Isoxazole hydroxamic acids as histone deacetylase 6 inhibitors

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] Government Rights Statement This invention was made with government support under Grant No. 5R01NS079183 awarded by the National Institutes of Health. The United States Government has certain rights in this invention.

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

[0003] 2. Background of the Invention Covalent post-translational modifications (PTMs) of epigenomic proteins contribute to the biological roles of those proteins and act as carriers of epigenetic information from one cell generation to the next. Epigenetics means on top or above genetics and refers to external modifications to DNA and associated histones that turn genes "on" or "off." These modifications do not change the DNA sequence, but instead, these modifications affect how the cell "reads" genes. PTMs play important roles in regulating protein function, transcription, DNA replication, and repair of DNA damage.

[0004] The main events surrounding epigenetic regulation are centered around three modes of action: writers, readers and erasers. Writers are responsible for imparting various PTM marks to histones, including, among others, acetylation catalyzed by histone acetyltransferases (HATs). Readers refer to proteins that recognize and bind these PTM marks, thus mediating their action, and erasers encompass various enzymes such as histone deacetylases (HDACs) that catalyze the removal of these marks. In the case of acetylated histone lysine residues, HDACs are responsible for catalyzing the hydrolysis of the acetyl mark to give 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. HDACs 1, 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 show tissue-specific expression and shuttling between the nucleus and the cytoplasm. These enzymes, which are homologous to yeast Hda1, are subdivided into class IIa (HDACs 4, 5, 7, and 9) and class IIb (HDACs 6 and 10). HDAC11, the only member of the class IV subfamily, shows similarity to the catalytic domains of both class I and class II enzymes. Class I, II, and IV HDACs require Zn as a cofactor for deacetylase activity. 2+ Sirtuins 1 to 7 are also called conventional HDACs, and their activity depends on nicotinamide adenine dinucleotide and they form class III HDACs.

[0005] Pharmacological manipulation of enzymes involved in the regulation of protein PTMs, especially those that bind to highly specific PTM signatures, holds great promise in better understanding how cells work. The discovery of selective small molecule modulators of these enzymes is likely to provide chemical tools to better understand the role of these PTMs at the cellular level, but may also lead to important disease modifiers. In the field of HDACs, blocking deacetylase enzymes has There are numerous compounds that inhibit HDACs, and several have made their way to the market for the treatment of cancer. However, the majority of these HDACIs are not very isoform selective. Many of the HDACIs inhibit more than one whole class of HDAC enzymes, and are therefore classified as pan-selective. Among the various HDAC isoforms that appear to be promising therapeutic targets for treating human diseases such as cancer and certain CNS disorders, HDAC6 has emerged as a particularly attractive target, especially in light of the fact that HDAC6 knockout animals remain viable. HDAC6 does not have an obvious role in the PTM of histone proteins, but rather is involved in regulating the acetylation state of α-tubulin, HSP-90, cortactin, HSF-1, and other protein targets. This enzyme also plays a role in the recognition and clearance of misfolded polyubiquitinated proteins from cells to aggresome formation. HDACs are disclosed in WO2017 / 040564. There is a continuing need for new agents, e.g., small molecules, for treating and / or preventing cancer and other diseases that respond to the inhibition of HDACs. [Prior art documents] [Patent documents]

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

[0007] Summary of the Invention In one aspect, the present disclosure provides compounds having any one of the following formulas I-V, collectively referred to as "compounds of the present disclosure", as well as pharma- ceutically acceptable salts, solvates, such as hydrates, and prodrugs thereof. The compounds of the present disclosure are histone deacetylase inhibitors.

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

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

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

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

[0012] In another aspect, the disclosure provides for the use of the compounds of the disclosure in combination with other drugs and / or therapeutic procedures.

[0013] In another aspect, the disclosure provides compounds of the disclosure that exhibit selectivity for a particular HDAC isozyme, such as HDAC6, over other HDAC isozymes.

[0014] In another aspect, the disclosure provides a compound of the disclosure for use in treating a disease or condition of interest, such as cancer, a neurological disease, a psychiatric illness, a neurodegenerative disorder, a peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and an autoimmune disease.

[0015] In another aspect, the disclosure provides the use of a compound of the disclosure for the manufacture of a medicament for treating a disease or condition of interest, such as cancer, a nervous system disease, a psychiatric illness, a neurodegenerative disorder, a peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and an autoimmune disease.

[0016] In another aspect, the disclosure provides kits comprising a packaged composition comprising a compound of the disclosure, and optionally a second therapeutic agent useful for treating the disease or condition of interest, and a package insert containing instructions for use to treat the disease or condition, e.g., cancer, nervous system disease, psychiatric illness, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases.

[0017] In another aspect, the disclosure provides methods of preparing the compounds of the disclosure.

[0018] Additional embodiments and advantages of the disclosure will be set forth in part in the description which follows and in part will arise from the description or may be learned by the practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0019] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief description of the drawings]

[0020] [Figure 1]FIG. 1 is an illustration of an immunoblot showing the activity of SS-01-100 in the WM164 human melanoma cell line in the presence or absence of IFNg.

[0021] [Diagram 2] FIG. 2 is an illustration of an immunoblot showing the activity of SS-01-100 in the WM164 human melanoma cell line in the presence or absence of IL-6.

[0022] [Diagram 3] FIG. 3 is an illustration of an immunoblot showing the activity of SS-02-08 in the WM164 human melanoma cell line.

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

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

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

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

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

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

[0029] [Figure 10] FIG. 10 contains two line graphs showing the activity (cell killing and HDAC inhibition) of SS-2-08 in the PC3 human prostate cell line compared to Nexturastat A and Tubastatin A.

[0030] [Figure 11] FIG. 11 contains two line graphs showing the activity (cell killing and HDAC inhibition) of SS-2-08 in 5637 human bladder cells compared to Nextulastat A and Tubastatin A.

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

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

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

[0034] [Figure 15] FIG. 15 is a line graph showing the viability of SS-2-08, Nextulastat A, Tubastatin A and LBH589 in melanoma cells.

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

[0036] [Figure 17] FIG. 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 a tubulin acetylation study in a HEK293 cell line. The blot on the left is acetyl-tubulin and the blot on the right (upside down) 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 vehicle. The next lanes are increasing concentrations of SS-1-100 and SS-2-08 from 10 nM to 10 μM. The SS-2-08 blot is run in duplicate at a dose of 10 μM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] Detailed Description of the Invention In one embodiment, the present disclosure provides an HDACI having formula I: [ka] and pharma- ceutically acceptable salts, solvates and prodrugs thereof, wherein: X is: [ka] is selected from the group consisting of R 1 is selected from the group consisting of hydrogen and C1-4 alkyl; R2 is selected from the group consisting of optionally substituted C6-C14 aryl and aralkyl; R3 is an optionally substituted C6-C14 aryl, an optionally substituted 5-14 membered heteroaryl, or -C(=O)NR d R e is selected from the group consisting of R 4a , R 4b , R 4e and R 4f is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; R 4c and R 4d is hydrogen and C 1~4 alkyl; or R 4c and R 4d together with the carbon atom to which they are attached form -C(=O)-, R 5a , R 5b , R 5c and R 5d is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; Z is -O-, -N(R 8 )- and -C(=O)-, or Z does not exist, R8 is hydrogen, C 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 selected from the group consisting of aryl, aralkyl, optionally substituted 5-14 membered heteroaryl and heteroaralkyl; m is 0, 1 or 2; n is 1, 2, 3, 4, 5 or 6; [ka] represents a single or double bond, R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 aryl, optionally substituted 5-14 membered heteroaryl, or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; R d and R e together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; R c is C 1~4 (It is alkyl).

[0039] In another embodiment, the disclosure provides HDACIs having formula I, and pharma- ceutically acceptable salts, solvates, and prodrugs thereof, with the proviso that when Z is absent, R 3 is a bicyclic or tricyclic C 10~14 Aryl, 9-14 membered bicyclic or tricyclic heteroaryl, or -C(=O)NR d Re This is subject to the condition that:

[0040] In one embodiment, the present disclosure provides a compound according to the present invention, wherein X is X-1, X-2, X-3 or X-4; Z is -O-; R 1 But hydrogen and C 1~4 is selected from the group consisting of alkyl, R 2 C, with substitutions as necessary 6 ~C 14 is aryl, R 3 C, with substitutions as necessary 6 ~C 14 selected from the group consisting of aryl and optionally substituted 5-14 membered heteroaryl; R 4a and R 4b is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; R 4c and R 4d But hydrogen and C 1~4 independently selected from the group consisting of alkyl, R 5a , R 5b , R 5c and R 5d is 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, C1~6 Alkoxy, C 1~6 independently selected from the group consisting of haloalkyl and haloalkoxy; R a and R b But hydrogen and C 1~6 alkyl; or R a and R b form a 3- to 7-membered heterocycle together with the nitrogen atom to which they are attached; R c But, C 1~4 is alkyl, HDACIs having Formula I, and pharma- ceutically acceptable salts, solvates and prodrugs thereof, are provided.

[0041] In another embodiment, the disclosure provides an HDACI having formula I, wherein X is X-1, and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof. 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 an aralkyl.

[0042] In another embodiment, the disclosure provides an HDACI having formula I, wherein X is X-2, and Pharmaceutically acceptable salts, solvates, e.g., hydrates, and prodrugs 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 replaced as necessary 6 ~C 14 In another embodiment, R 3is an optionally substituted 5-14 membered heteroaryl. In another embodiment, R 3 is -C(=O)NR d R e In another embodiment, Z is absent and R 3 is a bicyclic or tricyclic C 10~14 Aryl, 9-14 membered bicyclic or tricyclic heteroaryl, or -C(=O)NR d R e It is.

[0043] In another embodiment, the disclosure provides HDACIs having formula I, where X is X-3, and pharma- ceutically acceptable salts, solvates, such as hydrates, and prodrugs thereof.

[0044] In another embodiment, the disclosure provides HDACIs having formula I, wherein X is X-4, and pharma- ceutically acceptable salts, solvates, such as hydrates, and prodrugs thereof.

[0045] In another embodiment, the disclosure provides HDACIs having formula I, where X is X-5, and pharma- ceutically acceptable salts, solvates, such as hydrates, and prodrugs thereof.

[0046] In another embodiment, the present disclosure provides an HDACI having formula II: [ka] and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, wherein R 6a , R 6b , R 6c , R 6d and R 6e is 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, C2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, optionally substituted C 3~6 each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycle; R c is C 1~4 is alkyl, n is 1, 2 or 3.

[0047] In another embodiment, the present disclosure provides a method for the preparation of a compound comprising: 6a , R 6b , R 6c , R 6d and R 6e is 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 In another embodiment, R is an HDACI having formula II, each independently selected from the group consisting of haloalkyl, and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof. 6a , R 6b , R 6c , R 6d and R 6e is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 alkoxy.

[0048] In another embodiment, the disclosure provides an HDACI having formula II, and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, wherein n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

[0049] In another embodiment, the present disclosure provides an HDACI having formula III: [ka] and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, During the ceremony, R 7a , R 7b , R 7c , R 7d and R 7e is 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 each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycle; R c is C 1~4 is alkyl, n is 1, 2 or 3.

[0050] In another embodiment, the present disclosure provides a method for the preparation of a compound comprising: 7a , R 7b , R 7c , R 7d and R 7e is 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 In another embodiment, R is an HDACI having formula III, each independently selected from the group consisting of haloalkyl, and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof. 7a , R 7b , R 7c , R 7d and R 7e is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 alkoxy.

[0051] In another embodiment, the disclosure provides an HDACI having formula III, and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, wherein n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

[0052] In another embodiment, the present disclosure provides an HDACI having formula IV: [ka] and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, During the ceremony, R 4a and R 4b is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4independently selected from the group consisting of alkoxy; R 4c and R 4d is independently selected from the group consisting of hydrogen and methyl; m is 0 or 1; n is 1, 2 or 3; [ka] represents a single bond or a double bond.

[0053] In another embodiment, the present disclosure provides a method for the preparation of a compound according to the present invention, wherein m is 0; [ka] represents a double bond, as well as pharma- ceutically acceptable salts, solvates, eg, hydrates, and prodrugs thereof.

[0054] In another embodiment, the present disclosure provides a method for the preparation of a compound according to the present invention, [ka] represents a single bond, as well as pharma- ceutically acceptable salts, solvates, eg, hydrates, and prodrugs thereof.

[0055] In another embodiment, the disclosure provides an HDACI having formula IV, and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, wherein n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

[0056] In another embodiment, the present disclosure provides an HDACI having formula V: [ka] and pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, During the ceremony, R 5a and R 5cis hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 independently selected from the group consisting of alkoxy; n is 1, 2 or 3.

[0057] In another embodiment, the disclosure provides an HDACI having formula V, wherein n is 1, as well as pharma- ceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof. In another embodiment, n is 2. In another embodiment, n is 3.

[0058] In another embodiment, the compound of the disclosure is any one or more of the compounds having formula I in Table 1, and pharma- ceutically acceptable salts, solvates, such as 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 a compound of the disclosure and a pharma- ceutically acceptable carrier.

[0060] In another embodiment, the present disclosure provides a compound of the present disclosure for use in the therapeutic treatment of, for example, cancer, inflammation, traumatic brain injury, neurodegenerative disorders, nervous system diseases, peripheral neuropathy, stroke, hypertension, autoimmune diseases, inflammatory diseases and malaria.In another embodiment, the present disclosure provides a compound of the present disclosure for use in the therapeutic treatment of cancer.

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

[0062] In another embodiment, the disclosure provides compounds of the disclosure that selectively inhibit HDAC6 over other HDAC isozymes.

[0063] In another embodiment, the disclosure provides the use of a compound of the disclosure for the manufacture of a medicament for treating a disease or condition of interest, such as cancer, a nervous system disease, a psychiatric illness, a neurodegenerative disorder, a peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and an autoimmune disease.

[0064] In another embodiment, the disclosure provides kits comprising a packaged composition comprising a compound of the disclosure, and optionally a second therapeutic agent useful for treating the disease or condition of interest, and a package insert containing instructions for use to treat the disease or condition, e.g., cancer, nervous system disease, psychiatric illness, neurodegenerative disorders, peripheral neuropathy, stroke, hypertension, inflammation, traumatic brain injury, rheumatoid arthritis, allograft rejection, and autoimmune diseases.

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

[0066] In another embodiment, the present disclosure provides a compound having formula VI: [ka] Provide 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 formula I); R 1 is hydrogen and C 1~4 is selected from the group consisting of alkyl, R 2 is replaced as necessary 6 ~C 14 selected from the group consisting of aryl and aralkyl; R 3 is replaced as necessary 6 ~C 14 Aryl, optionally substituted 5-14 membered heteroaryl and -C(=O)NR d R e Selected from the group consisting of , R 4a , R 4b , R 4e and R 4f is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; R 4c and R 4d is hydrogen and C 1~4 alkyl; or R 4c and R 4d together with the carbon atom to which they are attached form -C(=O)-, R 5a , R 5b , R 5c and R 5d is hydrogen, halogen, hydroxy, nitro, cyano, -NR a Rb , -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 independently selected from the group consisting of haloalkyl and haloalkoxy; Z is -O-, -N(R 8 )- and -C(=O)-, or Z does not exist, R 8 is hydrogen, C 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 selected from the group consisting of aryl, aralkyl, optionally substituted 5-14 membered heteroaryl and heteroaralkyl; R 9 is C 1~4 is alkyl, m is 0, 1 or 2; n is 1, 2, 3, 4, 5 or 6; [ka] represents a single or double bond, R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 aryl, optionally substituted 5-14 membered heteroaryl, or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocycle; or R d and R e together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; R c is C 1~4 It is an alkyl.

[0067] In another embodiment, the disclosure provides a compound having formula VI, with the proviso that when Z is absent, R 3 is a bicyclic or tricyclic C 10~14 Aryl, 9-14 membered bicyclic or tricyclic heteroaryl, or -C(=O)NR d R e This is subject to the condition that:

[0068] In one embodiment, the present disclosure provides a compound according to the present invention, wherein X is X-1, X-2, X-3 or X-4; Z is -O-; R 1 But hydrogen and C 1~4 is selected from the group consisting of alkyl, R 2 C, with substitutions as necessary 6 ~C 14 is aryl, R 3 C, with substitutions as necessary 6 ~C 14 selected from the group consisting of aryl and optionally substituted 5-14 membered heteroaryl; R 4a and R 4b is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; R4c and R 4d But hydrogen and C 1~4 independently selected from the group consisting of alkyl, R 5a , R 5b , R 5c and R 5d is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; R a and R b But hydrogen and C 1~6 alkyl; or R a and R b form a 3- to 7-membered heterocycle together with the nitrogen atom to which they are attached; R c But, C 1~4 is alkyl, Compounds having formula VI, and pharma- ceutically acceptable salts, solvates and prodrugs thereof, are provided.

[0069] In another embodiment, the disclosure provides a compound having formula VI, where X is X-1. 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 an aralkyl.

[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 is replaced as necessary 6 ~C 14 In another embodiment, R 3 is an optionally substituted 5-14 membered heteroaryl. In another embodiment, R 3 is -C(=O)NR d R e In another embodiment, Z is absent and R 3 is a bicyclic or tricyclic C 10~14 Aryl, 9-14 membered bicyclic or tricyclic heteroaryl, or -C(=O)NR d R e It is.

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

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

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

[0074] In another embodiment, the present disclosure provides a compound having formula VII: [ka] Provide During the ceremony, R 6a , R 6b , R 6c , R 6d and R 6e is hydrogen, halogen, hydroxy, nitro, cyano, -NR a R b , -C(=O)NR a Rb , -C(=O)R c , C 1~6 Al Kill, C. 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, haloalkoxy, optionally substituted C 3~6 each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycle; R c is C 1~4 is alkyl, n is 1, 2 or 3; R 9 is C 1~4 It is an alkyl.

[0075] In another embodiment, the present disclosure provides a method for the preparation of a compound comprising: 6a , R 6b , R 6c , R 6d and R 6e is 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 In another embodiment, R 6a , R 6b , R 6c , R 6d and R6e is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 alkoxy.

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

[0077] In another embodiment, the present disclosure provides a compound having formula VIII: [ka] Provide During the ceremony, R 7a , R 7b , R 7c , R 7d and R 7e is 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 each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycle; R c is C1~4 is alkyl, n is 1, 2 or 3; R 9 is C 1~4 It is an alkyl.

[0078] In another embodiment, the present disclosure provides a method for the preparation of a compound comprising: 7a , R 7b , R 7c , R 7d and R 7e is 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 In another embodiment, R is an alkyl group selected from the group consisting of haloalkyl. 7a , R 7b , R 7c , R 7d and R 7e is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 alkoxy.

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

[0080] In another embodiment, the present disclosure provides a compound having formula IX: [ka] Provide During the ceremony, R 4a and R 4b is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 independently selected from the group consisting of alkoxy; R 4c and R 4d is independently selected from the group consisting of hydrogen and methyl; m is 0 or 1; n is 1, 2 or 3; [ka] represents a single or double bond, R 9 is C 1~4 It is an alkyl.

[0081] In another embodiment, the present disclosure provides a method for the preparation of a compound according to the present invention, wherein m is 0; [ka] represents a double bond.

[0082] In another embodiment, the present disclosure provides a method for the preparation of a compound according to the present invention, [ka] 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 another embodiment, n is 3.

[0084] In another embodiment, the present disclosure provides a compound having formula X: [ka] Provide During the ceremony, R 5a and R 5c is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 independently selected from the group consisting of alkoxy; n is 1, 2 or 3; R 9 is C 1~4It is an alkyl.

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

[0086] In another embodiment, the present disclosure provides a method for the preparation of a compound comprising: 9 But -CH 2 CH 3 The present invention provides a compound having any one of formulas VI to X,

[0087] In another embodiment, the intermediate of the present disclosure is any one or more of the 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 of preparing a compound of the disclosure.

[0089] In another embodiment, the disclosure provides a method of making a compound having formula I, comprising: (1) reacting a compound having formula VI with NH in the presence of a solvent. 2 and optionally, (2) isolating the compound having formula I.

[0090] In another embodiment, the disclosure provides a method of making a compound having formula II, comprising: (1) reacting a compound having formula VII with an NH 2 (2) contacting a compound having formula II with a fluorinated alkyl group; and optionally isolating the compound having formula II.

[0091] In another embodiment, the disclosure provides a method of making a compound having formula III, comprising: (1) reacting a compound having formula VIII with NH in the presence of a solvent. 2 (2) contacting a compound having formula III with OH, and optionally isolating the compound having formula III.

[0092] In another embodiment, the disclosure provides a method of making a compound having formula IV, comprising: (1) reacting a compound having formula IX with NH in the presence of a solvent. 2 (2) contacting a compound having formula IV with OH, and optionally isolating the compound having formula IV.

[0093] In another embodiment, the disclosure provides a method of making a compound having formula X, comprising: (1) reacting a compound having formula X with NH in the presence of a solvent. 2 (1) contacting a compound having formula X with OH; and optionally isolating the compound having formula X.

[0094] In another embodiment, the disclosure provides a method of making a compound having any one of formulas V-X, comprising: 2 The method further includes contacting the OH with a base, hi one embodiment, the base is NaOH.

[0095] In another embodiment, the disclosure provides a method of making a compound having any one of formulas V-X, comprising: 2 The method further comprises contacting OH at a temperature of about 20° C. or less. In one embodiment, the temperature is about 0° C.

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

[0097] In this disclosure, the term "halo" or "halogen" used by itself or as part of another group refers to -Cl, -F, -Br or -I. In one embodiment, halo is -Cl or -F. In one embodiment, halo is -Cl.

[0098] In this disclosure, the term "nitro" used by itself or as part of another group refers to -NO 2 Refers to...

[0099] As used in this disclosure, the term "cyano" used by itself or as part of another group refers to --CN.

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

[0101] In this disclosure, the term "alkyl" used by itself or as part of another group refers to an unsubstituted straight or branched chain aliphatic hydrocarbon containing 1 to 12 carbon atoms, i.e., C 1~12 Alkyl, or an unsubstituted straight or branched chain aliphatic hydrocarbon containing the specified number of carbon atoms, e.g., C such as methyl 1 C such as alkyl and ethyl 2 C such as alkyl, propyl or isopropyl 3 C such as alkyl, methyl, ethyl, propyl or isopropyl 1~3 In one embodiment, alkyl refers to C 1~10 In another embodiment, the alkyl is C 1~6 In another embodiment, the alkyl is C 1~4 In another embodiment, the alkyl is a straight chain C 1~10In another embodiment, the alkyl is a branched C 3~10 In another embodiment, the alkyl is a straight chain C 1~6 In another embodiment, the alkyl is a branched C 3~6 In another embodiment, the alkyl is a straight chain C 1~4 In another embodiment, the alkyl is a branched C 3~4 In another embodiment, the alkyl is a straight or branched chain C 3~4 Non-limiting 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. 1~4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and iso-butyl.

[0102] In this disclosure, the term "cycloalkyl" used by itself or as part of another group refers to an alkyl group having 3 to 12 carbon atoms (i.e., C 3~12 cycloalkyl), or the specified number of carbon atoms In one embodiment, a cycloalkyl group has two rings. In one embodiment, a cycloalkyl group has one ring. In another embodiment, a cycloalkyl group has one ring. 3~8 In another embodiment, the cycloalkyl group is selected from the group consisting of C 3~6 Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and cyclopentenyl, cyclohexenyl.

[0103] In this disclosure, the term "optionally substituted cycloalkyl," used by itself or as part of another group, refers to cycloalkyl, as defined above, that is unsubstituted or substituted with halogen, hydroxy, nitro, cyano, -SCH 3 , -SCF 3 , -NR a R b , -C(O)NR a R b , -C(=O)CH 3 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, optionally substituted C 3~8 It means that it is substituted by one, two or three substituents independently selected from the group consisting of cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo. In one embodiment, the optionally substituted cycloalkyl is substituted by two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted by one substituent.

[0104] In this disclosure, the term "alkenyl" used by itself or as part of another group refers to an alkyl, as defined above, containing one, two or three carbon-carbon double bonds. In one embodiment, an alkenyl group is 2~6 In another embodiment, the alkenyl group is selected from the group consisting of C 2~4 alkenyl groups. Non-limiting 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, an alkynyl group has one carbon-carbon triple bond. In one embodiment, an alkynyl group is a C 2~6 In another embodiment, the alkynyl group is selected from the group consisting of C 2~4 alkynyl groups. Non-limiting 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 selected from the group consisting of C 1~6 In another embodiment, the haloalkyl group is 1~4 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" 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 attached to a terminal oxygen atom. In one embodiment, the alkoxy group is 1~4 Arco In another embodiment, the alkoxy group is selected from the group consisting of 1~6 In another embodiment, the alkoxy group is selected from a C 1~4Alkyl, for example, is selected from methoxy, ethoxy and tert-butoxy.

[0108] In this disclosure, the term "haloalkoxy" used by itself or as part of another group refers to a C 1~4

[0033] refers to haloalkyl. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

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

[0110] In the present disclosure, the term "optionally substituted aryl" as used herein by itself or as part of another group refers to aryl, as defined above, which is unsubstituted or substituted with halogen, hydroxy, nitro, cyano, -SCH 3 , -SCF 3 , -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 3~12Cycloalkyl, optionally substituted C 6 ~C 14 Aryl, optionally substituted 5-14 membered heteroaryl and optionally substituted 3-14 membered heterocyclo (R a and R b is hydrogen and C 1~6 alkyl, or R a and R b together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle, R c is C 1~4 It means that the group is substituted by 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, aryl and alkyl.

[0111] In one embodiment, the optionally substituted aryl is an 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 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-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The term optionally substituted aryl is intended to include optionally substituted fused cycloalkyls and groups having optionally substituted fused heterocyclo rings. Non-limiting examples include the following: [ka] Includes:

[0112] In the present disclosure, the term "heteroaryl" refers to monocyclic, bicyclic and tricyclic aromatic ring systems having 5-14 ring atoms, i.e., 5-14 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 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. In one embodiment, the heteroaryl has 3 heteroatoms. In another embodiment, the heteroaryl has 2 heteroatoms. In another embodiment, the heteroaryl has 1 heteroatom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, isoindolyl, 3H-indolyl, iso ... Examples include ndazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl.In one embodiment, heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, , pyrimidin-4-yl and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl and oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl) and indazolyl (e.g., 1H-indazol-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 5-membered or 6-membered heteroaryl. In one embodiment, the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms, where at least one carbon atom of the ring is replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur. Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and isoxazolyl.

[0114] In another embodiment, the heteroaryl is a 6-membered heteroaryl, e.g., the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms, in which at least one carbon atom of the ring is replaced by a nitrogen atom. Non-limiting exemplary 6-membered heteroaryls include: Aryl groups include pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

[0115] In another embodiment, the heteroaryl is a 9-14 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 9-14 membered bicyclic aromatic ring systems include the following: [ka] Includes:

[0116] In this disclosure, the term "optionally substituted heteroaryl," used by itself or as part of another group, refers to heteroaryl, as defined above, that is unsubstituted or substituted with halogen, hydroxy, nitro, cyano, -SCH 3 , -SCF 3 , -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 3~12 Cycloalkyl, optionally substituted C 6 ~C 14 Aryl, optionally substituted 5-14 membered heteroaryl and optionally substituted 3-14 membered heterocyclo (R a and R b is hydrogen and C 1~6 alkyl, or Ra and R b together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle, R c is C 1~4 In one embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.

[0117] In this disclosure, the term "heterocycle" or "heterocyclo" used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two or three rings having 3-14 ring members, i.e., 3-14 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, including sulfoxide and sulfone, and / or nitrogen atoms, which may be oxidized or quaternized. The term "heterocyclo" refers to the ring -CH 2 It is intended to include groups in which - is replaced by -C(=O)-, e.g., cyclic ureido groups such as 2-imidazolidinone, and cyclic amide groups such as β-lactam, γ-lactam, δ-lactam, ε-lactam and piperazin-2-one. The term "heterocyclo" is also intended to include groups having an optionally substituted fused aryl group, e.g., indolinyl. In one embodiment, the heterocyclo group is selected from a 5- or 6-membered cyclic group containing one ring and one or two oxygen and / or nitrogen atoms. The heterocyclo can be optionally linked to the remainder of the molecule through either an available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include dioxanyl, tetrahydropyranyl, 2-oxopyrrolidin-3-yl, piperazin-2-one, piperazine-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

[0118] In this disclosure, the term "optionally substituted heterocyclo" used by itself or as part of another group refers to heterocyclo as defined above that is unsubstituted or substituted with halogen, hydroxy, nitro, cyano, -SCH 3 , -SCF 3 , -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 3~12 Cycloalkyl, optionally substituted C 6 ~C 14 Aryl, optionally substituted 5-14 membered heteroaryl and optionally substituted 3-14 membered heterocyclo (R a and R b is hydrogen and C 1~6 alkyl, or R a and R b together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle, R c is C 1~4 It means that the group is substituted by 1 to 4 substituents independently selected from the group consisting of alkyl, aryl, aryl and alkyl.

[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, an optionally substituted aralkyl group is a C substituted with one optionally substituted aryl group. 1~4 In one embodiment, the aralkyl group is a C substituted with one optionally substituted aryl group.1 or C 2 In one embodiment, the aralkyl group is a C substituted with one optionally substituted phenyl group. 1 or C 2 Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh 2 , -CH 2 (4-F-Ph), -CH 2 (4-Me-Ph), -CH 2 (4-CF 3 -Ph) and -CH(4-F-Ph) 2 Includes:

[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, a heteroaralkyl group is a C substituted with one optionally substituted heteroaryl group. 1~4 In one embodiment, the aralkyl group is a C substituted with one optionally substituted heteroaryl group. 1 or C 2 In one embodiment, the heteroaralkyl group is a C substituted with one optionally substituted heteroaryl group. 1 or C 2 Non-limiting exemplary heteroaralkyl groups are: [ka] Includes.

[0121] The term "contacting" is used as known in the art and generally refers to bringing together, e.g., reacting, reactants, solvents, catalysts, and reactive groups in such a way that they can interact at the molecular level to achieve the desired chemical or physical transformation. In some embodiments, the contacting involves two reactants or reagents, with one or more equivalents of one reactant / reagent being used relative to the other. The contacting step of the disclosed method can be carried out for a time and under conditions suitable to prepare 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 with or without heat, and can be added under an inert atmosphere, if necessary.

[0122] The term "disease or condition benefiting from inhibition of HDACs" refers to a disease or condition in which HDACs and / or the action of HDACs is beneficial, e.g., a disease or condition in which HDACs and / or the action of HDACs are beneficial, e.g., a disease or condition in which HDAC inhibitors (e.g., TSA, pivaloyloxymethylbutane (AN-9; Pivanex), FK-228 (depsipeptide), PXD-101, NVP-LAQ824, SAHA, MS The present invention relates to conditions that are important or necessary for the onset, progression, or development of a disease or condition known to be treated by MG-275 and / or MGCD0103. 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 chorea, amyotrophic lateral sclerosis, spinocerebellar degeneration, Rett syndrome), peripheral neuropathy (Charcot-Marie-Tooth disease, giant axonal neurodegeneration (GAN)), inflammatory diseases (e.g., osteoarthritis, rheumatoid arthritis, colitis), and angiogenesis. The diseases that can be treated with HDAC include diseases that affect the immune system (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 treats a disease or condition mediated by HDAC for any particular cell type, for example, by an assay that can be conveniently used to evaluate the activity of a particular compound.

[0123] The term "second therapeutic agent" refers to a therapeutic agent other than the compound of the present disclosure, which is known to treat the disease or condition of interest.For example, when cancer is the disease or condition of interest, the second therapeutic agent can be a known chemotherapeutic agent, such as taxol or radiation.

[0124] The term "HDAC" refers to a family of enzymes that remove acetyl groups from the ε-amino groups of lysine residues at the N-terminus of proteins, such as histones.HDACs can be human HDACs, including HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10 and HDAC11.HDACs can also be derived from protozoan or fungal sources.

[0125] The terms "treat", "treating", "treatment" and the like refer to the elimination, reduction, alleviation, reversal and / or amelioration of a disease or disorder and / or symptoms associated therewith. Treatment of a disease or condition does not require or exclude the complete elimination of the disease, condition or symptoms associated therewith, including the treatment of acute or chronic signs, symptoms and / or dysfunctions. As used herein, the terms "treat", "treating", "treatment" and the like can include "prophylactic treatment", which refers to reducing the likelihood of re-developing a disease or condition or the likelihood of recurrence of a previously controlled disease or condition in a subject who does not have the disease or condition but is at risk of or susceptible to re-developing or recurrence of the disease or condition, and thus "treatment" also includes the prevention of relapse or prevention of recurrent periods. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound of the present disclosure to an individual, for example, a mammalian patient, including but not limited to humans and veterinary animals, in need of such treatment. Treatment can be symptomatically directed, e.g., to suppress symptoms. Treatment can be short-term, e.g., in the context of maintenance therapy, can be directed over the medium term, or can be long-term treatment.

[0126] The term "therapeutically effective amount" or "effective dose," as used herein, refers to an amount of an active ingredient sufficient upon administration to effectively deliver the active ingredient to an individual, e.g., a human patient in need thereof, for the treatment of a condition or disease of interest. In the case of cancer or other proliferation disorders, a therapeutically effective amount of an agent reduces (i.e., slows to some extent and preferably stops) the proliferation of undesirable cells, reduces the number of cancer cells, shrinks tumor size, reduces the number of cancer cells ... The compounds or compositions administered may be capable of preventing (i.e., slowing to some extent and preferably halting) invasion of tumor cells into peripheral organs, inhibiting (i.e., slowing to some extent and preferably halting) tumor metastasis, inhibiting to some extent tumor growth, reducing HDAC signaling in target cells, and / or alleviating to some extent one or more symptoms associated with cancer. To the extent that the administered compound or composition prevents the growth and / or kills existing cancer cells, it may be cytostatic and / or cytotoxic.

[0127] "Concurrent administration", "combined administration", "simultaneous administration" and similar phrases refer to the administration of two or more agents to a subject being treated at the same time. "Concurrently" refers to the administration of each agent at different times, in any order, either simultaneously or sequentially. However, if not administered at the same time, it means that they are administered to an individual in a time sequence and close enough together to act in concert to achieve the desired therapeutic effect. For example, a compound of the present disclosure can be administered as a second therapeutic agent at different times, in any order, simultaneously or sequentially. The compound of the present disclosure and the second therapeutic agent can be administered separately in any suitable form and by any suitable route. If the compound of the present disclosure and the second therapeutic agent are not administered at the same time, it is understood that they can be administered to a subject in need thereof in any order. For example, a compound of the disclosure can be administered to an individual in need thereof prior to (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 prior to) administration of a second therapeutic treatment modality (e.g., radiation therapy), simultaneously 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 after) administration of a second therapeutic treatment modality. In various embodiments, the compound of the disclosure and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 to 2 hours apart, 2 to 3 hours apart, 3 to 4 hours apart, 4 to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 to 10 hours apart, 10 to 11 hours apart, 11 to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart.In one embodiment, the components of the combination therapy are administered between 1 minute and 24 hours apart.

[0128] In the context of describing this disclosure (especially in the context of the claims), the use of the terms "a", "an", "the" and similar referents should be construed to cover both the singular and the plural unless otherwise indicated. The recitation of ranges of values ​​herein merely serves as a shorthand for individually referring to each individual value falling within the range, unless otherwise indicated herein, and each individual value and subrange is incorporated herein as if it were individually recited herein. The use of any examples or exemplary language provided herein (e.g., "such as" and "like") is intended to better illustrate the disclosure, unless otherwise claimed, and is not a limitation on the scope of the disclosure. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0129] The term "about" as used herein includes the recited number plus or minus 10%. Thus, "about 10" means 9 to 11.

[0130] Prodrugs of the compounds of the present disclosure are also included in the present disclosure. It is well established that prodrug approaches, in which a compound is derivatized into a form suitable for administration and then released as a drug in vivo, have been successfully used to transiently (e.g., bioreversibly) modify the physicochemical properties of a compound (see, "Design of a Drug-Responsive ... of Prodrugs, Elsevier, Amsterdam, (1985); R.B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego, Chapter 8 (1992); K.M. Hillgren et al., Med. Res. Rev., vol. 15, p. 83 (1995). Certain prodrugs of HDAC inhibitors are discussed in WO2008 / 055068.

[0131] The compounds of the present disclosure can exist as salts. As used herein, the term "pharmaceutical acceptable salts" refers to the salts or zwitterionic forms of the compounds. The salts of the compounds can be prepared during the final isolation and purification of the compounds, or separately, by reacting the compounds with an acid having a suitable cation. The pharmaceutical acceptable salts of the compounds can be acid addition salts formed with pharmaceutical acceptable acids. Examples of acids that can be used to form pharmaceutical acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, tartaric acid and citric acid. Non-limiting examples of salts of the compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate. Salts of the disclosed compounds include salts, propionates, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates, paratoluenesulfonates, undecanoates, lactates, citrates, tartrates, gluconates, methanesulfonates, ethanedisulfonates, benzenesulfonates and p-toluenesulfonates.In addition, the available amino groups present in the compounds of the present disclosure can be quaternized with methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl chlorides, bromides and iodides, lauryl, myristyl and stearyl chlorides, bromides and iodides; and benzyl and phenethyl bromides.All references to the compounds of the present disclosure appearing herein are intended to include the compounds of the present disclosure and their pharma- ceutically acceptable salts, solvates, hydrates or prodrugs.

[0132] The compounds of the present disclosure may also be conjugated or linked to auxiliary moieties that promote the beneficial properties of the compounds in therapeutic use methods. Such conjugates can enhance the delivery of the compounds to specific anatomical sites or regions of interest (e.g., tumors), allow sustained therapeutic concentrations of the compounds in target cells, modify the pharmacokinetic and pharmacodynamic properties of the compounds, and / or improve the therapeutic index or safety profile of the compounds. Suitable auxiliary moieties include, for example, amino acids, oligopeptides or polypeptides, for example, antibodies, such as monoclonal antibodies and other engineered antibodies; and natural or synthetic ligands for receptors in target cells or tissues. Other suitable auxiliary agents include fatty acid or lipid moieties that promote the biodistribution and / or uptake of the compounds by target cells (see, for example, Bradley et al., Clin. Cancer Res. (2001) 7:3229).

[0133] The compounds of the present disclosure inhibit HDAC and are useful in the treatment of a variety of diseases and conditions. In particular, the compounds of the present disclosure are useful in the treatment of diseases or conditions in which inhibition of HDAC is beneficial, such as cancer. The compounds of the present disclosure are used in methods of treating neurological disorders, neurodegenerative conditions, peripheral neuropathy, autoimmune diseases, inflammatory diseases and conditions, stroke, hypertension, traumatic brain injury, autism, and malaria, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0134] The method also includes administering to the individual, in addition to the compound of the present disclosure, a second therapeutic agent, which is selected from drugs and adjuvants known to be useful for treating the disease or condition from which the individual suffers, such as chemotherapeutic agents and / or radiation known to be useful for treating certain cancers.

[0135] The compounds of the present disclosure were evaluated for their activity in HDAC6 and their selectivity for HDAC6 compared to HDAC1.Selective HDAC6 inhibitors have been implicated in a variety of disease states, including but not limited to arthritis, autoimmune disorders, inflammatory disorders, cancer, nervous system diseases (such as Rett syndrome), peripheral neuropathy (such as CMT), stroke, hypertension, and diseases in which oxidative stress is a causative factor or a consequence.Similarly, selective HDAC6 inhibitors, when administered in combination with rapamycin, extended the life span of mice bearing kidney xenografts.This model was used to evaluate the immunosuppressive properties of the compounds and serve as a model of transplant rejection.In addition, selective HDAC6 inhibitors provide neuroprotection in a rat primary cortical neuron model of oxidative stress.These studies identify selective HDAC6 inhibitors as non-toxic neuroprotective agents.

[0136] The compounds of the present disclosure are selective HDAC6 agents that possess drug-like physicochemical properties.

[0137] Thus, in one embodiment, the disclosure provides a method of treating an individual suffering from a disease or condition, e.g., a disease or condition for which inhibition of HDAC would be beneficial, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the disclosure.

[0138] The methods of the present disclosure can be carried out by administering the compounds of the present disclosure as neat compounds or as pharmaceutical compositions. The administration of the pharmaceutical compositions or the compounds of the present disclosure alone can be carried out during or after the onset of the disease or condition of interest. Typically, pharmaceutical compositions are sterile and do not contain toxic, carcinogenic or mutagenic compounds that would cause adverse reactions when administered.

[0139] In some embodiments, the compound of the present disclosure may be administered together with a second therapeutic agent that is useful for treating diseases or conditions that benefit from the inhibition of HDAC.The second therapeutic agent is different from the compound of the present disclosure.The compound of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially.Furthermore, the compound of the present disclosure and the second therapeutic agent can be administered from a single composition or two separate compositions.The compound of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.

[0140] The second therapeutic agent is administered in an amount that achieves its desired therapeutic effect. Effective dosage ranges for each of the second therapeutic agents are known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.

[0141] Thus, the disclosure provides compositions and methods of using the compounds of the disclosure, and optionally, a second therapeutic agent, in treating diseases or conditions in which inhibition of HDAC would be beneficial.

[0142] The disclosure also provides pharmaceutical compositions comprising the compounds of the disclosure, and optionally a second therapeutic agent, useful for treating diseases and conditions where inhibition of HDAC would be beneficial.

[0143] Further provided are kits containing a compound of the present disclosure and optionally a second therapeutic agent, packaged separately or together, useful for treating diseases and conditions where inhibition of HDAC would be beneficial, as well as a package insert with instructions for using these active agents.

[0144] The compound of the present disclosure and the second therapeutic agent can be administered together as a single unit dose, or separately as multiple unit doses, in which the compound of the present disclosure is administered before the second therapeutic agent, or vice versa.One or more doses of the compound of the present disclosure and / or one or more doses of the second therapeutic agent can be administered.Therefore, the compound of the present disclosure can be used in combination with one or more second therapeutic agents, for example, but not limited to, anticancer agents.

[0145] Within the meaning of the present disclosure, the term "disease" or "condition" generally refers to a disturbance and / or abnormality that is considered a pathological condition or pathological function, and that may be expressed in the form of specific signs, symptoms and / or dysfunction. As demonstrated below, the compounds of the present disclosure are inhibitors of HDAC and can be used to treat diseases and conditions in which inhibition of HDAC is beneficial, such as cancer, nervous system diseases, neurodegenerative conditions, traumatic brain injury, stroke, inflammation, autoimmune diseases and autism.

[0146] In one embodiment, the present disclosure provides a method for treating cancer, including but not limited to killing cancer or neoplastic cells, inhibiting the growth of cancer or neoplastic cells, inhibiting the replication of cancer or neoplastic cells, or improving their symptoms, comprising administering to a subject in need thereof a sufficient amount of the compound of the present disclosure, as well as its pharma- ceutically acceptable salts, solvates, such as hydrates and prodrugs, to treat cancer.In addition, it should be noted that the selected compounds of the present disclosure can promote the killing of cancer cells by reactivating the immune system through a mechanism involving PDI receptors.The compounds of the present disclosure can be used as anti-cancer agents alone or in combination with other anti-cancer treatments, such as radiation, chemotherapy and surgery.

[0147] In another embodiment, the disclosure provides a method for increasing the sensitivity of a cancer cell to the cytotoxic effects of radiation therapy and / or chemotherapy, comprising contacting the cell with a compound of the disclosure, and pharma- ceutically acceptable salts, solvates, e.g., hydrates and prodrugs thereof, in an amount sufficient to increase the sensitivity of the cell to the cytotoxic effects of radiation therapy and / or chemotherapy.

[0148] In a further embodiment, the disclosure provides a method of treating cancer comprising: (a) administering to an individual in need thereof an amount of a compound of the disclosure; and (b) administering to the individual an amount of radiation therapy, chemotherapy, or both. The amounts administered are each effective to treat the cancer. In another embodiment, the amounts are together effective to treat the cancer.

[0149] Therefore, this combination therapy of the present disclosure can be used in various settings for the treatment of various cancers.In a specific embodiment, the individual in need of treatment has previously undergone treatment for cancer.Such previous treatment includes, but is not limited to, previous chemotherapy, radiation therapy, surgery, or immunotherapy such as cancer vaccine.

[0150] In another embodiment, the cancer being treated is one that has demonstrated sensitivity to or is known to respond to radiation therapy and / or chemotherapy. Such cancers include, but are not limited to, non-Hodgkin's 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 to be treated has demonstrated resistance to radiation therapy and / or chemotherapy or is known to be refractory to radiation therapy and / or chemotherapy. A cancer is refractory to treatment when at least a significant portion of cancer cells are not killed or their cell division is not inhibited in response to treatment. Such 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-accepted meaning of "refractory" in this context. In a specific embodiment, a cancer is refractory when the number of cancer cells does not decrease or increases significantly.

[0152] Other cancers that can be treated with the compounds and methods of the disclosure include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovium, 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 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, seminoma, embryonal carcinoma, 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, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma; including, 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 megakaryoblastic leukemia, acute myelo ... These include, but are not limited to, myeloid leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute anaplastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia and multiple myeloma; acute and chronic leukemias: blood borne cancers including lymphoblastic myeloid and myeloid leukemia; lymphomas: Hodgkin's disease and non-Hodgkin's lymphoma; multiple myeloma; Waldenstrom's macroglobulinemia; heavy chain disease; and polycythemia vera.

[0153] The compounds of the present disclosure may also be administered to prevent progression to neoplastic or malignant conditions, including, but not limited to, the cancers listed above. Such prophylactic use has application in known or suspected conditions preceding progression to neoplasia or cancer, particularly in this case hyperplasia, dysplasia, or growth of non-neoplastic cells, the majority of which is specifically dysplasia (for a review of such abnormal growth conditions, see Robbins and Angell, 1976, Basic Pathology, 2nd ed., WB Saunders Co., Philadelphia, pp. 68-79). Hyperplasia is a form of controlled cell growth involving an increase in cell number in a tissue or organ without significant alteration of structure or function. For example, endometrial hyperplasia often progresses to endometrial cancer, and precancerous colonic polyps often transform into cancerous lesions. Metaplasia 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. Metaplasia can occur in epithelial or connective tissue cells. Typical metaplasia involves some disordered metaplastic epithelium. Dysplasia is often the precursor of cancer and is found primarily in epithelium. Dysplasia is a non-neoplastic process involving loss of homogeneity of individual cells and structural adaptability of cells. Dysplasia is the most disabling form of growth of adult cells. Dysplastic cells often have abnormally large, deep, infiltrated nuclei and exhibit pleomorphism. Dysplasia characteristically occurs where there is chronic irritation or inflammation and is often found in the cervix, airways, oral cavity, and gallbladder.

[0154] Alternatively, or in addition to the presence of abnormal cell growth characterized as hyperplasia, metaplasia, or dysplasia, the presence of one or more characteristics of a transformed or malignant phenotype exhibited in vivo or in vitro by a cell sample derived from a subject may indicate the desirability of prophylactic / therapeutic administration of a composition of the present disclosure. Such characteristics of a transformed phenotype include, for example, morphological changes, loosening of basal lamina attachment, loss of contact inhibition, loss of anchorage dependency, protease release, increased sugar transport, reduced serum requirement, expression of fetal antigens, and loss of the 250,000 dalton cell surface protein.

[0155] In specific embodiments, leukoplakia, a benign hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, carcinoma in situ, are preneoplastic lesions indicating the appropriateness of preventive intervention.

[0156] In another embodiment, fibrocystic diseases (cystic hyperplasia, breast dysplasia, especially adenopathy (benign epithelial hyperplasia)) indicate the appropriateness of preventive intervention.

[0157] The prophylactic use of the disclosed compounds and methods also has application in several viral infections that can lead to cancer. For example, human papillomavirus can lead to cervical cancer (see, e.g., Hernandez-Avila et al., Archives of Medical Research (1997) 28:265-271), and Epstein-Barr virus (EBV) can lead to lymphoma (see, e.g., Herrmann et al., J Pathol (2003) 1997). (2):140-5), hepatitis B or C viruses can lead to liver cancer (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8), human T-cell leukemia virus (HTLV)-I can lead to T-cell leukemia (see, e.g., Mortreux et al., Leukemia (2003) 17(1):26-38), human herpesvirus-8 infection can lead to Kaposi's sarcoma (see, e.g., Kadow et al., Curr Opin Investig Drugs (2002) 3(11):1574-9), and human immunodeficiency virus (HIV) infection can contribute to the development of cancer as a result of immune deficiency (see, e.g., Dal Maso (see, e.g., Lancet Oncol (2003) 4(2):110-9).

[0158] In other embodiments, subjects exhibiting one or more of the following predispositions to malignancies may be treated by administration of the compounds and methods of the present disclosure: chromosomal translocations associated with malignancies (e.g., Philadelphia chromosome in chronic myeloid leukemia, t(14;18) in follicular lymphoma, etc.), familial polyposis or Gardner's syndrome (possible precursors of colon cancer), benign monoclonal gammopathy (possible precursors of multiple myeloma), cancers or precancerous diseases exhibiting Mendelian (genetic) inheritance patterns. First-degree consanguinity with a person with a disease (e.g., familial polyposis of the colon, Gardens syndrome, hereditary exostoses, polyendocrine neoplasia, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, von Recklinghausen neurofibromatosis, retinoblastoma, carotid bulb tumors, cutaneous melanomatosis, intraocular melanoma, xeroderma pigmentosum, ataxia-telangiectasia, Chediak-Higashi syndrome, albinism, Fanconi aplastic anemia, and Bloom syndrome; Robbins and Angell , 1976, Basic Pathology, 2nd edition, WB Saunders Co., Philadelphia, 11 2-113), and exposure to carcinogens (e.g., smoking and inhaling or contact with certain chemicals).

[0159] In another specific embodiment, the disclosed compounds and methods are directed to treating breast, colon, The compound is administered to a human subject to prevent the progression of cancer, ovarian cancer or cervical cancer.

[0160] In one embodiment, the disclosure provides a method of treating cancer, comprising: (a) administering to an individual in need thereof an amount of a compound of the disclosure; and (b) administering to the individual one or more additional anti-cancer treatment modalities, including but not limited to radiation therapy, chemotherapy, surgery, or immunotherapy, such as a cancer vaccine. In one embodiment, administering step (a) is prior to administering step (b). In another embodiment, administering step (a) is after administering step (b). In yet another embodiment, administering step (a) is concurrent with administering step (b).

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

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

[0163] In one embodiment, the compounds of the present disclosure are administered adjunctively with an additional anti-cancer treatment modality.

[0164] In another embodiment, the additional anti-cancer treatment modality is radiation therapy. Any radiation therapy protocol can be used in the methods of the present disclosure, depending on the type of cancer being treated. The embodiments of the present disclosure include the following electromagnetic radiation: gamma radiation (10 -20 ~10 -13 m), X-ray radiation (10 -12 ~10-9 m), ultraviolet (10nm to 400nm), visible light (400nm to 700nm), infrared (700nm to 1mm) and microwave radiation (1mm to 30cm).

[0165] For example, but not limited to, X-ray radiation can be administered. Particularly high-energy megavoltage (radiation with energy higher than 1 MeV) can be used for deep tumors, and electron beam and orthovoltage X-ray radiation can be used for skin cancer. Gamma-emitting radioisotopes, such as radioactive isotopes of radium, cobalt and other elements, can also be administered. Exemplary radiation therapy protocols useful in the present disclosure include, but are not limited to, stereotactic methods, in which multiple sources of low-dose radiation are simultaneously focused on tissue volumes from multiple angles; "internal radiation therapy," such as brachytherapy, interstitial irradiation and intracavitary irradiation, which involves placing radioactive implants directly into tumors or other target tissues; intraoperative irradiation, in which multiple doses of external radiation are directed to target tissues exposed during surgery; and particle beam radiation therapy, which includes the use of high-speed elementary particles to treat localized cancers.

[0166] Many cancer treatment protocols currently use 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 therapeutically effective analogs and derivatives thereof.

[0167] Photodynamic therapy (PDT) of cancer uses visible light as a radioactivator of a sensitizer. Examples of photodynamic radiosensitizers include, but are not limited to, hematoporphyrin derivatives, PHOTOFRIN®, benzoporphyrin derivatives, NPe6, tin etioposide, and tin tetrahydrofuran. Lufilin (SnET2), pheoborbide-a, bacteriochloro These include Phil-a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and their therapeutically effective analogs and derivatives.

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

[0169] In one embodiment, a compound of the present disclosure is administered prior to administration of radiation therapy and / or chemotherapy.

[0170] In another embodiment, the compounds of the present disclosure are administered adjunctively with radiation therapy and / or chemotherapy.

[0171] The compounds of the present disclosure and the additional treatment modalities can act additively or synergistically (i.e., the combination of the compounds of the present disclosure and the additional anti-cancer treatment modalities is more effective than the additive effects of each when administered alone). A synergistic combination allows for the use of lower doses of the compounds of the present disclosure and / or the additional treatment modalities and / or less frequent administration of the compounds of the present disclosure and / or the additional treatment modalities to a subject with cancer. The ability to utilize lower doses of the compounds of the present disclosure and / or the additional treatment modalities and / or administer the compounds of the present disclosure and / or the additional treatment modalities less frequently can reduce toxicity associated with administration without reducing the efficacy of the compounds of the present disclosure and / or the additional treatment modalities in treating cancer. Furthermore, synergistic effects can result in improved efficacy of cancer treatment and / or reduced adverse or undesirable side effects associated with administration of the compounds of the present disclosure and / or the additional anti-cancer treatment modalities as monotherapy.

[0172] In one embodiment, the compounds of the present disclosure can act synergistically with radiation therapy when administered at doses that are typically used when such HDACIs are used alone to treat cancer. In another embodiment, the compounds of the present disclosure can act synergistically with radiation therapy when administered at doses that are less than the doses that are typically used when such HDACIs are used as monotherapy to treat cancer.

[0173] In one embodiment, radiation therapy can act synergistically with the compounds of the present disclosure when administered at doses typically used when radiation therapy is used as a monotherapy to treat cancer. In another embodiment, radiation therapy can act synergistically with the compounds of the present disclosure when administered at doses less than those typically used when radiation therapy is used as a monotherapy to treat cancer.

[0174] The effectiveness of the compounds of the present disclosure as HDAC inhibitors for sensitizing cancer cells to the effects of radiation therapy can be determined in vitro and / or in vivo using techniques known in the art. This can be determined by assessing survival after treatment in vivo. For in vitro determinations, exponentially growing cells can be exposed to known doses of radiation and cell survival monitored. Irradiated cells are plated and cultured for about 14 to about 21 days and colonies are stained. Viability is the number of colonies divided by the plating rate of non-irradiated cells. Plotting viability on a logarithmic scale versus absorbed dose on a linear scale generates a survival curve. Survival curves generally show an exponential decline in the percentage of cells surviving at higher radiation doses after an initial shoulder region where the dose becomes sublethal. Similar protocols can be used for chemical agents when used in the combination therapy of the present disclosure.

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

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

[0177] The present disclosure provides a method for treating cancer, for example, administering an effective amount of the compound of the present disclosure in conjunction with recognized methods of surgery, radiation therapy and chemotherapy, including chemo-based sham radiation therapy, thereby achieving synergistic enhancement of the effectiveness of recognized therapeutic methods.The effectiveness of treatment can be measured in clinical studies or in model systems such as tumor models in mice or cell culture susceptibility assays.

[0178] The present disclosure provides combination therapies that result in improved efficacy and / or reduced toxicity. Thus, in one aspect, the present disclosure relates to the use of compounds of the present disclosure as radiosensitizers in conjunction with radiation therapy.

[0179] When the combination therapy of the present disclosure comprises administering the compound of the present disclosure together with one or more additional anticancer drugs, the compound of the present disclosure and the additional anticancer drugs can be administered simultaneously or sequentially to an individual.The drug can also be administered cyclically.Cyclic therapy includes administering one or more anticancer drugs for a period of time, then administering one or more different anticancer drugs for a period of time, and repeating this sequential administration, i.e., this cycle, in order to reduce the development of resistance to the one or more anticancer drugs administered, to avoid or reduce the side effects of the one or more anticancer drugs administered, and / or to improve the efficacy of treatment.

[0180] The additional anti-cancer drugs may be administered over a series of sessions. Any one or combination of the additional anti-cancer drugs listed below may be administered.

[0181] The present disclosure includes a method of treating cancer, comprising administering to an individual in need thereof a compound of the present disclosure and one or more additional anti-cancer agents, or pharma- ceutically acceptable salts thereof. The compound of the present disclosure and the additional anti-cancer agent can act additively or synergistically. Suitable anti-cancer 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, doxorubicin, cyclophosphamide, ifosfamide, nitrosourea, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campateein, bleomycin, doxorubicin, cyclophosphamide, ifosfamide, cyclophosphamide, ifosfamide, nitrosourea, mitomycin, cyclophosphamide, ifosf ... These include cyclosporine, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil (5-FU), taxanes (such as docetaxel and paclitaxel), leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustard, BCNU, nitrosoureas (such as carmustine and lomustine), platinum complexes (such as cisplatin, carboplatin, and oxaliplatin), imatinib mesylate, hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, and lavendustin A.

[0182] In one embodiment, the anticancer drug is selected from the group consisting of, but not limited to, alkylating agents, nitrogen mustards, cyclophosphamide, trofosfamide, chlorambucil, nitrosoureas, carmustine (BCNU), lomustine (CCNU), alkylsulfonates, busulfan, treosulfan, triazines, plant alkaloids, vinca alkaloids (vineristine, vinblastine, vindesine, vinorelbine), taxoids, DNA topoisomerase inhibitor, epipodophyllin ), 9-aminocamptothecin, camptothecin, crisnatol, mitomycin, mitomycin C, antimetabolites, antifolates, DHFR inhibitors, trimetrexate, IMP dehydrogenase inhibitors, mycophenolic acid, tiazofurin, ribavirin, EICAR, ribonucleotide reductase inhibitors, hydroxyurea, deferoxamine, pyrimidine analogs, uracil analogs, floxuridine, doxifluridine, latitrexed, cytosine analogs, cytarabine (ara C), cytosine arabinoside, fludarabine, purine analogs, mercaptopurine, thioguanine, DNA antimetabolites, 3-HP, 2'-deoxy-5-fluorouridine, 5-HP, alpha-TGDR, aphidicolin glycinate, ara-C, 5-aza-2'-deoxycytidine, beta-TGDR, cyclocytidine, guanazole (inosine glycodialdehyde), macbecin II, pyrazoloimidazole, hormone therapy, receptor antagonists, antiestrogens, tamoxifen, raloxifene, megestrol, LHRH agonists, goserelin, leuprolide acetate, antiandrogens, flutamide, bicalutamide, retinoids / deltoids, cis-retinoic acid, vitamin A derivatives, All-trans retinoic acid (ATRA-IV), vitamin D3 analogues, El1089, CB1093, ICH1060, photodynamic therapy, verteporfin, B PD-MA, phthalocyanine, photosensitizer Pc4, demethoxy-hypocrelin A (2BA-2-DMHA), cytokine, interferon-a, interferon-I3, interferon-y, tumor necrosis factor, angiogenesis inhibitor, angiostatin (plasminogen fragment), angiostatic 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-inducible protein (IP-10), interleukin-12, kringle 5 (plasminogen fragment), marimastat, 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), prinomastat, prolactin 161 (D fragment), proliferin-related protein (PRP), PTK787 / ZK222594, retinoids, solimatat, 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, farnesyl transferase inhibitors (FTIs), bisphosphonates, antimitotics, allocolchicine, halichondrin B, colchicine, colchicine derivatives, dolstatin 10, maytansine, rhizoxin, thiocolchicine , trityl cysteine, isoprenylation inhibitors, dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium ion, cell cycle inhibitors, staurosporine, actinomycin, actinomycin D, dactinomycin, bleomycin, bleomycin A2, bleomycin B2, peplomycin, anthracyclines, adriamycin, epirubicin, pirarubicin, zorubicin, mitoxantrone, MDR inhibitors, Verapamil, Ca 2+ The drug may be selected from the group consisting of an ATPase inhibitor, and thapsigargin.

[0183] Other anti-cancer drugs that can be used in the present disclosure include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; arnbomycin; amethantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; aspartame; Paraginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Visnafide dimesylate; Bizelcsin; Bleomycin sulfate; Brequinar sodium; Bleomycin sulfate; lopirimine; busul fan; cactinomycin; calsterone; caracemide; carbetimer; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; ciloremycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexorrnaplatin; dezaguanine; dezaguanine Mesylate;Diaziquone;Docetaxel;Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflomitine hydrochloride;Elsamitrucin;Enloplatin;Enpromate;Epipropizin;Epirubicin hydrochloride;Elubrozole;Esorubicin hydrochloride;Estramustine;Estramustine phosphate sodium;Etanidazole;Phosphorus etoposide acid; etopurine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; foskidone; fostriecin sodium; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; irmofosine; 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; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride );Megestrol acetate;Melengestrol acetate;Melphalan;Menogaril;Mercaptopurine;Methotrexate sodium;Metoprine;Meturedepa;Mitindomide;Mitocalcin;Mitochromine;Mitodiline;Mitomarcin;Mitomycin;Mitusper;Mitotane;Mitoxantrone hydrochloride;Mycophenolic acid;Nocodazole;Nogalamycin;Ormaplatin;Oxisuran;Pegaspargase;Periomycin;Pentamustine;Peplomycin sulfate;Perfosfarnide;Pipobromo Mann;Piposulfan;Piroxantrone hydrochloride;Plicamycin;Promestane;Porfimer sodium;Porfiromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Riboprin;Rogletimide;Safingol; . Safingol hydrochloride;Semustine;Simtrazene;Sparphosate sodium;Sparsornycin;Spirogermanium hydrochloride;Spirogermanium hydrochloride Lomustine;Spiroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Toremifene citrate;Trestorone acetate;Triciribine phosphate;Trimetrexate;Trimetrexate glucuronate;Triptorelin;Tubrozole hydrochloride;Uracil mustard;Uredep;Vapreotide;Be Vinblastine sulfate; Vincristine sulfate; Vin These include vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleucosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozolc; zeniplatin; zinostatin; zorubicin hydrochloride.

[0184] Additional anti-cancer drugs that can be used in the present disclosure include, but are not limited to, 17-AAG; 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adzelesin; aldesleukin; ALL TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; a Musacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-dorsal morphogenesis anti-dorsalizing morphogenetic protein 1;antiandrogens, prostate cancer;antiestrogens;antineoplastons;antisense oligonucleotides;aphidicolin glycine salt;apoptotic gene modulators;apoptotic regulators;apurinic acid;araCDP DL PTBA;arginine deaminase;asulacrine;atamestane;atrimustine;axinastatin 1;axinastatin 2;axinastatin 3;azasetron;azatoxin;azatyrosine;baccatin III derivatives;balanol;batimastat;BCR-ABL antagonists;benzochlorines;benzoylstaurosporine;beta-lactam derivatives;beta-arretin;beta-clarnycin B;betulinic acid;bFGF inhibitors;bicalutamide;bisanthrene bisaziridinylsperrnine; bisnafide; bistratene A; bizelesin; bortezomib; breflate; bromine Pyrimine;Budotitanium;Buthionine sulfoximine;Calcipotriol;Calphostin C;Camptothecin derivatives;Canarypox IL-2;Carboxamide aminotriazole;Carboxarnidotriazole;CaRest M3;CARN700;cartilage-derived inhibitor;carzelesin;casein kinase inhibitor;castanospermine;cecropin B;cetrorelix;chlorin;chloroquinoxaline sulfonamide;cicaprost;cisporphyrin;cladribine;clomiphene analogs;clotrimazole;collismycin A;collismycin B;combretastatin A4;combretastatin analogs;conagenin;crambesidin 816;crisnatol;cryptophycin 8;cryptophycin A derivatives;curacin A;cyclopentaneseraquinones;cycloplatam;cypemycin;cytarabine ocphosphate;cytolytic factors;cytostatin;dacliximab;decitabine;dehydrodidemnin B;deslorelin;dexamethasone;dexphosphamide;dexrazoxane;dexverapamil;diaziquone;didemnin B; Didox;Diethylnorspermine;Dihydro-5-azacytidine;Dihydrotaxol, 9;Dioxamycin;Diphenylspiromustine;Docetaxel;Docosanol;Dolasetron;Doxifluridine;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;Edelfosine;Edrecolomab;Eflomitine;Elemene;Emitefur;Epirubicin;Epristeride;Estramustine analogs;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flazelastine;Fluasterone;Fludarabine;Fluorodaunoruniein hydrochloride hydrochloride); Forfenimex; Formestane; Fostriecin; Fotemus tin;gadolinium texaphyrin;gallium nitrate;galocitabine;ganirelix;gelatinase inhibitors;glutathione inhibitors;hepsulfam;heregulin;hexamethylene bisacetamide;hypericin;ibandronic acid;idarubicin;idoxifene;idramantone;ilmofosine;ilomastat;imidazoacridone;imiquimod;immunostimulatory peptides;insulin-like growth factor 1 receptor inhibitors;interferon agonists;interferon;interleukin;iobenguane;iododoxorubiein;ipomeanol 4;iropract;irsogladine;isobengazole;isohomohalichondrin B;itasetron;jasplakinolide;kahala Lido F; larnellarin N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum complexes; lysocrinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; li Zofilin;cytolytic peptides;maytansine;mannostatin A;marimastat;masoprocol;maspin;matrilysin inhibitors;matrix metalloproteinase inhibitors;menogaril;merbarone;meterelin;methioninase;metoclopramide;MIF inhibitors;mifepristone;miltefosine;mirimostim;mismatched double-stranded RNA;mitoguazone;mitolactol;mitomycin analogs;mitonafide;mitotoxin fibroblast growth factor saporin;mitoxantrone;mofalotene;molgramostim; Monoclonal antibodies, human chorionic gonadotropin;monophosphoryl lipid A + myobacterium cell wall sk;mopidamol;multidrug resistance gene inhibitors;multitumor suppressor 1-based therapeutics;mustard anticancer drugs;mycaperoxide B;mycobacterium cell wall extract;myriaporone;N-acetyldinaline;N-substituted benzamides;nafarelin;nagressip;naloxone + pentazocine;napavine;naphterpine;nartograstim;nedaplatin;nemorubicin;neridronic acid;neutral endopeptidase;nilutamide;nisamycin;monoacid Nitric oxide modulators;Nitric oxide antioxidants;Nitrulline;O6 benzylguanine;Octreotide;Oxenone;Oligonucleotides;Onapristone;Ondansetron;Ondansetron;Oracin;Oral cytokine inducers;Ormaplatin;Osateron;Oxaliplatin;Oxaunomycin;Paclitaxel;Paclitaxel analogs;Paclitaxel derivatives;Palaumin;Palmitoyl rhizoxin;Pamidronic acid;Panaxytriol;Panomyphen;Parabactin;Pazeliptin;Pegaspargase;Perdecine;Pentosan polysulfate sodium;Pentostatin;Pentrozole;Perflubron;Perphosphamide;Perillyl alcohol;Phenazinomycin;Phenylacetate;Phosphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Pracetin A;Pracetin B;Plasminogen activator inhibitors;Platinum complexes;Platinum complexes;Platinum triamine complexes;Porfimer sodium;Porfiromycin;Prednisone;Acridone;Prostaglandin J2;Proteasome inhibitors;Protein A-based immunomodulators;Protein kinase C inhibitors;Protein kinase C inhibitors, microalgae;Protein tyrosine phosphatase inhibitors;Purine nucleoside phosphorylase inhibitors;Purpurin;Pyrazolo acridine (pyrazoloaeridine); pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; rasGAP inhibitors; demethylreterolipidin; rhenium Re186 etidronate; rhizoxin; ribozymes; RH retinamide; logretimide; rohitukin; romurtide; roquinimex; rubiginone BI; ruboxil; safingol; saintopine; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetics; semustine; senescence-derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding proteins; ;Sizofiran;Sobuzoxane;Borocaptate sodium;Sodium phenylacetate;Sorberol;Somatomedin binding protein;Sonermin;Sparfosic acid;Spicamycin D;Spiromustine;Splenopentin;Spongistatin 1;Squalamine;Stem cell inhibitors;Stem cell division inhibitors;Stypiamide;Stromelysin inhibitors;Sulfinosine;Hyperactive vasoactive intestinal peptide antagonists;Sladista;Suramin;Swainsonine;Synthetic glycosaminoglycans;Talimustine; Tamoxifen methiodide;Tauromustine;Tazarotene;Tecogalan sodium;Tegafur;Terlapyrylium;Telomerase inhibitors;Temoporfin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Taliblastine;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin;Thymopoietin receptor agonists;Thymotrin;Thyroid-stimulating hormone;Ethyl etiopurinse;Tirapazamine;Titanocene dichloride bichloride); topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, erythrocyte gene therapy; veraresol; veramine; verdin systems; verteporfin; vinorelbine; vinxartin; vitaxin; vorozole; zanoterone; zeniplatin; zilascorub; and zinostatin stimalamer.

[0185] It is a further aspect of the present disclosure that the compounds of the present disclosure can be administered with chemical agents that are understood to mimic the effects of radiation therapy and / or function by directly contacting DNA.Drugs that can be used in combination with the compounds of the present 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] Additionally, the present disclosure provides methods of treating cancer using compounds of the present disclosure as an alternative to chemotherapy or radiation therapy alone where chemotherapy or radiation therapy have proven or may prove too toxic, e.g., resulting in unacceptable or intolerable side effects for the subject being treated. The individual being treated may optionally 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 the present disclosure can also be used in an in vitro or ex vivo manner, such as for the treatment of certain cancers, including, but not limited to, leukemia and lymphoma, and such treatments include autologous stem cell transplantation. This can include a multi-step method of harvesting the subject's autologous hematopoietic stem cells to remove all cancer cells from them, then administering to the subject an effective amount of a compound of the present disclosure to eradicate the subject's remaining bone marrow cell population, and then infusing the stem cell transplant back into the subject. Bone marrow function is then restored, and supportive care is provided while the subject is recovering.

[0188] The method for treating cancer can further comprise the administration of the compound of the present disclosure and an additional therapeutic agent, or its pharma- ceutically acceptable salt or hydrate.In one embodiment, the composition comprising the compound of the present disclosure is administered simultaneously with the administration of one or more additional therapeutic agents, which may be part of the same composition, or may be in a different composition from the composition comprising the compound of the present disclosure.In another embodiment, the compound of the present disclosure is administered before or after the administration of another therapeutic agent.

[0189] In the present methods of treating cancer, the other therapeutic agent may be an antiemetic agent. Suitable antiemetic agents include , including, but not limited to, metoclopramide, domperidone, prochlorperazine, prolnetazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methalathal, metopimazine, nabilone, oxyperundyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, and tropisetron.

[0190] In one embodiment, the antiemetic agent 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, molgramostin 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, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprozine, diphenoxylate, fentanyl, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone, and propoxyphene. Suitable non-opioid analgesics include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflucinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam, and sulindac. Includes:

[0192] In yet another embodiment, the other therapeutic agent may be an anti-anxiety agent. Suitable anti-anxiety agents include, but are not limited to, buspirene and benzodiazepines such as diazepam, lorazepam, oxapam, chlorazepate, clonazepam, chlordiazepoxide, and alprazolam.

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

[0194] The compounds of the present disclosure also provide therapeutic benefit in models of peripheral neuropathy, such as CMT.HDAC6 inhibitors have been found to cross the blood-nerve barrier and rescue the phenotype observed in transgenic mice that show symptoms of distal hereditary motor neuropathy.Administering HDAC6 inhibitors to symptomatic mice increases acetylated α-tubulin levels, restores proper mitochondrial movement and axonal transport, and increases muscle nerve regeneration.Other peripheral neuropathy includes, but is not limited to, giant axonal neurodegeneration, and various forms of mononeuropathy, polyneuropathy, autonomic neuropathy, and neuritis.

[0195] The compounds of the present disclosure can be administered to treat a nervous system disorder by administering an effective amount of a compound of the present disclosure to treat the nervous system disorder, or by administering a pharmaceutical composition comprising an effective amount of a compound of the present disclosure to treat the nervous system disorder. The present invention is useful for treating nervous system diseases by administering the compound of formula (I) to the subject. The nervous system diseases that can be treated include, but are not limited to, Huntington's disease, lupus, schizophrenia, multiple sclerosis, muscular dystrophy, pallidoluysian atrophy (DRRLA), spinal-bulbar muscular atrophy (SBMA) and spinocerebellar ataxia (SCA1, SCA2, SCA3 / MJD (Machado-Joseph disease), SCA6 and SCA7), drug-induced movement disorder, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, Pick's disease, Alzheimer's disease, and Alzheimer's disease. These conditions include Marr's disease, dementia with Lewy bodies, corticobasal degeneration, dystonia, myoclonus, Tourette's syndrome, tremor, chorea, restless legs syndrome, Parkinson's disease, Parkinsonian syndrome, anxiety, depression, psychosis, bipolar disorder, Friedreich's ataxia, Fragile X syndrome, spinal muscular dystrophy, Rett syndrome, Rubinstein-Taybi syndrome, Wilson's disease, multi-infarct states, CMT, GAN and other peripheral neuropathies.

[0196] In certain embodiments, the nervous system disease 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 inherited neuropathies affecting approximately 1 per 2,500 individuals in the United States. CMT affects both motor and sensory nerves, which can result in foot drop and a chicken-like gait with frequent ups and downs. Mutations in small heat shock protein 27 (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). Expression of mutant HSPB1 induces severe axonal transport defects by reducing acetylated α-tubulin levels. Pharmacological inhibition of histone deacetylase 6 (HDAC6)-induced α-tubulin deacetylation, caused by the HDAC6i tubastatin A, corrects the axonal transport defects 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 mutant HSPB1-induced neuropathy, providing promising prospects for HDAC6 inhibitors as a therapeutic strategy for inherited axonal degeneration. Compounds of the present disclosure show potent HDAC6 isoform inhibition, high HDAC6 selectivity, and excellent α-tubulin acetylation in various cell lines.

[0198] Thus, in another embodiment, the nervous system disease is Charcot-Marie-Tooth disease.

[0199] The compounds of the present disclosure can also be used together with a second therapeutic agent in the method of treating conditions, diseases, damage to CNS.Such second therapeutic agent is a drug known in the art to treat certain conditions, diseases or damage, for example, but not limited to, lithium in treating mood disorders, estradiol benzoate and nicotinamide in treating Huntington's disease.

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

[0201] TBI produces several lesions, including axonal injury, cell death, contusion, and inflammation. The inflammatory cascade is characterized by proinflammatory cytokines and activation of microglia that may exacerbate other lesions. Although the role of inflammation in TBI is well established, there are no effective anti-inflammatory therapies currently available for the treatment of TBI.

[0202] Several known HDAC inhibitors have been shown to be effective in treating acute and chronic neurodegenerative injuries and diseases, e.g. For example, HDACIs have been found 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-bulbar muscular atrophy (SBMA). Recent studies in experimental pediatric TBI have reported that reduced hippocampal CA3 histone H3 acetylation persists for hours to days after injury. These changes contribute to the documented upstream excitotoxicity and stress cascades associated with TBI. HDACIs have also been reported to have anti-inflammatory effects that act through acetylation of non-histone proteins. It was found that the HDAC6-selective inhibitor 4-dimethylamino-N-[5-(2-mercaptoacetylamino)pentyl]benzamide (DMA-PB) could increase histone H3 acetylation and reduce the microglial inflammatory response after traumatic brain injury in rats, demonstrating that HDACIs can be used as therapeutic agents to inhibit neuroinflammation associated with TBI.

[0203] Thus, the compounds of the present disclosure are also useful in the treatment of inflammation and stroke, as well as in the treatment of autism and autism spectrum disorders. The compounds of the present disclosure can also be used to treat parasitic infections (e.g., malaria, toxoplasmosis, trypanosomiasis, helminthiasis, protozoan infections) (Andrews et al. Int. J. Parasitol. 2000, 3). 0(6), pp. 761-768.

[0204] In certain embodiments, the compounds of the present disclosure can be used to treat malaria.The compounds of the present disclosure can be co-administered with antimalarial compounds selected from the group consisting of arylamino alcohols, cinchona alkaloids, 4-aminoquinolines, folic acid synthesis inhibitors type 1 or type 2, 8-aminoquinolines, antibacterial agents, peroxides, naphthoquinones and iron chelators.Antimalarial compounds include, but are not limited to, quinine, quinidine, mefloquine, halfantrine, chloroquine, amodiaquine. , proguanil, chloroproquanil, pyrimethamine, primaquine , 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]quinoline succinate (WR238,605), tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones, artemether, areether, artesunate, artelic acid, atovaquone, and deferrioxamine. In one embodiment, the antimalarial compound is chloroquine.

[0205] The compounds of the present disclosure can also be used as imaging agents. In particular, by providing radiolabeled, isotopically labeled, or fluorescently labeled HDACIs, these labeled compounds can image HDACs, tissues and tumors that express HDACIs. The labeled compounds of the present disclosure can also image patients suffering from cancer or other HDACI-mediated diseases, such as stroke, by administering an effective amount of the labeled compounds or a composition containing the labeled compounds. In one embodiment, the labeled HDACIs can emit positron radiation and are suitable for use in positron emission tomography (PET). Typically, the labeled compounds of the present disclosure are used to identify tissues or target regions that express HDACIs at high concentrations. The extent of accumulation of the labeled HDACIs can be quantified using known methods for quantifying the amount of radioactive light emitted. In addition, the labeled HDACIs can contain fluorophores or similar reporters that can track the movement of specific HDACI 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 radiological device, such as PET, SPECT, gamma cameras, MRI and similar devices. The isotopes include tritium ( 3 H) and carbon ( 11 C). The HDACIs of the present disclosure also contain Fluorine for imaging methods ( 18 F) and iodine ( 123 Typically, the labeled compounds of the present disclosure include 11 C label, i.e. 11 C-alkyl groups containing methyl groups, or 18 F, 123 I, 125 I, 131 I, or combinations thereof.

[0207] Fluorescently labeled compounds of the present disclosure can also be used in the imaging methods of the present disclosure. Such compounds have FITC, carbosilamine moieties, or other fluorophores that allow visualization of HDAC proteins in vitro.

[0208] The labeled compounds and methods of use of the present disclosure may be for use in vivo, particularly with humans, using bodily fluids and cell samples, as well as in vitro, such as for diagnostic and research applications. Imaging methods are discussed in WO03 / 060523. Typically, the methods involve contacting cells or tissues with a compound of the present disclosure that is radiolabeled, isotopically labeled, fluorescently labeled, or tagged (such as tagged with biotin), and for the visualization method used, i.e., radiographic image, sufficient to provide about 1 to about 30 mCi of the radiolabeled compound. Depending on the amount required, this may involve producing a radiographic image, a fluorescent image or a similar image type.

[0209] The imaging methods include the use of labeled compounds of the present disclosure capable of producing a target to background ratio of emission intensity of at least 2:1, or a target to background ratio of emission intensity of about 5:1, about 10:1 or about 15:1.

[0210] In some methods, the labeled compounds of the present disclosure are rapidly excreted from the tissues of the body to avoid long-term exposure of the radiolabeled compounds administered to an individual to radiation. In some embodiments, the labeled compounds of the present disclosure are excreted from the body in less than about 24 hours. In some embodiments, the labeled compounds of the present disclosure are excreted 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 present disclosure are excreted from the body in about 60 minutes to about 120 minutes.

[0211] In addition to isotopically and fluorescently labeled derivatives, the present disclosure also embodies the use of derivatives that contain tags (such as biotin) to identify biomolecules associated with HDAC isoforms of interest for diagnostic, therapeutic or research purposes.

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

[0213] Despite the success of modern transplantation programs, nephrotoxicity, cardiovascular disease, diabetes, and hyperlipidemia associated with current treatment regimens, as well as the emergence of post-transplant malignancies and graft loss due to chronic rejection, have driven efforts to achieve long-term allograft function associated with minimal immunosuppression. Similarly, the emergence of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is increasing. Animal studies have shown that T regulatory cells (Tregs), which express the forkhead transcription family member Foxp3, are important in limiting autoreactive and alloreactive immunity. Furthermore, Tregs can be adoptively transferred into naive hosts to realize therapeutic benefit after induction by costimulatory blockade, immunosuppression, or other strategies. However, in clinical trials, attempts to generate enough Tregs to maintain their suppressive function after transfer have been unsuccessful. Mouse studies have shown that HDACIs limit immune responses, at least in significant part, by increasing the suppressive function of Tregs (R. Tao et al., Nat Med, vol. 13, pp. 1299-1307). (2007)), and selective targeting of HDAC6, among others, has been shown to be effective in this regard.

[0214] With organ transplantation, rejection begins to develop immediately after a few days of transplantation, so prevention of rejection, rather than treatment, is a prime consideration. The reverse of autoimmunity is true when patients present with disease that is already causing problems. Therefore, we evaluate whether HDAC6- / - mice treated with low doses of RPM (rapamycin) for 14 days show signs of resistance to induction and development of chronic rejection in a clinical transplant population, with continued significant loss of long-term graft function. Tolerance is evaluated by testing whether mice with long-term viable allografts reject subsequent third-party heart grafts and accept additional donor allografts without any immunosuppression, as can occur with the use of nonselective HDACIs and RPMs. These in vivo studies are based on the ELI method, which uses recipient lymphocytes challenged with donor cells. This involves assessment of SPOT and MLR activity. Protection against chronic rejection is assessed by analysis of host anti-donor humoral responses, as well as graft-associated arteriosclerosis and interstitial fibrosis in long-term surviving allograft recipients.

[0215] The importance of targeting HDAC6 will be evaluated in additional transplantation models that pursue biochemically relevant readouts as monitored clinically. Thus, the effect of HDAC6 in targeting in kidney transplant recipients (monitoring BUN, which is proteinuria) and islet allografts (monitoring blood glucose levels) will be evaluated. Kidney transplantation is the most common organ transplantation performed, and since the kidney performs multiple functions, such as regulating acid / base metabolism, blood pressure, and erythropoiesis, efficacy in this model will be shown to be available for HDAC6 targeting. Similarly, islet transplantation remains a large unmet need, considering that clinical islet allografts are usually lost after the first year or two after transplantation. Having a safe and non-toxic means to extend islet survival without CNI maintenance therapy would be an important advance. Transplantation studies will also be strengthened by the use of mice with floxed HDAC6. Existing Foxp3-Cre mice will be used to test the impact of deleting just HDAC6 in Tregs. This approach can be expanded to target HDAC6, for example, in T cells (CD4-Cre) and dendritic cells (CD11c-Cre). Using tamoxifen-regulated Cre, the importance of induced HDAC6 for engraftment maintenance (relevant for short-term vs. HDAC6I maintenance therapy) is assessed by administering tamoxifen at various times post-engraftment to induce HDAC6 deletion.

[0216] Autoimmunity will also be investigated. In this case, blocking existing disease is particularly important and targeting HDAC6 can be effective without any requirement for additional treatment (as opposed to the short-term low-dose RPM required in the highly invasive full MHC mismatched transplantation model). Studies in mice with colitis show that HDAC6- / - Tregs are more effective at controlling disease than WT Tregs and that Tubacin can rescue mice if treatment is started once colitis has developed. These studies will be expanded by assessing whether deletion of HDAC6 in Tregs (Foxp3 / Cre) versus T cells (CD4=Cre) versus DCs (CD11c-Cre) differentially affects the onset and severity of colitis. Similarly, control of colitis will be assessed by inducing HDAC6 deletion at various intervals after onset of colitis with tamoxifen-regulated Cre.

[0217] It is anticipated that the compound will demonstrate anti-arthritic efficacy in a collagen-induced arthritis model in DBA1 / J mice. DBA1 / J mice (male, 7-8 weeks) will be used in this study, with 8 animals per group. Systemic arthritis will be induced by the administration of type II bovine collagen and and CFA, and an IFA booster injection on day 21. Compounds of the present disclosure are administered at 50 mg / kg and 100 mg / kg on day 28 for two consecutive weeks, and the effects are determined from the mean arthritis score versus days of treatment data.

[0218] Despite efforts to avoid graft rejection by matching host-donor tissue types, in the majority of transplant procedures immunosuppressive treatment is critical to the survival of the donor organ in the host. A variety of immunosuppressive agents have been used in transplant procedures, including azathioprine, methotrexate, cyclophosphamide, FK-506, rapamycin and corticosteroids.

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

[0220] Therapeutically effective amounts of the compounds of the present disclosure can be used for immunosuppression, including, for example, to prevent organ rejection or graft-versus-host disease, and to treat 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, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, dermatomyositis, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, arthritis (rheumatoid arthritis, chronic progressive arthritis (arthritis chronic progrediente and osteoarthritis) and rheumatic diseases, autoimmune hematological disorders (hemolytic anemia, aplastic anemia, true erythrocytic anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener's 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 mellitus (type I diabetes), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis.

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

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

[0223] In this method, a therapeutically effective amount of one or more compounds of the present disclosure, which are usually formulated according to medical practice, is administered to a person in need thereof.Whether such treatment is indicated depends on each individual case and is dependent on medical assessment (diagnosis) that takes into account the signs, symptoms and / or dysfunctions present, the risk of developing certain signs, symptoms and / or dysfunctions, and other factors.

[0224] The compounds of the present disclosure can be administered by any suitable route, for example, orally, bucally, by inhalation, topically, sublingually, rectally, vaginally, intravesically, or intrathecally via lumbar puncture, transurethrally, nasally, transdermally, i.e., transdermally or parenterally (intravenously, intramuscularly, subcutaneously, intracoronary, intradermal, intramammary, intraperitoneally, intraarticular, intrathecal, Administration can be by intravenous administration (including retrobulbar, intrapulmonary injection and / or surgical implantation at specific sites). Parenteral administration can be accomplished using a needle or syringe or using high pressure techniques.

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

[0226] The toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined, for example, by LD 50 (the dose at which 50% of the population is lethal) and ED 50The dose that is therapeutically effective in 50% of the population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and this index is defined as the LD 50 and ED 50 Therapeutic indices are expressed as a ratio between the ED and the ED. Compounds that exhibit large therapeutic indices are preferred. Data obtained from such procedures can be used to formulate a range of dosages for use in humans. The dosages are chosen so that they are consistent with the ED with little or no toxicity. 50 It is preferred that the therapeutically effective amount of the compound will fall within a range of systemic circulating concentrations that includes: 1) a therapeutically effective amount of at least 100 mg / kg / day, 2) a therapeutically effective amount of at least 100 mg / kg / day, and 3) a therapeutically effective amount of at least 100 mg / kg / day. Dosages may vary within this range depending upon the dosage form employed and the route of administration utilized. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0227] The therapeutically effective amount of the compound of the present disclosure required for use in treatment varies according to the nature of the condition to be treated, the time period of its desired activity, and the age and condition of the patient, and is ultimately determined by the attending physician.Dosage amount and interval can be individually adjusted to achieve the plasma level of HDACI sufficient to maintain the desired therapeutic effect.Desired dosage can be conveniently administered as a single dose or multiple doses administered at appropriate intervals, for example, as 1, 2, 3, 4 or more divided doses per day.Multiple doses are often desirable or necessary. For example, compounds of the disclosure can be administered at the following frequencies: 4 doses delivered as 1 dose per day, 4 days apart (q4d×4); 4 doses delivered as 1 dose per day, 3 days apart (q3d×4); 1 dose per day, 5 days apart (qd×5); 1 dose per week for 3 weeks (qwk3); 5 doses per day, with 2 days of rest, and another 5 doses per day (5 / 2 / 5); or any dosing regimen determined to be suitable for the situation.

[0228] The dosage of a composition comprising a compound of the present disclosure, or a composition containing the same, can be about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight. The dosage of the composition may be, but is not limited to, about 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 / The dosage may be any amount including 100 mg / kg or 200 mg / kg. The dosage amounts above are exemplary of the average case, but there may be individual cases in which a higher or lower dosage may be beneficial, and such are within the scope of this disclosure. In practice, the physician will determine the actual dosage regimen that is most suitable for an individual patient, which may vary with the age, weight and response of the particular patient.

[0229] The compounds of the present disclosure used in the methods of the present disclosure are typically administered in an amount 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 present disclosure can be administered in an amount 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, including all doses between 0.005 and 500 milligrams.

[0230] The compound of the present disclosure is usually administered in a mixture containing a pharmaceutical carrier selected with respect to intended administration route and standard pharmaceutical practice.The pharmaceutical composition for use according to the present disclosure is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of the compound of the present disclosure.

[0231] The term "carrier" refers to a diluent, adjuvant or excipient with which the compound of the present disclosure is administered. Such pharmaceutical carriers can be liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickening agents, lubricants and coloring agents can be used. Pharmaceutically acceptable carriers are sterile. When the compound of the present disclosure is administered intravenously, water is the carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injection solutions. Suitable pharmaceutical carriers include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. The compositions of the invention, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0232] The present disclosure encompasses the preparation and use of solvates of the compounds of the present disclosure. Solvates generally do not significantly alter the physiological activity or toxicity of the compound and can function as pharmacological equivalents as such. The term "solvate" as used herein refers to a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule, such as a disolvate, a monosolvate or a hemisolvate, in which the ratio of the solvent molecule to the compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate may be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solvent phase and isolatable solvates. The compounds of the present disclosure may exist as solvated forms with pharma-ceutically acceptable solvents, such as water, methanol and ethanol, and the present disclosure is intended to include both solvated and unsolvated forms of the compounds of the present 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 known in the art. For example, see M. Caira et al., J. Pharmaceut. Sci., Vol. 93(3):601-611, which describes the preparation of solvates of fluconazole with ethyl acetate and with water. 2004). The preparation of similar solvates, hemisolvates, hydrates, etc. is described in van Tonder et al., AAPS Pharm. Sci. Tech., Vol. 5(1): Paper 12 (2004) and and AL Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting method for preparing a solvate includes dissolving a compound of the present disclosure in a desired solvent (organic, water, or a mixture thereof) at a temperature of greater than 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, for example, filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in the solvate crystals.

[0233] These pharmaceutical compositions can be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Appropriate formulations depend on the route of administration selected. When a therapeutically effective amount of the compound of the present disclosure is administered orally, the composition will usually be in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition can further contain a solid carrier such as gelatin or an adjuvant. The tablets, capsules, and powders contain about 0.01% to about 95%, preferably about 1% to about 50%, of the compound of the present disclosure. When administered in liquid form, a liquid carrier such as water, petroleum, or oil of animal or vegetable origin can be added. The liquid form of the composition can further contain a saline solution, dextrose or other saccharide solution, or 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 the present disclosure.

[0234] When a therapeutically effective amount of the disclosed compound is administered by intravenous, cutaneous or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, taking into consideration pH, isotonicity, stability, etc., is within the skill of the art. A preferred composition for intravenous, cutaneous or subcutaneous injection usually contains an isotonic vehicle. The disclosed compound may be infused with other fluids over an interval of 10 to 30 minutes or over a period of several hours.

[0235] The compounds of the present disclosure can be easily combined with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the active agent to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compounds of the present disclosure to solid excipients, grinding the resulting mixture as necessary, and processing the mixture of granules after adding suitable auxiliary agents, if desired, to obtain the core of tablets or dragees. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrants can be added.

[0236] The compound of the present disclosure can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.The preparation for injection can be provided in unit dosage form, for example, in ampoules or in multi-dose containers with added preservative.The composition can take the form of suspension, solution or emulsion in oily or aqueous vehicle, and can contain formulation agents such as suspending agents, stabilizing agents and / or dispersing agents.

[0237] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. In addition, the suspension of the compound of the present disclosure can be prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. If necessary, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound, allowing the preparation of highly concentrated solutions. Alternatively, the composition can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0238] The compounds of the present disclosure can also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases.In addition to the formulations described above, the compounds of the present disclosure can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compounds of the present disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in acceptable oil), or ion exchange resins.

[0239] In particular, the compounds of the present disclosure can be administered orally, bucally 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 can be prepared with pharma- ceutically acceptable additives, such as suspending agents.The compounds of the present disclosure can also be parenterally injected, for example, intravenously, intramuscularly, subcutaneously or intracoronarily.For parenteral administration, the compounds of the present disclosure are best used in the form of a sterile aqueous solution, which may contain other substances, for example, salts, or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.

[0240] As an additional embodiment, the present disclosure includes a kit that includes one or more compounds or compositions packaged in a manner that facilitates their use to carry out the method of the present disclosure. In a simple embodiment, the kit includes a compound or composition described herein that is useful for carrying out the method (e.g., a composition that includes a compound of the present disclosure and an optional second therapeutic agent) packaged in a container such as a sealed bottle or container, with a label attached to the container or included in the kit that describes the use of the compound or composition to carry out the method of the present disclosure. Preferably, the compound or composition is packaged in a unit dosage form. The kit can include a suitable device for administering the composition by the intended route of administration, such as a syringe, drip bag, or patch. In another embodiment, the compound is a lyophilizate. In this example, the kit can further include an additional container that contains a solution useful for reconstituting the lyophilizate.

[0241] The compounds of the present disclosure demonstrate HDAC6 potency and improved BEI and selectivity for HDAC1 and HDAC8 compared to previous compounds. The improved properties of the compounds, particularly the improved BEI and reduced potency at HDAC8, indicate that the compounds are useful for applications such as, but not limited to, immunosuppressants and neuroprotectants. For example, the compounds of the present disclosure typically have binding affinities (IC) for HDAC6 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 ). EXAMPLES

[0242] General synthesis and procedures All starting materials and solvents were purchased from commercial suppliers at reagent purity and were used as received without any further purification unless otherwise noted. Dry solvents used as media in moisture-sensitive reactions were purchased in anhydrous grade from Sigma-Aldrich and handled under argon. All reactions were carried out under inert (argon) atmosphere and in dry conditions. Microwave reactions were carried out in a Biotage Initiator microwave reactor. Reactions were monitored on silica gel coated glass plates (TLC LuxPlate Silica Gel 60F 254 All reactions were monitored by thin layer chromatography on a CombiFlas (Merck) at 254 nm and visualized using appropriate dyes. Where indicated, synthetic intermediates were synthesized using appropriate solvent mixtures on a CombiFlas The final product was purified by flash chromatography on 230-400 mesh silica gel on a 100-h 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 / H 2 O, 30 min; 100% MeOH, 5 min; 100–25% MeOH / H 2 O, 4 minutes. Method 2: 8~100% MeOH / H 2 O, 30 min; 100% MeOH, 5 min; 100–8% MeOH / H 2 Method 3: 0% MeOH, 5 min; 0–100% MeOH / H 2 O, 25 min; 100% MeOH, 5 min; 100–0% MeOH / H 2 0, 4 min. Flow rate = 17 mL / min] with monitoring at 254 and 280 nm. Both solvents were spiked with 0.05% TFA. 1 H and 13 C NMR spectra were recorded at 400 MHz and 100.6 MHz using a Bruker DPX-400 or AVANCE-400 spectrometer, respectively. Chemical shifts (δ scale) are reported in parts per million (ppm) relative to TMS.1 H NMR spectra are reported in the following order: multiplicity and number of protons; 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). 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 HO / 0.05% TFA in MeOH; flow rate = 1.0 mL / min]. All compounds were tested with a purity of >95% as determined by HPLC analysis. Example 1 Synthesis of 5-(2-benzamidoethyl)-N-hydroxyisoxazole-3-carboxamide (SS-1-100) [ka]

[0243] SS-1-95: 3-butyn-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol) and PPh 3 (682 mg, 2.6 mmol) was added to a stirred solution of DEAD (525 mg, 2.6 mmol) under Ar protection at 0 °C. The resulting mixture was allowed to warm slowly to room temperature and stirred at the same temperature for 2.5 hours. The reaction was then 2 The mixture was quenched with O and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc / Hexene) to give the title compound as a white powder (370 mg, 93%). 1 H NMR (400 MHz, CDCl 3) 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 = 2.7Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 168.04, 134.05, 132.01, 123.39, 80.27, 70.26, 36.55, 18.36.

[0244] SS-1-97B: A stirred solution of SS-1-95 (180 mg, 0.9 mmol) in MeOH (5 mL) was added with N 2 H 4 (0.06 mL, 1.13 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Then, the participate was filtered off. The filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. The solution was concentrated under vacuum to give 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) was added TEA (0.37 mL, 2.7 mmol) and benzoyl chloride (252 mg, 1.8 mmol) at 0° C. The resulting mixture was then stirred at the same temperature for 30 min. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% EtOAc / Hexene) to give the title compound as a white powder (140 mg, 90%). 1 H NMR (400 MHz, acetone-d 6 ) 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 reactor, a solution of SS-1-97B (140 mg, 0.8 mmol) in EtOAc (2 mL) was added with NaHCO 3 (201 mg, 2.4 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (367 mg, 2.4 mmol) were added. The mixture was heated in a microwave reactor at 100° C. for 1 h. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-50% EtOAc / Hexene) to give the title compound as a colorless oil (140 mg, 61%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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, dissolve NaOH (160 mg, 4.0 mmol) in 50% aqueous NH 2The mixture was dissolved in 1:1 THF / MeOH (1.6 mL, ca. 50 equiv.). A solution of SS-1-99 (140 mg, 0.5 mmol) in 1:1 THF / MeOH (6 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 6N HCl and extracted with EtOAc (3×15 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The crude product was washed with EtOAc to give the desired product as a white powder (60 mg, 43%). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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 calculated value C 13 H 1 4 N 3 O 4 :[M+H] + , m / z 276.0979; measured value: 276.0984. Example 2 Synthesis of 5-(2-(3,4-dichlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-2-08) [ka]

[0247] SS-2-05: 3-butyn-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol) and PPh 3 (682 mg, 2.6 mmol) was added to a stirred solution of DEAD (525 mg, 2.6 mmol) under Ar protection at 0° C. The resulting mixture was allowed to warm slowly to room temperature and stirred for 2.5 h at the same temperature. The reaction was then subjected to H 2 The mixture was quenched with O and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc / Hexene) to give the title compound as a white powder (260 mg, 65%).

[0248] SS-2-06: To a stirred solution of SS-2-05 (260 mg, 1.3 mmol) in MeOH (5 mL) was added N2H4 (0.1 mL, 3.2 mmol). The resulting mixture was stirred at room temperature for 16 h. The precipitate was then filtered off and the filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. The solution was concentrated in vacuo to give the desired product as a white powder. The crude product was used directly in the next step. To a stirred solution of the intermediate in DCM (5 mL) at 0 °C was added TEA (0.54 mL, 3.9 mmol). ) and 3,4-dichlorobenzoyl chloride (543 mg, 2.6 mmol) were added. The resulting mixture was then stirred at the same temperature for 30 min. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc / Hexene) to give the title compound as a colorless solid (220 mg, 70%). 1 H NMR (400 MHz, CDCl 3) 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 reactor, a solution of SS-2-06 (220 mg, 0.9 mmol) in EtOAc (2 mL) was added with NaHCO 3 (227 mg, 2.7 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (408 mg, 2.7 mmol) were added. The mixture was heated in a microwave reactor at 100° C. for 1 h. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-80% EtOAc / Hexene) to give the title compound as a white solid (250 mg, 78%). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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, dissolve NaOH (224 mg, 5.6 mmol) in 50% aqueous NH 2 The mixture was dissolved in 1:1 THF / MeOH (2.0 mL, ca. 50 equiv.). A solution of SS-1-99 (250 mg, 0.7 mmol) in 1:1 THF / MeOH (10 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 6N HCl and extracted with EtOAc (3×15 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The crude product was dried over Et 2 Washing with O / EtOAc (10:1) afforded the desired product as a white powder (70 mg, 29%). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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 Cl 2 N 3 O 4 :[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-(but-3-yn-1-yl)isoindoline-1,3-dione (SS-1-95): 3-butyn-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol) and PPh 3 (682 mg, 2.6 mmol) was added to a stirred solution of DEAD (525 mg, 2.6 mmol) under Ar protection at 0° C. The resulting mixture was allowed to warm slowly to room temperature and stirred for 2.5 h at the same temperature. The reaction was then subjected to H 2 The mixture was quenched with O and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc / hexanes) to give the title compound as a white powder (370 mg, 93%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ 168.0, 134.1, 132.0, 123.4, 80.3, 70.3, 36.6, 18.4.

[0252] Synthesis of N-(but-3-yn-1-yl)-2-naphthamide (SS-3-62): To a stirred solution of SS-1-95 (215 mg, 1.08 mmol) in MeOH (5 mL), 2 H 4(0.1 mL, 2.7 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. Then, the precipitate was filtered off, and the filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. The solution was concentrated under vacuum to give 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) at 0° C., TEA (0.25 mL, 1.6 mmol) and 2-naphthoyl chloride (246 mg, 1.3 mmol) were added. The resulting mixture was then stirred at the same temperature for 30 min. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated under vacuum. Flash chromatography The crude product was purified by filtration (0-30% EtOAc / hexanes) to give the title compound as a white powder (170 mg, 70%, crude).

[0253] Synthesis of ethyl 5-(2-(2-naphthamido)ethyl)isoxazole-3-carboxylate (SS-2-64): In a microwave reactor, a solution of SS-2-62 (170 mg, 0.76 mmol) in EtOAc (2 mL) was added with NaHCO 3 (191 mg, 2.28 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (344 mg, 2.28 mmol) were added. The mixture was heated at 100° C. for 1 h in a microwave reactor. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-50% EtOAc / Hexanes) to give the title compound as a white solid (150 mg, 58%). 1 H NMR (400 MHz, CDCl 3) 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, CDCl 3 ) 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, dissolve NaOH (142 mg, 3.55 mmol) in 50% aqueous NH 2 The mixture was dissolved in 1:1 THF / MeOH (1.4 mL, ca. 50 equiv.). A solution of SS-3-64 (150 mg, 0.44 mmol) in 1:1 THF / MeOH (5 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 6N HCl and extracted with EtOAc (3×10 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The crude product was purified by flash chromatography (0-10% MeOH / DCM) and preparative HPLC (Method 2) and lyophilized to give the desired product as a white powder (15 mg, 10%). 1 H NMR (400 MHz, DMSO-d 6) 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 N 3 O 4 :[M+H] + , m / z 326.1135; measured value: 326.1137. Example 4 Synthesis of 5-(2-([1,1'-biphenyl]-3-carboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-67) [ka]

[0255] Synthesis of 2-(but-3-yn-1-yl)isoindoline-1,3-dione (SS-1-95): 3-butyn-1-ol (140 mg, 2.0 mmol), phthalimide (382 mg, 2.6 mmol) and PPh 3 (682 mg, 2.6 mmol) was added to a stirred solution of DEAD (525 mg, 2.6 mmol) under Ar protection at 0° C. The resulting mixture was allowed to warm slowly to room temperature and stirred for 2.5 h at the same temperature. The reaction was then subjected to H 2 The mixture was quenched with O and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc / hexanes) to give the title compound as a white powder (370 mg, 93%). 1 H NMR (400 MHz, CDCl 3) 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, CDCl 3 ) δ 168.0, 134.1, 132.0, 123.4, 80.3, 70.3, 36.6, 18.4.

[0256] Synthesis of N-(but-3-yn-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), 2 H 4 (0.1 mL, 2.7 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The precipitate was then filtered off, and the filtrate was quenched with water (5 mL) and acidified to pH 2 with 2N HCl. The solution was concentrated under vacuum to give 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) at 0° C. was added TEA (0.25 mL, 1.6 mmol) and [1,1′-biphenyl]-3-carbonyl chloride (280 mg, 1.3 mmol). The resulting mixture was then stirred at the same temperature for 30 min. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated under vacuum. Flash chromatography (0–30% Et The crude product was purified by elution with hexanes (OAc / hexanes) to give the title compound as a white powder (140 mg, 52%, crude).

[0257] Synthesis of ethyl 5-(2-([1,1'-biphenyl]-3-ylcarboxamido)ethyl)isoxazole-3-carboxylate (SS-3-65): In a microwave reactor, a solution of SS-3-63 (170 mg, 0.56 mmol) in EtOAc (2 mL) was added with NaHCO 3 (144 mg, 1.69 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (255 mg, 1.69 mmol) were added. The mixture was heated at 100° C. for 1 h in a microwave reactor. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-50% EtOAc / Hexanes) to give the title compound as a colorless oil (100 mg, 49%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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-ylcarboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-67): In a round-bottom flask, add NaOH (90 mg, 2.2 mmol) to 50% aqueous NH 2The mixture was dissolved in 1:1 THF / MeOH (0.9 mL, ca. 50 equiv.). A solution of SS-3-65 (100 mg, 0.27 mmol) in 1:1 THF / MeOH (4 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 6N HCl and extracted with EtOAc (3×10 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The crude product was purified by flash chromatography (0-10% MeOH / DCM) and preparative HPLC (Method 2) and lyophilized to give the desired product as an off-white powder (30 mg, 32%). 1 H NMR (400 MHz, DMSO-d 6 ) 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 N 3 O 4 :[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, a solution of 5-hexyn-1-ol (300 mg, 3.57 mmol) in EtOAc (5 mL) was added with NaHCO 3 (900 mg, 10.7 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (1.6 g, 10.7 mmol) were added. The mixture was heated at 100° C. for 1 h in a microwave reactor. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-80% EtOAc / Hexanes) to give the title compound as a colorless oil (680 mg, 96%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ 175.2, 160.3, 156.5, 101.8, 62.2, 61.3, 30.2, 23.3, 14.2.

[0260] Synthesis of ethyl 5-(3-bromopropyl)isoxazole-3-carboxylate (SS-4-08): A stirred solution of SS-4-07 (680 mg, 3.42 mmol) in DCM (30 mL) was added with CBr 4 (1.70g, 5.13mmol) and Ph 3P (1.35 g, 5.13 mmol) was added. The resulting mixture was then stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-40% EtOAc / Hexanes) to give the title compound as a colorless oil (850 mg, 83%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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): A stirred solution of SS-4-08 (464 mg, 2.85 mmol) in DMF (15 mL) was added with 3,4-dichlorophenol (850 mg, 3.41 mmol) and Cs at room temperature. 2 CO 3 (1.87 g, 5.70 mmol) was added. The resulting mixture was heated at 80° C. for 2 h. The reaction was diluted with saturated aqueous NH 4 The mixture was quenched with Cl (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-30% EtOAc / Hexanes) to give 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, CDCl 3 ) 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, add NaOH (150 mg, 3.72 mmol) to 50% aqueous NH 2 The mixture was dissolved in 1:1 THF / MeOH (1.5 mL, ca. 50 equiv.). A solution of SS-4-09 (160 mg, 0.47 mmol) in 1:1 THF / MeOH (6 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 2N HCl and extracted with EtOAc (3×10 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The crude product was purified by HPLC (Method 2) and lyophilized to give the desired product as a white powder (65 mg, 40%). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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 Cl 2 N 2 O 4 :[M+H] + , m / z 331.0247; measured value: 331.0264. Example 6 Synthesis of 5-(4-(5,6-dichloro-1H-indol-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, a solution of 5-hexyn-1-ol (200 mg, 2.0 mmol) in EtOAc (3 mL) was added with NaHCO 3(504 mg, 6.0 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (906 mg, 6.0 mmol) were added. The mixture was heated in a microwave reactor at 100° C. for 1 h. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (0-80% EtOAc / Hexanes) to give the title compound as a colorless oil (370 mg, 87%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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): A stirred solution of SS-3-86 (100 mg, 0.47 mmol) in DCM (5 mL) was added with CBr 4 (232mg, 0.47mmol) and Ph 3 P (184 mg, 0.47 mmol) was added. The resulting mixture was then stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-40% EtOAc / hexanes) to give the title compound as a colorless oil (90 mg, 89%). 1 H NMR (400 MHz, CDCl 3) 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, CDCl 3 ) 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-indol-1-yl)butyl)isoxazole-3-carboxylate (SS-3-92): A stirred solution of SS-3-88 (90 mg, 0.33 mmol) in DMF (3 mL) was added with 5,6-dichloro-1H-indole (56 mg, 0.30 mmol) and Cs at room temperature. 2 CO 3 (217 mg, 0.66 mmol) was added. The resulting mixture was heated at 80° C. overnight. The reaction was diluted with saturated aqueous NH 4 The mixture was quenched with Cl (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-30% EtOAc / Hexanes) to give the title compound as a colorless oil (90 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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-indol-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-3-94): In a round-bottom flask, dissolve NaOH (76 mg, 1.9 mmol) in 50% aqueous NH 2 The mixture was dissolved in 1:1 THF / MeOH (0.9 mL, ca. 50 equiv.). A solution of SS-3-92 (90 mg, 0.24 mmol) in 1:1 THF / MeOH (4 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 2N HCl and extracted with EtOAc (3×10 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The crude product was purified by HPLC (Method 2) and lyophilized to give the desired product as an off-white powder (35 mg, 39%). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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 N 3 O 3 Cl 2 :[M+H] + , m / z 368.0563; measured value: 368.0545. Example 7 Synthesis of 5-(4-(6-chloro-3,4-dihydroquinolin-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, a solution of 5-hexyn-1-ol (200 mg, 2.0 mmol) in EtOAc (3 mL) was added with NaHCO 3 (504 mg, 6.0 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (906 mg, 6.0 mmol) were added. The mixture was heated in a microwave reactor at 100° C. for 1 h. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-80% EtOAc / Hexanes) to give the title compound as a colorless oil (370 mg, 87%). 1 H NMR (400 MHz, CDCl 3) 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, CDCl 3 ) 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) at room temperature was added pyridinium chlorochromate (300 mg, 1.4 mmol). The resulting mixture was stirred at the same temperature for 2 h. Then, the excess solid was filtered off and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-60% EtOAc / Hexanes) to give the title compound as a colorless oil (130 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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. 13C NMR (100 MHz, CDCl 3 ) 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-dihydroquinolin-1(2H)-yl)butyl)isoxazole-3-carboxylate (SS-3-99): A stirred solution of SS-3-98 (130 mg, 0.62 mmol) and 6-chloro-1,2,3,4-tetrahydroquinoline (104 mg, 0.62 mmol) in EtOH / AcOH (5 mL / 0.5 mL) was added with NaBH(OAc) at room temperature. 3 (262.8 mg, 1.24 mmol) was added. The resulting mixture was then stirred at the same temperature overnight. The reaction was then diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution (5 mL) and extracted with DCM (3×10 mL). The organic layer was separated and washed with brine and 2 SO 4 The mixture was dried at rt and concentrated in vacuo The crude product was purified by flash chromatography (0-20% EtOAc / Hexanes) to give the title compound as a colorless oil (130 mg, 58%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3) 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-dihydroquinolin-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-01): In a round-bottom flask, dissolve NaOH (116 mg, 2.9 mmol) in 50% aqueous NH 2 The mixture was dissolved in 1:1 THF / MeOH (1.0 mL, ca. 50 equiv.). A solution of SS-3-99 (130 mg, 0.36 mmol) in 1:1 THF / MeOH (6 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 2N HCl and extracted with EtOAc (3×10 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The mixture was dried at rt and concentrated in vacuo. The crude product was purified by HPLC (Method 2) and lyophilized to give the desired product as an off-white powder (100 mg, 62%, TFA salt). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6) 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 N 3 O 3 Cl: [M+H] + , m / z 350.1266; measured value: 350.1251. Example 8 Synthesis of 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinolin-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, a solution of 5-hexyn-1-ol (200 mg, 2.0 mmol) in EtOAc (3 mL) was added with NaHCO 3 (504 mg, 6.0 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (906 mg, 6.0 mmol) were added. The mixture was heated in a microwave reactor at 100° C. for 1 h. After completion of the reaction, the precipitated solid was filtered off and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-80% EtOAc / Hexanes) to give the title compound as a colorless oil (370 mg, 87%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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) at room temperature was added pyridinium chlorochromate (300 mg, 1.4 mmol). The resulting mixture was stirred at the same temperature for 2 h. Then, the excess solid was filtered off and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (0-60% EtOAc / Hexanes) to give the title compound as a colorless oil (130 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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, CDCl 3) 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-dihydroquinolin-1(2H)-yl)butyl)isoxazole-3-carboxylate (SS-3-100): A stirred 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) in EtOH / AcOH (5 mL / 0.5 mL) was added with NaBH(OAc) at room temperature. 3 (262.8 mg, 1.24 mmol) was added. The resulting mixture was then stirred at the same temperature overnight. The reaction was then diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution (5 mL) and extracted with DCM (3×10 mL). The organic layer was separated and washed with brine and 2 SO 4 The mixture was dried at rt and concentrated in vacuo The crude product was purified by flash chromatography (0-20% EtOAc / Hexanes) to give the title compound as a colorless oil (100 mg, 42%). 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3) 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-dihydroquinolin-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-4-02): In a round-bottom flask, dissolve NaOH (89 mg, 2.2 mmol) in 50% aqueous NH 2 The mixture was dissolved in 1:1 THF / MeOH (0.9 mL, ca. 50 equiv.). A solution of SS-3-99 (100 mg, 0.28 mmol) in 1:1 THF / MeOH (4 mL) was added dropwise and stirring was continued for 30 min while warming to room temperature. The solution was neutralized with 2N HCl and extracted with EtOAc (3×10 mL). The organic layer was separated and washed with brine and diluted with Na 2 SO 4 The crude product was purified by HPLC (Method 2) and lyophilized to give the desired product as an off-white powder (100 mg, 75%, TFA salt). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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 calculated value C 19 H 24 N 3 O 3 Cl: [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]azepin-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 added slowly. The mixture was stirred at room temperature for 15 min, and then 1,6-dibromobutane (364 mg, 1.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. After completion of the reaction, 1N aqueous HCl was added to neutralize the pH to 6-7. The reaction solution was then extracted three times with EtOAc and water. The combined organic layer was separated, washed with water and brine, and Na 2 SO 4 The crude product was purified by column chromatography using a gradient of EtOAc / hexanes (1-3%) to give the desired product SS-1-49 as a colorless oil, which was used directly in the next step.

[0276] Synthesis of 2,8-dichloro-5-(hex-5-yn-1-yl)-10,11-dihydro-5H-dibenzo[b,f]azepine (SS-1-50): To a stirred solution of SS-1-49 (200 mg, 0.5 mmol) in xylene / DMF (2 / 2 mL) was added sodium acetylide suspension (0.2 mL, 18 wt% slurry in xylene) at room temperature under Ar protection. The mixture was then stirred at 40° C. overnight. After completion of the reaction, the reaction solution was extracted with EtOAc and water three times. The combined organic layer was separated and washed with water and brine, and the Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography using a gradient of EtOAc / hexanes (1-3%) to afford the desired product SS-1-50 as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 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]azepin-5-yl)butyl)isoxazole-3-carboxylate (SS-1-52): In a microwave reactor, a solution of SS-1-50 (100 mg, 0.30 mmol) in EtOAc (3 mL) was added with NaHCO 3 (75 mg, 0.90 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (135 mg, 0.90 mmol). was added. The mixture was heated in a microwave reactor at 100° C. for 1 h. After completion of the reaction, the precipitated solid was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography using a gradient of EtOAc / Hexanes (1-20%) to afford the desired product SS-1-52 as a light yellow oil. 1 H NMR (400 MHz, CDCl 3 ) 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]azepin-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide (SS-1-54): Solid NaOH (80 mg, 2.0 mmol) was dissolved in NH 2 The mixture was dissolved in a 50% aqueous solution of SS-1-52 (100 mg, 0.20 mmol) in 1:1 THF / MeOH (2 / 2 mL) at 0° C. for 30 min. to the above vigorously stirred hydroxylamine solution. After completion of the reaction, 1N aqueous HCl was added to neutralize the pH to 6-7. The mixture was then extracted three times with EtOAc and water. The combined organic layers were separated, washed with water and brine, and concentrated to 100% NaCl. 2 SO 4 The mixture was dried in MeOH (0.05% TFA) / H 2 The crude product was purified by preparative HPLC using an O (0.05% TFA) gradient (5 to 100%, Method 2) to afford the desired product SS-1-54 as a white powder. 1 H NMR (400 MHz, CDCl 3) 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 Cl 2 N 3 O 3 :[M+H] + , m / z 446 .1033;Actual value:446.1020. Example 10 HDAC isoform inhibition

[0279] IC of compounds of Examples 1 to 9 against 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. HDAC3 / NcoR2 complex was used for HDAC3 assay. Substrate for HDAC1, 2, 3, 6, 10 and 11 assay is a fluorescent peptide derived from p53 residues 379-382 (RHKKAc). Substrate for HDAC8 is a fluorescent diacylated peptide based on p53 residues 379-382 (RHKAcKAc). Acetyl-Lys(trifluoroacetyl)-AMC substrate was used for HDAC4, 5, 7 and 9 assay. Compounds were dissolved in DMSO and tested in IC50 mode at 10 doses with 3-fold serial dilutions starting at 30 μM. Control compound trichostatin A (TSA) was tested at 10 doses with 3-fold serial dilutions starting at 5 μM. IC 50 Values ​​were extracted by curve fitting to the dose / response slope. Assays were performed in duplicate and IC 50 Values ​​are the average of data from both experiments. material

[0281] Human HDAC1 (GenBank accession no. NM_004964): Full-length (MW=79.9 kDa) with a C-terminal GST tag expressed by the baculovirus expression system in Sf9 cells. The enzyme is in 50 mM Tris-HCl, pH 8.0, 138 mM NaCl, 20 mM glutathione, and 10% glycerol and is stable at -80°C for >6 months. Purity is >10% by SDS-PAGE. Specific activity is 0.01 mM in 25 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 Under assay conditions of 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 No. BC069243): Full-length (MW=159 kDa) with an N-terminal GST tag expressed by the baculovirus expression system in Sf9 cells. The enzyme is in 50 mM Tris-HCl, pH 8.0, 138 mM NaCl, 20 mM glutathione, and 10% glycerol and is stable at -80°C for >6 months. Purity is >90% by SDS-PAGE. Specific activity is 25 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 , and 50 U / μg (1 U=1 pmol / min) under assay conditions of 0.1 mg / ml BSA, 30 μM HDAC substrate and 5 ng / μl HDAC6, incubated at 30° C. for 60 minutes.

[0283] Substrates for HDAC1 and HDAC6: Acetylated peptide substrates for HDACs based on residues 379-382 of p53 (Arg-His-Lys-Lys(Ac)), the site of regulated acetylation by p300 and CBP acetyltransferases (lysines 381, 382) 1-6, are the best for HDACs among 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 99) Vol. 19, p. 1202; A. Ito et al., EMBO J., (2001) Vol. 20, p. 1331 pp. 1243; N. A. Barlev et al., Mal. Cell, (2001) 8, 1243; and A. Ito et al. , EMBO J., (2002) Volume 21, Page 6236.

[0285] Reaction buffer: 50mM Tris-HCl, pH8.0, 137mM NaCl, 2.7mM KCl, 1mM MgCl 2 , 1mg / ml BSA. Assay conditions

[0286] HDAC1: 75 nM HDAC1 and 50 μM HDAC substrate in reaction buffer, 1% DMSO final. Incubate at 30° C. for 2 hours. HDAC6: 12.6 nM HDAC6 and 50 μM HDAC substrate in reaction buffer, 1% DMSO final. Incubate at 30° C. for 2 hours. I C 50 Calculation of

[0287] I C 50 All values ​​are calculated automatically using GraphPad Prism version 5 and the formula for sigmoidal dose-response (variable slope): Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)*HillSlope)) where X is the log of the concentration and Y is the response, Y starts at the bottom and goes to the top with a sigmoidal shape. In most cases "Bottom" is set to 0 and "Top" is set to "<120%". This is the same as the four parameter logistic formula. IC 50 The curves can also be displayed in GraphPad Lines were drawn using Prism. The results are shown in Table 1B. [Table 1B-1] [Table 1B-2] Example 11 Screening of SS-2-08

[0288] The activity of SS-2-08 in several preclinical screening assays is presented in Table 2. SS-2-08 lacks Ames activity and shows good potency against HDAC6 and selectivity against HDAC1 and HDAC11. SS-2-08 was incubated with two strains of Salmonella typhimurium (TA98 and TA1537) in the presence and absence of mammalian microsomal enzymes (S9 mix) to examine the possible mutagenicity of this compound. No significant number of revertant colonies were observed against either strain, thus supporting the lack of mutagenicity of SS-2-08 under the conditions of the mini-Ames assay. SS-2-08 has an IC of >30 μM against hERG. 50 has. [Table 2] Example 12 cell culture

[0289] 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% NaHCO 3 Mouse neuroblastoma (N2a) cells were cultured in a 1:1 mixture of DMEM (Dulbecco's modified Eagle's medium) and F12 medium supplemented with 100 mM NaCl (Invitrogen) at 37°C and 7.5% CO. 2To split 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 dissected from the spinal cord and cultured in cold HBSS (MgCl 2 and CaCl 2 The cells were maintained in a 5% CO2-free ... , 10% fetal bovine serum (GreinerBio), 50 μg / mL streptomycin, 50 U / mL penicillin (Invitrogen), 0.045% NaHCO 3 N2a cells and DRG neurons were grown in a 1:1 mixture of DMEM and F12 medium supplemented with 100 mM NaCl (Invitrogen) and 1.6 μg nerve growth factor (Millipore). N2a cells and DRG neurons were treated overnight at 37°C with doses ranging from 10 nM to 1 μM of compound or an equal volume of DMSO (Sigma-Aldrich). Western blot analysis

[0290] Treated cells were washed with phosphate-buffered saline (PBS) and harvested using an EpiQuik Total Histone Extraction Kit (EpiGentek) according to the manufacturer's instructions. Tissues were excised from mice and snap frozen in liquid nitrogen. Tissue dissociation was performed by using tubes containing LysisMatrix D beads. Protein concentration was determined using a microBCA kit (Thermo Fisher Scientific Inc., Pittsburgh, PA, USA) according to the manufacturer's instructions. Samples containing equal amounts of protein were supplemented with reducing sample buffer (Thermo Scientific) and heated at 95°C for 5 min before separating the samples on a 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel. After electrophoresis, proteins were transferred to a polyvinylidene difluoride (PVDF) membrane (Millipore Corp., Bedford, MA, USA). Non-specific binding was blocked by incubating the membranes for 1 h at room temperature in 5% bovine serum albumin (BSA) diluted in Tris-buffered saline Tween (TBST), 50 mM TRIS, 150 mM NaCl, 0.1% Tween-20 (Applichem, Darmstadt, Germany), followed by overnight incubation with primary antibodies. Antibodies (diluted in TBS-T) were directed against 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 primary antibody signals were detected using secondary antibodies conjugated to alkaline phosphatase (anti-mouse or anti-rabbit, 1 / 5000, Sigma-Aldrich). Blots were stained with ECF substrate (Enhanced Chemical Fluorescence, GE The blots were visualized by adding 100% PBS (Millipore Healthcare, Uppsala, Sweden) and imaged on an ImageQuant LAS4000. Mild reblotting buffer (Millipore) was applied and the blots were stripped. The blots were 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) under humidified conditions at 37 °C and 5% CO. 2 It was grown in. Immunoblot

[0292] Cells were lysed in a buffer containing 280 mM NaCl, 50 mM Tris HCL PH 8.0, 0.5% Igepal, 5 mM MgCl2, 10% glycerol and 1X protease inhibitors (Roche), phosphatase inhibitors (Santa Cruz Biotechnology). The lysate was sonicated on ice for 8 minutes (2 cycles of 30 seconds, 30 seconds rest), then mixed with 6X gel loading buffer and sonicated for 5 minutes. The blots were then separated on 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 with a LI-COR Odyssey imaging system using both the 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-Acetyl-STAT3 (2523) were purchased from Cell signaling. Anti-PD-L1 (PA5-28115) was obtained from Thermo Scientific. Anti-FLAG (F1804) antibody was from 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, were increased in all of the conditions tested. See Figures 1-3. Example 14 cell culture

[0294] All cells were cultured in RPMI 1640 medium supplemented with 10% FBS, penicillin / streptomycin (50 U / ml), L-glutamine (2 mM) and 2-mercaptoethanol (50 μM) (complete medium) under humidified conditions at 37 °C and 5% CO. 2 It was grown in. Cytotoxicity assay

[0295] Cells were plated at the desired density in black, clear, flat-bottom 96-well plates. After 24 hours of cell growth, the medium was removed from all wells and fresh medium was added with fluorescent CellTox dye using the manufacture's protocol. The plates were then treated with the compound of interest at various concentrations of compound. A baseline reading was taken immediately after plating. The plates were then incubated for 24 hours before the next reading was taken, which was considered the 24 hour reading. SoftMax Pro Microplates paired with a Molecular Devices spectrophotometer (SpectraMax) Assay measurements were collected using Data Acquisition and Analysis software. HDAC assay

[0296] Cells were plated at a density of 10,000 cells / well in white, clear, flat-bottom 96-well plates overnight. After 24 hours, the plates were then treated with the desired concentration of the compound of interest and incubated at 37° C. and 5% CO 2 After incubation with the compounds, the developer was added to the substrate, mixed, and added directly to the plate according to the manufacture's protocol. 6 Plates were read immediately after plating for 1 hour and 15 minutes, with readings taken every 2 minutes using SpectraMax.

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

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

[0299] The cytotoxicity and HDAC activity inhibition of SS-2-08 in several cell lines was compared to known HDAC6 inhibitors, Nextulastat A and Tubastatin A. See Figures 10-13. Example 15 cell culture

[0300] Mouse melanoma SM1 cells were cultured in RPMI 1640 medium supplemented with 1% minimum essential media (MEM) non-essential amino acid solution, 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (P / S) and then incubated at 37 °C and 5% CO under humidified conditions. 2 It was grown in. ApoTox-Glo Triplex Assay® Controls

[0301] Assay controls digitonin (D141-100MG), ionomycin (I064-1MG) and mitomycin C (M4287-2MG) were purchased from Sigma. Control plate culture evaluation selected optimal control concentrations of HDACi for compound plating (30 μg / mL digitonin, 100 μM ionomycin and 25 μg / mL mitomycin). ApoTox-Glo Triplex Assay®

[0302] Mouse melanoma cells were treated with individual HDACi along with protocol recommended assay controls. Viability / toxicity reagent was added according to manufacturer's protocol. Fluorescence was measured at one wavelength 400Ex / 505Em (viability) and 485Ex / 520Em (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 known HDAC6 inhibitors Nextulastat A and Tubastatin A and pan-HDAC inhibitor LBH589. See Figures 14-16. Example 16 Study design

[0304] All animal studies involving mice were performed 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 administered 1.0 × 10 IgG1-positive mice suspended in 100 μL of 1 × phosphate-buffered saline (PBS). 6 SM1 melanoma cells were injected subcutaneously into the right flank. After subcutaneous injection, tumor growth was monitored until the tumor was easily palpable. Once palpable (5-8 mm in diameter), animals were then treated intraperitoneally with vehicle control or SS-2-08 at doses of 25 mg / kg and 50 mg / kg, three times a week. Tumor growth was recorded twice a week. When tumors reached 4000 mm 3 Mice were euthanized when tumor volume reached 100 mm. Values ​​collected were expressed as mean tumor volume (mm) for treatment group. 3 ) and standard deviation.

[0305] SS-2-08 reduced tumor growth of SM1 melanoma tumors in syngeneic mice, as shown in FIG.

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

[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 pharma- ceutically acceptable salt, solvate or prodrug thereof, wherein: X is [ka] is selected from the group consisting of R 1 is hydrogen and C 1~4 is selected from the group consisting of alkyl, R 2 is replaced as necessary 6 ~C 14 selected from the group consisting of aryl and aralkyl; R 3 is replaced as necessary 6 ~C 14 Aryl, optionally substituted 5-14 membered heteroaryl and -C(=O)NR d R e is selected from the group consisting of R 4a , R 4b , R 4e and R 4f is 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 1~6independently selected from the group consisting of haloalkyl and haloalkoxy; R 4c and R 4d is hydrogen and C 1~4 alkyl; or R 4c and R 4d together with the carbon atom to which they are attached form -C(=O)-, R 5a , R 5b , R 5c and R 5d is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; Z is -O-, -N(R 8 )- and -C(=O)-, or Z does not exist, R 8 is hydrogen, C 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 selected from the group consisting of aryl, aralkyl, optionally substituted 5-14 membered heteroaryl and heteroaralkyl; m is 0, 1 or 2; n is 1, 2, 3, 4, 5 or 6; [ka] represents a single or double bond, R a , R b , R d and R eis hydrogen, C 1~6 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 aryl, optionally substituted 5-14 membered heteroaryl, or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocycle; or R d and R e together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; R c is C 1~4 Alkyl, provided that: If Z is not present, R 3 is a bicyclic or tricyclic C 10~14 Aryl, 9-14 membered bicyclic or tricyclic heteroaryl, or -C(=O)NR d R e Provided that, The compound or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 2) The compound according to the above item 1, wherein X is X-1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 3) R 2 The compound according to item 1 or 2 above, wherein is optionally substituted phenyl, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 4) R 2 The compound according to item 1 or 2 above, wherein is optionally substituted 1-naphthyl, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 5) R 2The compound according to item 1 or 2 above, wherein is optionally substituted 2-naphthyl, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 6) The compound according to the above item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, wherein X is X-2. (Section 7) Item 7. The compound according to item 6 above, wherein Z is --O--, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 8) The compound according to the above item 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X is X-3. A drug or prodrug. (Section 9) The compound according to the above item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, wherein X is X-4. (Section 10) The compound according to the above item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, wherein X is X-5. (Section 11) Formula II: [ka] The compound according to the above item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, having the formula: R 6a , R 6b , R 6c , R 6d and R 6e is 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 3~6each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycle; R c is C 1~4 is alkyl, n is 1, 2 or 3; The compound or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 12) R 6a , R 6b , R 6c , R 6d and R 6e is 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 12. The compound according to claim 11, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, each independently selected from the group consisting of haloalkyl. (Section 13) R 6a , R 6b , R 6c , R 6d and R 6e But hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 Item 14: The compound according to item 12, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, each independently selected from the group consisting of alkoxy. Formula III: [ka] The compound according to the above item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, having the formula: R 7a , R 7b , R 7c , R 7d and R 7e is 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 each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycle; R c is C 1~4 is alkyl, n is 1, 2 or 3; The compound or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 15) R 7a , R 7b , R 7c , R 7d and R 7e is hydrogen, halogen, hydroxy, nitro, cyano, -NRa R b , -C(=O)NR a R b , -C(=O)R c , C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 15. The compound according to claim 14, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, each independently selected from the group consisting of haloalkyl. (Section 16) R 7a , R 7b , R 7c , R 7d and R 7e But hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 Item 17: The compound according to item 15, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, each independently selected from the group consisting of alkoxy. Formula IV: [ka] The compound according to the above item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, having the formula: 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 0 or 1; n is 1, 2 or 3; [ka] represents a single or double bond, The compound or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 18) m is 0, [ka] Item 18. The compound according to item 17, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, wherein represents a double bond. (Section 19) m is 1, [ka] Item 18. The compound according to item 17, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, wherein represents a single bond. (Section 20) Formula V: [ka] The compound according to the above item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, having the formula: R 5a and R 5c is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 independently selected from the group consisting of alkoxy; n is 1, 2 or 3; The compound or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 21) 21. The compound according to any one of the above items 1 to 20, wherein n is 1 or 2, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 22) 5-(2-benzamidoethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3,4-dichlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(2-naphthamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-([1,1'-biphenyl]-3-carboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(5,6-dichloro-1H-indol-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinolin-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 Zepin-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-bromobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-chlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-Hydroxy-5-(2-(4-methoxybenzamido)ethyl)isoxazole-3-carboxamide; 5-(2-(4-(dimethylamino)benzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-cyclopropylbenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3,4-difluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3-chloro-4-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-chloro-3-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3-(dimethylamino)benzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(3-(pyridin-3-yl)benzamido)ethyl)isoxazole-3-carboxamide; 5-(3-benzamidopropyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-(trifluoromethoxy)benzamido)ethyl)isoxazole-3-carboxamide; 5-(2-(4,5-dichloroindoline-1-carboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((6,7-dichloroisoquinolin-3-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((5,6-dichloro-1-methyl-1H-benzo[d]imidazol-2-yl)oxy)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-((trifluoromethyl)thio)benzamido)ethyl)isoxazole-3-carboxamide; 5-(4-(4,5-dichloroindolin-1-yl)-4-oxobutyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((6,7-dichloroquinolin-2-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(5,6-dichlorobenzo[d]thiazol-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(5,6-dichlorobenzo[d]oxazol-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-(trifluoromethyl)benzamido)ethyl)isoxazole-3-carboxamide; 2-(3-(hydroxycarbamoyl)isoxazol-5-yl)ethyl 4,5-dichloroindoline-1-carboxylate; 5-(2-((6,7-dichloronaphthalene-2-yl)amino)ethyl)-N-hydrochloride Roxyisoxazole-3-carboxamide; 5-(2-((5,6-dichlorobenzo[d]thiazol-2-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(phenanthridin-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-dihydroisoquinolin-2(1H)-yl)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-((5,6-dichloroisoquinolin-1-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-Hydroxy-5-(2-(2-phenylacetamido)ethyl)isoxazole-3-carboxamide; 2-(3-(hydroxycarbamoyl)isoxazol-5-yl)ethyl(3,4-dichlorophenyl)(methyl)carbamate; 5-(2-((5,6-dichloroisoquinolin-1-yl)oxy)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(N-butylbenzamido)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-(naphthalen-1-ylamino)propyl)isoxazole-3-carboxamide; N-hydroxy-5-(3-(quinolin-8-ylamino)propyl)isoxazole-3-carboxamide; 5-(4-(8-chloro-2-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-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-(naphthalen-1-yloxy)propyl)isoxazole-3-carboxamide; and N-Hydroxy-5-(3-(quinolin-8-yloxy)propyl)isoxazole-3-carboxamide Item 1. The compound according to item 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, selected from the group consisting of: (Section 23) A composition comprising the compound according to any one of the above items 1 to 22 or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and a pharma- ceutically acceptable excipient and / or carrier. (Section 24) (a) A compound according to any one of the above items 1 to 22, or a pharma- ceutically acceptable salt, solvate or prodrug thereof; (b) a second, useful in the treatment of a disease or condition in which inhibition of HDAC is beneficial; Therapeutic agents, and (c) Optional excipients and / or pharma- ceutically acceptable carriers. A composition comprising: (Section 25) 25. The composition according to item 24, wherein the second therapeutic agent comprises a chemotherapeutic agent useful for the treatment of cancer. (Section 26) A method for treating a disease or condition in which inhibition of HDAC is beneficial, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of paragraphs 1 to 22 above, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. (Section 27) 27. The method according to claim 26, wherein the HDAC is HDAC6. (Section 28) 27. The method according to claim 26, further comprising administering a therapeutically effective amount of a second therapeutic agent useful for treating the disease or condition. (Section 29) The method according to the above item 28, wherein the compound according to any one of the above items 1 to 22 or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and the second therapeutic agent are administered simultaneously. (Section 30) The method according to the above item 28, wherein the compound according to any one of the above items 1 to 22 or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and the second therapeutic agent are administered separately. (Section 31) 27. The method according to claim 26, wherein the disease or condition is cancer. (Section 32) 29. The method according to claim 28, wherein the disease is cancer and the second therapeutic agent is one or more of a chemotherapy agent, radiation, and immunotherapy. (Section 33) 29. The method according to claim 28, wherein the second therapeutic agent comprises radiation, and the radiation is optionally administered together with a radiosensitizer and / or a therapeutic agent. (Section 34) 27. The method according to claim 26, wherein the disease or condition is a nervous system disease, a neurodegenerative disorder, a peripheral neuropathy, a psychiatric illness or a traumatic brain injury. (Section 35) 27. The method according to claim 26, wherein the disease or condition is stroke. (Section 36) 27. The method according to claim 26, wherein the disease or condition is an inflammatory or autoimmune disease. (Section 37) 27. The method according to claim 26, wherein the disease or condition is Charcot-Marie-Tooth disease. (Section 38) Item 37. 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 the inflammation. (Section 39) 27. The method according to claim 26, wherein the disease or condition is autism or an autism spectrum disorder, including Rett syndrome. (Section 40) 27. The method according to claim 26, wherein the disease or condition is depression or bipolar disorder. (Section 41) 23. 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 a compound according to any one of items 1 to 22 above or a pharma- ceutically acceptable salt, solvate or prodrug thereof in an amount sufficient to increase the sensitivity of the cells to the radiotherapy and / or chemotherapy. (Section 42) 42. The method according to claim 41, wherein the cell is an in vivo cell. (Section 43) A method for producing immunosuppression, comprising the step of administering to an individual in need thereof an effective amount of the compound according to any one of items 1 to 22 above, or a pharma- ceutically 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 23. The compound according to any one of the above items 1 to 22, which is labeled with a radioisotope selected from I, a molecular tag, or a mixture thereof. (Section 45) The label is C 11 45. The compound according to claim 44, which contains a methyl group. (Section 46) 45. A radioimaging method, said method comprising the step of contacting a cell or tissue with the radiolabeled compound according to claim 44. (Section 47) 47. The method according to claim 46, further comprising the step of producing a radiological image of the contacted cells or tissue. (Section 48) Compounds having formula VI: [ka] wherein X is [ka] is selected from the group consisting of R 1 is hydrogen and C 1~4 is selected from the group consisting of alkyl, R 2 is replaced as necessary 6 ~C 14 selected from the group consisting of aryl and aralkyl; R 3 is replaced as necessary 6 ~C 14 Aryl, optionally substituted 5-14 membered heteroaryl and -C(=O)NR d R e is selected from the group consisting of R 4a , R 4b , R 4e and R 4f is 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, C1~6 independently selected from the group consisting of haloalkyl and haloalkoxy; R 4c and R 4d is hydrogen and C 1~4 alkyl; or R 4c and R 4d together with the carbon atom to which they are attached form -C(=O)-, R 5a , R 5b , R 5c and R 5d is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; Z is -O-, -N(R 8 )- and -C(=O)-, or Z does not exist, R 8 is hydrogen, C 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 selected from the group consisting of aryl, aralkyl, optionally substituted 5-14 membered heteroaryl and heteroaralkyl; R 9 is C 1~4 is alkyl, m is 0, 1 or 2; n is 1, 2, 3, 4, 5 or 6; [ka] represents a single or double bond, R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 aryl, optionally substituted 5-14 membered heteroaryl, or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocycle; or R d and R e together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; R c is C 1~4 Although it is an alkyl However, if Z does not exist, R 3 is a bicyclic or tricyclic C 10~14 Aryl, 9-14 membered bicyclic or tricyclic heteroaryl, or -C(=O)NR d R e Provided that, compound. (Section 49) 50. The compound according to item 49, wherein X is X-1. (Section 50) R 2 is optionally substituted phenyl; Compound. (Section 51) R 2 50. The compound according to claim 48 or 49, wherein is optionally substituted 1-naphthyl. (Section 52) R 2 50. The compound according to claim 48 or 49, wherein is optionally substituted 2-naphthyl. (Section 53) 49. The compound according to the above item 48, wherein X is X-2. (Section 54) 54. The compound according to item 48 or 53, wherein Z is -O-. (Section 55) 49. The compound according to the above item 48, wherein X is X-3. (Section 56) 49. The compound according to the above item 48, wherein X is X-4. (Section 57) 49. The compound according to the above item 48, wherein X is X-5. (Section 58) Formula VII: [ka] 49. The compound according to claim 48, having the formula: R 6a , R 6b , R 6c , R 6d and R 6e is 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 each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycle; Rc is C 1~4 is alkyl, n is 1, 2 or 3; compound. (Section 59) Formula VIII: [ka] 49. The compound according to claim 48, having the formula: R 7a , R 7b , R 7c , R 7d and R 7e is 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 each independently selected from the group consisting of 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 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycle; R c is C 1~4 is alkyl, n is 1, 2 or 3; compound. (Section 60) Formula IX: [ka] 49. The compound according to claim 48, having the formula: R 4a and R 4b is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 independently selected from the group consisting of alkoxy; R 4c and R 4d is independently selected from the group consisting of hydrogen and methyl; m is 0 or 1; n is 1, 2 or 3; compound. (Section 61) Formula X: [ka] 49. The compound according to claim 48, having the formula: R 5a and R 5c is hydrogen, halogen, cyano, C 1~4 Alkyl and C 1~4 independently selected from the group consisting of alkoxy; n is 1, 2 or 3; compound. (Section 62) Ethyl 5-(2-benzamidoethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(3,4-dichlorobenzamido)ethyl)isoxazole-3- carboxylate; Ethyl 5-(2-(2-naphthamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-([1,1'-biphenyl]-3-carboxamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(4-(5,6-dichloro-1H-indol-1-yl)butyl)isoxazole-3-carboxylate; Ethyl 5-(4-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)butyl)isoxazole-3-carboxylate; Ethyl 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinolin-1(2H)-yl)butyl)isoxazole-3-carboxylate; Ethyl 5-(3-(3,4-dichlorophenoxy)propyl)isoxazole-3-carboxylate; Ethyl 5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)butyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-bromobenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-fluorobenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-chlorobenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-methoxybenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-(dimethylamino)benzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-cyclopropylbenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(3,4-difluorobenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(3-chloro-4-fluorobenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-chloro-3-fluorobenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(3-(dimethylamino)benzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(3-(pyridin-3-yl)benzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(3-benzamidopropyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-(trifluoromethoxy)benzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4,5-dichloroindoline-1-carboxamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-((6,7-dichloroisoquinolin-3-yl)amino)ethyl)isoxazole-3-carboxylate; Ethyl 5-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)propyl)isoxazole-3-carboxylate; Ethyl 5-(2-((5,6-dichloro-1-methyl-1H-benzo[d]imidazol-2-yl)oxy)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-((trifluoromethyl)thio)benzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(4-(4,5-dichloroindolin-1-yl)-4-oxobutyl)isoxazole-3-carboxylate; Ethyl 5-(2-((6,7-dichloroquinolin-2-yl)amino)ethyl)isoxazole-3-carboxylate; Ethyl 5-(3-(5,6-dichlorobenzo[d]thiazol-2-yl)propyl)isoxazole-3-carboxylate; Ethyl 5-(3-(5,6-dichlorobenzo[d]oxazol-2-yl)propyl)isoxazole-3-carboxylate; Ethyl 5-(2-(4-(trifluoromethyl)benzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-((4,5-dichloroindoline-1-carbonyl)oxy)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-((6,7-dichloronaphthalen-2-yl)amino)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-((5,6-dichlorobenzo[d]thiazol-2-yl)amino)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(phenanthridin-6-ylamino)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(2-(3,4-dichlorophenyl)acetamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(6,7-dichloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-((5,6-dichloroisoquinolin-1-yl)amino)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(2-phenylacetamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(((3,4-dichlorophenyl)(methyl)carbamoyl)oxy)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-((5,6-dichloroisoquinolin-1-yl)oxy)ethyl)isoxazole-3-carboxylate; Ethyl 5-(2-(N-butylbenzamido)ethyl)isoxazole-3-carboxylate; Ethyl 5-(4-((3,4-dichlorophenyl)amino)butyl)isoxazole-3-carboxylate; Ethyl 5-(3-((3,4-dichlorophenyl)amino)propyl)isoxazole-3-carboxylate; Ethyl 5-(3-(naphthalen-1-ylamino)propyl)isoxazole-3-carboxylate; Ethyl 5-(3-(quinolin-8-ylamino)propyl)isoxazole-3-carboxylate; Ethyl 5-(4-(8-chloro-2-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)butyl)isoxazole-3-carboxylate; Ethyl 5-(4-((4-chlorophenyl)(cyclohexyl)amino)butyl)isoxazole-3-carboxylate; Ethyl 5-(4-(bis(4-chlorophenyl)amino)butyl)isoxazole-3-carboxylate; Ethyl 5-(4-((4-chlorobenzyl)(4-chlorophenyl)amino)butyl)isoxazole-3-carboxylate; Ethyl 5-(3-(naphthalene-1-yloxy)propyl)isoxazole-3- carboxylate; and Ethyl 5-(3-(quinolin-8-yloxy)propyl)isoxazole-3-carboxylate 49. The compound according to claim 48, selected from the group consisting of: (Section 63) A method for preparing the compound according to item 1, comprising the steps of: (1) A compound having formula VI: [ka] wherein X is [ka] is selected from the group consisting of R 1 is hydrogen and C 1~4 is selected from the group consisting of alkyl, R 2 is replaced as necessary 6 ~C 14 selected from the group consisting of aryl and aralkyl; R 3 is replaced as necessary 6 ~C 14 Aryl, optionally substituted 5-14 membered heteroaryl and -C(=O)NR d R e is selected from the group consisting of R 4a , R 4b , R 4e and R 4f is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; R 4c and R 4d is hydrogen and C 1~4 alkyl; or R 4c and R 4d together with the carbon atom to which they are attached form -C(=O)-, R 5a , R 5b , R 5c and R 5d is 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 independently selected from the group consisting of haloalkyl and haloalkoxy; Z is -O-, -N(R 8 )- and -C(=O)-, or Z does not exist, R 8 is hydrogen, C 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 selected from the group consisting of aryl, aralkyl, optionally substituted 5-14 membered heteroaryl and heteroaralkyl; R 9 is C 1~4 is alkyl, m is 0, 1 or 2; n is 1, 2, 3, 4, 5 or 6; [ka] represents a single or double bond, R a , R b , R d and R e is hydrogen, C 1~6 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 6 ~C 14 aryl, optionally substituted 5-14 membered heteroaryl, or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocycle; or R d and R e together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; R c is C 1~4 Although it is an alkyl However, if Z does not exist, R 3 is a bicyclic or tricyclic C 10~14 Aryl, 9-14 membered bicyclic or tricyclic heteroaryl, or -C(=O)NR d R e Provided that, The compound having formula VI is reacted with NH 2 OH, and (2) isolating the compound having formula I A method comprising: (Section 64) The compound having formula VI is reacted with NH 2 64. The method of claim 63, wherein the step of contacting with OH is carried out in the presence of NaOH. (Section 65) The compound having formula VI is reacted with NH 2 65. The method of claim 63 or 64, wherein the step of contacting with OH is carried out at a temperature of about 0° C. (Section 66) 66. The method according to any one of the above items 63 to 65, wherein the solvent comprises water, methanol or tetrahydrofuran, or a mixture thereof.

Claims

[Claim 1] The invention described in the specification.

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