer. Mouse studies have shown that HDACI limits the immune response, at least to a considerable extent, by increasing the repressive function of Tregs (R. Tao et al., Nat Med, vol. 13, 1299-1307). The selective targeting of HDAC6, in particular, has been shown to be effective in this regard.

[0214] In organ transplantation, rejection can begin immediately within a few days of transplantation, making prevention, rather than treatment, the most important consideration. This is especially true when the patient already has a disease causing problems, or when autoimmunity is reversed. Therefore, we evaluate whether HDAC6- / - mice treated with low-dose RPM (rapamycin) for 14 days show signs of resistance to chronic rejection induction and its development, and whether they exhibit significant long-term graft function loss in a clinical transplant population. Resistance will be assessed by testing whether mice with long-term viable allografts reject subsequent third-party heart grafts and accept further donor allografts without any immunosuppression, as this can occur with non-selective HDACI and RPM. These in vivo studies (sutides) will use recipe entries of challenged donor cells, ELI. This involves evaluation of SPOT and MLR activity. Protection against chronic rejection is assessed in long-term surviving allograft recipients by analyzing the host's anti-donor humoral response, as well as by analyzing atherosclerosis and interstitial fibrosis following graft transplantation.

[0215] The importance of HDAC6 targeting will be evaluated in additional transplant models that pursue biochemically significant readouts so that they can be clinically monitored. Therefore, the effects of HDAC6 targeting in kidney transplant recipients (monitoring BUN, which is proteinuria) and in islet allografts (monitoring blood glucose levels) will be evaluated. Kidney transplantation is the most common organ transplant performed, and since the kidney is multifunctional, regulating acid / base metabolism, blood pressure, and erythropoiesis, the efficacy in this model will be shown to be applicable to HDAC6 targeting. Similarly, islet transplantation remains a significant unmet need, given that clinical islet allografts are typically lost within the first year or two after transplantation. Having a safe and non-toxic means to extend islet survival without CNI maintenance therapy would be a significant advance. The transplant study will also be enhanced by the use of mice with floxed HDAC6. Existing Foxp3-Cre mice will be used to test the effects of HDAC6 deletion specifically in Tregs. This technique can be extended, for example, to target HDAC6 in T cells (CD4-Cre) and dendritic cells (CD11c-Cre). Using tamoxifen-modified Cre, the importance of induction of HDAC6 for transplant maintenance (related to short-term vs. HDAC6I maintenance therapy) is evaluated by inducing HDAC6 deletion by administering tamoxifen at various post-transplant periods.

[0216] We will also investigate autoimmune mechanisms. In this case, blocking pre-existing disease is particularly important, and targeting HDAC6 may be effective without any requirement for additional treatment (in contrast to the highly invasive complete MHC mismatch transplantation model, which requires short-term, low-dose RPM). Studies in mice with colitis have shown that HDAC6- / -Tregs are more effective than WT Tregs in modulating the disease, and that tubacin can rescue mice if treatment is initiated once colitis has developed. We will expand these investigations by evaluating whether HDAC6 deletion in Tregs (Foxp3 / Cre) vs. T cells (CD4=Cre) vs. DCs (CD11c-Cre) affects the onset and severity of colitis differently. Similarly, we will evaluate the control of colitis by inducing HDAC6 deletion at various intervals after the onset of tamoxifen-regulated Cre-mediated colitis.

[0217] This compound is expected to demonstrate anti-arthritis efficacy in a collagen-induced arthritis model in DBA1 / J mice. This study will use DBA1 / J mice (male, 7-8 weeks old), with 8 animals per group. Systemic arthritis is associated with type II bovine collagen and CFA is administered, and then an IFA booster injection is given on day 21 to induce arthritis. The compounds of this disclosure are administered at doses of 50 mg / kg and 100 mg / kg for two consecutive weeks starting on day 28, and the effect is determined from the mean arthritis score versus the number of days of treatment data.

[0218] Despite efforts to avoid graft rejection through host-donor tissue type matching, immunosuppressive therapy is crucial for donor organ survival in the host in most transplant procedures. A variety of immunosuppressants, including azathioprine, methotrexate, cyclophosphamide, FK-506, rapamycin, and corticosteroids, have been used in transplant procedures.

[0219] The compounds of this disclosure can be used as immunosuppressants to suppress humoral and cell-mediated immune responses, such as allograft rejection, delayed-type hypersensitivity, experimental autoimmune encephalomyelitis, Freund's adjuvant arthritis, and graft-versus-host disease. The compounds of this disclosure are useful for the treatment of rheumatoid arthritis, for the treatment of psoriasis, and for the prevention of organ rejection after organ transplantation for the treatment of other autoimmune diseases such as type 1 diabetes, Crohn's disease, and lupus.

[0220] A therapeutically effective amount of the compounds of this disclosure can be used for immunosuppression, including, for the purpose of preventing organ rejection or graft-versus-host disease, and for the purpose of treating diseases and conditions, particularly autoimmune diseases, and inflammatory diseases and conditions. Examples of autoimmune and inflammatory diseases include, but are not limited to, Hashimoto's thyroiditis, pernicious anemia, Addison's disease, psoriasis, diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, dermatomyositis, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, arthritis (rheumatoid arthritis), chronic progressive arthritis (chronic arthritis). This includes progesterone and osteoarthritis, rheumatic diseases, autoimmune hematological disorders (hemolytic anemia, aplastic anemia, euerythrocytic anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma (sclerodoma), Wegner granulomatosis, dermatomyositis, chronic active hepatitis, psoriasis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (ulcerative colitis and Crohn's disease), endocrine eye diseases, Graves' disease, sarcoidosis, primary biliary cirrhosis, juvenile diabetes (type 1 diabetes), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis.

[0221] The compounds of this disclosure can be used alone or in combination with a second therapeutic agent known to be useful for treating autoimmune diseases, inflammation, transplantation, and grafts, such as cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, corticosteroids, and similar agents known to those skilled in the art.

[0222] Further diseases and conditions mediated by HDACs, particularly HDAC6, include, but are not limited to, asthma, cardiac hypertrophy, giant axonal degeneration, mononeuropathy, mononeuritis, polyneuropathy, autonomic neuropathy, neuritis in general, and neurosis in general. These diseases and conditions can also be treated by the methods of this disclosure.

[0223] In this method, in accordance with pharmaceutical practice, a therapeutically effective dose of one or more compounds of the disclosed herein, as typically formulated, is administered to a person in need. Whether such treatment is appropriate depends on the individual case and is subject to a medical assessment (diagnosis) that takes into account any existing signs, symptoms, and / or dysfunctions, the risk of developing specific signs, symptoms, and / or dysfunctions, and other factors.

[0224] The compounds disclosed herein can be administered by any preferred route, for example, orally, orally, by inhalation, topically, sublingually, rectally, vaginally, intrasacral, or intracavitary, transurethral, ​​nasal, or percutaneously, i.e., percutaneously or parenterally (intravenously, intramuscularly, subcutaneously, intracoronally, intradermally, intramammaryly, abdominally, intraarticularly, intracavitarially, intrasacrally, It can be administered by postocular injection, intrapulmonary injection, and / or surgical implantation at a specific site. Parenteral administration can be performed using a needle or syringe, or by using a high-pressure technique.

[0225] Pharmaceutical compositions include those in which the compounds of this disclosure are present in an amount sufficient to be administered in an effective dose to achieve their intended purpose. The exact formulation, route of administration, and dosage are determined by the individual physician in consideration of the diagnosed condition or disease. Dosage and interval can be individually adjusted to achieve levels of the compounds of this disclosure sufficient to maintain the therapeutic effect.

[0226] The toxicity and therapeutic efficacy of the compounds disclosed herein are, for example, LD50. 50 (Dose at which 50% of the population is lethal) and ED 50To determine the therapeutic dose (effective in 50% of the population), it can be determined in cell cultures or experimental animals using standard medical procedures. The dose-to-therapeutic ratio is the therapeutic index, and this index is the LD50. 50 and ED 50 It is expressed as a ratio between [the two values]. Compounds exhibiting a high therapeutic index are preferred. Data obtained from such procedures can be used to formulate dosage ranges for use in humans. Doses are used to achieve ED with little to no toxicity. 50 It is preferable that the concentration of the circulating compound, including the compound, falls within a certain range. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. Determining the therapeutically effective dose is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosures presented herein.

[0227] The therapeutically effective dose of the compounds disclosed herein required for therapeutic use will vary depending on the nature of the condition being treated, the desired duration of its activity, and the patient's age and condition, and will ultimately be determined by the attending physician. Dosage and intervals can be individually adjusted to achieve plasma levels of HDACI sufficient to maintain the desired therapeutic effect. The desired dose can be conveniently administered as a single dose or as multiple doses at appropriate intervals, for example, one, two, three, four, or more divided doses per day. Multiple doses are often preferred or necessary. For example, the compounds of this disclosure may be administered in the following frequencies: 4 doses delivered at 4-day intervals, 1 dose per day (q4d×4); 4 doses delivered at 3-day intervals, 1 dose per day (q3d×4); 1 dose per day at 5-day intervals (qd×5); 1 dose per week for 3 weeks (qwk3); 5 doses per day, with a 2-day break, and another 5 doses per day (5 / 2 / 5); or any dose regimen determined to be suitable for the situation.

[0228] The dosage of a composition containing the compound of this disclosure, or a composition containing the same, may be approximately 1 ng / kg to approximately 200 mg / kg, approximately 1 μg / kg to approximately 100 mg / kg, or approximately 1 mg / kg to approximately 50 mg / kg per body weight. The dosage of the composition is provided as follows, but is approximately 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 75 μg / kg, 100 μg / kg, 125 μg / kg, 150 μg / kg, 175 μg / kg, 200 μg / kg, 225 μg / kg, 250 μg / kg, 275 μg / kg, 300 μg / kg, 325 μg / kg, 350 μg / kg, 375 μg / kg, 400 μg / kg, 425 μg / kg, 450 μg / kg, 475 μg / kg, 500 μg / kg, 525 μg / kg, 550 μg / kg, 575 μg / kg, 600 μg / kg, 625 μg / kg, 650 μg / kg. 675μg / kg, 700μg / kg, 725μg / kg, 750μg / kg, 775μg / kg, 800μg / kg, 825μg / kg, 850μ g / kg, 875μg / kg, 900μg / kg, 925μg / kg, 950μg / kg, 975μg / kg, 1mg / kg, 5mg / kg, 10m g / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 60mg / kg, 70mg / kg, 80mg / kg, 90mg / kg, 100mg / kg, 125mg / kg, 150mg / kg, 175mg / Any dosage may be used, including kg or 200 mg / kg. While the above dosages are examples of average cases, there may be individual cases where higher or lower dosages are beneficial, and such cases are also within the scope of this disclosure. In practice, physicians will determine the optimal actual dosing regimen for each individual patient, which may vary depending on the specific patient's age, weight, and response.

[0229] The compounds of the Disclosure used in the methods of the Disclosure are typically administered in amounts of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, the compounds of the Disclosure can be administered in amounts of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 milligrams per dose, all of which are between 0.005 and 500 milligrams.

[0230] The compounds of this disclosure are typically administered in a mixture containing a pharmaceutical carrier selected with respect to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use according to this disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the compounds of this disclosure.

[0231] The term "carrier" refers to a diluent, adjuvant, or excipient with which the compounds of this disclosure are administered. Such pharmaceutical carriers can be liquids such as water and oil, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Further, auxiliaries, stabilizers, thickeners, lubricants, and colorants may be used. A pharmaceutically acceptable carrier is sterile. When the compounds of this disclosure are administered intravenously, water serves as the carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly in injectable solutions. Suitable pharmaceutical carriers include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk powder, glycerol, propylene glycol, water, and ethanol. The compositions of the present invention may also contain small amounts of wetting agents, emulsifiers, or pH buffering agents, if desired.

[0232] This disclosure encompasses the preparation and use of solvates of the compounds of this disclosure. Solvates can typically function as pharmacological equivalents without significantly altering the physiological activity or toxicity of the compounds. The term “solvate” as used herein refers to combinations, physical associations, and / or solvations of the compounds of this disclosure and solvent molecules, such as disolvates, monosolvates, or hemisolvates, where the ratio of solvent molecules to the compounds of this disclosure is about 2:1, about 1:1, or about 1:2, respectively. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, solvates can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both the solvent phase and the isolateable solvate. The compounds of this disclosure can exist in solvate forms with pharmaceutically acceptable solvents such as water, methanol, and ethanol, and this disclosure is intended to include both solvate and non-solvate forms of the compounds of this disclosure. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can usually function as pharmacological equivalents. The preparation of solvates is well known in this art. For example, the preparation of solvates of fluconazole with ethyl acetate and water is described in M. Caira et al., J. Pharmaceut. Sci., vol. 93(3):601-611. See (2004). Similar preparations of solvates, semi-solvates, hydrates, etc., are described in van Tonder et al., AAPS Pharm. Sci. Tech., Vol. 5 (No. 1): Article 12 (2004) As described by AL Bingham et al., Chem. Commun. pp. 603-604 (2001) A typical and non-limiting method for preparing a solvate involves dissolving the compound of the disclosure in a desired solvent (organic matter, water, or a mixture thereof) at a temperature of over 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by a known method, such as filtration. The presence of the solvent in the solvate crystals can be confirmed using analytical techniques such as infrared spectroscopy.

[0233] These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolution, granulation, dragée production, emulsification, encapsulation, capture, or lyophilization. The appropriate formulation depends on the chosen route of administration. When a therapeutically effective amount of the compound of this disclosure is administered orally, the composition is typically in the form of tablets, capsules, powders, solutions, or elixirs. When administered in tablet form, the composition may further contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules, and powders contain about 0.01% to about 95%, preferably about 1% to about 50%, of the compound of this disclosure. When administered in liquid form, a liquid carrier such as water, petroleum, or animal or plant-derived oil may be added. The liquid form of the composition may further contain a saline solution, a dextrose or other saccharide solution, or a glycol. When administered in liquid form, the composition contains about 0.1% to about 90% by weight, preferably about 1% to about 50% by weight, of the compound of this disclosure.

[0234] When a therapeutically effective dose of the compounds of this disclosure is administered intravenously, cutaneously, or subcutaneously, the composition is in the form of a parenterally acceptable aqueous solution free of pyrogens. The preparation of such parenterally acceptable solutions, taking into account pH, isotonicity, stability, etc., is within the scope of the art. Compositions preferred for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle. The compounds of this disclosure may be injected with other fluids over intervals of 10 to 30 minutes or over several hours.

[0235] The compounds of this disclosure can be readily combined with pharmaceutically acceptable carriers known in the art. Such carriers allow the activators to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral administration to patients under treatment. Pharmaceutical preparations for oral use can be obtained by adding the compounds of this disclosure to a solid excipient, grinding the resulting mixture as needed, adding suitable adjuvants if desired, and then processing the granular mixture to obtain a tablet or dragee core. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants may be added if desired.

[0236] The compounds of this disclosure can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The injectable formulations may be supplied in unit dosage forms, for example, in ampoules or in multi-dose containers with added preservatives. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers and / or dispersants.

[0237] Pharmaceutical compositions for parenteral administration include aqueous solutions of an activator in a water-soluble form. Furthermore, suspensions of the compounds of this disclosure can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. The aqueous injectable suspension may contain substances that improve the viscosity of the suspension. If necessary, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, enabling the preparation of very high-concentration solutions. Alternatively, the composition may be in powder form for use with a suitable vehicle, such as a sterile pyrogen-free water-based vehicle, before use.

[0238] The compounds of this disclosure may also be formulated in rectal compositions, such as suppositories or enemas, containing, for example, a conventional suppository base. In addition to the formulations described herein, the compounds of this disclosure may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Accordingly, for example, the compounds of this disclosure may be formulated using suitable polymeric substances or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins.

[0239] In particular, the compounds of the present disclosure may be administered orally, orally, or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or in mixtures with excipients, or in the form of elixirs or suspensions containing flavorings or colorings. Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspending agents. The compounds of the present disclosure may also be administered parenterally, for example, by intravenous, intramuscular, subcutaneous, or coronary artery injection. In the case of parenteral administration, the compounds of the present disclosure may be best used in the form of a sterile aqueous solution which may contain other substances, such as salts or monosaccharides such as mannitol or glucose, to prepare a solution isotonic with blood.

[0240] As an additional embodiment, the Disclosure includes a kit comprising one or more compounds or compositions packaged in a manner that facilitates their use for carrying out the methods of the Disclosure. In a simple embodiment, the kit comprises a compound or composition described herein (e.g., a composition comprising the compounds of the Disclosure and, if necessary, a second therapeutic agent) packaged in a container such as a sealed bottle or container, together with a label affixed to the container or included in the kit describing the use of the compound or composition for carrying out the methods of the Disclosure. Preferably, the compound or composition is packaged in a unit dosage form. The kit may include a suitable device for administering the composition by an intended route of administration, e.g., a syringe, a drip bag or a patch. In another embodiment, the compound is a lyophilized form. In this example, the kit may further include an additional container containing a solution useful for reconstituting the lyophilized form.

[0241] The compounds disclosed herein demonstrate improved HDAC6 efficacy, improved BEI, and enhanced selectivity for HDAC1 and HDAC8 compared to conventional compounds. The improved properties of these compounds, particularly the improved BEI and reduced efficacy at HDAC8, indicate their potential use in applications such as immunosuppressants and neuroprotective agents, but are not limited to those listed below. For example, the compounds disclosed herein typically exhibit binding affinity (IC) to HDAC6 at concentrations of less than 100 μM, less than 25 μM, less than 10 μM, less than 1 μM, less than 0.5 μM, and less than 0.2 μM. 50 ) has. [Examples]

[0242] General synthesis methods and procedures All starting materials and solvents were purchased from commercial suppliers at reagent purity and used as received without any further purification unless otherwise specified. Dry solvents used as media in moisture-sensitive reactions were purchased from Sigma-Aldrich in anhydrous grade and handled under argon. All reactions were carried out under dry conditions in an inert (argon) atmosphere. Microwave reactions were carried out in a Biotage Initiator microwave reactor. Reactions were performed on glass plates coated with silica gel (TLC). LuxPlate Silica Gel 60F 254 The process was monitored by thin-layer chromatography on a Merck (Merck) at 254 nm and / or visualized using appropriate dyes. Where indicated, the synthetic intermediates were visualized using an appropriate solvent mixture on CombiFlas. The product was purified by silica gel flash chromatography using a 230-400 mesh system. The final product was purified by preparative HPLC using a Shimadzu preparative liquid chromatograph [ACE 5AQ (150 × 21.2 mm) 5 μm particle size. Method 1: 25-100% MeOH / H2O, 30 min; 100% MeOH, 5 min; 100-25% Method 1: MeOH / H2O, 4 minutes. Method 2: 8-100% MeOH / H2O, 30 minutes; 100% MeOH, 5 minutes; 100-8% MeOH / H2O, 4 minutes. Method 3: 0% MeOH, 5 minutes; 0-100% MeOH / H2O, 25 minutes; 100% MeOH, 5 minutes; 100-0% MeOH / H2O, 4 minutes. Purification was performed at a flow rate of 17 mL / min while monitoring at 254 and 280 nm. Both solvents were spiked with 0.05% TFA. 1 H and 13 ¹³C NMR spectra were recorded using a Bruker DPX-400 or AVANCE-400 spectrometer at 400 MHz and 100.6 MHz, respectively. Chemical shifts (δ scale) are reported in parts per million (ppm) compared to TMS. 1The 1H NMR spectra are reported in the following order: proton multiplicity and number; the signals are characterized as follows: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), bs (broad signal). HRMS spectra were recorded using ESI by LCMS-IT-TOF (Shimadzu). The purity of all final compounds was determined by analytical HPLC [ACE 3AQ C18 column (150 × 4.6 mm, particle size 3 μM); gradient elution system of 0.05% TFA in H2O / 0.05% TFA in MeOH; flow rate = 1.0 mL / min]. All compounds were tested for purity >95% as determined by HPLC analysis. Example 1 Synthesis of 5-(2-benzamidoethyl)-N-hydroxyisoxazole-3-carboxamide (SS-1-100) [ka]

[0243] To a stirred solution of SS-1-95:3-buty-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol), and PPh3 (682 mg, 2.6 mmol), DEAD (525 mg, 2.6 mmol) was added at 0°C under Ar protection. The resulting mixture was slowly warmed to room temperature and stirred at the same temperature for 2.5 hours. Next, the reaction product was quenched with H2O and extracted with RINKAN (3 × 20 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% RINKAN / hexene) to obtain the title compound as a white powder (370 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 5.5, 3.0 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 3.89 (t, J = 7.1 Hz, 2H), 2.62 (td, J = 7.1, 2.7 Hz, 2H), 1.96 (t, J = 2.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 168.04, 134.05, 132.01, 123.39, 80.27, 70.26, 36.55, 18.36.

[0244] To a stirred MeOH (5 mL) solution of SS-1-97B:SS-1-95 (180 mg, 0.9 mmol), N2H4 (0.06 mL, 1.13 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Next, the precipitate (participate) was filtered off. The filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. This solution was concentrated under vacuum to obtain SS-1-97A as a white powder. The crude product was used directly in the next step. To a stirred solution of SS-1-97A in DCM (5 mL), TEA (0.37 mL, 2.7 mmol) and benzoyl chloride (252 mg, 1.8 mmol) were added at 0°C. The resulting mixture was then stirred at the same temperature for 30 minutes. This reaction product was quenched with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% siRNA / hexene) to obtain the title compound as a white powder (140 mg, 90%). 1 ¹H NMR (400 MHz, acetone-d6) δ 7.93 (dd, J = 5.3, 3.2 Hz) 3H), 7.58 - 7.53 (m, 1H), 7.49 (dd, J = 8.1, 6.6 Hz, 2H), 3.57 (td, J = 7.1, 6.0 Hz, 2H), 2.55 (td, J = 7.1, 2.7 Hz, 2H), 2.43 (t, J = 2.7Hz, 1H).

[0245] SS-1-99: In a microwave reaction tube, SS-1-97B (140 mg, 0.8 mmol) in SiO (2 mL) was mixed with NaHCO3 (201 mg, 2.4 mmol) and 2-chloro-2-(hydroxyimino)ethyl acetate (367 mg, 2.4 mmol). This mixture was heated in a microwave reactor at 100°C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-50% SiO / hexene) to obtain the title compound as a colorless oil (140 mg, 61%). 1 H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 5.2, 3.2 Hz, 2H), 7.50 (ddd, J = 6.6, 3.9, 1.3 Hz, 1H), 7.46 - 7.36 (m, 2H), 6.51 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.82 (q, J = 6.4 Hz, 2H), 3.19 (t, J = 6.5 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 172.65, 167.78, 159.92, 156.62, 134.05, 131.76, 128.67, 126.91, 102.74, 62.21, 37.89, 27.16, 14.13.

[0246] SS-1-100: In a round-bottom flask, NaOH (160 mg, 4.0 mmol) was dissolved in 50% aqueous NH2OH (1.6 mL, approximately 50 equivalents) at 0°C. A solution of SS-1-99 (140 mg, 0.5 mmol) in 1:1 THF / MeOH (6 mL) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. This solution was neutralized with 6N HCl and extracted with ELISA (3 × 15 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. Washing the crude product with ELISA yielded the desired product as a white powder (60 mg, 43%). 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 5.5 Hz, 1H), 7.81 (d, J = 7.1 Hz, 2H), 7 .53 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 6.63 (s, 1H), 3.60 (q, J = 6.6 Hz, 2H), 3.09 (t, J = 6.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.44, 166.42, 157.44, 156.17, 134.28, 131.25, 128.31(2C), 127.12(2C), 101.13, 37.22, 26.29.ESI HRMS calculation value C 13 H1 4N3O4:[M+H] + m / z 276.0979; measured value: 276.0984. Example 2 Synthesis of 5-(2-(3,4-dichlorobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-2-08) [ka]

[0247] SS-2-05: A stirred solution of 3-buty-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol), and PPh3 (682 mg, 2.6 mmol) was mixed with DEAD (525 mg, 2.6 mmol) at 0°C under protection with Ar. The resulting mixture was slowly warmed to room temperature and stirred at the same temperature for 2.5 hours. The reaction product was then quenched with H2O and extracted with RINKAN (3 × 20 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% RINKAN / hexene) to obtain the title compound as a white powder (260 mg, 65%).

[0248] To a stirred MeOH (5 mL) solution of SS-2-06:SS-2-05 (260 mg, 1.3 mmol), N2H4 (0.1 mL, 3.2 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Next, the precipitate was filtered off, and the filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. When this solution was concentrated under vacuum, the desired product was obtained as a white powder. The crude product was used directly in the next step. To a stirred DCM (5 mL) solution of the intermediate, TEA (0.54 mL, 3.9 mmol) was added at 0°C. ) and 3,4-dichlorobenzoyl chloride (543 mg, 2.6 mmol) were added. Next, the resulting mixture was stirred at the same temperature for 30 minutes. The reaction product was quenched with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% siRNA / hexene) to obtain the title compound as a colorless solid (220 mg, 70%). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.3, 2.1 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.41 (s, 1H), 3.61 (q, J = 6.2 Hz, 2H), 2.53 (td, J = 6.3, 2.6 Hz, 2H), 2.07 (t, J = 2.6 Hz, 1H).

[0249] SS-2-07: In a microwave reaction tube, 227 mg (2.7 mmol) of SS-2-06 (0.9 mmol) was dissolved in 2 mL of siRNA, to which 227 mg (2.7 mmol) of NaHCO3 and 408 mg (2.7 mmol) of ethyl 2-chloro-2-(hydroxyimino)ethyl acetate were added. This mixture was heated in a microwave reactor at 100 °C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-80% siRNA / hexene), yielding the title compound as a white solid (250 mg, 78%). 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.5 Hz, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.82 - 7.71 (m, 2H), 6.76 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.5 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 173.53, 164.23, 159.60, 156.10, 134.60, 134.17, 131.34, 130.84, 129.16, 127.54, 102.46, 61.80, 37.40, 26.31, 14.01.

[0250] SS-2-08: In a round-bottom flask, NaOH (224 mg, 5.6 mmol) was dissolved in 50% aqueous NH2OH (2.0 mL, approximately 50 equivalents) at 0°C. A 1:1 THF / MeOH (10 mL) solution of SS-1-99 (250 mg, 0.7 mmol) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. This solution was neutralized with 6N HCl and extracted with SiO2 (3 × 15 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The crude product was washed with Et2O / SiO2 (10:1) to obtain the desired product as a white powder (70 mg, 29%). 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.33 (s, 1H), 8.87 (t, J = 5.3 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.83 - 7.72 (m, 2H), 6.63 (s, 1H), 3.59 (q, J = 6.4 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.27, 164.14, 157.44, 156.18, 134.53, 134.10, 131.28, 130.76, 129.11, 127.48, 101.20, 37.40, 26.13.ESI HRMS calculated value C 13 H 12 Cl2N3O4:[M+H] + m / z 344.0205; measured value: 344.0198. Example 3 Synthesis of 5-(2-(2-naphthamido)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-66) [ka]

[0251] Synthesis of 2-(buta-3-in-1-yl)isoindorin-1,3-dione (SS-1-95): 3-buty-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol), and PPh3 (682 mg, 2.6 mmol) were stirred together. DEAD (525 mg, 2.6 mmol) was added at 0°C under Ar protection. The resulting mixture was slowly warmed to room temperature and stirred at the same temperature for 2.5 hours. The reaction product was then quenched with H2O and extracted with siRNA (3 × 20 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% siRNA / hexane) to obtain the title compound as a white powder (370 mg, 93%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 5.5, 3.0 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 3.89 (t, J = 7.1 Hz, 2H), 2.62 (td, J = 7.1, 2.7 Hz, 2H), 1.96 (t, J = 2.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 168.0, 134.1, 132.0, 123.4, 80.3, 70.3, 36.6, 18.4.

[0252] Synthesis of N-(buta-3-in-1-yl)-2-naphthoamide (SS-3-62): To a stirred solution of SS-1-95 (215 mg, 1.08 mmol) in MeOH (5 mL), N2H4 (0.1 mL, 2.7 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Next, the precipitate was filtered off, and the filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. When this solution was concentrated under vacuum, SS-1-97A was obtained as a white powder. The crude product was used directly in the next step. To a stirred solution of SS-1-97A in DCM (5 mL), TEA (0.25 mL, 1.6 mmol) and 2-naphthoyl chloride (246 mg, 1.3 mmol) were added at 0°C. Next, the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. Flash chromatography Purification of the crude product with roughe (0-30% phenylalanine / hexane) yielded the title compound as a white powder (170 mg, 70%, crude).

[0253] Synthesis of ethyl 5-(2-(2-naphthamidoethyl)isoxazole-3-carboxylate (SS-2-64): In a microwave reactor, SS-2-62 (170 mg, 0.76 mmol) was dissolved in ethyl ammonium (2 mL), to which NaHCO3 (191 mg, 2.28 mmol) and ethyl 2-chloro-2-(hydroxyimino)ethyl acetate (344 mg, 2.28 mmol) were added. This mixture was heated in a microwave reactor at 100 °C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-50% ammonium / hexane) to obtain the title compound as a white solid (150 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.86 - 7.77 (m, 4H), 7.57 - 7.45 (m, 2H), 6.90 (t, J = 5.7 Hz, 1H), 6.50 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.85 (q, J = 6.5 Hz, 2H), 3.20 (t, J = 6.6 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 172.8, 168.0, 160.02, 156.7, 134.9, 132.7, 131.3, 129.0, 128.6, 127.9, 127.8, 127.6, 126.9, 123.6, 102.8, 62.3, 38.1, 27.3, 14.2.

[0254] Synthesis of 5-(2-(2-naphthamido)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-66): In a round-bottom flask, NaOH (142 mg, 3.55 mmol) was dissolved in 50% aqueous NH2OH (1.4 mL, approximately 50 equivalents) at 0°C. A 1:1 THF / MeOH (5 mL) solution of SS-3-64 (150 mg, 0.44 mmol) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. This solution was neutralized with 6N HCl and extracted with ELISA (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography (0-10% MeOH / DCM) and preparative HPLC (Method 2), and lyophilized to obtain the desired product as a white powder (15 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 9.33 (br s, 1H), 8.85 (t, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.03 - 7.88 (m, 3H), 7.90 (d, J = 8.6 Hz, 1H), 7.63 - 7.57 (m, 2H), 6.66 (s, 1H), 3.66 (q, J = 6.5 Hz, 2H), 3.14 (t, J = 6.7 Hz, 2H).ESI HRMS calculated value C 17 H 16 N3O4:[M+H] + m / z 326.1135; measured value: 326.1137. Example 4 Synthesis of 5-(2-([1,1'-biphenyl]-3-carboxamide)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-67) [ka]

[0255] Synthesis of 2-(buta-3-in-1-yl)isoindorin-1,3-dione (SS-1-95): 3-buty-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol), and PPh3 (682 mg, 2.6 mmol) were stirred together. DEAD (525 mg, 2.6 mmol) was added at 0°C under Ar protection. The resulting mixture was slowly warmed to room temperature and stirred at the same temperature for 2.5 hours. The reaction product was then quenched with H2O and extracted with siRNA (3 × 20 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% siRNA / hexane) to obtain the title compound as a white powder (370 mg, 93%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 5.5, 3.0 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 3.89 (t, J = 7.1 Hz, 2H), 2.62 (td, J = 7.1, 2.7 Hz, 2H), 1.96 (t, J = 2.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 168.0, 134.1, 132.0, 123.4, 80.3, 70.3, 36.6, 18.4.

[0256] Synthesis of N-(buta-3-in-1-yl)-[1,1'-biphenyl]-3-carboxamide (SS-3-63): To a stirred solution of SS-1-95 (215 mg, 1.08 mmol) in MeOH (5 mL), N2H4 (0.1 mL, 2.7 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Next, the precipitate was filtered off, and the filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. When this solution was concentrated under vacuum, SS-1-97A was obtained as a white powder. The crude product was used directly in the next step. To a stirred solution of SS-1-97A in DCM (5 mL), TEA (0.25 mL, 1.6 mmol) and chloride [1,1'-biphenyl]-3-carbonyl (280 mg, 1.3 mmol) were added at 0°C. Next, the resulting mixture was stirred at the same temperature for 30 minutes. The reaction product was quenched with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was washed with brine (40 mL), dehydrated with sodium sulfate, and concentrated under vacuum. Flash chromatography (0-30% Et) was performed. Purification of the crude product with OAc / hexane yielded the title compound as a white powder (140 mg, 52%, crude).

[0257] Synthesis of ethyl 5-(2-([1,1'-biphenyl]-3-ylcarboxamide)ethyl)isoxazole-3-carboxylate (SS-3-65): In a microwave reactor, SS-3-63 (170 mg, 0.56 mmol) was dissolved in ethyl HCl (2 mL), to which NaHCO3 (144 mg, 1.69 mmol) and ethyl 2-chloro-2-(hydroxyimino)ethyl acetate (255 mg, 1.69 mmol) were added. This mixture was heated in a microwave reactor at 100 °C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-50% ethyl HCl / hexane) to obtain the title compound as a colorless oil (100 mg, 49%). 1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.76 - 7.65 (m, 2H), 7.58 - 7.51 (m, 2H), 7.45 - 7.38 (m, 3H), 7.36 - 7.30 (m, 1H), 7.06 (t, J = 5.4 Hz, 1H), 6.47 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.78 (q, J = 6.5 Hz, 2H), 3.14 (t, J = 6.6 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 172.8, 168.0, 160.0, 156.6, 141.7, 140.1, 134.7, 130.3, 129.1, 128.9 (2C), 127.8, 127.2 (2C), 125.9, 125.8, 102.7, 62.2, 38.0, 27.1, 14.1.

[0258] Synthesis of 5-(2-([1,1'-biphenyl]-3-ylcarboxamide)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-67): In a round-bottom flask, NaOH (90 mg, 2.2 mmol) was dissolved in 50% aqueous NH2OH (0.9 mL, approximately 50 equivalents) at 0°C. A 1:1 THF / MeOH (4 mL) solution of SS-3-65 (100 mg, 0.27 mmol) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. This solution was neutralized with 6N HCl and extracted with ELISA (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography (0-10% MeOH / DCM) and preparative HPLC (Method 2), and then freeze-dried to obtain the desired product as an off-white powder (30 mg, 32%). 1 1H NMR (400 MHz, DMSO-d6) δ 11.47 (br s, 1H), 9.33 (br s, 1H), 8.81 (t, J = 5.6 Hz, 1H), 8.08 (s, 1H), 7.82 (t, J = 7.4 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.41 (t, ESI HRMS calculation value C 19 H 16 N3O4:[MH] + m / z 350.1146; measured value: 350.1132. Example 5 Synthesis of 5-(3-(3,4-dichlorophenoxy)propyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-10) [ka]

[0259] Synthesis of ethyl 5-(3-hydroxypropyl)isoxazole-3-carboxylate (SS-4-07): In a microwave reactor, 5-hexyn-1-ol (300 mg, 3.57 mmol) was dissolved in HCl (5 mL), to which NaHCO3 (900 mg, 10.7 mmol) and 2-chloro-2-(hydroxyimino)ethyl acetate (1.6 g, 10.7 mmol) were added. This mixture was heated in a microwave reactor at 100 °C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-80% HCl / hexane) to obtain the title compound as a colorless oil (680 mg, 96%). 1 1H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.70 (t, J = 6.1 Hz, 2H), 2.92 (t, J = 7.6 Hz, 2H), 1.97 - 1.88 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 175.2, 160.3, 156.5, 101.8, 62.2, 61.3, 30.2, 23.3, 14.2.

[0260] Synthesis of ethylethyl 5-(3-bromopropyl)isoxazole-3-carboxylate (SS-4-08): To a stirred solution of SS-4-07 (680 mg, 3.42 mmol) in DCM (30 mL), CBr4 (1.70 g, 5.13 mmol) and Ph3P (1.35 g, 5.13 mmol) were added at 0°C. The resulting mixture was then stirred at room temperature for 1 hour. The reaction product was quenched with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was washed with brine (30 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-40% Âxane / hexane) to obtain the title compound as a colorless oil (850 mg, 83%). 1 H NMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.43 (t, J = 6.3 Hz, 2H), 3.01 (t, J = 7.3 Hz, 2H), 2.33 - 2.18 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.6, 160.1, 156.6, 102.3, 62.3, 31.9, 30.2, 25.3, 14.3.

[0261] Synthesis of ethyl 5-(3-((3,4-dichlorophenyl)amino)propyl)isoxazole-3-carboxylate (SS-4-09): To a stirred solution of SS-4-08 (464 mg, 2.85 mmol) in DMF (15 mL), 3,4-dichlorophenol (850 mg, 3.41 mmol) and Cs2CO3 (1.87 g, 5.70 mmol) were added at room temperature. The resulting mixture was heated at 80°C for 2 hours. The reaction product was quenched with saturated aqueous solution NH4Cl (5 mL) and extracted with RINKAN (3 × 10 mL). The combined organic extracts were washed with brine (30 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-30% RINKAN / hexane) to obtain the title compound as a colorless oil (490 mg, 80%). 1 H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.71 (dd, J = 8.9, 2.9 Hz, 1H), 6.43 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.96 (t, J = 5.9 Hz, 2H), 3.00 (t, J = 7.5 Hz, 2H), 2.26 - 2.08 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 174.3, 160.1, 157.7, 156.5, 132.9, 130.8, 124.2, 116.4, 114.5, 102.0, 66.9, 62.2, 27.0, 23.4, 14.2.

[0262] Synthesis of 5-(3-((3,4-dichlorophenyl)amino)propyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-10): In a round-bottom flask, NaOH (150 mg, 3.72 mmol) was dissolved in 50% aqueous NH2OH (1.5 mL, approximately 50 equivalents) at 0°C. A 1:1 THF / MeOH (6 mL) solution of SS-4-09 (160 mg, 0.47 mmol) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. This solution was neutralized with 2N HCl and extracted with RINKAN (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC (Method 2), and lyophilized to obtain the desired product as a white powder (65 mg, 40%). 1 H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.33 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 2.9 Hz, 1H), 6.96 (dd, J = 8.9, 2.9 Hz, 1H), 6.60 (s, 1H), 4.06 (t, J = 6.1 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.15 - 2.03 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 173.8, 157.9, 157.5, 156.3, 131.6, 131.0, 122.4, 116.4, 115.5, 100.7, 67.2, 40.2, 39.9, 39.7, 39.5, 39.3, 39.1, 38.9, 26.4, 22.6.ESI HRMS calculated value C 13 H 13 Cl2N2O4:[M+H] + m / z 331.0247; measured value: 331.0264. Example 6 Synthesis of 5-(4-(5,6-dichloro-1H-indole-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-94) [ka]

[0263] Synthesis of ethyl 5-(4-hydroxybutyl)isoxazole-3-carboxylate (SS-3-86): In a microwave reactor, 5-hexyn-1-ol (200 mg, 2.0 mmol) in toluene (3 mL) was mixed with NaHCO3 (504 mg, 6.0 mmol) and ethyl 2-chloro-2-(hydroxyimino)ethyl acetate (906 mg, 6.0 mmol). This mixture was heated in a microwave reactor at 100 °C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-80% toluene / hexane) to obtain the title compound as a colorless oil (370 mg, 87%). 1 H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 4.42 (qd, J = 7.1, 1.3 Hz, 2H), 3.68 (td, J = 6.3, 1.3 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 1.90 - 1.76 (m, 2H), 1.67 - 1.60 (m, 2H), 1.40 (td, J = 7.1, 1.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 175.4, 160.3, 156.5, 101.7, 62.3, 62.2, 31.9, 26.6, 23.9, 14.3.

[0264] Synthesis of ethyl 5-(4-bromobutyl)isoxazole-3-carboxylate (SS-3-88): To a stirred solution of SS-3-86 (100 mg, 0.47 mmol) in DCM (5 mL), CBr4 (232 mg, 0.47 mmol) and Ph3P (184 mg, 0.47 mmol) were added at 0°C. The resulting mixture was then stirred at room temperature for 1 hour. The reaction product was quenched with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was washed with brine (30 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-40% Âxane / hexane) to obtain the title compound as a colorless oil (90 mg, 89%). 1 H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.40 (t, J = 6.2 Hz, 2H), 2.83 (t, J = 6.9 Hz, 2H), 1.89 - 1.87 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 174.7, 160.2, 156.5, 101.8, 62.1, 32.8, 31.8, 26.0, 25.9, 14.2.

[0265] Synthesis of ethyl 5-(4-(5,6-dichloro-1H-indole-1-yl)butyl)isoxazole-3-carboxylate (SS-3-92): To a stirred solution of SS-3-88 (90 mg, 0.33 mmol) in DMF (3 mL), 5,6-dichloro-1H-indole (56 mg, 0.30 mmol) and Cs2CO3 (217 mg, 0.66 mmol) were added at room temperature. The resulting mixture was heated overnight at 80°C. The reaction product was quenched with saturated aqueous solution NH4Cl (5 mL) and extracted with Âr (3 × 10 mL). The combined organic extract was washed with brine (30 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-30% Âr / hexane) to obtain the title compound as a colorless oil (90 mg, 80%). 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.39 (s, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.42 (dd, J = 3.1, 0.7 Hz, 1H), 6.35 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.09 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 1.92 - 1.85 (m, 2H), 1.77 - 1.65 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 174.5, 160.2, 156.6, 134.9, 129.7, 128.3, 125.7, 123.6, 122.1, 110.9, 101.9, 101.3, 62.3, 46.3, 29.5, 26.4, 25.0, 14.3.

[0266] Synthesis of 5-(4-(5,6-dichloro-1H-indole-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-94): In a round-bottom flask, NaOH (76 mg, 1.9 mmol) was dissolved in 50% aqueous NH2OH (0.9 mL, approximately 50 equivalents) at 0°C. A 1:1 THF / MeOH (4 mL) solution of SS-3-92 (90 mg, 0.24 mmol) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. This solution was neutralized with 2N HCl and extracted with ELISA (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC (Method 2) and lyophilized to obtain the desired product as an off-white powder (35 mg, 39%). 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.32 (d, J = 1.6 Hz, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.51 (d, J = 3.1 Hz, 1H), 6.51 (s, 1H), 6.46 (d, J = 3.1 Hz, 1H), 4.22 (t, J = 7.0 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 1.65 - 1.75 (m, 2H), 1.65 - 1.54 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 174.3, 157.4, 156.3, 134.7, 131.3, 127.9, 123.5, 121.5, 121.4, 111.7, 100.6, 100.5, 45.2, 29.14, 25.27, 24.12.ESI HRMS calculation value C 16 H 16 N3O3Cl2:[M+H] + m / z 368.0563; measured value: 368.0545. Example 7 Synthesis of 5-(4-(6-chloro-3,4-dihydroquinoline-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-01) [ka]

[0267] Synthesis of ethyl 5-(4-hydroxybutyl)isoxazole-3-carboxylate (SS-3-86): In a microwave reactor, 5-hexyn-1-ol (200 mg, 2.0 mmol) was dissolved in toluene (3 mL), to which NaHCO3 (504 mg, 6.0 mmol) and ethyl 2-chloro-2-(hydroxyimino)ethyl acetate (906 mg, 6.0 mmol) were added. This mixture was heated in a microwave reactor at 100 °C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-80% toluene / hexane) to obtain the title compound as a colorless oil (370 mg, 87%). 1 H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 4.42 (qd, J = 7.1, 1.3 Hz, 2H), 3.68 (td, J = 6.3, 1.3 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 1.90 - 1.76 (m, 2H), 1.67 - 1.60 (m, 2H), 1.40 (td, J = 7.1, 1.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 175.4, 160.3, 156.5, 101.7, 62.3, 62.2, 31.9, 26.6, 23.9, 14.3.

[0268] Synthesis of ethyl 5-(4-oxobutyl)isoxazole-3-carboxylate (SS-3-98): To a stirred solution of SS-3-86 (150 mg, 0.70 mmol) in DCM (5 mL), pyridinium chlorochromate (300 mg, 1.4 mmol) was added at room temperature. The resulting mixture was stirred at the same temperature for 2 hours. The excess solid was then filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-60% Âxane), yielding the title compound as a colorless oil (130 mg, 88%). 1 H NMR (400 MHz, CDCl3) δ 9.75 (t, J = 1.1 Hz, 1H), 6.40 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H), 2.53 (td, J = 7.1, 1.0 Hz, 2H), 2.11 - 1.94 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 200.91, 174.33, 160.07, 156.47, 101.93, 77.48, 77.16, 76.84, 62.13, 42.60, 25.84, 19.83, 14.15. 13 C NMR (100 MHz, CDCl3) δ 200.9, 174.3, 160.1, 156.5, 101.9, 62.1, 42.6, 25.8, 19.8, 14.1.

[0269] Synthesis of ethyl 5-(4-(6-chloro-3,4-dihydroquinoline-1(2H)-yl)butyl)isoxazole-3-carboxylate (SS-3-99): NaBH(OAc)3 (262.8 mg, 1.24 mmol) was added to a stirred EtOH / AcOH (5 mL / 0.5 mL) solution of SS-3-98 (130 mg, 0.62 mmol) and 6-chloro-1,2,3,4-tetrahydroquinoline (104 mg, 0.62 mmol) at room temperature. The resulting mixture was then stirred overnight at the same temperature. The reaction product was then quenched with saturated NaHCO3 aqueous solution (5 mL) and extracted with DCM (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. Purification of the crude product by flash chromatography (0-20% phenyl / hexane) yielded the title compound as a colorless oil (130 mg, 58%). 1 H NMR (400 MHz, CDCl3) δ 6.95 (dd, J = 8.7, 2.6 Hz, 1H), 6.88 (d, J = 2.6 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.29 - 3.12 (m, 4H), 2.84 (t, J = 7.3 Hz, 2H), 2.69 (t, J = 6.3 Hz, 2H), 1.94 - 1.88 (m, 2H), 1.80 - 1.72 (m, 2H), 1.67 - 1.60 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 175.1, 160.2, 156.5, 143.8, 128.8, 126.8, 124.1, 120.1, 111.5, 101.7, 62.2, 51.1, 49.5, 28.1, 26.7, 25.7, 25.2, 22.1, 14.2.

[0270] Synthesis of 5-(4-(6-chloro-3,4-dihydroquinoline-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-01): In a round-bottom flask, NaOH (116 mg, 2.9 mmol) was dissolved in 50% aqueous NH2OH (1.0 mL, approximately 50 equivalents) at 0°C. A 1:1 THF / MeOH (6 mL) solution of SS-3-99 (130 mg, 0.36 mmol) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. The solution was neutralized with 2N HCl and extracted with ELISA (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC (Method 2) and lyophilized to obtain the desired product as an off-white powder (100 mg, 62%, TFA salt). 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 6.93 (dd, J = 8.7, 2.6 Hz, 1H), 6.88 (d, J = 2.7 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 3.29 - 3.16 (m, 4H), 2.84 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 6.3 Hz, 2H), 1.86 - 1.77 (m, 2H), 1.69 - 1.64 (m, 2H), 1.57 - 1.50 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 174.5, 157.4, 156.3, 143.8, 128.1, 126.3, 123.8, 118.1, 111.6, 100.5, 50.0, 48.5, 27.4, 25.7, 24.7, 24.4, 21.3.ESI HRMS calculation value C 17 H 21 N3O3Cl:[M+H] + m / z 350.1266; measured value: 350.1251. Example 8 Synthesis of 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinoline-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-02) [ka]

[0271] Synthesis of ethyl 5-(4-hydroxybutyl)isoxazole-3-carboxylate (SS-3-86): In a microwave reactor, 5-hexyn-1-ol (200 mg, 2.0 mmol) was dissolved in toluene (3 mL), to which NaHCO3 (504 mg, 6.0 mmol) and ethyl 2-chloro-2-(hydroxyimino)ethyl acetate (906 mg, 6.0 mmol) were added. This mixture was heated in a microwave reactor at 100 °C for 1 hour. After the reaction was complete, the precipitated solid was filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-80% toluene / hexane) to obtain the title compound as a colorless oil (370 mg, 87%). 1 H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 4.42 (qd, J = 7.1, 1.3 Hz, 2H), 3.68 (td, J = 6.3, 1.3 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 1.90 - 1.76 (m, 2H), 1.67 - 1.60 (m, 2H), 1.40 (td, J = 7.1, 1.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 175.4, 160.3, 156.5, 101.7, 62.3, 62.2, 31.9, 26.6, 23.9, 14.3.

[0272] Synthesis of ethyl 5-(4-oxobutyl)isoxazole-3-carboxylate (SS-3-98): To a stirred solution of SS-3-86 (150 mg, 0.70 mmol) in DCM (5 mL), pyridinium chlorochromate (300 mg, 1.4 mmol) was added at room temperature. The resulting mixture was stirred at the same temperature for 2 hours. The excess solid was then filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-60% Âxane), yielding the title compound as a colorless oil (130 mg, 88%). 1 H NMR (400 MHz, CDCl3) δ 9.75 (t, J = 1.1 Hz, 1H), 6.40 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H), 2.53 (td, J = 7.1, 1.0 Hz, 2H), 2.11 - 1.94 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 200.91, 174.33, 160.07, 156.47, 101.93, 77.48, 77.16, 76.84, 62.13, 42.60, 25.84, 19.83, 14.15. 13 C NMR (100 MHz, CDCl3) δ 200.9, 174.3, 160.1, 156.5, 101.9, 62.1, 42.6, 25.8, 19.8, 14.1.

[0273] Synthesis of ethyl 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinoline-1(2H)-yl)butyl)isoxazole-3-carboxylate (SS-3-100): NaBH(OAc)3 (262.8 mg, 1.24 mmol) was added to a stirred EtOH / AcOH (5 mL / 0.5 mL) solution of SS-3-98 (130 mg, 0.62 mmol) and 6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (121 mg, 0.62 mmol) at room temperature. The resulting mixture was then stirred overnight at the same temperature. The reaction product was then quenched with saturated NaHCO3 aqueous solution (5 mL) and extracted with DCM (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. Purification of the crude product by flash chromatography (0-20% siRNA / hexane) yielded the title compound as a colorless oil (100 mg, 42%). 1 H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.8, 2.6 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H), 6.41 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.32 - 3.19 (m, 4H), 2.85 (t, J = 7.4 Hz, 2H), 1.80 - 1.64 (m, 6H), 1.41 (t, J = 7.1 Hz, 3H), 1.25 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 175.1, 160.3, 156.5, 142.5, 132.9, 126.6, 126.1, 120.3, 111.7, 101.8, 62.2, 51.3, 45.9, 36.8, 32.3, 30.6 (2C), 26.8, 25.6, 25.3, 14.3.

[0274] Synthesis of 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinoline-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-02): In a round-bottom flask, NaOH (89 mg, 2.2 mmol) was dissolved in 50% aqueous NH2OH (0.9 mL, approximately 50 equivalents) at 0°C. A 1:1 THF / MeOH (4 mL) solution of SS-3-99 (100 mg, 0.28 mmol) was added dropwise, and the mixture was stirred for 30 minutes while increasing the temperature to room temperature. This solution was neutralized with 2N HCl and extracted with ELISA (3 × 10 mL). The organic layer was separated, washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC (Method 2) and freeze-dried to obtain the desired product as an off-white powder (100 mg, 75%, TFA salt). 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.07 (d, J = 2.7 Hz, 1H), 6.94 (dd, J = 8.7, 2.6 Hz, 1H), 6.55 (s, 1H), 6.54 (s, 1H), 3.28 - 3.21 (m, 4H), 2.84 (t, J = 7.3 Hz, 2H), 1.71 - 1.46 (m, 6H), 1.19 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 174.5, 163.0, 157.4, 142.5, 132.5, 126.2, 125.3, 118.4, 111.9, 100.5, 50.2, 44.7, 40.2, 39.9, 39.7, 39.5, 39.3, 39.1, 38.9, 36.0, 31.8, 30.2 (2C), 25.6, 24.6, 24.5.ESI HRMS calculation value C 19 H 24 N3O3Cl:[M+H] + m / z 378.1579; measured value: 378.1566. Example 9 Synthesis of 5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-1-54) [ka]

[0275] Synthesis of 5-(4-bromobutyl)-2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepine (SS-1-49): To a stirred solution of SS-1-36 (300 mg, 1.15 mmol) in DMF (5 mL), NaH (60%, 140 mg, 3.45 mmol) was slowly added. The mixture was stirred at room temperature for 15 minutes, and then 1,6-dibromobutane (364 mg, 1.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 1N aqueous HCl was added to neutralize the pH to 6-7. Next, the reaction solution was extracted three times with SiO2 and water. The combined organic layers were separated, washed with water and brine, dehydrated with Na2SO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography using an HCl / hexane gradient (1-3%) yielded the desired product SS-1-49 as a colorless oil. This product was used directly in the next step.

[0276] Synthesis of 2,8-dichloro-5-(hexa-5-in-1-yl)-10,11-dihydro-5H-dibenzo[b,f]azepine (SS-1-50): To a stirred xylene / DMF (2 / 2 mL) solution of SS-1-49 (200 mg, 0.5 mmol), a sodium acetylide suspension (0.2 mL, 18 wt% slurry in xylene) was added at room temperature under protection with Ar. The mixture was then stirred overnight at 40°C. After the reaction was complete, the reaction solution was extracted three times with siRNA and water. The combined organic layers were separated, washed with water and brine, dehydrated with Na2SO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography using an siRNA / hexane gradient (1-3%) yielded the desired product SS-1-50 as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.09 - 7.07 (m, 4H), 6.97 (d, J = 9.0 Hz, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.10 (s, 4H), 2.14 (td, J = 7.0, 2.6 Hz, 2H), 1.89 (t, J = 2.6 Hz, 1H), 1.67- 1.64 (m, 2H), 1.55 - 1.51 (m, 2H).

[0277] Synthesis of ethyl 5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)butyl)isoxazole-3-carboxylate (SS-1-52): In a microwave reaction tube, SS-1-50 (100 mg, 0.30 mmol) is dissolved in  (3 mL) with NaHCO3 (75 mg, 0.90 mmol) and 2-chloro-2-(hydroxyimino)ethyl acetate (135 mg, 0.90 mmol). The mixture was added. This mixture was heated in a microwave reactor at 100°C for 1 hour. After the reaction was complete, the precipitated solid was filtered, and the filtrate was concentrated under reduced pressure. Purification of the crude product by column chromatography using an siRNA / hexane gradient (1-20%) yielded the desired product SS-1-52 as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.09 - 7.08 (m, 4H), 6.96 - 6.93 (m, 2H), 6.31 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.67 (t, J = 6.6 Hz, 2H), 3.10 (s, 4H), 2.74 (t, J = 7.4 Hz, 2H), 1.76 - 1.59 (m, 4H), 1.41 (t, J (= 7.1 Hz, 3H).

[0278] Synthesis of 5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-1-54): 80 mg of NaOH (2.0 mmol), solid at 0°C, was dissolved in a 50% aqueous solution of NH2OH (0.5 mL). Next, to the vigorously stirred hydroxylamine solution, a solution of SS-1-52 (100 mg, 0.20 mmol) in 1:1 THF / MeOH (2 / 2 mL) was added dropwise at 0°C for 30 minutes. After the reaction was complete, 1N HCl aqueous solution was added to neutralize the pH to 6-7. Next, this mixture was extracted three times with ELISA and water. The combined organic layers were separated, washed with water and brine, dehydrated with Na2SO4, and concentrated under reduced pressure. Purification of the crude product by preparative HPLC using a MeOH(0.05%TFA) / H2O(0.05%TFA) gradient (5-100%, Method 2) yielded the desired product SS-1-54 as a white powder. 1 H NMR (400 MHz, CDCl3) δ 7.09 - 7.07 (m, 4H), 6.95 - 6.92 (m, 2H), 6.37 (s, 1H), 3.66 (t, J = 6.5 Hz, 2H), 3.09 (s, 4H), 2.72 (t, J = 7.4 Hz, 2H), 1.76 - 1.68 (m, 2H), 1.63 - 1.57 (m, 2H);ESI HRMS calculated value C 22 H 22 Cl2N3O3:[M+H] +m / z446 .1033; Measured value: 446.1020. Example 10 HDAC isoform inhibition

[0279] Compound ICs of Examples 1-9 for HDAC1 and HDAC6 50 The values ​​were determined as follows:

[0280] Assays for HDAC1, 2, 4, 5, 6, 7, 8, 9, 10, and 11 used isolated recombinant human proteins. The HDAC3 / NcoR2 complex was used in the HDAC3 assay. The substrate for the HDAC1, 2, 3, 6, 10, and 11 assays is a fluorescent peptide derived from p53 residues 379-382 (RHKKAc). The substrate for HDAC8 is a fluorescent diacyl peptide based on p53 residues 379-382 (RHKAcKAc). Acetyl-Lys(trifluoroacetyl)-AMC substrates were used in the HDAC4, 5, 7, and 9 assays. The compounds were dissolved in DMSO and tested in IC50 mode at 10 doses in 3-fold serial dilutions starting at 30 μM. The control compound, trichostatin A (TSA), was tested in IC50 mode at 10 doses in 3-fold serial dilutions starting at 5 μM. 50 The values ​​were extracted by fitting a curve to the dose / response slope. The assay was performed in a double series, and IC50 was obtained. 50 The value is the average of the data from both experiments. material

[0281] Human HDAC1 (GenBank accession number NM_004964): Full-length (MW=79.9kDa) with a C-terminal GST tag, expressed in a baculovirus expression system in Sf9 cells. The enzyme is stable for >6 months at -80°C in 50mM Tris-HCl, pH 8.0, 138mM NaCl, 20mM glutathione, and 10% glycerol. Purity is >10% by SDS-PAGE. Specific activity is measured at 25mM Tris / Cl, pH 8.0, 137mM NaCl, 2.7mM KCl, and 1mM Under assay conditions consisting of MgCl2, 0.1 mg / ml BSA, 100 μM HDAC substrate, and 13.2 ng / μl HDACI, incubated at 30°C for 30 minutes, the concentration is 20 U / μg (1 U = 1 pmol / min).

[0282] Human HDAC6 (GenBank accession number BC069243): Full-length (MW=159kDa) with an N-terminal GST tag, expressed by a baculovirus expression system in Sf9 cells. The enzyme is stable for >6 months at -80°C in 50mM Tris-HCl, pH 8.0, 138mM NaCl, 20mM glutathione, and 10% glycerol. Purity is >90% by SDS-PAGE. Specific activity is 50 U / μg (1 U = 1 pmol / min) under assay conditions of 25mM Tris / Cl, pH 8.0, 137mM NaCl, 2.7mM KCl, 1mM MgCl2, and 0.1 mg / ml BSA, 30 μM HDAC substrate, and 5 ng / μl HDAC6, incubated at 30°C for 60 minutes.

[0283] Based on residues 379-382 of p53 (Arg-His-Lys-Lys(Ac)), which are the sites of regulatory acetylation by p300 and CBP acetyltransferase (lysine 381, 382) 1-6, the acetylated peptide substrates for HDACs are best suited to HDACs within a panel of substrates patterned on the histone H3 and histone H4 acetylation sites of p53.

[0284] References: W. Gu et al., Cell (1997) Vol. 90, p. 595; K. Sakaguchi et al., Genes Dev., (1998) vol. 12, p. 2831; L. Liu et al., Mal. Cell. Biol., (19 (1999) Vol. 19, p. 1202; A. Ito et al., EMBO J., (2001) Vol. 20, p. 1331 Page;NA Barlev et al., Mal. Cell, (2001) Vol. 8, p. 1243; and A. Ito et al. , EMBO J., (2002) Volume 21, Page 6236.

[0285] Reaction buffer: 50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 1 mg / ml BSA. Assay conditions

[0286] HDAC1: Prepare a reaction buffer containing 75 nM HDAC1 and 50 μM HDAC substrate, with 1% DMSO as the final dressing. Incubate at 30°C for 2 hours. HDAC6: Prepare a reaction buffer containing 12.6 nM HDAC6 and 50 μM HDAC substrate, with 1% DMSO as the final dressing. Incubate at 30°C for 2 hours. I C 50 Calculation

[0287] I C 50 All values ​​are automatically calculated using GraphPad Prism version 5 and the S-shaped dose-response (variable slope) formula: Y = bottom + (top - bottom) / (1 + 10^((LogEC50 - X)*HillSlope)) (where X is the logarithm of the concentration, Y is the response, and Y starts from the bottom and goes to the top which has an S-shaped form). In most cases, "bottom" is set to 0 and "top" is set to "less than 120%". This is the same as the four-parameter logistic equation. 50 Curves are also in GraphPad Lines were drawn using Prism. These results are shown in Table 1B. [Table 1B-1] [Table 1B-2] Example 11 Screening of SS-2-08

[0288] Table 2 shows the activity of SS-2-08 in several preclinical screening assays. SS-2-08 lacks Ames activity and exhibits good efficacy against HDAC6, as well as selectivity for HDAC1 and HDAC11. The possible mutagenicity of this compound was investigated by incubating SS-2-08 with two strains of Salmonella typhimurium (TA98 and TA1537) in the presence and absence of mammalian microsomal enzymes (S9 mix). No significant number of revertant mutant colonies were observed for either strain, thus supporting the absence of mutagenicity of SS-2-08 under the conditions of the mini-Ames assay. SS-2-08 exhibits IC50 >30 μM against hERG. 50 It holds. [Table 2] Example 12 cell culture

[0289] Mouse neuroblastoma (N2a) cells were grown at 37°C and 7.5% CO2 in a 1:1 mixture of DMEM (Dulbecco's Modified Eagle Medium) and F12 medium, supplemented with glutamax (Invitrogen), 100 μg / mL streptomycin, 100 U / mL penicillin (Invitrogen), 10% fetal bovine serum (Greiner Bio-one), 1% non-essential amino acids (Invitrogen), and 1.6% NaHCO3 (Invitrogen). To divide the cells, they were washed with Versene (Invitrogen) and dissociated with 0.05% trypsin-EDTA (Invitrogen). DRG neurons were cultured from 12-month-old adult Thy1.2-HSPB1 S135F mice. DRG neurons were excised from the spinal cord and maintained in cold HBSS (MgCl2 and CaCl2-free; Invitrogen). To extract DRG neurons, excised tissue was incubated with collagenase D (1 mg / mL) at 37°C for 45 minutes, and then incubated with 0.05% trypsin-EDTA (Invitrogen) at 37°C for 30 minutes. This cell suspension was washed with DRG PREP medium containing DMEM:F12 medium supplemented with 10% fetal bovine serum (Greiner-Bio), 1% non-essential amino acids (Invitrogen), 0.14% sodium bicarbonate (Invitrogen), and 200 nM L-glutamine (Invitrogen). DRG neurons were seeded on coverslips coated with poly-L-ornithine- (Sigma-Aldrich) and laminin- (Sigma-Aldrich), and then treated with 4 mM L-glutamax (Invitrogen). N2a cells and DRG neurons were grown in a 1:1 mixture of DMEM and F12 medium supplemented with 10% fetal bovine serum (GreinerBio), 50 μg / mL streptomycin, 50 U / mL penicillin (Invitrogen), 0.045% NaHCO3 (Invitrogen), and 1.6 μg nerve growth factor (Millipore). N2a cells and DRG neurons were treated overnight at 37°C with a dosage ranging from 10 nM to 1 μM of the compound, or an equal dose of DMSO (Sigma-Aldrich). Western blot analysis

[0290] Treated cells were washed with phosphate-buffered saline (PBS) and collected using the EpiQuik Total Histone Extraction Kit (EpiGentek) according to the manufacturer's instructions. Tissue was excised from mice and snap-frozen in liquid nitrogen. Tissue dissociation was performed using a tube containing LysisMatrix D beads. Protein concentration was determined using the microBCA kit (Thermo Fisher Scientific Inc., Pittsburgh, PA, USA) according to the manufacturer's instructions. Before separating the samples on a 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel, samples containing equal volumes of protein were supplemented with reducing sample buffer (Thermo Scientific) and heated at 95°C for 5 minutes. After electrophoresis, the proteins were transferred to a polyvinylidene difluoride (PVDF) membrane (Millipore Corp., Bedford, MA, USA). Nonspecific binding was blocked by incubating the membrane for 1 hour at room temperature in 5% bovine serum albumin (BSA) diluted in Tris-buffered saline Tween (TBST), 50 mM TRIS, 150 mM NaCl, and 0.1% Tween-20 (Applichem, Darmstadt, Germany), followed by overnight incubation with the primary antibody. The antibodies (diluted in TBS-T) were targeted to α-tubulin (1 / 5000, T6199, Sigma-Aldrich), acetylated α-tubulin (1 / 5000, T6793 monoclonal, Sigma-Aldrich), histone H3 acetyl k9+k14 (1 / 1000, 9677L, Cell Signaling), and histone 4 (1 / 1000, ab10158, Abcam). The signal from the primary antibody was detected using a secondary antibody conjugated to alkaline phosphatase (anti-mouse or anti-rabbit, 1 / 5000, Sigma-Aldrich). The blot was prepared using an ECF substrate (Enhanced Chemical Fluorescence, GE). The data was visualized by adding (Healthcare, Uppsala, Sweden) and imaged with ImageQuant LAS4000. The blot was stripped using a mild reblotting buffer (Millipore). The blot was quantified using ImageQuant TL version 7.0 software. See Figure 18. Example 13 cell culture

[0291] Human melanoma cells WM164 were cultured in RPMI1640 medium supplemented with 10% FBS, penicillin / streptomycin (50 U / ml), L-glutamine (2 mM), and 2-mercaptoethanol (50 μM) (complete medium), and grown under humidified conditions at 37°C and 5% CO2. Imbubrot

[0292] Cells were lysed in a buffer containing 280 mM NaCl, 50 mM Tris HCl PH8.0, 0.5% Igepal, 5 mM MgCl2, 10% glycerol, and a 1X protease inhibitor (Roche) and a phosphatase inhibitor (Santa Cruz Biotechnology). The lysates were ultrasonically irradiated on ice for 8 minutes (2 cycles of 30 seconds each, followed by a 30-second rest), then mixed with 6× gel loading buffer and incubated for 5 minutes. The samples were boiled. Next, the samples were separated onto 10% or 4-15% gradient gels and transferred to nitrocellulose membranes. The membranes were blocked with 5% milk-PBS-Tween. Bands were detected by scanning the blots using the LI-COR Odyssey imaging system with both 700 and 800 channels. Antibodies used for immunoblotting included anti-acetyl-α-tubulin (SC-23950) and anti-α-tubulin (SC-32293), purchased from Santa Cruz Biotechnology. Anti-HDAC6 (C0226) was from Assay Biotech. Anti-GAPDH (68795) was from Sigma Aldrich. Anti-STAT3 (12640), anti-P-STAT3 Y-705 (9138), anti-P-STAT3 S727 (9136) and anti-Acetil-STAT3 (2523) were purchased from Cell Signaling. Anti-PD-L1 (PA5-28115) was obtained from Thermo Scientific. Anti-FLAG (F1804) antibody was manufactured by Sigma.

[0293] Human melanoma WM164 cells were treated with various concentrations of SS-01-100 and SS-02-08 in the presence or absence of IL-6 (30 ng / uL) or IFNg (100 ng / uL). Levels of acetylated tubulin, a natural substrate of HDAC6, increased under all tested conditions. See Figures 1-3. Example 14 cell culture

[0294] All cells were cultured in RPMI1640 medium supplemented with 10% FBS, penicillin / streptomycin (50 U / ml), L-glutamine (2 mM), and 2-mercaptoethanol (50 □ M) (complete medium), and grown under humidified conditions at 37°C and 5% CO2. Cytotoxicity assay

[0295] Cells were plate-cultured at the desired density in a black, transparent, flat-bottomed 96-well plate. After 24 hours of cell growth, the medium was removed from all wells, and fresh medium was added along with the fluorescent CellTox dye using the manufacturing protocol. The plate was then treated with the target compound at various concentrations. A baseline reading was taken immediately after plate culture. The plate was then incubated for 24 hours, after which another reading was taken and considered as the 24-hour reading. SoftMax Pro Microplate paired with Molecular Devices SpectraMax spectrophotometer. Assay measurements were collected using data acquisition and analysis software. HDAC assay

[0296] Cells were plate-cultured overnight in white, transparent, flat-bottomed 96-well plates at a density of 10,000 cells / well. Next, after 24 hours, these plates were treated with the target compound at the desired concentration and incubated at 37°C and 5% CO2 for 1 hour. After incubation with the compound, the developer was added to the substrate and mixed according to the manufacturing protocol, and then added directly to the plates. 6 Using SpectraMax, plates were read for 1 hour and 15 minutes immediately after plate culture, with readings taken every 2 minutes.

[0297] Human melanoma WM164 cells were treated with various concentrations of SS-2-08 and SS-01-100, and HDAC activity related to the potential cytotoxic effects of these compounds was evaluated. As shown in Figures 4–7, both compounds dose-dependently reduced HDAC activity in these cells while maintaining minimal cytotoxicity.

[0298] Following the same experimental procedure, the HDAC activity inhibition and cytotoxicity of SS-2-08 were evaluated in human cell lines (HCT116, H1299, H2122) and mice (4T1, FARN, LLC, GL261, B16). In all tested cell lines, SS-2-08 reduced HDAC activity. See Figure 9. Furthermore, the cytotoxicity of SS-2-08 was minimal, down to 10 μM. See Figure 9.

[0299] In several cell lines, the cytotoxicity and HDAC activity inhibition of SS-2-08 were compared with the known HDAC6 inhibitors, nextulastat A and tuberstatin A. See Figures 10-13. Example 15 cell culture

[0300] Mouse melanoma SM1 cells were cultured in RPMI1640 medium supplemented with 1% minimal essential medium (MEM) non-essential amino acid solution, 10% fetal bovine serum (FBS), and 1% penicillin-streptomycin (P / S), and then grown under humidified conditions at 37°C and 5% CO2. ApoTox-Glo Triplex Assay (registered trademark) control

[0301] The assay controls, digitonin (D141-100MG), ionomycin (I064-1MG), and mitomycin C (M4287-2MG), were purchased from Sigma. Optimal control concentrations of HDACi were selected for each compound plate (30 μg / mL digitonin, 100 μM ionomycin, and 25 μg / mL mitomycin) by evaluating the control plate cultures. ApoTox-Glo Triplex Assay (registered trademark)

[0302] Mouse melanoma cells were treated with individual HDACi along with the protocol-recommended assay control. Viability / toxicity reagents were added according to the manufacturer's protocol. Fluorescence was measured at two wavelengths: 400 Ex / 505 Em (viability) and 485 Ex / 520 Em (cytotoxicity). Caspase 3 / 7 reagent was then added, and after incubation, luminescence was measured with Lm578 (apoptosis). Assay measurements were collected using SpectraMax. LBH was used as a control compound during analysis.

[0303] SS-2-08 does not induce apoptosis in melanoma cells. Apoptosis, viability, and cytotoxicity were evaluated against the known HDAC6 inhibitors nextulastat A and tubastatin A, and the pan-HDAC inhibitor LBH589. See Figures 14-16. Example 16 Design Study

[0304] All animal experiments, including those involving mice, were conducted in accordance with protocols approved by the IACUC at George Washington University. C57 / BL / 6 mice were obtained from Charles River (Massachusetts-Wilmington, USA). Mice for in vivo tumor studies were suspended in 100 μL of 1× phosphate-buffered saline (PBS) and given 1.0×10⁶ cells. 6Individual SM1 melanoma cells were subcutaneously injected into the right flank. After subcutaneous injection, tumor growth was monitored until the tumor was easily palpable. Once palpable (diameter 5-8 mm), the animals were then treated intraperitoneally with SS-2-08 at doses of 25 mg / kg and 50 mg / kg three times a week, either as a vehicle control or as a whole. Tumor growth was recorded twice a week. The tumor reached 4000 mm. 3 When this was reached, the mice were euthanized. The collected values ​​were compared to the average tumor volume (mm²) of the treatment group. 3 It is expressed as the coefficient of gravity and the standard deviation.

[0305] As shown in Figure 17, SS-2-08 reduced tumor growth in SM1 melanoma tumors in syngeneic mice.

[0306] All patents and publications cited herein are incorporated in their entirety by reference.

[0307] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds having formula I: [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the formula, X is [ka] Selected from the group consisting of, R 1 is hydrogen and C 1~4 Selected from the group consisting of alkyl groups, R 2 C6~C are substituted as needed. 14 Selected from the group consisting of aryl and aralkyl, R 3 C6~C are substituted as needed. 14 Aryls, 5- to 14-membered heteroaryls and -C(=O)NRs as needed. d Re Selected from the group consisting of, R 4a , R 4b , R 4e and R 4f These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, R 4c and R 4d is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R 4c and R 4d These, together with the carbon atoms to which they are bonded, form -C(=O)-, R 5a , R 5b , R 5c and R 5d These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, Z is -O-, -N(R 8 Selected from the group consisting of )- and -C(=O)-, Z does not exist. R 8 is hydrogen, C 1~4 Alkyl, substituted C as needed 3~6Cycloalkyl, C6-C as needed. 14 Selected from the group consisting of aryls, aralkyls, and 5-14 member heteroaryls and heteroaralkyls which are substituted as needed, m is 0, 1, or 2. n is 1, 2, 3, 4, 5, or 6. [ka] This represents a single bond or a double bond. R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, substituted C as needed 3~6 Cycloalkyl, C6-C as needed. 14 They are independently selected from the group consisting of aryls and 5- to 14-membered heteroaryls which are substituted as needed, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 12-membered heterocyclone which is substituted as needed, or R d and R e These, together with the nitrogen atoms to which they are bonded, form 3- to 12-membered heterocycloids, which are substituted as needed. R c C 1~4 It is alkyl, however, If Z does not exist, R 3 This is a biring or triring C 10~14 Aryls, 9-14 member bicyclic or tricyclic heteroaryls, or -C(=O)NR d R e The condition is that A compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof. (Section 2) A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is X-1. (Section 3) R 2 However, the compounds described in item 1 or 2 above, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, are phenyl which is substituted as necessary. (Section 4) R 2 The compounds described in item 1 or 2 above, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein 1-naphthyl is substituted as necessary. (Section 5) R 2 The compounds described in item 1 or 2 above, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein 2-naphthyl is substituted as necessary. (Section 6) A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is X-2. (Section 7) A compound described in item 6 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Z is -O-. (Section 8) The compound described in item 1 above, or a pharmaceutically acceptable salt thereof, where X is X-3, solvated A substance or prodrug. (Section 9) A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is X-4. (Section 10) A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is X-5. (Section 11) Formula II: [ka] A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having, R 6a , R 6b , R 6c , R 6d and R 6eThese are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~6 Each is independently selected from the group consisting of cycloalkyls, optionally substituted phenyls, optionally substituted 5- or 6-membered heteroaryls, and optionally substituted 5- or 6-membered heterocyclos. R a and R b is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocyclo. R c C 1~4 It is alkyl, n is 1, 2, or 3. A compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof. (Section 12) R 6a , R 6b , R 6c , R 6d and R 6e However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 Compounds described in item 11 above, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each independently selected from the group consisting of haloalkyls. (Section 13) R 6a , R 6b , R 6c , R 6d and R 6e However, hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 A compound described in item 12 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, independently selected from the group consisting of alkoxys. (Item 14) Formula III: [ka] A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having, R 7a , R 7b , R 7c , R 7d and R 7e These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, and substituted C as needed. 3~6 Each is independently selected from the group consisting of cycloalkyls, optionally substituted phenyls, optionally substituted 5- or 6-membered heteroaryls, and optionally substituted 5- or 6-membered heterocyclos. R a and R b is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocyclo. Rc C 1~4 It is alkyl, n is 1, 2, or 3. A compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof. (Section 15) R 7a , R 7b , R 7c , R 7d and R 7e However, hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 Compounds described in item 14 above, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, each independently selected from the group consisting of haloalkyls. (Section 16) R 7a , R 7b , R 7c , R 7d and R 7e However, hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 A compound described in item 15 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, independently selected from the group consisting of alkoxys. (Item 17) Formula IV: [ka] A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having, R 4a And R4b is independently selected from the group consisting of hydrogen, halogen, cyano, C1-4 alkyl and C1-4 alkoxy, R4c and R4d are independently selected from the group consisting of hydrogen and methyl. m is either 0 or 1. n is 1, 2, or 3. [ka] This represents a single bond or a double bond. A compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof. (Section 18) m is 0, [ka] However, the compounds described in item 17 above, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, that represent a double bond. (Section 19) m is 1, [ka] However, the compounds described in item 17 above, or pharmaceutically acceptable salts, solvates, or prodrugs thereof that represent a single bond. (Section 20) Formula V: [ka] A compound described in item 1 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having, R 5a and R 5c These are hydrogen, halogen, cyano, and C 1~4 Alkyl and C 1~4 Independently selected from the group consisting of alkoxys, n is 1, 2, or 3. A compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof. (Section 21) A compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof as described in any one of items 1 to 20 above, wherein n is 1 or 2. (Section 22) 5-(2-benzamidoethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3,4-dichlorobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(2-naphthamidoethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-([1,1'-biphenyl]-3-carboxamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(5,6-dichloro-1H-indole-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(6-chloro-3,4-dihydroquinoline-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinoline-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(3,4-dichlorophenoxy)propyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]a Zepine-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-bromobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-fluorobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-chlorobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-methoxybenzamide)ethyl)isoxazole-3-carboxamide; 5-(2-(4-(dimethylamino)benzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-cyclopropylbenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3,4-difluorobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3-chloro-4-fluorobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-chloro-3-fluorobenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3-(dimethylamino)benzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(3-(pyridine-3-yl)benzamide)ethyl)isoxazole-3-carboxamide; 5-(3-benzamidopropyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-(trifluoromethoxy)benzamide)ethyl)isoxazole-3-carboxamide; 5-(2-(4,5-dichloroindoline-1-carboxamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((6,7-dichloroisoquinoline-3-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(5,6-dichloro-1H-benzo[d]imidazole-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((5,6-dichloro-1-methyl-1H-benzo[d]imidazole-2-yl)oxy)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-((trifluoromethyl)thio)benzamide)ethyl)isoxazole-3-carboxamide; 5-(4-(4,5-dichloroindoline-1-yl)-4-oxobutyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((6,7-dichloroquinoline-2-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(5,6-dichlorobenzo[d]thiazole-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(5,6-dichlorobenzo[d]oxazole-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-(trifluoromethyl)benzamide)ethyl)isoxazole-3-carboxamide; 2-(3-(hydroxycarbamoyl)isoxazole-5-yl)ethyl 4,5-dichloroindoline-1-carboxylate; 5-(2-((6,7-dichloronaphthalene-2-yl)aminoethyl)-N-Hyd Roxyisoxazole-3-carboxamide; 5-(2-((5,6-dichlorobenzo[d]thiazole-2-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(phenanthridine-6-ylamino)ethyl)isoxazole-3-carboxamide; 5-(2-(2-(3,4-dichlorophenyl)acetamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(6,7-dichloro-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((5,6-dichloroisoquinoline-1-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(2-phenylacetamido)ethyl)isoxazole-3-carboxamide; 2-(3-(hydroxycarbamoyl)isoxazole-5-yl)ethyl(3,4-dichlorophenyl)(methyl)carbamate; 5-(2-((5,6-dichloroisoquinoline-1-yl)oxy)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(N-butylbenzamide)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-((3,4-dichlorophenyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-((3,4-dichlorophenyl)amino)propyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(3-(naphthalene-1-ylamino)propyl)isoxazole-3-carboxamide; N-hydroxy-5-(3-(quinoline-8-ylamino)propyl)isoxazole-3-carboxamide; 5-(4-(8-chloro-2-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-((4-chlorophenyl)(cyclohexyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(bis(4-chlorophenyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-((4-chlorobenzyl)(4-chlorophenyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(3-(naphthalene-1-yloxy)propyl)isoxazole-3-carboxamide; and N-hydroxy-5-(3-(quinoline-8-yloxy)propyl)isoxazole-3-carboxamide A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as described in item 1 above. (Section 23) A composition comprising a compound described in any one of items 1 to 22 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient and / or carrier. (Section 24) (a) A compound described in any one of paragraphs 1 to 22 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, (b) A second useful in treating a disease or condition in which inhibition of HDACs would be beneficial. Therapeutic agents, and (c) Excipients and / or pharmaceutically acceptable carriers as needed A composition containing the following: (Section 25) The composition according to item 24, wherein the second therapeutic agent comprises a chemotherapeutic agent useful for treating cancer. (Section 26) A method for treating a disease or condition in which inhibition of an HDAC is beneficial, the method comprising the step of administering to an individual in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof described in any one of the above items 1 to 22. (Section 27) The method according to item 26 above, wherein the HDAC is HDAC6. (Section 28) The method according to item 26, further comprising the step of administering a therapeutically effective amount of a second therapeutic agent useful for treating the aforementioned disease or condition. (Section 29) The method according to item 28, wherein a compound described in any one of items 1 to 22 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and the second therapeutic agent are administered simultaneously. (Section 30) The method according to item 28, wherein a compound described in any one of items 1 to 22 above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and the second therapeutic agent are administered separately. (Section 31) The method according to item 26 above, wherein the disease or condition is cancer. (Section 32) The method according to item 28, wherein the disease is cancer, and the second therapeutic agent is one or more of a chemotherapeutic agent, radiotherapy, and immunotherapy. (Section 33) The method according to item 28, wherein the second therapeutic agent comprises radiation, and the radiation is administered together with a radiosensitizer and / or therapeutic agent, if necessary. (Section 34) The method according to item 26 above, wherein the disease or condition is a neurological disorder, neurodegenerative disorder, peripheral neuropathy, psychiatric disorder, or traumatic brain injury. (Section 35) The method according to item 26 above, wherein the disease or condition is a stroke. (Section 36) The method according to item 26 above, wherein the disease or condition is an inflammatory or autoimmune disease. (Section 37) The method according to item 26 above, wherein the disease or condition is Charcot-Marie-Tooth disease. (Section 38) The method according to item 36, further comprising the step of administering a therapeutically effective amount of a second therapeutic agent useful for treating the autoimmune disease or inflammation. (Section 39) The method according to paragraph 26 above, wherein the disease or condition is autism or an autism spectrum disorder, including Rett syndrome. (Section 40) The method according to paragraph 26 above, wherein the disease or condition is depression or bipolar disorder. (Section 41) A method for increasing the sensitivity of cancer cells to the cytotoxic effects of radiotherapy and / or chemotherapy, the method comprising the step of contacting the cells with a compound or pharmaceutically acceptable salt, solvate, or prodrug described in any one of the above items 1 to 22 in an amount sufficient to increase the sensitivity of the cells to the radiotherapy and / or chemotherapy. (Section 42) The method according to item 41 above, wherein the cells are in vivo cells. (Section 43) A method for inducing immunosuppression, the method comprising the step of administering to an individual in need thereof an effective amount of a compound described in any one of the above items 1 to 22 or a pharmaceutically acceptable salt, solvate, or prodrug thereof. (Section 44) The compound is a fluorescent dye, 3 H, 11 C, 18 F, 123 I, 125 I and 131 A compound according to any one of the above items 1 to 22, labeled with a radioactive isotope, molecular tag, or mixture thereof selected from I. (Section 45) The aforementioned sign is C 11 A compound according to item 44 above, comprising a methyl group. (Section 46) A method for radiographic imaging, wherein the method includes the step of bringing cells or tissue into contact with a radiolabeled compound as described in item 44 above. (Section 47) The method according to item 46, further comprising the step of preparing a radiographic image of the cells or tissues that have been in contact. (Section 48) Compounds having formula VI: [ka] And in the formula, X is [ka] Selected from the group consisting of, R 1 is hydrogen and C 1~4 Selected from the group consisting of alkyl groups, R 2 C6~C are substituted as needed. 14 Selected from the group consisting of aryl and aralkyl, R 3 C6~C are substituted as needed. 14Aryls, 5- to 14-membered heteroaryls and -C(=O)NRs as needed. d R e Selected from the group consisting of, R 4a , R 4b , R 4e and R 4f These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, R 4c and R 4d is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, or R 4c and R 4d These, together with the carbon atoms to which they are bonded, form -C(=O)-, R 5a , R 5b , R 5c and R 5d These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR a R b -C(=O)NR a R b -C(=O)R c , C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Independently selected from the group consisting of haloalkyl and haloalkoxy, Z is -O-, -N(R 8 Selected from the group consisting of )- and -C(=O)-, Z does not exist. R 8 is hydrogen, C 1~4Alkyl, substituted C as needed 3~6 Cycloalkyl, C6-C as needed. 14 Selected from the group consisting of aryls, aralkyls, and 5-14 member heteroaryls and heteroaralkyls which are substituted as needed, R 9 C 1~4 It is alkyl, m is 0, 1, or 2. n is 1, 2, 3, 4, 5, or 6. [ka] This represents a single bond or a double bond. R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, substituted C as needed 3~6 Cycloalkyl, C6-C as needed. 14 They are independently selected from the group consisting of aryls and 5- to 14-membered heteroaryls which are substituted as needed, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 3- to 12-membered heterocyclone which is substituted as needed, or R d and R e These, together with the nitrogen atoms to which they are bonded, form 3- to 12-membered heterocycloids, which are substituted as needed. R c C 1~4 It is alkyl, However, if Z does not exist, R 3 This is a biring or triring C 10~14 Aryls, 9-14 member bicyclic or tricyclic heteroaryls, or -C(=O)NR d R e The condition is that compound. (Section 49) The compound according to item 49 above, wherein X is X-1. (Item 50) R 2 is phenyl optionally substituted, the compound according to item 48 or 49 above . (Item 51) R 2 is 1-naphthyl optionally substituted, the compound according to item 48 or 49 above. (Item 52) R 2 is 2-naphthyl optionally substituted, the compound according to item 48 or 49 above. (Item 53) The compound according to item 48 above, wherein X is X-2. (Item 54) The compound according to item 48 or 53 above, wherein Z is -O-. (Item 55) The compound according to item 48 above, wherein X is X-3. (Item 56) The compound according to item 48 above, wherein X is X-4. (Item 57) The compound according to item 48 above, wherein X is X-5. (Item 58) Formula VII:

Chemical Formula

Claims

1. A composition for treating a clinical condition selected from the group consisting of neurological disorders, psychiatric disorders, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammatory diseases, traumatic brain injury, rheumatoid arthritis, allograft rejection, hematopoietic disorders, microbial infections, and autoimmune diseases, comprising a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is of formula: 【Chemistry 1】 It is, and here: R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , and R ６ｅ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, -NR ａ R ｂ , -C(=O)NR ａ R ｂ , -C(=O)R ｃ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, C １～６ haloalkyl, haloalkoxy, optionally substituted C ３～６ cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, and optionally substituted 5- or 6-membered heterocyclo, R ａ and R ｂ is hydrogen and C １～４ Independently selected from the group consisting of alkyls, or R ａ and R ｂ These, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocyclo. R ｃ C １～４ It is alkyl, and n is 1, 2, or 3. composition.

2. R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , and R ６ｅ Each of these is hydrogen, halogen, hydroxyl, nitro, cyano, -NR ａ R ｂ , -C(=O)NR ａ R ｂ , -C(=O)R ｃ , C １～４ Alkyl, C １～４ Alkoxy, and C １～４ The composition according to claim 1, independently selected from the group consisting of haloalkyls.

3. R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , and R ６ｅ However, hydrogen, halogen, cyano, C １～４ Alkyl and C １～４ A composition according to any one of claims 1 to 2, each independently selected from the group consisting of alkoxys.

4. The composition according to any one of claims 1 to 3, wherein the inflammatory disease includes osteoarthritis, rheumatoid arthritis, or colitis.

5. The composition according to any one of claims 1 to 3, wherein the hematopoietic disorder includes anemia, sickle cell disease, or thalassemia.

6. The composition according to any one of claims 1 to 3, wherein the microbial infection includes a fungal infection, a protozoan infection, a bacterial infection, or a viral infection.

7. The composition according to any one of claims 1 to 3, wherein the autoimmune disease includes multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergy, asthma, allergic rhinitis, or inflammatory bowel disease.

8. A composition for selectively inhibiting HDAC in a target, wherein the composition comprises the formula: 【Chemistry 13】 This includes compounds of or pharmaceutically acceptable salts or solvates thereof, where: R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , and R ６ｅ These are hydrogen, halogen, hydroxyl, nitro, cyano, -NR ａ R ｂ , -C(=O)NR ａ R ｂ , -C(=O)R ｃ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, C １～６ Haloalkyl, haloalkoxy, and optionally substituted C ３～６ Each is independently selected from the group consisting of cycloalkyls, optionally substituted phenyls, optionally substituted five- or six-membered heteroaryls, and optionally substituted five- or six-membered heterocyclos. R ａ and R ｂ is hydrogen and C １～４ Independently selected from the group consisting of alkyls, or R ａ and R ｂ These, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocyclo. R ｃ C １～４ It is alkyl, and n is 1, 2, or 3. Here, the compound selectively inhibits HDAC6 more than other HDAC isozymes. composition.

9. R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , and R ６ｅ The composition according to claim 8, wherein each of is independently selected from the group consisting of hydrogen or halogen.

10. R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , and R ６ｅ The composition according to any one of claims 8 to 9, wherein each is independently selected from the group consisting of hydrogen or chlorine.

11. The composition according to any one of claims 8 to 10, wherein the compound has higher selectivity for HDAC6 compared to HDAC1.

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