HDAC6 inhibitor and contrast medium

Abstract

To provide a method for imaging HDAC enzyme by using a compound useful for inhibiting a histone deacetylase (HDAC) enzyme, a compound useful for treating diseases related to irregular development level and / or activity of the HDAC enzyme (a marking compound or non-marking compound), as well as radiation marking compounds.SOLUTION: A compound shown in a formula below is used. (wherein, X1 is -N (RN)- or -CH (RC)-; X2 is CR2 or N; X3 is CR3 or N; RN is H, C1-6 alkyl, or C1-6 haloalkyl; RC is H, C1-6 alkyl, or C1-6 haloalkyl; L1 is bonded or C1-6 alkylene group; L2 is bonded or C1-6 alkylene group; R1 is C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, or C6-10 aryl; R2,R3,R4 and R5 are H, C1-6 alkyl, halo, or C1-6 haloalkyl.)SELECTED DRAWING: None

Description

[Technical field]

[0001] Federally funded research or development This invention was made under grant number R01 NS099250 awarded by the National Institutes of Health. This invention was made with Government support under the terms of the present invention. The Government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 484,207, filed April 11, 2017. The benefit of this application is claimed, the disclosure of which is incorporated herein by reference in its entirety.

[0003] The present application provides compounds useful for inhibiting histone deacetylase (HDAC) enzymes. The present application relates to a method for detecting abnormal expression levels and / or activity of histone deacetylase (HDAC) enzymes. Compounds (e.g., labeled or unlabeled compounds) useful in the treatment of disorders related to sex, and Further provided is a method for imaging HDAC enzymes using radiolabeled compounds. [Background technology]

[0004] Histone deacetylases (HDACs) regulate DNA packaging and gene expression. A family of chromatin-modifying enzymes that act at the cellular level to alter behavior at the organismal level. Evidence suggests that epigenetic Targeting chromatin-mediated neuroplasticity with toxic mechanisms There is increasing support that treatment of neuropsychiatric disorders may be improved by Summary of the Invention [Means for solving the problem]

[0005] The present application relates in particular to compounds of formula I: [ka] or a pharma- ceutically acceptable salt thereof, X 1 is -N(R N )- or -CH(R C )-and; X 2 CR 2 or N; X 3 CR 3 or N; R N , H, C 1~6 Alkyl, and C 1~6 haloalkyl; R C , H, C 1~6 Alkyl, and C 1~6 haloalkyl; L 1 is a bond or C 1~6 Alkylene group, C for connectivity 3~10 Cycloalkane and a linking 4- to 10-membered heterocycloalkyl group, The 4-10 membered heterocycloalkyl group is one or two independent C 1~6 Alkyl group is optionally substituted, L 2 is a bond or C 1~6 is an alkylene group; R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl, C 3~10 Cycloalkyl and C 6~10 a Each aryl is optionally substituted with one or two independently selected halo groups. And, R 2, R 3 , R 4 , and R 5 are each independently H, halo, or C 1~6 Hello Aruki 3, selected from the group consisting of A compound or a pharma- ceutically acceptable salt thereof is provided.

[0006] In some embodiments, X 1 -N(R N In some embodiments, R N is H and methyl.

[0007] In some embodiments, X 1 -CH(R C In some embodiments, R C H It is.

[0008] In some embodiments, L 1 is a bond. In some embodiments, L 1 is C 1~6 Al Xylene group, C for connectivity 3~10 Cycloalkyl groups and 4-10 membered heterocyclic groups The 4- to 10-membered heterocycloalkyl group is selected from the group consisting of 1 One or two independent C 1~6 Optionally substituted with an alkyl group. In this state, L 1 is methylene, [ka] is selected from the group consisting of [ka] L 1 and X 1 indicates the bond between [ka] L 1 and R 1 The bond between

[0009] In some embodiments, L 2 is a bond. In some embodiments, L 2 is methylene .

[0010] In some embodiments, R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 S chloroalkyl, and phenyl, wherein the phenyl is selected from the group consisting of one or two In some embodiments, R 1 teeth , methyl, methoxy, cyclohexyl, adamantyl, norbornyl, phenyl, and 3 -fluorophenyl.

[0011] In some embodiments, X 2 is N. In some embodiments, X 2 is CR 2 It is. In some embodiments, R 2 is H or F. In some embodiments, R 2 is F.

[0012] In some embodiments, X 3 is N. In some embodiments, X 3 is CR 3 It is. In some embodiments, R 3 is H or F. In some embodiments, R 3 is H.

[0013] In some embodiments, X 2 and X 3 Each X is N. 2 teeth CR2 And X 3 is CR 3 In some embodiments, R 2 is F and R 3 is H.

[0014] In some embodiments, R 4 is H or CF. In some embodiments, R 4 is H do.

[0015] In some embodiments, R 5 is H or CF3.

[0016] In some embodiments, R 5 is H.

[0017] In some embodiments, R 2 is F and R 3 , R 4 , and R 5 are H, respectively.

[0018] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N: X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or C 1~3 Alkylene group, C for connectivity 6~10 Cycloalkane and a linking 4- to 10-membered heterocycloalkyl group, The 4-10 membered heterocycloalkyl group is one or two independent C 1~3 Alkyl group is optionally substituted; L2 is a bond or methylene; R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Cycloalkyl and phenyl, wherein the phenyl is selected from the group consisting of one or two independently selected halides. optionally substituted with a group; R 2 is selected from the group consisting of H and halo; and R 3 , R 4 , and R 5 are H, respectively.

[0019] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or methylene, [ka] is selected from the group consisting of [ka] L 1 and X 1 indicates the bond between and [ka] L 1 and R 1 indicates the bond between L 2 is a bond or methylene; R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Cycloalkyl and phenyl, wherein the phenyl is selected from the group consisting of one or two independently selected halides. optionally substituted with a group; R 2 is selected from the group consisting of H and halo; and R 3 , R 4 , and R 5 are H, respectively.

[0020] In some embodiments, the compound of formula I has formula II: [ka] or a pharma- ceutically acceptable salt thereof.

[0021] In some embodiments, the compound of formula I has formula III: [ka] or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments, the compound of formula I has formula IV: [ka] or a pharma- ceutically acceptable salt thereof.

[0023] In some embodiments, the compound of formula I has formula V: [ka] or a pharma- ceutically acceptable salt thereof.

[0024] In some embodiments, the compounds or pharma- ceutically acceptable salts provided herein comprise at least In some embodiments, the compounds or The pharma- ceutically acceptable salts are 11 C and 18 At least one selected from the group consisting of F In some embodiments, the compounds or pharma- ceuticals provided herein include a radioisotope of Acceptable salts are those that contain at least one 18 Contains F radioisotope.

[0025] In some embodiments, the compound of formula I has formula VI: [ka] or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, the compound of formula I is [ka] or a pharma- ceutically acceptable salt thereof.

[0027] In some embodiments, the compound of formula I is [ka] or a pharma- ceutically acceptable salt thereof.

[0028] The present application relates to pharmaceutical compositions, comprising the compounds provided herein or pharma- ceuticals thereof. The present invention further provides a pharmaceutical composition comprising a salt of the compound of the present invention and at least one pharma- ceutically acceptable carrier. do.

[0029] The present application provides a method for inhibiting the activity of a histone deacetylase (HDAC) enzyme, comprising: Contacting an HDAC enzyme with a compound provided herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the method further comprises: Inhibiting the activity of histone deacetylase (HDAC) enzymes is a In some embodiments, the histone deregulating The acetylase (HDAC) enzyme is HDAC6. In some embodiments, the compound is HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC Select one or more of HDAC6, HDAC9, HDAC10, and HDAC11. Selectively inhibits.

[0030] In some embodiments, the method is an in vitro method. The method is an in vivo method.

[0031] The present application relates to a method of imaging an object, comprising: i) administering to the subject a radiolabeled compound provided herein or a pharma- ceutically acceptable salt thereof. administering; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0032] The present application relates to imaging histone deacetylase (HDAC) enzymes in cells or tissues. 1. A method comprising: i) combining said cells or tissue with a radiolabeled compound provided herein or a pharma- ceutical acceptable salt thereof; contacting said compound with a salt to be treated; and ii) Imaging the cell or tissue with an imaging technique. The present invention further provides a method comprising:

[0033] The present application relates to a method for imaging histone deacetylase (HDAC) enzymes in a subject. , i) administering to the subject a radiolabeled compound provided herein or a pharma- ceutically acceptable salt thereof. administering; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0034] The present application relates to a method for detecting abnormal expression or expression of histone deacetylase (HDAC) enzymes in a subject. A method for imaging a disease associated with abnormal activity, comprising: i) administering to the subject a radiolabeled compound provided herein or a pharma- ceutically acceptable salt thereof. administering; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0035] The present application relates to a method for detecting abnormal expression or expression of histone deacetylase (HDAC) enzymes in a subject. A method for monitoring the treatment of a disease associated with abnormal activity, comprising: i) imaging the object using an imaging technique; ii) treating said subject with a compound provided herein, or a pharma- ceutically acceptable salt thereof. administering an amount effective to iii) imaging the object using an imaging technique; and iv) comparing the image of step i) with the image of step iii); The present invention further provides a method comprising:

[0036] In some embodiments, the imaging technique is single photon emission computed tomography, positron emission tomography, or the like. Neutron emission tomography imaging, computed tomography, computed tomography imaging Positron Emission Tomography with Magnetic Resonance Imaging, Positron Emission Tomography with Magnetic Resonance Imaging In some embodiments, the imaging technique is selected from the group consisting of positron emission tomography (PET) imaging. In some embodiments, the histone deacetylase (HDA) C) The enzyme is HDAC6.

[0037] The present application provides a method of imaging the brain of a subject, comprising: i) administering to the subject a radiolabeled compound provided herein or a pharma- ceutically acceptable salt thereof. administering; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0038] The present application relates to a method of treating a disease in a subject in need thereof, the method comprising administering to the subject administering a therapeutically effective amount of a compound provided herein or a pharma- ceutical acceptable salt thereof to The diseases include cancer, diseases of the central nervous system, and inflammatory autoimmune diseases. Further provided is a method, wherein the method is selected from the group:

[0039] In some embodiments, the disease is cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, and non-small cell lung cancer. In some embodiments, the cancer is a blood cancer. The liquid cancer is selected from the group consisting of leukemia and lymphoma. In some embodiments, the cancer is It is associated with abnormal expression or activity of histone deacetylase (HDAC) enzymes. In some embodiments, the cancer is associated with aberrant expression or activity of HDAC6.

[0040] In some embodiments, the disease is a disease of the central nervous system. The disease of the central nervous system comprises a neurodegenerative disease. In some embodiments, the disease of the central nervous system is In some embodiments, the central nervous system disease is schizophrenia, bipolar disorder, In some embodiments, the disease is selected from the group consisting of Alzheimer's disease and Huntington's disease. In some embodiments, the central nervous system disorder further comprises depression. The disease is associated with abnormal expression or activity of histone deacetylase (HDAC) enzymes. In some embodiments, the central nervous system disorder is caused by aberrant expression or abnormalities of HDAC6. is associated with

[0041] In some embodiments, the disease is an inflammatory autoimmune disease. Inflammatory and autoimmune diseases are caused by abnormal expression or dysregulation of histone deacetylase (HDAC) enzymes. In some embodiments, the inflammatory autoimmune disease is associated with abnormal activity of HDAC6 It is associated with abnormal expression or activity of.

[0042] In some embodiments, about 0.1% to about 5% of the administered compound crosses the blood-brain barrier. In some embodiments, the administered compound provides a brain:plasma ratio of at least about 1:1 to less than 1:2. Both are about 50:1.

[0043] The present application provides a method of treating cancer in a subject, comprising: i) the cancer is caused by aberrant activity or expression of histone deacetylase (HDAC) enzymes; Identifying as being related to; and ii) treating said subject with a compound provided herein, or a pharma- ceutically acceptable salt thereof. and administering an effective amount thereof. The present invention further provides a method comprising:

[0044] The present application provides a method of treating a central nervous system disorder in a subject, comprising: i) This central nervous system disorder is caused by abnormal activity of histone deacetylase (HDAC) enzymes. or to identify it as being associated with abnormal expression; and ii) treating said subject with a compound provided herein, or a pharma- ceutically acceptable salt thereof. and administering an effective amount thereof. The present invention further provides a method comprising:

[0045] The present application provides a method of treating an inflammatory autoimmune disease in a subject, comprising: i) This inflammatory autoimmune disease is caused by abnormal activity of histone deacetylase (HDAC) enzymes. Identifying the genetic material as being associated with sexual or abnormal expression; and ii) treating said subject with a compound provided herein, or a pharma- ceutically acceptable salt thereof. and administering an effective amount thereof. The present invention further provides a method comprising:

[0046] In some embodiments, the histone deacetylase (HDAC) enzyme is HDAC6. do.

[0047] Unless otherwise defined, all technical and scientific terms used herein are intended to be understood as meaning the invention. As used herein, the term "oxygen" has the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials are described herein for this purpose, other suitable methods and materials known in the art can be used. The materials, methods, and examples are illustrative only and are intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other information referred to herein are the property of their respective owners. In the event of a conflict, the following entries, and other references, are incorporated by reference in their entireties: The present specification, including definitions, will control. [Brief description of the drawings]

[0048] [Figure 1] FIG. 1 shows the results of human neural progenitor cell histone and tubulin acetylation assays. [Figure 2A] Figure 2: Figure 2A shows averaged (n=3) time-activity curves of whole brain ROIs of Sprague-Dawley rats injected with [18F] radiolabeled 4-(((((3s)-adamantan-1-yl)methyl)(methyl)amino)methyl)-3-fluoro-N-hydroxybenzamide (Example 2). In blocked animals, 1 mg / kg of unlabeled 4-(((((3s)-adamantan-1-yl)methyl)(methyl)amino)methyl)-3-fluoro-N-hydroxybenzamide (Example 1) was injected immediately prior to administration of the radiotracer, and baseline animals were treated with vehicle. [Figure 2B] Figure 2B shows a PET image of a Sprague-Dawley rat injected with [18F] radiolabeled 4-(((((3s)-adamantan-1-yl)methyl)(methyl)amino)methyl)-3-fluoro-N-hydroxybenzamide (Example 2). The image shows sagittal slices compiled from 30-90 min. [Diagram 3] FIG. 3 shows representative autoradiography images of sagittal slices of the brain from Sprague-Dawley rats exposed to the compound of Example 1 or the radiolabeled compound of Example 2 in the presence of tubastatin. [Figure 4] Figure 4 shows a comparison of SUV analysis, baseline distribution and pretreatment distribution of 15 regions in the baboon brain using the black baboon atlas. Each region of interest (ROI) is shown as the distribution of SUV values ​​(average 60-120 min) for each voxel within the ROI. ACC = anterior cingulate cortex, amgyg = amygdala, CB = cerebellum, DLPFC = dorsolateral prefrontal cortex, HC = hippocampus, M1 = primary motor cortex, NAc = nucleus accumbens, OFC = orbitofrontal cortex, PCC = posterior cingulate cortex, Pu = putamen, SMA = supplementary motor area, Th = thalamus, V1 = primary sensory cortex, WM = white matter. [Diagram 5]Figure 5 shows a comparison of SUV and VT. The region of interest data from Example 2 was plotted as SUV values ​​(average 60-120 min) versus volume of distribution (Vt) to demonstrate the linearity of the two measurements. This data supports the potential use of a reference strategy for quantification of the signal. [Figure 6] 6A-B show average uptake images and time-activity curves for comparison between baseline (Example 2) and pretreatment PET scans, where the target was pre-saturated by administration of the non-radiolabeled form of Example 1. [Figure 7] Figures 7A-B show in vitro autoradiography data from the competition assay: Figure 7B, top panel: Example 2, no competitor; middle panel: Example 2 + Example 1; bottom panel: Example 2 + Tubastatin A. [Figure 8] 8A-B show the compound of Example 2 docked into the CD2 hHDAC6 complex. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] Histone deacetylases have emerged as drug targets with a variety of promising indications. Several drugs target multiple of the 11 isoforms of Zn-dependent HDACs. pan-HDAC inhibitors are either FDA approved or currently in clinical trials (For example, Mottamal et al,Molecules(Basel,Swit (See Zerland, 2015, 20(3):3898-3941). However, these non-selective agents generally cause undesirable side effects (e.g., Es Tiu et al,Bioorganic & Medicinal Chemist ry,2010,18(11):4103-4110;Estiu et al. rnal of Medicinal Chemistry,2008,51(10): 2898-2906; and Difei et al,Current Topics i Medicinal Chemistry, 2009, 9(3): 241-256 Please refer to.

[0050] The cytoplasmic location and structure of HDAC6 are unique among HDAC isoforms, 6Selective treatment regimens avoid many of the side effects of first-generation pan-HDAC inhibitors (e.g., Santo et al., Blood, 2012, 1 19(11):2579-2589). Isoform selectivity can be manipulated. HDAC6 is structurally distinct from other isoforms, making it difficult to develop selective inhibitors. This provides a starting point for the rational design of

[0051] Abnormal HDAC6 expression levels have been reported in glioblastoma multiforme (e.g., Li et al., Tumor or Biology,2015,36(12):9661-9665;Wang et al,Cancer Letters,2016,379(1):134-142; and Lucio-Eterovic et al, BMC Cancer, 2008, 8( 1):243), Rett syndrome (see, e.g., Delepine et al. ,Human Molecular Genetics,2015,25(1):146 -157; and Gold et al, Journal of Molecular M edicine, 2015, 93(1):63-72), Alzheimer's Disease (e.g., Anderson et al, PLOS ONE, 2015, 10(5) :e0126592; and Cuadrado-Tejedor et al, Neuro psychopharmacology,2017,42(2):524-539), average and Parkinson's disease (e.g., d'Ydewalle et al., Traffic, 2013). 012,13(6):771-779;Su et al,Journal of Ne urochemistry, 2011, 117(1):112-120; and Du et al. al,Neurobiology of Aging,2014,35(10):23 16-2328), but these phases in the living human brain Our understanding of the relationship between HDAC6 and brain-penetrant HDAC6 is limited. Moreover, designing brain-penetrant HDAC6-selective agents is challenging. It has been shown that high doses are required to achieve the functional effects of HDAC6 inhibition. It is often necessary (e.g., Jochems et al., Neuropsychiatry pharmacology, 2014, 39(2):389-400).

[0052] Positron emission tomography (PET) can be used to study human neuroepigenetics and related processes Probes to study HDAC6 may enhance our understanding of brain function and Insights into the molecular basis of brain diseases and validation of therapeutic targets and small molecules Thus, the present application provides a method for the development of selective HDAC6 inhibitors that are brain penetrant. This paper describes the development of PET-based PET imaging and its application in PET imaging.

[0053] compound The present application relates to a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, X 1 is -N(R N )- or -CH(R C )- and; X 2 CR 2 or N; X 3 CR 3 or N; R N , H, C 1~6 Alkyl, and C 1~6 haloalkyl; R C , H, C 1~6 Alkyl, and C 1~6 haloalkyl; L 1 is a bond or C 1~6 Alkylene group, C for connectivity 3~10 Cycloalkane a 4- to 10-membered heterocycloalkyl group; The 10-membered heterocycloalkyl group may have one or two independent C 1~6 Any alkyl group is selectively substituted, L 2 is a bond or C 1~6 is an alkylene group; R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl, 3~10 Cycloalkyl and C 6~1 0 aryl is C 1~6 1 or 2 independently selected from alkyl and halo and optionally substituted with a group R 2 , R 3 , R 4 , and R 5 are independently H, C 1~6Alkyl, halo, and C 1~6 haloalkyl A compound or a pharma- ceutically acceptable salt thereof is provided.

[0054] In some embodiments, the compound of formula I is [ka] or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, X 1 is -N(R N )- or -CH(R C )- and; X 2 CR 2 or N; X 3 CR 3 or N; R N , H, C 1~6 Alkyl, and C 1~6 haloalkyl; R C , H, C 1~6 Alkyl, and C 1~6 haloalkyl; L 1 is a bond or C 1~6 is an alkylene group; L 2 is a bond or C 1~6 is an alkylene group; R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl, 3~10 Cycloalkyl and C 6~1 0 aryl is C 1~61 or 2 independently selected from alkyl and halo and optionally substituted with a group R 2 , R 3 , R 4 , and R 5 are independently H, C 1~6 Alkyl, halo, and C 1~6 haloalkyl.

[0056] In some embodiments, X 1 is -N(R N )- or -CH(R C )- and; X 2 CR 2 or N; X 3 CR 3 or N; R N , H, C 1~6 Alkyl, and C 1~6 haloalkyl; R C , H, C 1~6 Alkyl, and C 1~6 haloalkyl; L 1 is a bond or C 1~6 Alkylene group, C for connectivity 3~10 Cycloalkane a 4- to 10-membered heterocycloalkyl group; The 10-membered heterocycloalkyl group may have one or two independent C 1~6 Any alkyl group is selectively substituted, L 2 is a bond or C 1~6 is an alkylene group; R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl, 3~10 Cycloalkyl and C 6~1 Each aryl is optionally substituted with 1 or 2 independently selected halo groups. It is; R 2 , R 3 , R 4 , and R 5 are each independently H, halo, or C 1~6 Hello Aruki The compound is selected from the group consisting of

[0057] In some embodiments, X 1 -N(R N In some embodiments, R N is H , C 1~3 Alkyl, and C 1~3 In some embodiments, the alkyl group is selected from the group consisting of haloalkyl. In terms of form, R N H and C 1~3 In some embodiments, the alkyl group is selected from the group consisting of alkyl. So, R N is selected from the group consisting of H and methyl. N is C 1~6 In some embodiments, R N is methyl and pentyl (e.g. n- pentyl). In some embodiments, R N is H, methyl, and pentyl.

[0058] In some embodiments, X 1 -CH(R C )-.

[0059] In some embodiments, R C , H, C 1~3 Alkyl, and C 1~3 From haloalkyl In some embodiments, R C H and C 1~3 Consists of alkyl In some embodiments, R C is H.

[0060] In some embodiments, L 1 is a bond. In some embodiments, L 1 is C 1~6 Al Xylene group, C for connectivity 3~10 Cycloalkyl groups and 4-10 membered heterocyclic groups The 4- to 10-membered heterocycloalkyl group is selected from the group consisting of 1 One or two independent C 1~6 Optionally substituted with an alkyl group. In this state, L 1 is C 1~3 Alkylene group, C for connectivity 6~10 Cycloalkyl groups and The 4 to 10 membered heterocycloalkyl groups are selected from the group consisting of cyclic 4 to 10 membered heterocycloalkyl groups. The heterocycloalkyl group may be one or two independent C 1~3 Optionally with an alkyl group Has been replaced.

[0061] In some embodiments, L 1 is C 1~6 In some embodiments, L is an alkylene group. 1 is C 1~3 In some embodiments, L is an alkylene group. 1 methylene and propylene (e.g., -CH2CH(CH3)- or -CH(CH2CH3)-) It is selected.

[0062] In some embodiments, L 1 is methylene, propylene, [ka] is selected from the group consisting of [ka] L 1 and X 1 indicates the bond between [ka] L 1 and R 1 The bond between

[0063] In some embodiments, L 1 is methylene, [ka] is selected from the group consisting of [ka] L 1 and X 1 indicates the bond between [ka] L 1 and R 1 The bond between

[0064] In some embodiments, L 2 is a bond. In some embodiments, L 2 is C 1~3 Alki In some embodiments, L is a cyclohexane group. 2 is methylene.

[0065] In some embodiments, R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 S chloroalkyl, and phenyl, 6~10 Cycloalkyl and and phenyl are C 1~3Optionally, one or two groups independently selected from alkyl and halo In some embodiments, R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 cycloalkyl, and phenyl, 6~10 Cycloalkyl and phenyl are independently selected from methyl and fluoro. In some embodiments, R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 From the group consisting of cycloalkyl and phenyl wherein the phenyl is optionally substituted with one or two independently selected halo groups. In some embodiments, R 1 is C 1~3 Alkyl, C 1~3 Alkoxy , C 6~10 cycloalkyl, and phenyl, wherein the phenyl is 1 Optionally substituted with one or two fluoro groups.

[0066] In some embodiments, R 1 is C 6~10 From the group consisting of cycloalkyl and phenyl Selected, this C 6~10 Cycloalkyl and phenyl are each C 1~6 Alkyl and and halo, In some embodiments, R 1 is C 6~10 From the group consisting of cycloalkyl and phenyl This C 6~10 Cycloalkyl and phenyl are each C 1~3 Alkyl and fluoro, In some embodiments, R 1 is C 6~10 cycloalkyl, and this C 6~1 Cycloalkyl is C 1~6 Any one or two groups independently selected from alkyl groups. In some embodiments, R 1 is C 6~10 Cycloalkyl This C 6~10 Cycloalkyl is C 1~3 one independently selected from alkyl groups or is optionally substituted with two groups.

[0067] In some embodiments, R 1 is methyl, methoxy, cyclohexyl, adamantyl, bornyl, phenyl, 6,6-dimethylbicyclo[3.1.1]heptanyl (e.g., 6,6-dimethylbicyclo[3.1.1]heptan-3-yl), and 3-fluorophenanthracene In some embodiments, R 1 is methyl, methoxy, cyclo The aryl groups consist of 3-fluorophenyl, 4-hexyl ... In some embodiments, R 1 Adamantyl or 6,6-dimethyl Bicyclo[3.1.1]heptanyl (e.g., 6,6-dimethylbicyclo[3.1.1] heptan-3-yl). In some embodiments, R 1 is adamantyl. In embodiments, R 1 is 6,6-dimethylbicyclo[3.1.1]heptanyl (e.g., 6 ,6-dimethylbicyclo[3.1.1]heptan-3-yl).

[0068] In some embodiments, X 2 is N.

[0069] In some embodiments, X 2 is CR 2 It is.

[0070] In some embodiments, R 2 is H or F. In some embodiments, R 2 is F In some embodiments, R 2 is H. In some embodiments, R 2 , H, C 1~6 a In some embodiments, R is selected from the group consisting of alkyl, alkylalkyl, and halo. 2 is H, methyl , F, Cl, and Br. In some embodiments, R 2 H, M is selected from the group consisting of ethyl, ethyl, ethyl, and F.

[0071] In some embodiments, X 3 is N.

[0072] In some embodiments, X 3 is CR 3 It is.

[0073] In some embodiments, R 3 is H or F. In some embodiments, R 3 is H In some embodiments, R 3 , H, C 1~6 Selected from the group consisting of alkyl, and halo. In some embodiments, R 3 is selected from the group consisting of H, methyl, F, Cl, and Br. In some embodiments, R 3 is selected from the group consisting of H, methyl, and F. .

[0074] In some embodiments, X 2 and X 3 are N respectively.

[0075] In some embodiments, X 2 is CR 2 And X 3 is CR 3 It is.

[0076] In some embodiments, X 2 is N and X 3 is CR 3 It is.

[0077] In some embodiments, X 2 is CR 2 And X 3 is N.

[0078] In some embodiments, R 2 is F and R 3 is H. In some embodiments, R 2 and R 3 Each is H. In some embodiments, R 2 and R 3 are halos, In some embodiments, R 2 and R 3 are F respectively.

[0079] In some embodiments, R 4 H, halo, and C 1~3 From the group consisting of fluoroalkyl In some embodiments, R 4 is selected from the group consisting of H, F, and CF3 In some embodiments, R 4 is H.

[0080] In some embodiments, R 5 H, halo, and C 1~3 From the group consisting of fluoroalkyl In some embodiments, R 5is selected from the group consisting of H, F, and CF3 In some embodiments, R 5 is H.

[0081] In some embodiments, R 2 , R 3 , R 4 , and R 5 At least one of the 1~6 Alkyl group, halo group, or C 1~6 In some embodiments, R 2 , R 3 , R 4 , and R 5 At least one of the groups is a halo group or C 1~6 Haloalkyl group In some embodiments, R 2 , R 3 , R 4 , and R 5 At least one of the groups is a halo group. In some embodiments, R 2 , R 3 , R 4 , and R 5 At least one of the following is C 1~ 6 alkyl group. In some embodiments, R 2 , R 3 , R 4 , and R 5 At least one of The other is F. In some embodiments, R 2 , R 3 , R 4 , and R 5 At least One is methyl. In some embodiments, R 2 , R 3 , R 4 , and R 5 One of them is F and each of the other variables is H. is R 2 , R 3 , R4 , and R 5 One of the variables is methyl, and the other variables are In some embodiments, R 2 , R 3 , R 4 , and R 5 One of the 18 F and each other variable is H. In some embodiments, R 2 is F, and R 3 , R 4 , and R 5 are H, respectively.

[0082] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N: X 3 CR 3 or N; R N H and C 1~6 selected from the group consisting of alkyl; L 1 is a bond or C 1~3 Alkylene group, C for connectivity 6~10 Cycloalkane and a linking 4- to 10-membered heterocycloalkyl group, The 4-10 membered heterocycloalkyl group is one or two independent C 1~3 Alkyl group is optionally substituted; L 2 is a bond or methylene; R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Cycloalkyl and wherein the C is selected from the group consisting of phenyl, 6~10 Cycloalkyl and phenyl are C1~ 3 optionally substituted with 1 or 2 groups independently selected from alkyl and halo; Cage; R 2 , H, C 1~6 selected from the group consisting of alkyl, and halo; and R 3 , R 4 , and R 5 are H, respectively.

[0083] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N: X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or C 1~3 Alkylene group, C for connectivity 6~10 Cycloalkane and a linking 4- to 10-membered heterocycloalkyl group, The 4-10 membered heterocycloalkyl group is one or two independent C 1~3 Alkyl group is optionally substituted; L 2 is a bond or methylene; R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Cycloalkyl and phenyl, wherein the phenyl is selected from the group consisting of one or two independently selected halo. optionally substituted with a group; R 2 is selected from the group consisting of H and halo; and R 3 , R 4 , and R 5 are H, respectively.

[0084] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; R N H and C 1~6 selected from the group consisting of alkyl; L 1 is a bond or methylene, propylene, [ka] is selected from the group consisting of [ka] L 1 and X 1 indicates the bond between and [ka] L 1 and R 1 indicates the bond between L 2 is a bond or methylene; R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Cycloalkyl and wherein the C is selected from the group consisting of phenyl, 6~10 Cycloalkyl and phenyl are C 1~ 6 optionally substituted with one or two groups independently selected from alkyl and halo; Cage; R2 , H, C 1~6 selected from the group consisting of alkyl, and halo; and R 3 , R 4 , and R 5 are H, respectively.

[0085] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or methylene, [ka] is selected from the group consisting of [ka] L 1 and X 1 indicates the bond between and [ka] L 1 and R 1 indicates the bond between L 2 is a bond or methylene; R 1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Cycloalkyl and phenyl, wherein the phenyl is selected from the group consisting of one or two independently selected halides. is optionally substituted with a aryl group; R 2is selected from the group consisting of H and halo; and R 3 , R 4 , and R 5 are H, respectively.

[0086] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or methylene, [ka] is selected from the group consisting of [ka] L 1 and X 1 indicates the bond between and [ka] L 1 and R 1 indicates the bond between L 2 is a bond or methylene; R 1 is methyl, methoxy, cyclohexyl, adamantyl, norbornyl, phenyl and 3-fluorophenyl; R 2 is selected from the group consisting of H and halo; and R 3 , R 4 , and R 5 are H, respectively.

[0087] In some embodiments, X 1 -N(R N )- and; X 2 is CR 2 and; X 3 is CR 3 and; R N is C 1~3 is alkyl; L 1 and L 2 are each independently selected C 1~3 is an alkylene group; R 1 is C 6~10 is a cycloalkyl group; R 2 and R 3 are each independently selected from the group consisting of H and halo; and R 4 and R 5 are H, respectively.

[0088] In some embodiments, X 1 -N(R N )- and; X 2 is CR 2 and; X 3 is CR 3 and; R N is C 1~3 is alkyl; L 1 and L 2 are each independently selected C 1~3 is an alkylene group; R 1 is adamantyl or 6,6-dimethylbicyclo[3.1.1]heptanyl (e.g. For example, 6,6-dimethylbicyclo[3.1.1]heptan-3-yl); R 2 and R 3are each independently selected from the group consisting of H and halo; and R 4 and R 5 are H, respectively.

[0089] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or C 1~3 is an alkylene group; L 2 is a bond or methylene; R 1 is C 6~10 cycloalkyl and phenyl, 6~ 10 Cycloalkyl and phenyl are each C 1~3 independently selected from alkyl and halo optionally substituted with one or two groups selected from R 2 is selected from the group consisting of H and halo; R 3 , R 4 and R 5 are H, respectively.

[0090] In some embodiments, X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; RN is selected from the group consisting of H and methyl; L 1 is a bond or is selected from the group consisting of methylene and propylene; L 2 is a bond or methylene; R 1 is C 6~10 cycloalkyl and phenyl, 6~ 10 Cycloalkyl and phenyl are each C 1~3 independently selected from alkyl and halo optionally substituted with one or two groups selected from R 2 is selected from the group consisting of H and halo; R 3 , R 4 and R 5 are H, respectively.

[0091] In some embodiments, the compound of formula I has formula II: [ka] or a pharma- ceutically acceptable salt thereof, and the variable R 1 , X 1 , X 2 and X 3 teeth, It is defined according to the definitions set forth herein for compounds of formula I.

[0092] In some embodiments, the compound of formula I has formula III: [ka] or a pharma- ceutically acceptable salt thereof, and the variable R 1 , L 1 , X 1 , X 2 and X 3 is defined according to the definitions set forth herein for compounds of formula I.

[0093] In some embodiments, the compound of formula I has formula IV: [ka] or a pharma- ceutically acceptable salt thereof, and the variable R 1 , R N , X 2 and X 3 teeth, It is defined according to the definitions set forth herein for compounds of formula I.

[0094] In some embodiments, the compound of formula I has formula V: [ka] or a pharma- ceutically acceptable salt thereof, and the variable R 1 and R N is a compound of formula I is defined in accordance with the definitions set forth herein.

[0095] Unless specifically defined, the compounds and salts provided herein may be in the form of intermediates or final products. Also includes all isotopes of atoms present in the compound. Isotopes are compounds with the same atomic number but different masses. Contains different numbers of atoms.

[0096] In some embodiments, a compound provided herein (e.g., a compound represented by any of Formulas I-V) is The compound or a pharma- ceutically acceptable salt thereof contains at least one radioactive isotope. As used herein, the term "radioisotope" refers to an isotope whose atomic mass or mass number is generally not found in nature. "Radiolabel" refers to an atom that is different from its atomic mass or mass number as found (i.e., naturally occurring). A "recognized compound" is a compound provided herein in which one or more atoms are in an atomic mass. The atomic masses or mass numbers as those amounts or mass numbers are typically found in nature (i.e., naturally occurring). A compound in which is replaced by or with a different atom. Examples of gender isotopes include, but are not limited to: 11 C. 13 N, 15 O , 18 F, 34m Cl, 38 K, 45 Ti, 51 Mn, 52m Mn, 52 Fe, 55 Co , 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 71 As , 72 As, 74 As, 75 Br, 76 Br, 82 Rb, 86 Y, 89 Zr, 90 Nb, 94m Tc, 99m Tc, 110m In, 111 In, 118 Sb, 120 I, 121 I , 122 I, 123 I, 124 I, 124 I, 131 I, and 201 Tl.

[0097] In some embodiments, the radioisotope is a positron emitter. The term "positron emitter" refers to a radioactive isotope in which protons are converted into neutrons, thereby In some embodiments, the term refers to a radioactive isotope that emits positrons and electron neutrinos. , this positron emitter 11 C or18 It's F.

[0098] In some embodiments, the compounds or pharma- ceutically acceptable salts provided herein are 11 C and 18 F. In embodiments, the compound or pharma- ceutically acceptable salt comprises at least one 18 F radioactive In some embodiments, at least one halo of the compounds provided herein is In some embodiments, at least one of the compounds provided herein is a radioisotope. Another halo group is 18 In some embodiments, at least one of the compounds provided herein is F. At least one haloalkyl or fluoroalkyl group is substituted with at least one radioisotope. In some embodiments, at least one haloa of the compounds provided herein is The alkyl or fluoroalkyl group is at least one 18 Contains F radioisotope.

[0099] In some embodiments, R N comprises at least one radioisotope. is R N contains one radioisotope. In some embodiments, R N is one 18 F radioactive Contains isotopes.

[0100] In some embodiments, R C comprises at least one radioisotope. is R C contains one radioisotope. In some embodiments, R C is one 18 F radioactive Contains isotopes.

[0101] In some embodiments, R 1 comprises at least one radioisotope. is R 1 contains one radioisotope. In some embodiments, R 1 is one 18 F radioactive Contains isotopes.

[0102] In some embodiments, R 2 comprises at least one radioisotope. is R 2 contains one radioisotope. In some embodiments, R 2 is one 18 F radioactive Contains isotopes.

[0103] In some embodiments, R 3 comprises at least one radioisotope. is R 3 contains one radioisotope. In some embodiments, R 3 is one 18 F radioactive Contains isotopes.

[0104] In some embodiments, R 4 comprises at least one radioisotope. is R 4 contains one radioisotope. In some embodiments, R 4 is one 18 F radioactive Contains isotopes.

[0105] In some embodiments, R 5 comprises at least one radioisotope. is R 5 contains one radioisotope. In some embodiments, R 5 is one 18 F radioactive Contains isotopes.

[0106] In some embodiments, the compound of formula I has formula VI: [ka] or a pharma- ceutically acceptable salt thereof, and the variable R 1 and R N is a compound of formula I is defined in accordance with the definitions set forth herein.

[0107] Unless otherwise stated, atoms are isotopes or radioisotopes (e.g., deuterium, 11 C. 18 F), this atom is designated as the natural occurrence of this isotope or radioisotope. is understood to include isotopes or radioisotopes in amounts at least greater than the amount of If the atom is designated "D" or "deuterium", the position is 0.015% having deuterium at an abundance at least 3000 times greater than the natural abundance of deuterium (i.e. , an incorporation of at least 45% deuterium).

[0108] As used herein, the term "Ci" refers to the unit of radioactivity, "Curie." .

[0109] As used herein, the term "specific activity" refers to the amount of radioactivity of a given radioisotope per unit mass. Refers to the radioactivity of the body (e.g. Ci / g).

[0110] In some embodiments, the compound of formula I is [ka] or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the compound of formula I is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the compound of formula I is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the compound of formula I is [ka] or a pharma- ceutically acceptable salt thereof.

[0114] synthesis As will be appreciated, the compounds provided herein, including their salts, can be synthesized by any method known in the art. They can be prepared using techniques and can be synthesized according to any of a number of possible synthetic routes. .

[0115] Compounds provided herein can be prepared, for example, according to the representative procedures shown in Scheme 1. For example, air-stable ruthenium complexes can be used to 6 -Coordinated phenol precursor The ion exchange cartridge was then used to prepare the eluate. 18 Elution to elute [F] fluoride The reagent was used without further purification. Labeling generally gave high conversions (by TLC). Subsequent transacylation in the same pot resulted in the final A labeled product was obtained (eg, Example 2). [ka]

[0116] Additional synthetic methods for incorporating radioisotopes into organic compounds are known in the art and may be used in Those skilled in the art will readily recognize other methods that are applicable for the preparation of the radiolabeled compounds and salts provided herein. will recognize.

[0117] It should be understood that the processes described are not the only means by which the compounds provided herein may be synthesized. and a broad repertoire of synthetic organic reactions potential for the synthesis of the compounds provided herein. It will be appreciated by those skilled in the art that the synthesis of the compounds of the present invention may be utilized in a variety of ways. Know how to synthesize and carry out suitable synthetic routes for starting materials, intermediates, and products, e.g. They may be identified by reference to literature, such as the following reference sources: Advances in H eterocyclic Chemistry,Vols.1-107(Elsevie r,1963-2012);Journal of Heterocyclic Che mistry Vols.1-49(Journal of Heterocyclic Chemistry,1964-2012);Carreira,et al.(Ed .)Science of Synthesis,Vols.1-48(2001-20 10) and Knowledge Updates KU2010 / 1-4;2011 / 1 -4;2012 / 1-2(Thieme,2001-2012);Katritzky, et al.(Ed.) Comprehensive Organic Function nal Group Transformations,(Pergamon Pres. s,1996);Katritzky et al.(Ed.);Comprehens ive Organic Functional Group Transformat ions II (Elsevier, 2 nd Edition, 2004);Katri tzky et al.(Ed.),Comprehensive Heterocyc lic Chemistry(Pergamon Press,1984);Katri tzky et al.,Comprehensive Heterocyclic C hemistry II,(Pergamon Press,1996);Smith et al., March's Advanced Organic Chemistry y:Reactions, Mechanisms, and Structure,6 th Ed.(Wiley,2007);Trost et al.(Ed.), Compr. ehensive Organic Synthesis(Pergamon Pres. s,1991).

[0118] The preparation of the compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemical properties of the protecting groups are described, for example, in TW Greene and PG M Huts. ,Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999) can be found at.

[0119] The reaction may be monitored according to any suitable method known in the art. For example, production The formation of the product can be monitored by spectroscopic means (e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Red Can it be monitored by infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry)? or chromatographic methods (e.g., high performance liquid chromatography (HPLC), liquid chromatography, etc. Chromatography-Mass Spectrometry (LCMS) or Thin Layer Chromatography (TLC) Compounds can be monitored by a variety of methods, such as high performance liquid chromatography. (HPLC and normal phase silica chromatography) by those skilled in the art. .

[0120] At various points in the specification, the term "divalent linking substituent" is used. nt) are described. Each divalent linking substituent is connected to the front and back of the linking substituent. Both forms are specifically intended to be included. For example, -NR(CR'R'') n -teeth, -NR(CR'R'') n -and-(CR'R'') n The structure includes both NR- and Where a group is clearly required, the Markush variables listed for this group are It is understood that the group is a

[0121] As used herein, the phrase "optionally substituted" means unsubstituted. As used herein, the term "substituted" means "Has been removed" means that a hydrogen atom has been removed and replaced with a substituent. It is understood that substitution at the atom is limited by valence.

[0122] Throughout the definition, the term "C n~m " indicates a range including the endpoints, and n and m are integers. and the number of carbon atoms. For example, C 1~4 , C 1~6 , and the like.

[0123] As used herein, the term "C n~m "Alkylene" has n to m carbon atoms It refers to a divalent alkyl linking group. Examples of alkylene groups are methylene, ethane-1,2-di propane-1,3-diyl, propane-1,2-diyl, and the like. In some embodiments, the alkylene moiety is 1 to 6, 1 to 6, Contains 3 or 1 to 2 carbon atoms.

[0124] As used herein, the term "above" may be used alone or in combination with other terms. The term "C n~m "Alkyl" refers to a saturated alkyl group having n to m carbon atoms, which may be linear or branched. Refers to a hydrocarbon group. Examples of alkyl moieties include, but are not limited to: Chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert -butyl, isobutyl, sec-butyl; higher homologues, e.g., 2-methyl-1-butyl , n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and In some embodiments, the alkyl group has 1 to 6 carbon atoms, 1 to 4 It contains a carbon atom, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0125] As used herein, the term "above" may be used alone or in combination with other terms. The term "C n~m "Alkoxy" means a radical of the formula -O-alkyl, the alkyl radical being n alkoxy refers to a group having m carbon atoms. Examples of alkoxy groups are methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and In some embodiments, the alkyl group may be 1 to 6, 1 to 4, or the like. or having 1 to 3 carbon atoms.

[0126] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, the halo is 18 It's F.

[0127] As used herein, the term "C n~m "Haloalkyl" means a group consisting of one halogen atom Alkyl groups having 2s+1 halogen atoms (which may be the same or different) where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is an alkyl group having 1 to 2 carbon atoms. Only fluorinated (e.g., C 1~6 In some embodiments, The alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. In the form, the haloalkyl group may be one or more 18 Contains F radioisotope. In embodiments, the haloalkyl group is one 18 Contains F radioisotope.

[0128] As used herein, the term "aryl" refers to a monocyclic or polycyclic (e.g., The term refers to an aromatic hydrocarbon group which may have 2, 3, or 4 fused rings. "Cn~m "Aryl" refers to an aryl group having n to m ring carbon atoms. Examples of the aryl group include phenyl, naphthyl, anthracenyl, phenanthrenyl, and indanyl. In some embodiments, the aryl group is selected from the group consisting of 6 to 10 alkyl groups. It has about 20 carbon atoms, 6 to about 15 carbon atoms, or 6 to about 10 carbon atoms. In some embodiments, the aryl group is a substituted or unsubstituted phenyl.

[0129] As used herein, "cycloalkyl" refers to alkyl and / or aryl groups that are cyclic. Cycloalkyl groups are either monocyclic or polycyclic. (eg, having 2, 3, or 4 fused rings) groups and spirocycles. The cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 rings. It may have carbon (i.e., C 3~10 Cycloalkyl group). Ring carbon of cycloalkyl group The atom may be optionally substituted with oxo or sulfido (e.g., C(=O) or C (=S)). Examples of cycloalkyl groups include, but are not limited to: Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, In some embodiments, the cycloalkyl is aryl, aryloxy ... is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, and adamantyl. In embodiments, the cycloalkyl has 6 to 10 ring-forming carbon atoms (i.e., C6 ~10In one embodiment, the cycloalkyl group is a cycloalkyl group having 3 to 6 ring-forming rings. Having carbon atoms (i.e., C 3~6 In some embodiments, the cycloalkyl group is The alkyl group is an adamantyl group.

[0130] As used herein, the term "linked cycloalkyl" refers to a divalent cycloalkyl. The linking cycloalkyl group may be a monocyclic or polycyclic (e.g., 2, 3, or 4 fused rings) and spiro rings. Cycloalkyl groups include It may have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e. , C 3~10 Cycloalkyl groups). Also included in the definition of cycloalkyl are cycloalkyl groups. One or more fused to an alkyl ring (i.e., sharing a common bond with a cycloalkyl ring) Moieties containing aromatic rings (e.g., benzo derivatives of cyclopentane, cyclohexane, and Exemplary linking cycloalkyl groups include 1,3-cyclobutylene, 1,3-cyclobutylene, and the like. Cyclohexylene, 1,4-cyclohexylene, 1,3-cyclohexylene, 1,1-cyclohexylene Exemplary polycyclic linked cycloaliphatic rings include, but are not limited to, As an alkyl group, [ka] and the like.

[0131] As used herein, "heterocycloalkyl" is selected from O, N, or S. A non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms. Heterocycloalkyl groups include monocyclic 4-, 5-, 6-membered, and Heterocycloalkyl groups are 7-membered. Heterocycloalkyl groups also include spiro rings. Examples of heterocycloalkyl groups include: pyrrolidin-2-one. , 1,3-Isoxazolidin-2-one, pyranyl, tetrahydrofuran, oxetani aryl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl , tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiocyanyl Azolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl , azepanil, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a chloroalkyl group are optionally substituted with oxo (=O). A heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Similarly, included within the definition of heterocycloalkyl are groups fused to a cycloalkyl ring (i.e., A moiety having one or more aromatic rings (e.g., a cycloalkyl ring) with a common bond For example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings may be substituted with any of the ring-forming atoms of the fused aromatic rings. In some embodiments, heterocycloalkyl can be attached through a nitrogen, acid, 4 to 10, 4 having 1 or 2 heteroatoms independently selected from nitrogen, nitrogen, or sulfur It has from 4 to 6 ring atoms.

[0132] As used herein, the term "linked heterocycloalkyl" refers to a divalent heterocyclic ring. Exemplary divalent heterocycloalkyl groups include, but are not limited to, the following: Not limited to: 1,4-piperidinylene, 4,4-piperidinylene, 1,3-azetidinylene Nylene, and benzo-fused heterocycloalkyl groups such as [ka] In some embodiments, the linking heterocycloalkyl is a nitrogen, 4 to 10, having 1 or 2 heteroatoms independently selected from oxygen, sulfur, It has 4 to 7, or 4 to 6 ring atoms.

[0133] The term "compound" as used herein includes all stereoisomers, geometric forms, and / or isomers of the depicted structure. Any isomers, tautomers, and isotopes are intended to be included. Compounds identified herein by name or structure as It is intended to include tautomeric forms of the formula:

[0134] The compounds provided herein also include tautomeric forms. Tautomeric forms are those in which the proton is attached to the As a result of the exchange of a single bond with an adjacent double bond, the tautomeric form is Prototropic tautomers, which are the protonation states of isomers with empirical formulas and total charges, are listed. Examples of prototropic tautomers include the following: ketone-enol pair , amide-imidate pairs, lactam-lactim pairs, enamine-imine pairs, and proton-complex pairs. Cyclic forms which may occupy more than one position on the ring system, for example 1H- and 3H-imidazole; 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. The tautomeric forms may be in equilibrium or may be appropriately The amino acid sequence can be sterically locked into one form by suitable substitutions.

[0135] All compounds and their pharma- ceutically acceptable salts may be used without any other substances (e.g., water and solvents). It may be found together (eg, as hydrates and solvates) or it may be isolated.

[0136] In some embodiments, preparation of a compound can be accomplished by, for example, catalysis of a desired reaction or by forming an acid addition salt, etc. This may involve the addition of an acid or base to effect the formation of the salt form.

[0137] Examples of acids may be inorganic or organic acids, and examples of acids include strong and weak acids. Some examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluene. Sulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoro Some of the weak acids are acetic acid, propionic acid, butanoic acid, ammonium acid, and nitric acid. carboxylic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanonic acid. These include, but are not limited to, cis acid.

[0138] Examples of bases are lithium hydroxide, sodium hydroxide, potassium hydroxide, and lithium carbonate. , sodium carbonate, potassium carbonate, and sodium bicarbonate. Examples of the metal hydroxides include metal alkoxides, metal amides, metal hydrides, and metal dialkylamines. Alkoxides include, but are not limited to, methyl amines, and aryl amines. Lithium, sodium and tert-butyl oxides, Examples of metal amides include sodium amide, potassium amide, and lithium amide. Examples of metal hydrides include sodium hydride, potassium hydride, and and lithium hydride. Metal dialkylamides include methyl-substituted amides, ethyl Substituted Amides, n-Propyl Substituted Amides, Isopropyl Substituted Amides, n-Butyl Substituted Amides , tert-butyl substituted amides, trimethylsilyl substituted amides, and cyclohexyl substituted amides. Included are the lithium, sodium, and potassium salts of amides.

[0139] In some embodiments, the compounds and salts provided herein are substantially isolated. "Substantially isolated" means that the compound is isolated from the environment in which it is formed or detected. Partial separation means at least partially or substantially separated from the boundary. For example, compositions enriched in the compounds provided herein may be included. At least about 50% by weight of a compound provided herein or a salt thereof, About 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight %, at least about 95%, at least about 97%, or at least about 99% by weight Methods for isolating compounds and their salts are routine in the art. It is.

[0140] The phrase "pharmacologically acceptable" is used herein to mean a compound that, within the bounds of sound medical judgment, is acceptable without excessive It has been successfully used in humans and animals without toxicity, irritation, allergic reactions, or other problems or complications. Suitable for use in contact with tissue of the subject and for a reasonable benefit / risk ratio The term "compounds," "materials," "compositions," and / or "dosage forms" are used to refer to compounds, materials, compositions, and / or dosage forms that

[0141] The present application also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "a pharma- ceutically acceptable salt" refers to a compound in which the parent compound is an existing acid moiety or salt. Derivatives of the compounds of the present disclosure that have been modified by converting radical moieties into their salt forms. Examples of pharma- ceutically acceptable salts include mineral or organic acid salts of basic residues such as amines. salts, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharma- ceutically acceptable salts of the present application include, for example, salts derived from non-toxic inorganic acids or These include the conventional non-toxic salts of the parent compound formed, for example, from organic acids. The salts that can be prepared are synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are obtained by reacting the salts in water, in an organic solvent, or in a mixture of the two. Reacting the free acid or free base form of this compound with a stoichiometric amount of an appropriate base or acid Generally, ethers, ethyl acetate, alcohols (e.g., meth alcohol, ethanol, isopropanol, or butanol), or acetonitrile ( A list of suitable salts can be found in Remington's s Pharmaceutical Sciences,17th ed.,Mack Publishing Company, Easton, Pa., 1985, p.141 8 and Journal of Pharmaceutical Science, 66, 2 (1977). Conventional methods for preparing salt forms can be found, for example, in Handb. ook of Pharmaceutical Salts:Properties,S This is explained in Election,and Use,Wiley-VCH,2002.

[0142] How to use The present application relates to methods for detecting histone deacetylases in a cell sample, in a tissue sample, or in a subject. Further provided herein is a method for inhibiting the activity of a HDAC enzyme. In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method. In some embodiments, the method includes the step of determining whether a cell or tissue that has an HDAC enzyme (e.g., a cell or tissue sample) and a compound provided herein (e.g., a compound represented by Formulas I-VI or a pharma- ceutically acceptable salt thereof. In embodiments, the method includes administering to the subject a compound provided herein or a pharma- ceutical acceptable salt thereof. In some embodiments, the method comprises administering a salt of the histone deacetylase (HDA) inhibitor. C) Inhibiting the activity of the enzyme deregulates histone deacetylase (HDAC) enzymes. This includes:

[0143] In some embodiments, the HDAC enzyme is a class IIb HDAC enzyme. In one embodiment, the histone deacetylase (HDAC) enzyme is HDAC6.

[0144] As used herein, the term "subject" refers to any animal, such as a mammal. Examples include mice, rats, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, In some embodiments, the subject is a human. In some embodiments, the method includes administering to the subject a compound provided herein (e.g., a compound of the formula A therapeutically effective amount of any one of compounds I to VI) or a pharma- ceutical acceptable salt thereof is administered to This includes:

[0145] The compounds provided herein can be selective HDAC inhibitors. The term "selective" refers to a compound that has a higher affinity for at least one other enzyme, respectively. In some embodiments, the term "antibody" refers to a compound that binds to or inhibits a specific enzyme with a specific activity or potency. In the form, selectivity is about 2-fold to 1-fold for a particular enzyme compared to at least one other enzyme. About 1000-fold selectivity, for example, about 2-fold to about 1000-fold, about 2-fold to about 500-fold, about 2x to approx. 100x, approx. 2x to approx. 50x, approx. 2x to approx. 20x, approx. 2x to approx. 10x, approx. 10x ~ About 1000 times, About 10 times - About 500 times, About 10 times - About 100 times, About 10 times - About 50 times, About 10 times to about 20 times, about 20 times to about 1000 times, about 20 times to about 500 times, about 20 times to about 1 00 times, about 20 times to about 50 times, about 50 times to about 1000 times, about 50 times to about 500 times, about 50 times to about 100 times, about 100 times to about 1000 times, about 100 times to about 500 times, or about 500 times ~About 1000 times more.

[0146] In some embodiments, the compounds provided herein, or pharma- ceutically acceptable salts thereof, HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC 8, HDAC6 over one or more of HDAC9, HDAC10, and HDAC11 Selectively inhibits.

[0147] The present application relates to a method of imaging an object, comprising: i) administering to the subject a radiolabeled compound provided herein (e.g., any of Formulas I-VI) administering a radiolabeled compound (or a pharma- ceutically acceptable salt thereof) to a subject in need of treatment with a medicament; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0148] The present application relates to imaging histone deacetylase (HDAC) enzymes in cells or tissues. 1. A method comprising: i) combining said cells or tissue with a radiolabeled compound provided herein or a pharma- ceutical acceptable salt thereof; contacting said compound with a salt to be treated; and ii) Imaging the cell or tissue with an imaging technique. The present invention further provides a method comprising:

[0149] The present application relates to a method for imaging histone deacetylase (HDAC) enzymes in a subject. , i) administering to the subject a radiolabeled compound provided herein or a pharma- ceutically acceptable salt thereof. administering; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0150] The present application provides a method of imaging a disease (e.g., a tumor) in a subject, comprising: i) administering to the subject a radiolabeled compound provided herein or a pharma- ceutically acceptable salt thereof. administering; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0151] The present application relates to a method for monitoring treatment of a disease in a subject, comprising: i) imaging the object using an imaging technique; ii) treating said subject with a compound provided herein, or a pharma- ceutically acceptable salt thereof. administering an amount effective to iii) imaging the object using an imaging technique; and iv) comparing the image of step i) with the image of step iii); The present invention further provides a method comprising:

[0152] In some embodiments, the method further comprises administering to the subject an imaging agent prior to the imaging of step i). In some embodiments, the method further comprises administering the imaging agent of step iii). In some embodiments, the method further comprises administering to the subject an imaging agent prior to the administration of the imaging agent. The imaging agent can be a radiolabeled compound provided herein (e.g., a radiolabeled compound of any of Formulas I-VI). In some embodiments, the compound administered in step ii) is an imaging agent. (eg, a fluorescent moiety or a radioisotope that can be imaged by an imaging technique).

[0153] In some embodiments, the disease is characterized by an increase in histone deacetylase (HDAC) in the subject. In some embodiments, the disease being imaged is associated with abnormal expression or activity of an enzyme. It is associated with abnormal expression or activity of HDAC6.

[0154] The present application provides a method of imaging the brain of a subject, comprising: i) administering to the subject a radiolabeled compound provided herein or a pharma- ceutically acceptable salt thereof. administering; and ii) Imaging the object using imaging techniques. The present invention further provides a method comprising:

[0155] In some embodiments, the imaging technique is a non-invasive imaging technique. This imaging technique is a minimally invasive imaging technique. As used herein, the term "minimally invasive imaging" refers to a technique that Imaging techniques include the use of internal probes or the injection of compounds (e.g., radiolabeled compounds) with a syringe. This includes imaging techniques using injections.

[0156] Examples of imaging techniques include, but are not limited to: Magnetic Resonance Imaging (MRI), ultrasound imaging, tomographic imaging, positron emission tomography imaging positron emission tomography, computed tomography imaging positron emission tomography, and positron emission tomography with magnetic resonance imaging.

[0157] In some embodiments, the imaging technique is single photon emission computed tomography, positron emission tomography, or the like. Neutron emission tomography imaging, computed tomography, computed tomography imaging Positron Emission Tomography with Magnetic Resonance Imaging, Positron Emission Tomography with Magnetic Resonance Imaging In some embodiments, the imaging technique is selected from the group consisting of positron emission tomography (PET) imaging. Layered imaging.

[0158] The present application relates to a method of treating a disease in a subject in need thereof, the method comprising administering to the subject administering a therapeutically effective amount of a compound provided herein or a pharma- ceutical acceptable salt thereof to In some embodiments, the disease is characterized by a histone deoxyribonuclease (Hd) domain. In some embodiments, the abnormal expression or activity of HDAC enzymes is associated with The disease is selected from the group consisting of cancer, diseases of the central nervous system, and inflammatory autoimmune diseases. can be.

[0159] In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, pre- prostate cancer, colon cancer, endometrial cancer, brain cancer (e.g. glioblastoma multiforme), bladder cancer, skin cancer, uterine cancer, The cancer is selected from the group consisting of ovarian cancer, lung cancer, pancreatic cancer, renal cancer, gastric cancer, and blood cancer. In some embodiments, the cancer comprises a solid tumor. The cancer is selected from the group consisting of non-small cell lung cancer and hematological cancer.

[0160] In some embodiments, the cancer is a blood cancer. In some embodiments, the blood cancer is a white blood cell cancer. In one embodiment, the hematological cancer is selected from the group consisting of acute myeloblastoma and lymphoma. Myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma Lymphoma, hairy cell leukemia, mantle cell lymphoma, Burkitt lymphoma, small lymphocytic leukemia Lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, active ABC diffuse large B-cell lymphoma and germinal center B-cell (GCB) diffuse large B-cell lymphoma In some embodiments, the cancer is selected from the group consisting of diffuse large B-cell lymphoma. is associated with aberrant expression or activity of HDAC6.

[0161] In some embodiments, the present application provides a method of treating cancer in a subject, comprising: i) The cancer is caused by an abnormality in histone deacetylase (HDAC) enzymes (e.g., HDAC6). Identifying a gene as being associated with abnormal activity or expression; and ii) the cancer is associated with abnormal activity of histone deacetylase (HDAC) enzymes; If a subject is identified as having a pulmonary function, the subject may be administered a compound provided herein or a pharma- ceutical acceptable salt thereof. administering a therapeutically effective amount of an acceptable salt; The present invention provides a method comprising:

[0162] In some embodiments, the disease being treated is a disease of the central nervous system. This central nervous system disorder is also known as Alzheimer's disease, Attention Deficit / Hyperactivity Disorder (ADHD), and Paralysis, bipolar disorder, catalepsy, cerebral palsy, epilepsy, encephalitis, Huntington's disease, confinement Syndrome, meningitis, migraine, multiple sclerosis (MS), Parkinson's disease, Rett syndrome, The disorder is selected from the group consisting of schizophrenia, tropical spastic paraparesis, and Tourette's syndrome. In some embodiments, the central nervous system disease is Alzheimer's disease, bipolar disorder, depression, Huntington's disease, and schizophrenia. Diseases of the central nervous system include neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (ALS), Parkinson disease, and In some embodiments, the diseases include those that cause rheumatoid arthritis, such as rheumatoid arthritis, Son's disease, Alzheimer's disease, Huntington's disease, and the like. So, what are the central nervous system disorders, including schizophrenia, bipolar disorder, Alzheimer's disease, and Hansen's disease? In some embodiments, the central nervous system disease is selected from the group consisting of depression. In some embodiments, the central nervous system disorder is depression. In some cases, this central nervous system disorder is associated with abnormal expression or activity of HDAC6. .

[0163] In some embodiments, the present application provides a method of treating a central nervous system disorder in a subject, comprising: i) The central nervous system disorder is caused by a histone deacetylase (HDAC) enzyme (e.g., HDAC). AC6) abnormal activity or abnormal expression; and ii) This central nervous system disorder is caused by abnormal activity of histone deacetylase (HDAC) enzymes. If a subject is identified as being associated with a genetic disorder or abnormal expression, the subject may be administered the methods provided herein. administering a therapeutically effective amount of a compound or a pharma- ceutical acceptable salt thereof to The present invention provides a method comprising:

[0164] In some embodiments, the disease to be treated is an inflammatory autoimmune disease. This inflammatory autoimmune disease can lead to alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, and skin ulcers. Dermatomyositis, diabetes mellitus (type 1), juvenile idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome Reay syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, myocarditis, pemphigus / pemphigoid, malignant anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Dermatosis / systemic sclerosis, Sjogren's syndrome, systemic lupus erythematosus, thyroiditis, grapes selected from the group consisting of vitiligo, vitiligo, and granulomatosis with polyangiitis (Wegener's granulomatosis) In some embodiments, the inflammatory autoimmune disease is caused by aberrant expression or abnormalities of HDAC6. It is associated with high activity.

[0165] In some embodiments, the present application provides a method of treating an inflammatory autoimmune disease in a subject, comprising: i) This inflammatory autoimmune disease is caused by a histone deacetylase (HDAC) enzyme (e.g., H Identifying the condition as being associated with abnormal activity or expression of DAC6; and ii) This inflammatory autoimmune disease is caused by abnormalities in the histone deacetylase (HDAC) enzymes. If a subject is identified as being associated with aberrant expression or activity, the subject may be administered the administering a therapeutically effective amount of the compound or a pharma- ceutical acceptable salt thereof to The present invention provides a method comprising:

[0166] In some embodiments, about 0.1 to about 5% of the compound or salt administered to the subject is in the blood-brain Passes through the barrier, for example, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2% , about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.1 % to about 0.25%, about 0.25% to about 5%, about 0.25% to about 4%, about 0.25% to about 3 %, about 0.25% to about 2%, about 0.25% to about 1%, about 0.25% to about 0.75%, about 0 .25% to approx. 0.5%, approx. 0.5% to approx. 5%, approx. 0.5% to approx. 4%, approx. 0.5% to approx. 3% , about 0.5% to about 2%, about 0.5% to about 1%, about 0.5% to about 0.75%, about 0.75% ~5%, ~4%, ~3%, ~2%, ~0.75% .75% to approx. 1%, approx. 1% to approx. 5%, approx. 1% to approx. 4%, approx. 1% to approx. 3%, approx. 1% to approx. 2% , about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4% , or about 4% to about 5% passes through.

[0167] In some embodiments, the compound administered to the subject is administered in a blood:plasma ratio of about 1:1 to about 10. 0:1, for example, about 1:1 to about 2:1, about 1:1 to about 3:1, about 1:1 to about 4:1 , about 1:1 to about 5:1, about 1:1 to about 10:1, about 1:1 to about 15:1, about 1:1 to about 2 0:1, approx. 1:1 to approx. 30:1, approx. 1:1 to approx. 1:40, approx. 1:1 to approx. 50:1, approx. 1: 1 to about 60:1, about 1:1 to about 70:1, about 1:1 to about 80:1, about 1:1 to about 90:1 , about 1:1 to about 100:1, about 1:1 to about 3:2, or about 1:1 to about 4:3. In this embodiment, the blood:plasma ratio is about 1:100 to about 1:1, e.g., about 1:1 00~approx. 1:1, approx. 1:100~approx. 1:2, approx. 1:100~approx. 1:3, approx. 1:100~approx. 1:4, approx. 1:100~approx. 1:5, approx. 1:100~approx. 1:10, approx. 1:100~approx. 1:1 5. Approx. 1:100 to 1:20, Approx. 1:100 to 1:30, Approx. 1:100 to 1:40 , about 1:100 to about 1:50, about 1:100 to about 1:60, about 1:100 to about 1:70, About 1:100 to about 1:80, about 1:100 to about 1:90, at least about 1:100, about 1 :100~approx. 2:3, approx. 1:100~approx. 2:5, approx. 1:100~approx. 3:4, approx. 1:100 In some embodiments, the ratio of the administered compound is from about 1:100 to about 3:5, or from about 1:100 to about 4:5. The product has a brain:plasma ratio of about 1:1 to about 50:1.

[0168] As used herein, the phrase "therapeutically effective amount" refers to a therapeutically effective amount that is administered by a researcher, veterinarian, physician, or other The desired biological response or therapeutic effect in a tissue, system, animal, individual, or human is determined by the clinical practitioner. The amount of active compound or drug that induces a biological response.

[0169] As used herein, the terms "treat" or "treatment" refer to (1) the inhibition of a disease. For example, experiencing or exhibiting the pathology or symptomology of a disease, condition, or disorder. inhibiting a disease, condition, or disorder in an individual (i.e., reducing or eliminating the pathology and / or symptomology of the disease, condition, or disorder); (2) ameliorating a disease; e.g., preventing the development of a disease, condition, or A disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disorder. To ameliorate (i.e., reverse the pathology and / or symptomatology of) the disease, e.g. Reducing the severity of the disease or relieving one or more symptoms of the disease or refers to one or more of the mitigating.

[0170] Combination therapy The compounds provided herein are useful for treating HDAC-associated diseases, disorders, or conditions. In combination with the compounds and salts, one or more additional therapeutic agents (e.g., chemotherapeutic agents, anti-inflammatory agents, Drugs such as immunosuppressants, steroids, immunosuppressants, therapeutic antibodies, and / or anesthetics may be used.

[0171] Examples of chemotherapeutic agents include proteosome inhibitors (e.g., bortezomib), thalidomide, , Revlimid, and DNA damaging agents (e.g., melphalan, doxorubicin, cyclophosphamide, familide, vincristine, etoposide, carmustine, and the like). .

[0172] Examples of anti-inflammatory agents include, but are not limited to, aspirin, salicylic acid, Choline acid, celecoxib, diclofenac potassium, diclofenac sodium, misoprostol Diclofenac sodium with Rostol, diflunisal, etodolac, fenoprofen fluprofen, ibuprofen, ketoprofen, sodium meclofenamate um, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxapro Zin, Piroxican, Rofecoxib, Salsalate, Sodium Salicylate, Sulinda , tolmetin sodium, and valdecoxib.

[0173] Examples of steroids include corticosteroids, such as cortisone, dexamethasone, These include dorocortisone, methylprednisolone, prednisolone, and prednisone. However, it is not limited to these.

[0174] Examples of immunosuppressants include azathioprine, chlorambucil, cyclophosphamide, and cyclosporine. rosporin, daclizumab, infliximab, methotrexate, and tacrolimus These include, but are not limited to:

[0175] Examples of anesthetic agents include, but are not limited to, local anesthetics (e.g., ribavirin, ribavirin, docaine, procaine, ropivacaine), and general anesthetics (e.g., desflurane, Flurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, molybdenum Barbital (mmobarbital), methohexital, thiamylal, thiopentaerythroxene Tar, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol Alfentanil, fentanyl, remifentanil, buprenorphine, butorphine morphine, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbu fin, oxymorphone, pentazocine).

[0176] In some embodiments, the additional therapeutic agent is administered contemporaneously with a compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered to a subject in need thereof. In some embodiments, the additional therapeutic agent is administered after administration of the salt. In some embodiments, the compound or salt provided herein is administered prior to administration of the compound or salt provided herein. In some embodiments, the compound or salt provided herein is administered during surgery. The compound or salt is administered in combination with an additional therapeutic agent during the surgical procedure.

[0177] Pharmaceutical Compositions and Formulations When used as pharmaceuticals, the compounds and salts provided herein can be administered in the form of pharmaceutical compositions. The compositions may be prepared as described herein or elsewhere, and may be administered topically. Depending on whether local or systemic treatment is desired and on the area to be treated, various Administration can be by a variety of routes. Administration can be topical (e.g., transdermal, epidermal, ocular, as well as mucosal (e.g., nasal, vaginal, and rectal delivery) or pulmonary (e.g., powder delivery by, for example, an aerosolizer). or by inhalation or insufflation of an aerosol; intratracheal, or intranasal) Parenteral administration can be by intravenous, intraarterial or intravenous route. intradermally, subcutaneously, intraperitoneally, intramuscularly, or by injection or infusion; or intracranially (e.g., intrathecally or Parenteral administration can be in the form of a single bolus or For example, the pumping may be a continuous perfusion pump. The compounds, salts, and pharmaceutical compositions described herein are suitable for parenteral administration. The compounds, salts, and pharmaceutical compositions provided herein are suitable for intravenous administration.

[0178] Pharmaceutical compositions and formulations for topical administration include transdermal patches, ointments, lotions, creams, and creams. These may include creams, gels, drops, suppositories, sprays, liquids, and powders. Pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like are essential. It may be necessary or desirable to

[0179] Also provided are pharmaceutical compositions comprising as an active ingredient a compound as provided herein. The compound or a pharma- ceutically acceptable salt thereof is mixed with one or more pharma- ceutically acceptable carriers (e.g., The present invention relates to a pharmaceutical composition comprising the composition of the present invention in combination with a pharmaceutical agent such as a medicament for use in treating or treating a chronic illness. In the formulation, the active ingredient is generally mixed with or diluted by an additive, or enclosed within such a carrier, for example in the form of a capsule, sachet, paper, or other container. When the additive functions as an excipient, it acts as a vehicle, carrier, or the like for the active ingredient. The material acting as the medium or medium may be a solid, semi-solid, or liquid material. The compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, preparations, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, Soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders The composition may be in the form of a pharmaceutical preparation.

[0180] Some examples of suitable additives include, but are not limited to: lactose Tocopherol, dextrose, sucrose, sorbitol, mannitol, starch, red almond gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose The formulation may further include, but is not limited to, a lubricant, such as talc. Wetting agents; emulsifying and suspending agents; preservatives, e.g., glyceryl stearate, magnesium stearate, and mineral oil. For example, methyl-benzoate and propyl hydroxy-benzoate; sweeteners; flavorings; is a combination of these.

[0181] The active ingredient can be effective over a wide dosage range and is generally administered in a pharma- ceutical effective amount. However, the amount of compound actually administered will usually vary depending on the relevant circumstances (e.g., treatment The condition being treated, the route of administration chosen, the actual compound being administered, the age, weight, and reaction time of the individual subject. The treatment should be determined by the physician according to the patient's condition, the severity of the patient's symptoms, and the like. It will be solved. EXAMPLES

[0182] The present invention will now be described in further detail with reference to specific examples. The following examples are provided for illustrative purposes. It is provided as an aid and is not intended to limit the invention in any manner. The inventors have discovered a variety of minor changes that can be altered or modified to obtain essentially the same results. The user will easily recognize the parameters.

[0183] General Materials and Methods All air- and moisture-insensitive reactions were carried out under ambient atmosphere and magnetically stirred. Tetrahydrofuran was distilled from deep purple sodium benzophenone ketyl. Dry DMF and dry DMSO were purchased from Acros Organics. Other anhydrous solvents (acetonitrile, diethyl ether, dichloromethane, pentane, and toluene), Dry columns using the mBraun system (e.g., Pangborn et al., Or Ganometallics, 1996, 15:1518-1520) All air- and moisture-sensitive operations were carried out under a nitrogen atmosphere in an oven. The experiment was carried out using glassware dried by filtration.

[0184] Thin layer chromatography (TLC) was performed using 250 μm thick silica gel 60F 254 play The results were performed on EMD TLC plates pre-coated with dimethylformamide (DMSO) and fluorescence quenching and The R and KMnO4 staining visualized the analytes. f Reach Use Silicycle columns as recommended based on the column size and mass. The reaction was performed on a BioOne (Biotage). Anhydrous acetonitrile was purchased from VWR and was Water acetone was purchased from Acros and sparged with nitrogen 30 min before use. Silica gel (230-400 mesh) purchased from le Inc. or as otherwise mentioned. flash chromatography was performed at Biotan with the Isolera purification system. The analysis was carried out using spherical silica gel cartridges (ZIP spheres) from GE.

[0185] All deuterated solvents were purchased from Cambridge Isotope Laboratories. The NMR spectrum was 1 V operating at 600MHz for H capture arian Unity / Inova 600 spectrometer, 1 H, 19 F, and 13 Capture of C Varia operates at 500MHz, 471MHz, and 125MHz for Unity / Inova 500 spectrometer, or 19 At 375MHz for F capture The chemical shifts were recorded on one of two Varian Mercury 400 spectrometers operating at 100 Hz. The concentrations are reported in ppm with the solvent resonance as the internal standard ( 1 H: Chloroform-d, δ 7.26; DMSO-d6, δ 2.50), ( 13 C: CDCl3, δ 77.16; DM SO-d6, δ 39.52). Data are reported as follows: s = singlet, d = doublet. , t = triplet, m = multiplet; coupling constants in Hz; integrals; carbon signals unless otherwise stated. All substrates were prepared as received from commercial suppliers unless otherwise stated. Ru(cod)(cp)Cl was synthesized as previously described.

[0186] Intermediate 1. Methyl-4-((((adamantan-1-yl)methyl)amino)methyl) -2-fluorobenzoate [ka] Methyl 2-fluoro-4-formylbenzoate (100 mg, 0.549 mol 1 .0eq.) and 1-adamantanemethylamine (100mg, 0.606mol, 1. A solution of 1 eq. of 1,2-dichlorophenyl ether in 2 mL of methanol was stirred at room temperature for 2 h. 50 mg of sodium urate was added and the reaction mixture was stirred until no starting material remained. The mixture was concentrated in vacuo, partitioned between ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The combined organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography. The title product (153 mg, 0.46 1 mmol, 92%) was obtained as a clear oil that solidified on standing. 1 H.N.M. R(500MHz, chloroform-d) δ 7.88(td, J=7.7, 1.0Hz, 1H),7.24-7.09(m,2H),3.92(d,J=1.2Hz,3H),3 .82(s,2H),2.21(d,J=1.0Hz,2H),1.97(t,J=3. 1Hz,3H),1.74-1.60(m,6H),1.52(d,J=2.9Hz,6 H).

[0187] Intermediate 2. Methyl-4-((((adamantan-1-yl)methyl)amino)methyl) -3,5-difluorobenzoate [ka] Methyl 3,5-difluoro-4-formylbenzoate (100 mg, 0.500 mo l 1.0eq.) and 1-adamantanemethylamine (100mg, 0.606mol A solution of 1.2 eq. of toluene in 2 mL of methanol was stirred at room temperature for 2 h. 150 mg of sodium triacetoxyborohydride was added and the reaction mixture was cooled to 0.5%. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. (62 mg, 0.177 mmol, 35%) was obtained as a clear oil. 1 H NMR (500MHz, chloroform-d) δ 6.90 (d, J=7.4Hz, 2H) ,4.69(s,3H),3.88(d,J=1.2Hz,2H),2.19(s,2H ),1.95(s,3H),1.77-1.54(m,6H),1.48(d,J=2. 8Hz,6H).

[0188] Intermediate 3. Methyl-4-((((adamantan-1-yl)methyl)amino)methyl) -3-Trifluoromethylbenzoate [ka] Methyl 3-trifluoromethyl-4-formylbenzoate (100 mg, 0.431 mol 1.0eq.) and 1-adamantanemethylamine (100mg, 0.606m A solution of 1.4 eq. of 1,2-dichlorophenyl ether (1.0 eq.) in 2 mL of methanol was stirred at room temperature for 2 hours. Then, 50 mg of sodium borohydride was added, and the reaction mixture was stirred until no starting material remained. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water, and the aqueous layer was diluted with acetic acid. The mixture was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. g, 0.171 mmol, 39.7%) as a clear oily substance that solidifies on standing. Got it.1 H NMR (500 MHz, chloroform-d) δ 8.31 (d, J = 2. 0Hz,1H),8.20(d,J=8.1Hz,1H),7.87(d,J=8.1H z,1H),4.01(s,2H),3.96(d,J=1.9Hz,3H),2.26 (d,J=1.6Hz,2H),1.99(s,3H),1.78-1.60(m,6H ),1.55(s,6H).

[0189] Intermediate 4. Methyl-4-((((adamantan-1-yl)methyl)amino)methyl) -3-Methylbenzoate [ka] Methyl 3-methyl-4-formylbenzoate (100 mg, 0.561 mol 1. 0 eq.) and 1-adamantanemethylamine (100 mg, 0.606 mol, 1.1 A solution of 2 mL of 1,2-dichlorophenyl ether (eq.) in methanol was stirred at room temperature for 2 hours. 50 mg of sodium hydroxide was added and the reaction mixture was stirred until no starting material remained. The mixture was concentrated in vacuo, partitioned between ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography. The title product (131 mg, 0.400 This was obtained as a clear oil which solidified on standing. 1 HN MR(500MHz, chloroform-d) δ 7.91-7.78(m,2H),7.4 2(d,J=7.8Hz,1H),3.91(d,J=1.2Hz,3H),3.79( s,2H),2.38(s,3H),2.29(d,J=1.4Hz,2H),1.98 (s,3H),1.80-1.49(m,12H).

[0190] Intermediate 5. Methyl-6-((((adamantan-1-yl)methyl)amino)methyl) -Nicotinic acid [ka] Methyl 4-formylnicotinate (100 mg, 0.606 mol 1.0 eq.) and 1-Adamantanemethylamine (100mg, 0.606mol, 1.0eq.) The solution was stirred at room temperature for 2 hours in 2 mL of ethanol. 150 mg of sodium chloride was added and the reaction mixture was stirred until no starting material remained. The mixture was concentrated in vacuo, partitioned between ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The combined organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography. The title product (75 mg, 0.239 The product was obtained as a clear oil (39%). Fluoroform-d) δ 9.15 (d, J = 2.2 Hz, 1H), 8.26 (dd, J = 8 .2,2.1Hz,1H),7.47(d,J=8.2Hz,1H),3.97(s,2 H),3.96(d,J=1.6Hz,3H),2.27(s,2H),1.98(s, 3H),1.80-1.61(m,6H),1.55(d,J=2.8Hz,6H).

[0191] Intermediate 6. Methyl 4-((((adamantan-1-yl)methyl)amino)methyl)- 3-Chlorobenzoate [ka] Methyl 3-chloro-4-formylbenzoate (100 mg, 0.505 mmol, 1 .0eq.) and 1-adamantanemethylamine (100mg, 0.606mol, 1. A solution of 2 eq. of triacetate in 2 mL of methanol was stirred at room temperature for 2 h. 150 mg of sodium borohydride was added and the reaction was cooled to room temperature without starting material. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water, and the aqueous layer was diluted with acetic acid. The mixture was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. , 0.207 mmol, 41%) was obtained as a clear oil. 0MHz, chloroform-d) δ 8.02(t,J=1.6Hz,1H),7.96- 7.87(m,1H),7.54(d,J=8.0Hz,1H),3.93(s,3H) ,3.92(s,2H),2.24(s,2H),2.18(s,1H),1.98(s ,3H),1.76-1.62(m,6H),1.54(d,J=2.7Hz,6H).

[0192] Intermediate 7. Methyl 4-((((adamantan-1-yl)methyl)amino)methyl)- 3-Bromobenzoate [ka] Methyl 3-bromo-4-formylbenzoate (100 mg, 0.412 mmol) .0eq.) and 1-adamantanemethylamine (100mg, 0.606mol, 1. A solution of 5 eq. of triacetate in 2 mL of methanol was stirred at room temperature for 2 hours. 150 mg of sodium borohydride was added and the reaction was cooled to room temperature without starting material. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water, and the aqueous layer was diluted with acetic acid. The mixture was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. g, 0.265 mmol, 64%) was obtained as a clear oil. 00MHz, chloroform-d) δ 8.21(d,J=1.7Hz,1H),8.06 -7.86(m,1H),7.53(d,J=8.0Hz,1H),3.93(s,3H ),3.89(s,2H),2.24(s,2H),2.18(s,1H),1.98( s,3H),1.82-1.60(m,6H),1.54(d,J=2.6Hz,6H) .

[0193] Intermediate 8. Methyl 4-(((((3r,5r,7r)-adamantan-1-yl)methyl (amino)methyl)benzoate [ka] Methyl 4-formylbenzoate (155 mg, 0.94 mol 1.1 eq.) and 1-Adamantanemethylamine (140mg, 0.85mol, 1eq.) in methanol The 3 mL solution was stirred at room temperature for 2 hours. Then, 210 mL of sodium borohydride was added. g was added in small portions and the reaction was stirred until no starting material remained (approximately 3.5 hours). The mixture was concentrated in vacuo, partitioned between ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The combined organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography. The title product (221 mg, 0.71 1 mmol, 75%) as a clear oil that solidified on standing. 1H NMR (Chloroform-d) δ 7.99(d,2H), 7.41(d,2H), 3.90(s ,1H),3.86(s,5H),2.23(s,2H),1.97(s,3H),1. 82-1.59(m,7H),1.59-1.44(m,7H).MS(m / z) C2 0H 27 Calculated value for NO2 [M+H] + 313.20;Actual value, 313.7.

[0194] Intermediate 9. Methyl 4-((((3s,5s,7s)-adamantan-1-yl)amino )Methyl)benzoate [ka] Methyl 4-bromomethylbenzoate (300 mg, 1.83 mmol, 1.4 eq. ) and 1-adamantanamine (201 mg, 1.33 mol, 1 eq.) in DMSO Add 1.5 mL of solution, 200 μL of N,N-diisopropylethylamine, and mix. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water and diluted with an aqueous solution of ethyl acetate and water. The aqueous layer was extracted two more times with ethyl acetate, and the combined organic phases were then extracted three times with water. The organic phase was then dried over sodium sulfate. The solvent was removed under reduced pressure to give the product. The product was purified by column chromatography. The title product (44.6 mg, 0.15 mm 1H NMR (NMR, 11%) was obtained as a clear oil that solidified on standing. Fluoroform-d) δ 7.98(d,2H), 7.43(d,2H), 3.89(s,5 H),2.12(s,3H),1.79-1.51(m,13H).MS(m / z) C 19 H 25Calculated value for NO2 [M+H] + 299.2;Actual value, 299.7.

[0195] Intermediate 10. Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl ) Propan-2-yl) amino) methyl) benzoate [ka] Methyl 4-formylbenzoate (198 mg, 1.21 mmol 1.75 eq.) and 1-(1-adamantyl)propan-1-amine) (134 mg, 0.69 mmol A solution of 1 eq. of 1,2-dichlorophenyl ether (1 eq.) in 6 mL of methanol was stirred at room temperature for 40 min. 200 mg of sodium borate was added in small portions and the reaction was stirred until no starting material remained. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was extracted two more times with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. The product was obtained as a clear oil (339 mg, 0.41 mmol, 60%). R(chloroform-d6) δ 8.00(d,2H),7.42(d,2H),3.84 (s,5H),2,80(m,1H),1.93(s,3H),1.82-1.42(m ,14H),1.34-1.20(m,2H),1.20-1.01(m,4H).MS (m / z) C 22 H 31 Calculated value for NO2 [M+H] + 341.24; measured value ,341.7.

[0196] Intermediate 11. Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl )Propyl)amino)methyl)benzoate [ka] Methyl 4-formylbenzoate (202 mg, 1.23 mmol, 1 eq.) and 1 -(1-adamantyl)propan-1-amine) (232 mg, 1.20 mmol, 1e A solution of q.) in 6 mL of methanol was stirred at room temperature for 45 minutes. 200 mg of sodium was added in small portions and the reaction was stirred until no starting material was left (approximately 3 The mixture was concentrated in vacuo and partitioned between ethyl acetate and water, and the aqueous layer was It was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate. The product was purified by column chromatography. mg, 0.413 mmol, 74.3%) as a transparent oily substance that solidifies on standing. 1H NMR (chloroform-d6) δ 7.9 (d, 2H), 7.4 (d, 2 H),4.08(m,4H),3.8(m,1H),1.99(m,3H),1.85( m,1H),1.78-1.44(m,15H),1.24-1.06(m,2H),1 .06-0.87(m,4H).MS(m / z) C 22 H 31 Calculated value for NO2 [M+H] + 341.2;Actual value, 341.7.

[0197] Intermediate 12. Methyl 4-((((6,6-dimethylbicyclo[3.1.1]heptane- 2-yl)methyl)amino)methyl)benzoate [ka] Methyl 4-formylbenzoate (0.306 mg, 1.86 mmol, 1.1 e q.) and (-)-cis-myrtanylamine (247 mg, 1.62 mmol, 1 eq A solution of 1.5 mL of borohydride in methanol was stirred at room temperature for 1.5 hours. 175 mg of sodium chloride was added in small portions and the reaction was stirred until no starting material was left (approximately The mixture was concentrated in vacuo and partitioned between ethyl acetate and water, and the aqueous layer was The extract was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. 3 mg, 1.54 mmol, 94%) was obtained as a yellowish oil. NMR(chloroform-d) δ 8.0(d,2H), 7.6(d,2H), 4.17- 3.77(m,3H),3.98(s,2H),2.77-1.65(m,11H),1 .65-0.43(m,11H).MS(m / z) C 19 H 27 Calculated value for NO2 [M+H] + 301.20;Actual value, 301.7.

[0198] Intermediate 13. Methyl 4-(((cyclohexylmethyl)amino)methyl)benzoate [ka] Methyl 4-formylbenzoate (0.303 mg, 1.84 mmol, 1.2 e q.) and cyclohexanemethylamine (174 mg, 1.53 mmol, 1 eq.) The solution in 5 mL of methanol was stirred at room temperature for 0.5 h. Then sodium borohydride was added. 170 mg of sodium was added in small portions and the reaction was stirred until no starting material was left (approximately 3 hours). The mixture was concentrated in vacuo and partitioned between ethyl acetate and water, and the aqueous layer was diluted with acetic acid. The mixture was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. The title product (363 mg 1.39 mmol, 91%) was obtained as a yellowish oil. (Chloroform-d) δ 8.0(d,2H), 7.4(d,3H), 4.0(s,2H ),2.45-1.97(m,2H),1.97-1.44(m,7H),1.44-0 .92(m,6H),0.93-0.53(m,2H).MS(m / z) C 16 H 23 Calculated value for NO2 [M+H] + 261.17;Actual value, 261.7.

[0199] Intermediate 14. [CpRu(cod)Cl] [ka] Step 1. [RuCl2(cod)] n A two-neck round bottom flask was flame dried and purged with N2. RuCl3·×H2O, 7.4g, 0.03mol, 1eq; RuCl·× H2O containing various water contents and total ruthenium content ranging from 40 to 43%. The flask was evacuated and held under vacuum for 1 hour, then purged with N2. Add 1,5-cyclooctadiene (20 mL, 18 g, 0.16 mol, 5 eq.) to the flask. ) and ethanol (0.14 L, c=0.2 M) were added to give a dark brown solution. The mixture was stirred and heated to reflux at 95°C for 48 hours, then cooled to 23°C. The resulting brown precipitate was filtered through a sintered glass funnel under air and diluted with ethanol (50 mL The brown solid was dried under vacuum for 48 hours to give [RuCl2 (cod)] n (8.2 g). This material was used in the next step without further purification. Used.

[0200] Step 2. [(cod)RuH(NH2NMe2)3]PF6 [ka] In an oven-dried, 250 mL, two-necked round-bottom flask equipped with a magnetic stir bar, was heated under N [RuCl2(cod)] n (5.50 g) was added to the flask. ethanol (55 mL), degassed water (13.8 mL), and freshly distilled degassed N,N'-dimethyl Hydrazine (55 mL, 43 g, 0.72 mol) was added. The mixture was heated at 95° C. The mixture was stirred at the same temperature for 45 minutes. The mixture was then stirred for 60 minutes. The reaction mixture was cooled to 23° C. over a period of time. Under N2, NH4PF6 (5.5 g, 3 A degassed solution of 4 mmol) in HO (55 mL) was added. The slurry was stirred for 12 h under N The resulting colorless precipitate was poured into a sintered glass funnel under air and then cooled to -20°C for 1 h. The filtrate was then concentrated under reduced pressure to half its volume and cooled to −20° C. for 60 min. The resulting colorless precipitate was filtered through a sintered glass funnel to give a second fraction of the product. The harvest was collected and combined with the previous fractions. The combined colorless precipitate was washed with ice-cold water (200 mL ) and dried under vacuum for 48 hours to give [(cod)RuH(NH2 NMe2)3]PF6 (4.9 g) was obtained. This material was used in the next step without further purification. It was used in the process.

[0201] Step 3. [CpRu(cod)Cl] [ka] In a nitrogen-filled glove box, a 250 In a two-necked round-bottom flask, add 5.0 mL of [(cod)RuH(Me2NNH2)3]PF6 ( 0 g) and thallium cyclopentadienide (2.78 g, 10.3 mmol). The flask was sealed with a second rubber septum and taken outside the glove box. To the mixture was added degassed acetone (88 mL) under N2. The mixture was heated at 65°C for 3 The mixture was stirred at the same temperature for 20 minutes. The resulting mixture was then heated to 23° C. for 20 minutes. The mixture was transferred via cannula to a Schlenk flask, sealed, and then poured into a flask. The mixture was filtered through a pad of Celite under vacuum. The filtrate was concentrated in vacuo to give a brown solid. 1 mL) was added and the mixture was shaken vigorously for 10 min. The solution was then drawn into a syringe, passed through a 0.2 nm PTFE syringe filter, and diluted with CCl4 (1.93 mL The solution was filtered into another 50 mL flask containing 10 mL of ethyl acetate. A yellow precipitate was observed. The addition of pentane (30 mL) to the brown solid was repeated. The supernatant was filtered again and This mixture was stirred in the glove box for 30 min. The flask was then removed from the glove box and the mixture was stirred under air. The solid was filtered through a sintered glass funnel, washed with pentane (30 mL) and concentrated under vacuum. [CpRu(cod)Cl] (1.21 g, 3.27 mmol, RuC From l3, 16±1%) was obtained as a dark yellow solid. 1 H NMR (500MHz, CDC l3,23 ℃,δ):5.32-5.29(m,2H),4.95(s,5H),4. 41-4.38(m,2H),2.62-2.59(m,2H),2.10-2.03( m, 4H), 2.00-1.93(m, 2H) (1H NMR spectroscopic data reported in the literature Corresponding to the data published in Chem. Eur. J. 2014, 20, 111 Please refer to 01-11110). 13 C NMR (125MHz, CDCl3,2 3℃,δ):128.8,87.1,85.9,78.7,32.6,28.1,28. 0.HRMS(m / z) C 13 H 17 Calculated value for ClRu [M-Cl] + ,27 5.0374;Actual value, 275.0367.

[0202] Example 1. 4-(((((3s)-adamantan-1-yl)methyl)(methyl)amine (N-methyl)-3-fluoro-N-hydroxybenzamide [ka] Step 1. Methyl 4-(((((3s)-adamantan-1-yl)methyl)amino)methyl (ethyl)-3-fluorobenzoate [ka] 250 mg (1.37 mmol) of methyl 3-fluoro-4-formylbenzoate and Adamantane methylamine 238 mg (1.44 mmol, 1.05 eq) in methanol The 2 mL solution was stirred at room temperature for 30 min. Then sodium borohydride 104 mg (2.74 mmol, 2.00 eq) was added and the reaction was cooled to room temperature with no starting material remaining. (about 3 h). The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate, and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. ((((adamantan-1-yl)methyl)amino)methyl)-3-fluorobenzoate 372 mg (1.12 mmol, 82%) of ethyl acetate was added to the flask, and the mixture was cooled to room temperature to obtain a transparent oily substance that solidified upon standing. R f (25% EtOAc, 75% hexane) = 0.49; 1 H NMR( 500MHz, chloroform-d) δ 7.79 (dd, J=7.9, 1.6Hz, 1H ),7.66(dd,J=10.5,1.6Hz,1H),7.49(t,J=7.6H z,1H),3.90(s,3H),3.88(s,2H),2.22(s,2H),1 .94(d,J=3.1Hz,2H),1.80-1.65(m,3H),1.65-1 .57(m,3H),1.51(d,J=3.0Hz,6H). 13 C NMR(126 MHz, chloroform-d) δ 164.49, 160.85 (d, J = 247.4 Hz ),132.34,131.35,129.58(d,J=13.3Hz),122.4 5,114.22(d,J=24.8Hz),70.83,56.96,45.36,4 0.88, 37.10, 34.97, 28.42. 19 F NMR (471MHz, chromium HRMS: m / z (+H + ) Calculated value: 332.2 020, Actual value: 332.2068.

[0203] Step 2. Methyl 4-(((((3s)-adamantan-1-yl)methyl)(methyl) Amino)methyl)-3-fluorobenzoate [ka] Methyl 4-((((adamantan-1-yl)methyl)amino)methyl)-3-fluoro 350 mg (1.06 mmol) of benzoate in 3 mL of methanol and 0.5 mL of formalin. The solution was stirred for 2 hours, and then 80 mL of sodium borohydride was added. .2mg (2.12mmol, 2eq) was added and the mixture was stirred for a further 1h. The mixture was concentrated in vacuo, partitioned between ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography. Methyl 4-(((((3s)-adamantyl Tan-1-yl)methyl)(methyl)amino)methyl)-3-fluorobenzoate 22 7 mg (0.657 mmol, 62%) as a clear oily substance that solidifies on standing Got it. R f (25% EtOAc, 75% hexane) = 0.75; 1 H NMR(60 0MHz, chloroform-d) δ 7.73(dd,J=7.9,1.6Hz,1H), 7.64-7.44(m,2H),3.83(s,3H),3.56(s,2H),2. 16(s,3H),2.06(s,2H),1.90-1.80(m,3H),1.63 (dd,J=12.2,3.3Hz,3H),1.59-1.52(m,3H),1.4 6-1.35(m,6H). 13 C NMR (126MHz, chloroform-d) δ 1 65.75,160.66(d,J=245.8Hz),132.49(d,J=14. 3Hz),130.62,130.26,124.94,116.06(d,J=24. 0Hz),71.00,57.15,51.98,45.52,40.91,37.12 ,35.06,28.42. 19 F NMR (471MHz, chloroform-d) δ - 117.64HRMS:m / z(+H + ) Calculated value: 346.2177, Measured value: 346 .2158.

[0204] Step 3. 4-(((((3s)-adamantan-1-yl)methyl)(methyl)amino )Methyl)-3-fluoro-N-hydroxybenzamide [ka] 200 mg (0.580 mmol) of ester in 2 mL of 1:1 THF / MeOH 0.5 mL of hydroxylamine (50% aq) and 0.1 mL of 5 M NaOH were added at 0°C. The reaction mixture was stirred for 2 h and then partitioned between DCM and water. The aqueous layer was extracted three more times with DCM and the combined organic phases were dried over sodium sulfate. The product was separated using a gradient of water and acetonitrile buffered with formic acid. Purification by HPLC gave the hydroxamate as a pale yellow oil which was purified in vacuo. Further drying gave a pale orange foamy solid, 123 mg (0.355 mmol, 61%). And it changed. 1 H NMR (600MHz, chloroform-d) δ 11.21(s, 1H),9.11(s,1H),7.59-7.50(m,2H),7.47(dd,J =10.9,1.6Hz,1H),3.56(s,2H),2.16(s,3H),2. 08(s,2H),1.88(s,3H),1.63(d,J=12.3Hz,3H), 1.55(d,J=12.2Hz,3H),1.43(s,6H). 13 C NMR(1 26MHz, chloroform-d) δ 164.49, 160.85(d, J=247.4 Hz),132.34,131.35,129.63,122.45,114.22(d ,J=24.8Hz),70.83,56.96,45.36,40.88,37.10 ,34.97,28.42. 19 F NMR (471MHz, chloroform-d) δ - 116.71.HRMS:m / z(+H + ) Calculated value: 347.2129, Measured value: 34 7.2560.

[0205] Example 2. 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl )-3-[ 18 F]Fluoro-N-hydroxybenzamide [ka] Step 1. Methyl 3-hydroxy-4-(hydroxymethyl)benzoate [ka] Dissolve 500 mg (2.38 mmol) of dimethyl hydroxyterephthalate in 5 mL of THF. 180 mg (4.76 mmol, 2 eq) of sodium borohydride was added to the solution. The resulting suspension was heated to reflux for 2 h. The solvent was removed in vacuo and the resulting residue was diluted with 5% water. The solution was then acidified with 1 M HCl and diluted with 0 mL of HCl until crystallization was observed. The product was purified by column chromatography to give 368 mg (2.0 2 mmol, 85%) was obtained as a white solid. f (25% EtOAc, 75% hexane San) = 0.11; 1 H NMR(600MHz,DMSO-d6)δ 9.83(s, 1H),7.42(dt,J=3.3,1.9Hz,2H),7.36(q,J=1.6 Hz,1H),5.16(s,1H),4.51(s,2H),3.81(dd,J=2 .2,1.1Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ 16 7.24,154.83,135.52,129.49,127.85,120.75, 115.56,58.90,52.87.HRMS:m / z(+Na + ).Calculated value: 20 5.0471, Actual value: 205.0471.

[0206] Step 2. Methyl 4-formyl-3-hydroxybenzoate [ka] Methyl 3-hydroxy-4-(hydroxymethyl)benzoate 250 mg (1.37 73 mg of Pd / C (10% Rhodidine) was added to 3 mL of a 10% aqueous methanol solution. ing, 0.034 mmol, 2.5 mol %, potassium carbonate 567 mg (4.11 mm ol, 3eq), and sodium borohydride 5.2mg (0.137, 0.1eq). was added and the mixture was stirred overnight under an atmosphere of oxygen. The mixture was concentrated in vacuo and diluted with ethyl acetate and water. The aqueous layer was partitioned and extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. 4-formyl-3-hydroxybenzoate 92 mg (0.506 mmol, 37%) was obtained as a white solid. f (25% EtOAc, 75% hexane) = 0.50; 1 H NMR (600MHz, chloroform-d) δ 10.94(s,1H), 9.9 8(s,1H),7.69-7.63(m,3H),3.94(s,3H). 13 CN MR(126MHz, chloroform-d) δ 196.44, 165.67, 161.2 4,137.30,133.62,122.86,120.40,119.12,52. 69.HRMS:m / z(+H + ).Calculated value: 181.0495, measured value: 181.04 94.

[0207] Step 3. Methyl 4-((((adamantan-1-yl)methyl)amino)methyl)-3 -Hydroxybenzoate [ka] Methyl 4-formyl-3-hydroxybenzoate 100 mg (0.556 mmol) and 96.4 mg (0.583 mmol, 1.05 eq) of adamantane methylamine The solution was stirred at room temperature for 30 minutes in 2 mL of ethanol. 37.8 mg (1.00 mmol, 1.80 eq) of glycerol was added and the reaction mixture was stirred for about 3 h. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The layers were extracted two more times with ethyl acetate, and the combined organic phases were then dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. -((((adamantan-1-yl)methyl)amino)methyl)-3-hydroxybenzo 136 mg (0.413 mmol, 74%) of ethyl acetate was added to the solution in a transparent oily solution that solidified on standing. Obtained as a substance. R f (25% EtOAc, 75% hexane) = 0.46; 1 HN MR(600MHz, chloroform-d) δ 7.52-7.37(m,1H),7.0 1(d,J=7.8Hz,0H),3.98(s,1H),3.86(s,1H),2. 30(s,1H),1.99-1.93(m,2H),1.70(d,J=12.6Hz ,1H),1.62(d,J=12.3Hz,1H),1.56-1.44(m,3H) . 13 C NMR (126MHz, chloroform-d δ 167.06, 158.36 ,130.57,128.19,127.71,120.16,117.30,61.7 7,53.27,51.99,40.64,36.97,33.04,28.25.HR MS: m / z (+H + ).Calculated value: 330.2064, Measured value: 330.1910.

[0208] Step 4. Methyl 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl (ethyl)-3-hydroxybenzoate [ka] Methyl 4-(adamantan-1-yl)methyl)amino)methyl)-3-hydroxybenzyl 100 mg (0.303 mmol) of benzoate in 3 mL of methanol and 0.5 mL of formalin L, and 1 drop of acetic acid solution was stirred for 2 hours, then sodium borohydride 22. 9 mg (0.606 mmol, 2 eq) was added and the mixture was stirred for a further hour. The mixture was concentrated in vacuo, partitioned between ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography. Methyl 4-((((adamantane-1- (yl)methyl)(methyl)amino)methyl)-3-hydroxybenzoate 67.7mg (0.197 mmol, 65%) was obtained as a clear oil that solidified on standing. R f (25% EtOAc, 75% hexane) = 0.64; 1 H NMR (600MH z, chloroform-d) δ 7.46(s,1H), 7.43(dd,J=7.8,1. 7Hz,2H),6.99(d,J=7.8Hz,2H),3.87(s,7H),3. 76(s,4H),2.26(s,7H),2.23(s,4H),1.76-1.68 (m,6H),1.69-1.60(m,7H),1.56(d,J=3.0Hz,12 H). 13 C NMR (126 MHz, chloroform-d) δ 167.07, 157. 93,130.62,128.28,127.37,120.21,116.97,72 .04,64.27,52.02,44.84,41.11,36.89,34.44, 28.30.HRMS: m / z(+H + ).Calculated value: 344.2220, Actual value: 344 .2230.

[0209] Step 5. 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl) -3-[ 18 F]Fluoro-N-hydroxybenzamide [ka] Hydrous cyclotron 18 [F] fluoride, 5.0 mg / mL of potassium carbonate hydrate The chromatograph was then preconditioned with 100% sodium chloride and then loaded onto a SPE Chromafix 30-PS-HCO3 cartridge. The column was then passed through the column and washed with 18 mL of Millipore Milli-Q water. 18 [F]fluoride was washed by passing 1 mL of ethanol through the cartridge. At the beginning of the synthesis, 657 mCi was measured on this cartridge. Methyl 4-((((Adam (methyl)amino)methyl)-3-hydroxybenzoate 5 mg, Ru(cp)(cod)Cl 10 mg, and N,N-bis-(2,6-diisopropyl) 30 mg of 8-propylphenyl-2-chloroimidazolium chloride was added over 30 min. The resulting solution was heated in 250 μL of ethanol at 5° C. The resulting solution was then loaded onto an anion exchange cartridge. The cartridge was filled with 400 μL of acetonitrile and collected in a drum vial. 400 μL of DMSO was then poured into the same vial and collected, followed by a Teflon-lined Seal with a Teflon lined cap and heat at 130°C for 30 minutes. Then, 1 mL of THF / MeOH (1:1), 0.4 mL of 50% aqueous NH2OH solution were added. 0.1 mL of 5M NaOH was added at room temperature and the reaction mixture was stirred for 5 min. The solution was diluted to 10 mL with water and added to an OASIS® MAX SPE column. Load onto a cartridge (60 mg), wash with 5 mL of water, and add ethanol / 0.1 M AcO The mixture was eluted with 2 mL of OH (1:1) and analyzed by semi-preparative HPLC (Agilent Eclipse C-18, 9.4×250mm, 5μm; flow ramp, 0-4 minutes 0.5 mL / min to 5 mL / min, then 5 mL / min; 0.01 N NaO 5% ACN in 0.01 NaOH, then gradient to 70% ACN in 0.01 NaOH in 45 min) The isolated fraction was purified using OASIS® MAX SPE cartridges (6 Reconstitute with 100 mg of ethanol (1:1), wash with 5 mL of water, and dissolve in 2 mL of ethanol / 0.1 M AcOH (1:1). eluted with 1 mL of 0.9% saline, diluted with 8 mL of 0.1 N NaOH to pH 5. In total, 53.3 mCi was isolated within 94 min (non-decay-corrected radioactivity). Chemical yield 8.1%).

[0210] Example 2A. 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl ru)-3-[ 18 Purification of [F]fluoro-N-hydroxybenzamide Semi-preparative HPLC The radiolabeled compound of Example 2 was subjected to semi-preparative HPLC using the following system and conditions: Purified by: Agilent Eclipse C-18, 9.4 x 250 mm, 5 μ m; flow rate gradient 0–4 min: 0.5 mL min -1 to 5 mL min -1 to 5 mL min - 1 , 5% ACN in 0.01N NaOH for 0–4 min, then 0.01 NaOH for 45 min. Gradient to 70% ACN in OH.

[0211] analyticalHPLC The radiolabeled compound of Example 2 was purified by analytical HPLC using the following system and conditions: Purified: Agilent Eclipse C-18, 4.6 x 10 mm, 5 μm, flow Volume 2mL min-1 , 5% ACN / H2O at 0 min, 0.1% TFA at 10 min to 9% Gradient to 5% ACN / H2O, 0.1% TFA.

[0212] Analytical HPLC co-injection with standards The radiolabeled compound of Example 2 was synthesized using the following system and conditions: Analyzed by analytical HPLC co-injection with: Agilent Eclipse C-18, 4.6×10mm, 5μm, flow rate 2mL min -1 , 5% ACN / H2O at 0 min, 0. Gradient from 1% TFA to 95% ACN / H2O, 0.1% TFA in 10 min.

[0213] Example 3. IC 50 Assay I C 50 Measurements were performed using a well-established fluorescent assay from BPS Biosciences. (Table 1) or Nanosyn (Table 1A). Table 1 shows known HDAC inhibitors, 4-, as compared to martinostat (structure shown below). (((((3s)-adamantan-1-yl)methyl)(methyl)amino)methyl)-3 Representative IC5 values ​​measured for -fluoro-N-hydroxybenzamide (Example 1) Indicates a 0 value. [ka]

[0214] [Table 1]

[0215] Table 1A shows the HDAC6 IC values ​​measured for the compounds of Examples 1 and 8 to 25. 50 Value show.

[0216] [Table 2]

[0217] Table 1B shows the HDAC1-HDAC1 activity measured for the compound of Example 1 compared to the following compounds: 11 IC 50 Showing a comparison of values: A = Martinostat (Caliper by Nanosyn (Microfluidics Transfer) Mobility shift detection ection))(same execution, duplicate)); B= [ka] (See, e.g., International Publication No. WO 2015 / 058106; Fluorescence Intensity based enzyme assays, multiple runs; duplicates); C= [ka] ; D = Tubastatin A (e.g., Butler et al., See JACS (2010) 132:10842-10846); E=ACY-1215 (e.g. Santo et al.,Blood(2012) 119:2579); and F = CI-994 (e.g., Seo et al., ACS Chem. Neuros ci.2014,5(7):588-596).

[0218] [Table 3]

[0219] Table 1C shows the known compounds tubastatin A, ACY-1215 (ricorinostat (ri colinostat), and CI-994 (i.e., tacedinaline Comparison of HDAC6 selectivity and potency for the compound of Example 1 compared to +++ = verified brain penetrant; + / - = moderate to no brain uptake; - = no brain uptake.

[0220] [Table 4]

[0221] Table 1D shows additional pharmacokinetic data measured for the compound of Example 1.

[0222] [Table 5]

[0223] Example 4. Acetylation Level Assay Fibroblast cell line GM08330 (Coriell Institute) from healthy control subjects Human iPSC-derived preneuronal cells from the National Institute for Medical Research Progenitor cells were generated using a previously reported method and incubated with DMS for 6 h at 37°C. O or a solution of HDAC inhibitors (ACY1215, final concentration 5 μM; Example 1, CI-99 4, Tubastatin A, final concentration 10 μM). Cell pellets (n=3 per condition) Lysis was performed using EDTA-free protease inhibitors (Sigma #4693159001). Radioimmunoprecipitation assay (RIPA) buffer (Boston BioProduct The lysates were centrifuged at 18,000 rpm for 15 min at 4°C. The supernatant was collected and the protein concentration was determined by BCA assay (Thermo Sc The results were measured using a chromatographic method (Epichromat #23227) and adjusted to 6 μg total protein / replicate. Western blot analysis was performed on the samples.

[0224] IC explained in Example 3 50 To confirm the high selectivity suggested by the values ​​above, As described, two non-coding genes, substrate and HDAC6, were expressed in IPS-derived human neural progenitor cell lines. The acetylation level of the substrate was examined. As shown in Figure 1, the results were compared with other tool compounds. Treatment with the compound of Example 1 and α-tubulin and histones (specifically H3K9 and Quantification of the acetylation status of H4K12 and H4K2 revealed selectivity for HDAC6 at the functional level. confirmed the gender.

[0225] Both Tubastatin A and ACY1215 have been shown to inhibit HDAC6. Both compounds increased the amount of acetyl-α-tubulin in cells, but not class I selection. The selective HDAC inhibitor CI-994 did not increase tubulin acetylation. As shown in FIG. 1, the compound of Example 1 also increased the amount of acetyl tubulin in the cells. , which showed involvement of HDAC6.

[0226] Histone acetylation is also regulated by the HDAC6-selective agent Tubastatin A. The compound of Example 1 remained unchanged. ACY1215 inhibits HDAC6. It showed low selectivity for H4K12 acetylation and inhibition of other HADC isoforms. Histone acetylation at both H3K9 and H4K12 was significantly increased in CI. In conclusion, as shown in Fig. 1, HDAC Changes in cellular protein acetylation in response to inhibitor treatment reveal the binding of HDAC6 to The functional selectivity of Example 1 was confirmed.

[0227] Example 5. Western blotting Proteins were stained with Criterion Stain-Free for 50 min at 200V. e Proteins were separated on a 4-20% gel (Biorad 567-8095). Low fluorescence PVDF membrane (Biorad 162-026) at 0.14 amps for 60 minutes The gels and membranes were transferred to a Chemidoc XRS system (B The membrane was treated as follows: at 4°C for 1 h. Overnight, the cells were incubated in Tris-buffered saline containing 5% blocker (Biorad 170-6404). Block with saline + Tween 20 (TBST, 0.1% Tween 20). The following steps were carried out at room temperature: the membrane was washed with TBST and then incubated with 1% blotting solution for 60 min. Acetyl histone H3 lysine 9: EMD Millipore 06-942- S 1:4000, Acetyl Histone H4 Lysine 12:EMD Millipore 0 Incubate with primary antibody in TBST containing 7-595 1:4000 and incubate with TB Wash with ST and incubate for 60 min in 1% blocker (anti-rabbit HRP: Cell Sig naling #7074S 1:5000, anti-mouse HRP: Cell Signal Incubate with secondary antibody in TBST containing 1:5000 ing #7076S Wash with TBST and incubate with ECL Prime Western Blotting Detection Reagent (GE R The images were developed using a 300 nm fluoride (PN2232) and visualized using a Chemidoc XRS system. 600 tan blot images were extracted from Image Lab 5.2.1 (.scn) files. The image was then opened in ImageJ. Converted to bits and subtracted a rolling ball radius of 50.0 pixels from the background The images were inverted and the average band intensity was quantified with the measurement tool.

[0228] Example 6. Autoradiography The selectivity of Example 1 in brain tissue was demonstrated using autoradiography ( Figure 3. Sagittal slices of the brain of Sprague-Dawley rats were taken using a cryostat (T The sections were cut at 10 μm using a Hermo Scientific HM550 and colorimeter was used. Frost Plus microscope slides (Fisher Scientific 12-5 The slides were mounted on 50-18) and stored at -20°C. DMSO solutions of blocking compounds (Example 1: 100 nM, 1 μM, and 10 μM) were used. 50 μL of room temperature buffer containing 100 μM final concentration, and Tubastatin A: 100 μM final concentration) (100 mM Tris, 50 mM NaCl, pH 7.5) in a 50 mL bath. After 15 minutes, 50 μCi of the radiolabeled compound of Example 2 was added to each bath. The plates were washed by immersion in buffer 10x, followed by 5 min at 4°C in buffer. The slides were then immersed in a 50 mL bath of 100 mL of PBS. The slides were dried in a vacuum chamber at 35° C. The screen (Perkin Elmer 7001723) was placed over the slides for 45 min. Both were exposed to light and then Cyclone Plus Storage Phosphor( Images were captured using a Perkin Elmer detector. Gaussian blurring was performed using ImageJ. Then, we apply smoothing (3.0 radius) and compare the brightness with a lookup table ( The raw intensity data from the gray and white matter were measured using the ImageJ measurement tool. The values ​​were quantified.

[0229] Slices of rat brain tissue were incubated with the radiolabelled compound of Example 2 in the presence of either Example 1 or Tubastatin. The binding was significantly reduced by 1 μM of Example 1. The compound, Tubastatin A, reduced the amount of bound radioactivity to the same background level as in Example 1 at 10 μM. These data suggest that IL-16 is selective for HDAC6 and can bind to brain tissue. This indicates that a combination will occur.

[0230] Example 7. PET / CT Imaging Imaging of rats Eight male Sprague-Dawley rats (Charles River La Anesthesia was administered using isoflurane in a medical oxygen carrier. This was achieved with Luran (3% for induction and 2% for maintenance). For intravenous administration, an extension line ( A catheter with an extension line was placed in the lateral tail vein of each animal. Immediately before injection of the radiotracer, the mice were injected with vehicle (1:1:8 DMSO / Tween 80 / saline) or blocking agent solution (1 mg / kg, 1:1:8 DMSO / Tw The subjects were given a bolus injection of either 1 mg / mL in een80 / normal saline.

[0231] Following injection of a bolus of radiotracer (approximately 700 μCi, Example 2), all animals Paired 90-minute dynamic PET scans were acquired using GammaMe The study was performed using a dica Triumph PET / CT / SPECT scanner. Attenuation was corrected by μ-maps obtained from corresponding CT images acquired immediately after implantation. Dynamic PET data were collected over 38 time frames (8 × 15 sec, 8 × 1 min, 10 × 2 min, 1 We binned the data into 2 × 5 and performed iterative MLEM (maximum likelihood estimation expectation maximization) with 16 iterations. imum likelihood expectation maximization )) and individually reconstructed using the algorithm.

[0232] PET images were coregistered to CT images acquired from the same animal using AMIDE. The dataset was trimmed and analyzed using PMOD 3.3 (PMOD Technology All further image analysis was performed using the NIRS (Zurich, Switzerland). For maximum consistency, data were analyzed using Schiffer Px Rat rat brain tissue. Plate co-recording and data were acquired from whole brain VOIs (regions of interest) in time activity curves. .

[0233] Primate Imaging PET-MR imaging was performed under anesthesia (ketamine, isoflurane) to minimize discomfort. The study was conducted on baboons (Papio anubis). Audio, visual, and tactile reinforcement was provided daily to promote cognitive functioning. To obtain the study results, non-human primates were not euthanized.

[0234] PET-MR images were acquired using a Biograph mMR scanner (Siemens, Munich, Germany). ch, Germany) and PET resolution of 5 mm and 59.4 and 25.8 cm (and PET-compatible eight-channel system for imaging non-human primate brains with transaxial and axial views, respectively Dynamic PET image acquisition was started, followed by injection of the radiotracer. The MEMPRAGE sequence was administered intravenously to obtain baseline anatomical co-registered sequences. To characterize specific binding, unlabeled IgG was added at the beginning of acquisition. A second imaging experiment was performed in which Example 1 was co-administered intravenously. Dynamic data from PET scans were The data were recorded in list mode and corrected for attenuation. The baboon data were analyzed using a full width at half maximum resolution of 4 mm. The images were reconstructed using 3D-OSEM.

[0235] PET imaging was further performed in the baboon brain. Figure 4 shows the PET images of the baboon brain using the black baboon atlas. Analysis of 15 regions, comparison of baseline distribution and pretreatment distribution are shown. I) The distribution of SUV values ​​(average 60-120 min) for each voxel within the ROI is shown. CC=anterior cingulate cortex, amgyg=amygdala, CB=cerebellum, DLPFC=dorsolateral prefrontal cortex, HC=hippocampus, M1=primary motor cortex, NAc=nucleus accumbens, OFC=orbitofrontal cortex, PCC=posterior zone Pu = putamen, SMA = supplementary motor area, Th = thalamus, V1 = primary sensory cortex, WM = white Figure 5 shows the SUV and the metabolite-corrected arterial plasma input function (Feng interpolation). V calculated by invasive Logan plot T A comparison with is shown below.

[0236] statistical analysis GraphPad Prism(Prism6,GraphPad Software Statistical testing was performed using the Quantitative Analysis Tool (Quantitative Analysis Tool) (Inc.). A Friedman test (a = 0.05 with Dunn's multiple comparison correction) was performed. We compared the SUV60-90 min between brain regions (Figure 2A-B). Pearson correlation analysis was performed between the SUV60-90 min values ​​for I (Figure 2B). ,Image-based outcome measurements (SUV60-90 min) are available with complete kinetic modeling data (V We assessed whether postmortem HDAC expression is an appropriate surrogate for that estimated by the 1990s genomic DNA repair technique (T). The difference in the current level, as well as the differences in nuclei density, size, and total area between SFG and CC, were compared. The correlation between the dorsolateral prefrontal cortex, hippocampus, and anterior cingulate cortex in postmortem HD patients was evaluated using unpaired t-tests. Differences in AC expression levels were analyzed using a conventional one-way ANOVA (with Tukey's multiple comparison correction) Histone acetylation and gene expression levels were evaluated compared to vehicle. Differences between the groups were analyzed using a two-way ANOVA for repeated measures (a = 0.05 with Dunnett's multiple comparison correction). Autoradiography assays showed that the [ 11 The difference between the C]Martinostat baseline and blocking intensity values ​​was calculated as Results were evaluated using ordinary two-way ANOVA (a = 0.05 with Sidak's multiple comparison correction).

[0237] The radiolabeled compound of Example 2 showed excellent brain uptake and retention. Treatment of animals with the non-radioactive compound of Example 1 resulted in a blockade of brain uptake, indicating specific binding. Compound 1m of Example 1 was administered 30 minutes after administration of the radioactive tracer. Treatment of animals with 100 mg / kg showed a clear deviation in the time-activity curve, which corresponds to the The off-rate in preclinical PET is slow, but 11 C]Martin Within the range of known kinetically well-characterized radiotracers such as ostat It seemed like it.

[0238] Example 8: 4-((((adamantan-1-yl)methyl)amino)methyl)-2-fluoro Fluoro-N-hydroxybenzamide [ka] Intermediate 1 (10 mg, 30 μmol, 1.0 eq) in 1:1 THF / MeOH 0. To the 4 mL solution, add 0.1 mL of hydroxylamine (50% aq) and aqueous NaOH solution ( 5.0M, 0.05 mL) was added. The reaction mixture was stirred for 35 min, then Dilute to 1 mL with water and perform semi-preparative HPLC (gradient: 0.025 over 45 min at 5 mL / min) 20% MeOH in 100% TFA to 95% MeOH (Luna C-18) The methanol was removed in vacuo and the remaining aqueous solution was lyophilized to give the title product 9. Obtained 0.7 mg (22 μmol, 72%) as a white fluffy solid. 1 H NMR (500MHz,DMSO-d6)δ 11.06(s,1H),9.30(s,1H) ,8.64(s,2H),7.61(t,J=7.6Hz,1H),7.48(d,J= 10.9Hz,1H),7.40(d,J=7.9Hz,1H),4.20(s,2H) ,2.77(s,2H),1.96(d,J=4.8Hz,3H),1.72-1.55 (m, 6H), 1.52 (d, J = 2.9 Hz, 6H).

[0239] Example 9. 4-((((adamantan-1-yl)methyl)amino)methyl)-3,5 -Difluoro-N-hydroxybenzamide [ka] Intermediate 2 (10 mg, 30 μmol, 1.0 eq) in 1:1 THF / MeOH 0. To the 4 mL solution, add 0.1 mL of hydroxylamine (50% aq) and 0.01 mL of aqueous NaOH (5.0 M, 0.05 mL) was added. The reaction mixture was stirred for 35 min and then washed with water. Dilute to 0.05 mL and analyze by semi-preparative HPLC (gradient: 0.025% T over 45 min at 5 mL / min). Purified with Luna C-18) from 20% MeOH in FA to 95% MeOH. The methanol is removed in vacuo and the remaining aqueous solution is freeze-dried to give 5.2 ml of the title product. g (11 μmol, 37%) as a white fluffy solid. 1 H NMR(50 0MHz,DMSO-d6)δ 11.53(s,1H),9.38(s,1H),8. 63(s,2H),7.56(d,J=8.2Hz,2H),4.25(s,2H),2 .77(s,2H),1.96(s,3H),1.70-1.52(m,12H).

[0240] Example 10: 4-((((adamantan-1-yl)methyl)amino)methyl)-3- Trifluoromethyl-N-hydroxybenzamide [ka] Intermediate 3 (10 mg, 26 μmol, 1.0 eq) in 1:1 THF / MeOH 0. To the 4 mL solution, add 0.1 mL of hydroxylamine (50% aq) and 0.01 mL of aqueous NaOH (5.0 M, 0.05 mL) was added. The reaction mixture was stirred for 35 min and then washed with water. Dilute to 0.05 mL and analyze by semi-preparative HPLC (gradient: 0.025% T over 45 min at 5 mL / min). Purified with Luna C-18) from 20% MeOH in FA to 95% MeOH. The methanol was removed in vacuo and the remaining aqueous solution was freeze-dried to give 7.3 ml of the title product. g (15 μmol, 57%) as a white fluffy solid. 1 H NMR(50 0MHz,DMSO-d6)δ 11.59(s,1H),9.32(s,1H),8. 75(s,2H),8.15(d,J=8.9Hz,2H),7.94(d,J=8.1 Hz,1H),4.34(s,2H),2.76(s,2H),1.96(s,3H), 1.78-1.34(m,12H).

[0241] Example 11: 4-((((adamantan-1-yl)methyl)amino)methyl)-3- Methyl-N-hydroxybenzamide [ka] Intermediate 4 (10 mg, 30 μmol, 1.0 eq) in 1:1 THF / MeOH 0. To the 8 mL solution, add 0.1 mL of hydroxylamine (50% aq) and 0.01 mL of aqueous NaOH (5.0 M, 0.05 mL) was added. The reaction mixture was stirred for 35 min and then washed with water. Dilute to 0.05 mL and analyze by semi-preparative HPLC (gradient: 0.025% T over 45 min at 5 mL / min). Purified with Luna C-18) from 20% MeOH in FA to 95% MeOH. The methanol is removed in vacuo and the remaining aqueous solution is freeze-dried to give 8.3 ml of the title product. g (19 μmol, 63%) as a white fluffy solid. 1 H NMR(50 0MHz,DMSO-d6)δ 11.26(s,1H),9.09(s,1H),8. 50(s,2H),7.71-7.59(m,2H),7.55(d,J=7.9Hz, 1H),4.19(d,J=5.9Hz,2H),2.70(d,J=7.6Hz,2H ),2.38(s,3H),1.96(s,3H),1.75-1.50(m,12H) .

[0242] Example 12. 4-(((((3r,5r,7r)-adamantan-1-yl)methyl) (Methyl)amino)methyl)-N-hydroxybenzamide [ka] Step 1. Methyl 4-(((((3r,5r,7r)-adamantan-1-yl)methyl) (Methyl)amino)methyl)benzoate 3 ml of formalin, 0.5 mL, and 1 drop of intermediate 8 (0.20 g, 0.64 mmol) The acetic acid solution was stirred for 2 hours, and then 200 mg of sodium borohydride was added in small portions. The mixture was concentrated in vacuo and diluted with ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate, and the combined organic phases were washed with sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. Methyl 4-(((((3r,5r,7r)-adamantan-1-yl)methyl)(methyl (amino)methyl)benzoate (80 mg, 0.26 mmol, 41%) was left This was obtained as a clear oily material which solidified at 37°C.

[0243] Step 2. 4-(((((3r,5r,7r)-adamantan-1-yl)methyl)(methyl) (ethyl)amino)methyl)-N-hydroxybenzamide [ka] Methyl 4-(((((3r,5r,7r)-adamantan-1-yl)methyl)(methyl (amino)methyl)benzoate (50 mg, 0.15 mmol, 1 eq) in a 1:1 ratio In a 2 mL solution of THF / MeOH, 0.50 mL of hydroxylamine (50% aq) and Aqueous NaOH (5.0 M, 0.10 mL) was added. The reaction mixture was allowed to stand at room temperature (RT). Stir for 2 hours, then add 80 μL of 6N HCl. The product is extracted with DCM. The organic layer was washed with water, dried over sodium sulfate, and then concentrated in vacuo. The globular residue was triturated with ether. 1 H NMR (500MHz, DMSO-d6) δ 11.34(s,1H),9.14(s,1H),8.77(s,1H),7.83( d,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H),4.48-4. 23(m,2H),2.88(d,J=4.8Hz,5H),1.90(s,3H),1 .66-1.42(m,12H).

[0244] Example 13: 6-((((adamantan-1-yl)methyl)amino)methyl)-N- Hydroxynicotinamide [ka] Intermediate 5 (10 mg, 31 μmol, 1.0 eq) in 1:1 THF / MeOH 0. To the 4 mL solution, add 0.1 mL of hydroxylamine (50% aq) and 0.01 mL of aqueous NaOH (5.0 M, 0.05 mL) was added. The reaction mixture was stirred for 35 min and then washed with water. Dilute to 0.05 mL and analyze by semi-preparative HPLC (gradient: 0.025% T over 45 min at 5 mL / min). Purified with Luna C-18) from 20% MeOH in FA to 95% MeOH. The methanol was removed in vacuo and the remaining aqueous solution was lyophilized to give 12 mg of the title product. (28 μmol, 90%) was obtained as a white fluffy solid. 1H NMR (500 MHz,DMSO-d6)δ 11.50(s,1H),10.14(s,1H),8. 96(s,2H),8.82(s,1H),8.23-8.15(m,1H),7.60 (d,J=8.2Hz,1H),4.37(d,J=12.5Hz,2H),2.63( s,2H),1.97(s,3H),1.70-1.58(m,6H),1.56(d, J=2.7Hz,6H).

[0245] Example 14: 4-((((adamantan-1-yl)methyl)amino)methyl)-3- Chloro-N-hydroxybenzamide [ka] Intermediate 6 (10 mg, 29 μmol, 1.0 eq) in 1:1 THF / MeOH 0. To the 4 mL solution, add 0.1 mL of hydroxylamine (50% aq) and 0.01 mL of aqueous NaOH (5.0 M, 0.05 mL) was added. The reaction mixture was stirred for 35 min and then washed with water. Dilute to 0.05 mL and analyze by semi-preparative HPLC (gradient: 0.025% T over 45 min at 5 mL / min). Purified with Luna C-18) from 20% MeOH in FA to 95% MeOH. The methanol is removed in vacuo and the remaining aqueous solution is freeze-dried to give 8.7 ml of the title product. g (25 μmol, 86%) was obtained as a white fluffy solid. 1H NMR (50 0MHz,DMSO-d6)δ 11.45(s,1H),9.25(s,1H),8. 63(s,2H),7.85(d,J=45.4Hz,3H),4.31(s,2H), 2.74(s,2H),1.96(s,3H),1.74-1.47(m,12H).

[0246] Example 15: 4-((((adamantan-1-yl)methyl)amino)methyl)-3- Bromo-N-hydroxybenzamide [ka] Intermediate 7 (10 mg, 26 μmol, 1.0 eq) in 1:1 THF / MeOH 0. To the 4 mL solution, add 0.1 mL of hydroxylamine (50% aq) and 0.01 mL of aqueous NaOH (5.0 M, 0.05 mL) was added. The reaction mixture was stirred for 35 min and then washed with water. Dilute to 0.05 mL and analyze by semi-preparative HPLC (gradient: 0.025% T over 45 min at 5 mL / min). Purified with Luna C-18) from 20% MeOH in FA to 95% MeOH. The methanol was removed in vacuo and the remaining aqueous solution was freeze-dried to give 11 mg of the title product. (22 μmol, 85%) was obtained as a white fluffy solid. 1H NMR (500 MHz,DMSO-d6)δ 11.45(s,1H),9.25(s,1H),8.7 3(s,2H),8.05(s,1H),7.80(m,2H),4.30(s,2H) ,2.74(s,2H),1.96(s,3H),1.74-1.52(m,12H).

[0247] Example 16. 4-(((((3r,5r,7r)-adamantan-1-yl)methyl) Amino)methyl)-3-fluoro-N-hydroxybenzamide [ka] Methyl 4-(((((3s)-adamantan-1-yl)methyl)amino)methyl)- 3-Fluorobenzoate (e.g., Strebl et al., ACS Cent. Sci.2017,3(9):1006-1014);102 mg, 0. 31 mmol, 1 eq) in 2 mL of 1:1 THF / MeOH. 0.50 mL of ethanol (50% aq, 0.25 g, 3.6 mmol, 12 eq) and aqueous NaO H (5.0 M, 0.10 mL, 0.50 mmol, 1.6 eq) was added to the reaction mixture. The mixture was stirred for 7 hours and then 100 μL of 2.5 N HCl was added. was purified by preparative HPLC with a gradient of 0.025% TFA in water and methanol. Drying in vacuum afforded the title product (50.3 mg, 0.15 mmol, 48%). The compound was obtained as a colored foamy solid. 1H NMR(DMSO-d6) δ 11.3(s,1H), 9.9(s,1H),8.69(m,2H),7.80-7.53(m,3H),4.2 3(s,2H),3.34(s,8H),2.67(s,2H),2.49(m,12H ),1.93(m,3H),1.76-1.44(m,14H).MS(m / z) C1 9H 25 Calculated value for FN2O2 [M+H] + 332.19 ;Actual value, 332. 7.

[0248] Example 17. 4-(((((3r,5r,7r)-adamantan-1-yl)methyl) Amino)methyl)-N-hydroxybenzamide [ka] Intermediate 8 (92 mg, 0.29 mmol, 1 eq) in 1:1 THF / MeOH 2mM In solution L, hydroxylamine (50% aq, 0.25 g, 3.6 mmol, 12 eq) 0.50mL and aqueous NaOH (5.0M, 0.10mL, 0.50mmol, 2eq) The reaction mixture was stirred for 5 hours and then 100% 2.5N HCl was added. The product was purified by elution with a gradient of 0.025% TFA in water and methanol. Purification by preparative HPLC was performed. Drying in vacuo afforded the title product (49.7 mg, 0.16 1 mmol, 55%) as a white solid. 1H NMR (DMSO-d6) δ 11. 3(s,1H),8.8(m,2H),7.79(d,2H),7.58(d,2H), 4.19(s,2H),3.49(s,5H),2.55(m,7H),1.91(m, 4H),1.78-1.39(m,17H).MS(m / z) C 19 H 26 N2O2 Calculated value for [M+H] + 314.2;Actual value, 314.7.

[0249] Example 18: 4-((((3s,5s,7s)-adamantan-1-yl)amino)methyl (ethyl)-N-hydroxybenzamide [ka] Intermediate 9 (34 mg, 0.11 mmol, 1 eq) in 1:1 THF / MeOH 2mM To the L solution, at 0° C., hydroxylamine (50% aq, 0.25 g, 3.6 mmol, 3 2eq) 0.50mL and aqueous NaOH (5.0M, 0.10mL, 0.50mmol, 5 eq) was added. The reaction mixture was stirred for 2 h. The product was extracted with water and methanol. The product was purified by preparative HPLC using a gradient of 0.025% TFA in alcohol. This gave the title product (32 mg, 0.1 mmol, 95%) as a white foamy solid. 1H NMR(DMSO-d6) δ 11.3(s,1H),9.0(s,1H), 8.8(d,2H),7.8(d,2H),4.1(s,2H),3.34(s,8H) ,2.49(m,8H),2.49(m,10H),2.16(m,3H),2.04- 1.84(m,6H),1.76-1.51(m,6H).MS(m / z) C 18 H2 Calculated for 4N2O2 [M+H]+, 300.40; Found, 300.7.

[0250] Example 19. 4-(((1-(adamantan-1-yl)propan-2-yl)amino )Methyl)-N-hydroxybenzamide [ka] Intermediate 10 (191 mg, 0.56 mmol, 6.4 eq) in 1:1 THF / MeO To a solution of 2 mL of H at 0°C, add hydroxylamine (50% aq, 0.25 g, 3.6 mmH ol, 6.4eq) 0.50mL and aqueous NaOH (5.0M, 0.10mL, 0.50 The reaction mixture was stirred for 3 hours and then diluted with 6N 80 μL of HCl was added. The product was purified by elution with 0.025% TFA in water and methanol. Purification was performed by gradient preparative HPLC. Drying in vacuum gave the product (103 mg, 0. 30 mmol, 53%) was obtained as a white solid. 1H NMR (DMSO-d6) δ 1 1.3(s,1H),8.8(d,2H),7.8(d,2H),7.5(d,2H), 4.1(s,2H),3.39(s,6H),2.49(m,7H),1.92(m,3 H),1.76-1.39(m,15H),1.39-1.21(m,5H).MS(m / z) C 21 H 30 Calculated value for N2O2 [M+H] + 342.23; measured value, 342.7.

[0251] Example 20. 4-(((1-(adamantan-1-yl)propan-2-yl)amino )Methyl)-N-hydroxybenzamide [ka] Step 1. Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl)propionate Propan-2-yl)(methyl)amino)methyl)benzoate [ka] 3 ml of formalin, 0.5 ml, and 1 drop of intermediate 10 (97 mg, 0.28 mmol) The acetic acid solution was stirred for 2 hours, and then 184 mg of sodium borohydride was added in small portions. The mixture was concentrated in vacuo and diluted with ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate, and the combined organic phases were washed with sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl)propane- 2-yl)(methyl)amino)methyl)benzoate (33 mg, 0.09 mmol, 3 3%) as a clear oily material that solidified on standing. MS(m / z) C 23 H 22 Calculated for NO2 [M+H]+, 355.25; found, 355.8.

[0252] Step 2. 4-(((1-(adamantan-1-yl)propan-2-yl)amino)methyl (ethyl)-N-hydroxybenzamide [ka] Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl)propane- 2-yl)(methyl)amino)methyl)benzoate (33 mg, 0.09 mmol, 1 eq) in 2 mL of 1:1 THF / MeOH, 0.25g, 3.6mmol, 37eq) 0.50mL and aqueous NaOH (5.0M, 0 The reaction mixture was stirred at RT for 2 h. The mixture was stirred for 10 min, then 80 μL of 6N HCl was added. The product was dissolved in water and methanol. The product was purified by preparative HPLC using a gradient of 0.025% TFA in water. The title product (31 mg, 0.087 mmol, 90%) was obtained as a white solid. NMR(DMSO-d6)δ 11.3(s,1H),7.8(d,2H),7.6( d,2H),4.4(m,1H),4.2(m,1H),3.6(m,11H),2.7 0-2.39(m,16H),2.05-1.82(m,4H),1.82-1.20( m,24H).MS(m / z) C 22 H 32 Calculated value for N2O2 [M+H] + 356.51;Actual value, 356.7.

[0253] Example 21: 4-(((1-((3r,5r,7r)-adamantan-1-yl)propane Pyr)amino)methyl)-N-hydroxybenzamide [ka] Intermediate 11 (89.7 mg, 0.26 mmol, 1 eq) in 1:1 THF / MeOH To a 2 mL solution, add hydroxylamine (50% aq, 0.25 g, 3.6 mmol) at 0 °C. l, 13.8eq) 0.50mL and aqueous NaOH (5.0M, 0.10mL, 0.50 The reaction mixture was stirred for 5 hours and then 80 μL of 6N HCl was added. The product was dissolved in 0.025% T in water and methanol. Purification by preparative HPLC with a gradient of FA. Drying in vacuum gave the title product (84 mg, 0.24 mmol, 93%) as a white foamy solid. 1H NMR (DMS O-d6)δ 11.3(s,1H),9.1(s,1H),8.9(s,1H), 7 .8(d,2H),7.6(d,2H),4.4(m,2H),3.3(m,7H),2 .5(s,9H),2.2(m,1H),2.02-1.87(m,3H),1.87- 1.72(m,1H),1.72-1.46(m,12H),1.45-1.34(m, 3H), 1.03-0.80(m,3H).MS(m / z) C 22 H 31 Against N2O2 Calculated value [M+H] + 342.23;Actual value, 342.9.

[0254] Example 22: 4-(((1-((3r,5r,7r)-adamantan-1-yl)propane Pyr)(methyl)amino)methyl)-N-hydroxybenzamide [ka] Step 1. Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl)propionate (propyl)(methyl)amino)methyl)benzoate [ka] 3 mL of formalin, 0.5 mL, and 1 drop of intermediate 11 (95 mg, 0.29 mmol) The acetic acid solution was stirred for 2 hours, and then 215 mg of sodium borohydride was added in small portions. The mixture was concentrated in vacuo and diluted with ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate, and the combined organic phases were washed with sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography. Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl)propyl) (Methyl)amino)methyl)benzoate (79.7 mg, 0.23 mmol, 79%) was obtained as a clear oily material that solidified on standing. MS(m / z) C 23 H 33 N Calculated value for O2 [M+H] + 355.2;Actual value, 355.7.

[0255] Step 2. 4-(((1-((3r,5r,7r)-adamantan-1-yl)propyl )(Methyl)amino)methyl)-N-hydroxybenzamide [ka] Methyl 4-(((1-((3r,5r,7r)-adamantan-1-yl)propyl) (Methyl)amino)methyl)benzoate (79 mg, 0.22 mmol, 1 eq.) In a 2 mL solution of 1:1 THF / MeOH at 0° C., hydroxylamine (50% aq., 0.25g, 3.6mmol, 16eq) 0.50mL and aqueous NaOH (5.0M, 0 The reaction mixture was stirred at RT for 3.5 h. The mixture was stirred for 10 min, then 80 μL of 6N HCl was added. The product was extracted with water and methanol. The product was purified by preparative HPLC using a gradient of 0.025% TFA in methanol. The product (45 mg, 0.13 mmol, 59%) was obtained as a white solid. MR(DMF-d6)δ 8.9(s,1H),8.14-7.73(m,7H),4. 84-4.47(m,2H),3.23-3.00(m,3H),3.00-2.66( m,8H),2.2(m,1H),2.07-1.33(m,27H),1.31-0. 91(m,4H).MS(m / z) C 22 H 32 Calculated value for N2O2 [M+H] + 356.25;Actual value, 356.7.

[0256] Example 23: 4-((((6,6-dimethylbicyclo[3.1.1]heptane-2-yl (methyl)amino)methyl)-N-hydroxybenzamide [ka] Intermediate 12 (73 mg, 0.24 mmol, 1 eq) in 1:1 THF / MeOH 2 1 mL solution of hydroxylamine (50% aq, 0.25 g, 3.6 mmol, 15 eq ) 0.50 mL and aqueous NaOH (5.0 M, 0.10 mL, 0.50 mmol, 2 eq The reaction mixture was stirred at RT for 3 h, and then the product was extracted with water and The mixture was purified by preparative HPLC using a gradient of 0.025% TFA in methanol and 0.5% hexane in vacuo. Drying afforded the title product (29 mg, 0.096 mmol, 40%) as a white solid. 1H NMR(DMSO-d6) δ 11.3(s,1H), 9.1(s,1H ),9.0(s,2H),7.78(d,2H),7.54(d,2H),4.2(m, 2H),3.34(s,2H),2.91(s,2H),2.58-2.23(m,7H ),2.03-1.71(m,5H),1.73-1.38(m,4H),1.59-1 .37(m,1H),1.23-1.07(m,3H),0.99-0.72(m,4H ).MS(m / z) C 18 H 26 Calculated value for N2O2 [M+H] + 302.2 ;Actual value: 302.7.

[0257] Example 24: 4-((((6,6-dimethylbicyclo[3.1.1]heptane-2-yl (methyl)(pentyl)amino)methyl)-N-hydroxybenzamide [ka] Step 1. Methyl 4-((((6,6-dimethylbicyclo[3.1.1]heptane-2- (yl)methyl)(pentyl)amino)methyl)benzoate [ka] Intermediate 12 (56 mg, 0.19 mmol) in DMSO 0.2 ml solution, 1-bromo 23 μL of pentane and 44 μL of N,N-diisopropylethylamine were added, and the mixture was stirred for 1 hour. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water and ethyl acetate. The mixture was partitioned between water and the aqueous layer was extracted twice more with ethyl acetate, and the combined organic phases were then washed with water. The organic phase was then dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography. Cyclo[3.1.1]heptan-2-yl)methyl)(pentyl)amino)methyl)benzene Zoate (25.8 mg, 0.07 mmol, 36%) was obtained as a yellowish oily substance. MS(m / z) C 24 H37 Calculated value for NO2 [M+H] + 371.3 ;Actual value: 313.7.

[0258] Step 2. 4-((((6,6-dimethylbicyclo[3.1.1]heptan-2-yl) Methyl)(pentyl)amino)methyl)-N-hydroxybenzamide [ka] Methyl 4-((((6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl (pentyl)amino)methyl)benzoate (approximately 25 mg, 0.07 mmol, 1 eq) in 2 mL of 1:1 THF / MeOH, 0.25 g, 3.6 mmol, 51 eq) 0.50 mL and aqueous NaOH (5.0 M, 0 The reaction mixture was stirred at RT for 3.5 h. The mixture is stirred for 10 min, then concentrated in vacuo and partitioned between dichloromethane and water, and the aqueous layer is The organic phase was dried over sodium sulfate and the solvent was reduced. The product was separated using a gradient of 0.025% TFA in water and methanol. Purification by HPLC was performed. Drying in vacuo gave the title product (9 mg, 0.024 mmol). l, 34%) was obtained as a yellowish oil. 1H NMR (DMSO-d6) δ 7.83-7.33(m,1H),3.71-3.20(m,18H),2.85- 2.23(m,72H),1.37-1.07(m,4H),1.07-0.73(m, 3H), 0.73-0.44(m,1H).MS(m / z) C 23 H 36 Against N2O2 Calculated value [M+H] +372,3;Actual value, 372.8.

[0259] Example 25: 4-(((cyclohexylmethyl)amino)methyl)-N-hydroxybenzyl Nzuamide [ka] Intermediate 13 (196 mg, 0.75 mmol 1 eq) in 1:1 THF / MeOH To a 2 mL solution, add hydroxylamine (50% aq, 0.25 g, 3.6 mmol, 4.8 eq) 0.50 mL and aqueous NaOH (5.0 M, 0.10 mL, 0.50 mmol, 0 The reaction mixture was stirred at RT for 4 h and then the product The material was purified by preparative HPLC with a gradient of 0.025% TFA in water and methanol. Drying in vacuum gave the title product (108 mg, 0.41 mmol, 55%). Obtained as a white slightly brownish solid. 1H NMR(DMSO-d6) δ 11 .3(s,1H),8.9(m,2H),7.77(d,2H),7.55(d,2H) ,4.18(s,2H),3.42(s,3H),2.77(m,2H),2.50(m ,4H),1.83-1.49(m,6H),1.31-1.02(m,3H),1.0 2-0.79(m,2H).MS(m / z) C 15 H 22 Calculated value for N2O2 [ M+H] + 262.17;Actual value, 262.7.

[0260] Example 26. Docking studies 4-(((((3s)-adamantan-1-yl)methyl)(methyl)amino)methyl )-3-Fluoro-N-hydroxybenzamide was synthesized using the method described in the Methods section. The complex between the catalytic zinc (purple sphere) and the hHDAC6 complex is shown in Figure 8A. The hydrogen bond network is shown, with the protein and ligand indicated by yellow dashed lines. As shown, 4-(((((3s)-adamantan-1-yl)methyl)(methyl)amino Fluorine on the linker phenyl ring of methyl-3-fluoro-N-hydroxybenzamide The primary substituents are then introduced into hollow clefts / cleavages in the hHDAC6 10 Å channel leading to the protein surface. It is modeled on a vector in the eye.

[0261] Other embodiments The present invention has been described in conjunction with the detailed description thereof, which is set forth in the appended claims. The present invention is intended to be illustrative and not limiting, and is defined by the following claims: It should be understood that other aspects, advantages, and modifications are set forth in the following claims. It is within range. The present invention may include the following aspects. [1] Formula I: [ka] or a pharma- ceutically acceptable salt thereof, X 1 is -N(R N )- or -CH(R C )- and; X 2 CR 2 or N; X 3 CR 3 or N; R N , H, C 1~6 Alkyl, and C 1~6 haloalkyl; R C , H, C 1~6 Alkyl, and C 1~6 haloalkyl; L 1 is a bond or C 1~6 is an alkylene group; L 2 is a bond or C 1~6 is an alkylene group; R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl, 3~10 Cycloalkyl and C 6~1 0 aryl is C 1~6 1 or 2 independently selected from alkyl and halo and optionally substituted with a group R 2 , R 3 , R 4 , and R 5 are independently H, C 1~6 Alkyl, halo, and C 1~6 haloalkyl A compound or a pharma- ceutically acceptable salt thereof. [2]X 1 -N(R N )-, or a pharma- ceutically acceptable salt thereof, Salt to be used. [3] R N is selected from the group consisting of H and methyl, or a pharma- ceutically acceptable salt thereof. [4]X 1 -CH(R C )-, Acceptable salt. [5] R c is H. Salt that can be used. [6]L 1is a bond, Pharmaceutically acceptable salts. [7]L 1 is C 1~6

[0026] The alkylene group according to any one of [1] to [5] above. or a pharma- ceutically acceptable salt thereof. [8] L 1 is selected from the group consisting of methylene and propylene, or a pharma- ceutically acceptable salt thereof. [9] L 2 is a bond, Pharmaceutically acceptable salts.

[10] L 2 is methylene. and a pharma- ceutically acceptable salt thereof.

[11] R 1 is one or two independently selected C 1~3 Alkyl groups are optional C has been replaced by 6~10 Any one of the above [1] to

[10] which is cycloalkyl. Item 1. The compound according to item 1, or a pharma- ceutically acceptable salt thereof.

[12] R 1 is cyclohexyl, adamantyl, norbornyl, and 6,6-dimethyl The above [1] to

[10] are selected from the group consisting of rubicyclo[3.1.1]heptanyl. 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof.

[13] R 1 is adamantyl. Compound.

[14] X 2 is N. A pharma- ceutically acceptable salt of

[15] X 2 is CR 2The compound according to any one of the above [1] to

[13] , and a pharma- ceutically acceptable salt thereof.

[16] R 2 is H or F, any one of [1] to

[13] or

[15] above The compound described herein or a pharma- ceutically acceptable salt thereof.

[17] R 2 is F, A compound or a pharma- ceutically acceptable salt thereof.

[18] X 3 is N. A pharma- ceutically acceptable salt of

[19] X 3 is CR 3 The compound according to any one of the above [1] to

[17] , and a pharma- ceutically acceptable salt thereof.

[20] R 3 is H or F, any one of [1] to

[17] or

[19] above The compound described herein or a pharma- ceutically acceptable salt thereof.

[21] R 3 is H, A compound or a pharma- ceutically acceptable salt thereof.

[22] X 2 and X 3 Each of the above [1] to

[13] is N. The compound or a pharma- ceutically acceptable salt thereof.

[23] X 2 is CR 2 And X 3 is CR 3 Any of the above [1] to

[13] The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[24] R 2 is F and R 3 is H, the above [1] to

[13] ,

[15] or

[19] The compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof.

[25] R 4 is H or CF3. or a pharma- ceutically acceptable salt thereof.

[26] R 4 is H. A pharma- ceutically acceptable salt of

[27] R 5 is H or CF3. or a pharma- ceutically acceptable salt thereof.

[28] R 5 is H. A pharma- ceutically acceptable salt of

[29] R 2 is F and R 3 , R 4 , and R 5 are H, respectively, as above [1] The compound or drug thereof according to any one of

[13] ,

[15] ,

[19] and

[23] . A physiologically acceptable salt.

[30] X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or C 1~3 is an alkylene group; L 2 is a bond or methylene; R 1 is C 6~10 cycloalkyl and phenyl, 6~ 10Cycloalkyl and phenyl are each C 1~3 independently selected from alkyl and halo optionally substituted with one or two groups selected from R 2 is selected from the group consisting of H and halo; R 3 , R 4 , and R 5 are H, The compound according to [1] above or a pharma- ceutically acceptable salt thereof.

[31] X 1 is -N(R N )- or -CH2-; X 2 CR 2 or N; X 3 CR 3 or N; R N is selected from the group consisting of H and methyl; L 1 is a bond or is selected from the group consisting of methylene and propylene; L 2 is a bond or methylene; R 1 is C 6~10 cycloalkyl and phenyl, 6~ 10 Cycloalkyl and phenyl are each C 1~3 independently selected from alkyl and halo optionally substituted with one or two groups selected from R 2 is selected from the group consisting of H and halo; R 3 , R 4 , and R 5 are H, The compound according to the above [1] or a pharma- ceutically acceptable salt thereof.

[32] The compound of formula I has formula II: [ka] or a pharma- ceutically acceptable salt thereof.

[33] The compound of formula I has formula III: [ka] or a pharma- ceutically acceptable salt thereof.

[34] The compound of formula I has formula IV: [ka] or a pharma- ceutically acceptable salt thereof.

[35] The compound of formula I has formula V: [ka] or a pharma- ceutically acceptable salt thereof.

[36] The compound or pharma- ceutically acceptable salt thereof contains at least one radioisotope. The compound according to any one of the above-mentioned [1] to

[35] or a pharma- ceutically acceptable salt thereof.

[37] The compound or a pharma- ceutically acceptable salt thereof is 11 C and 18 Selected from the group consisting of F Any one of the above [1] to

[35] containing at least one radioisotope selected from the group consisting of The compound described herein or a pharma- ceutically acceptable salt thereof.

[38] The compound or pharma- ceutically acceptable salt thereof comprises at least one 18 F radioisotope The compound according to any one of the above [1] to

[35] or a pharma- ceutically acceptable salt thereof. Salt.

[39] The compound of formula I has formula VI: [ka] or a pharma- ceutically acceptable salt thereof, A compound according to any one of claims 1 to 4.

[40] The compound of formula I is [ka] The compound according to the above [1], which is a compound selected from the group consisting of: The compounds listed above.

[41] The compound of formula I is [ka] [ka] or a pharma- ceutically acceptable salt thereof. thing.

[42] The compound of formula I is [ka] or a pharma- ceutically acceptable salt thereof. thing.

[43] The compound according to any one of the above [1] to

[42] or a pharma- ceutically acceptable salt thereof. and at least one pharma- ceutical composition comprising the salt and at least one pharma- ceutical acceptable carrier.

[44] A method for inhibiting the activity of a histone deacetylase (HDAC) enzyme, comprising the steps of: The HDAC enzyme and the compound or a pharmaceutical composition thereof according to any one of the above [1] to

[42] with a salt thereof that is acceptable for the purpose of the present invention.

[45] Inhibiting the activity of histone deacetylase (HDAC) enzymes can

[44] , comprising deregulating HDAC enzymes. method.

[46] The method described in

[0044] or

[45] above, wherein the histone deacetylase (HDAC) enzyme is HDAC6.

[47] The compound is selected from the group consisting of HDAC1, HDAC2, HDAC3, HDAC4, and HDAC5. 5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11 The method according to any one of the above

[44] to

[46] , which selectively inhibits one or more AC6s. Method of posting.

[48] ​​The method according to any one of the above

[44] to

[47] , which is an in vitro method. The method according to claim 5.

[49] Any one of the above

[44] to

[47] , wherein the method is an in vivo method. The method described above.

[50] A method for imaging an object, comprising: i) administering to the subject a radiolabel according to any one of the above

[36] to

[39] to

[42] administering a compound or a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique; The method includes:

[51] Imaging histone deacetylase (HDAC) enzymes in cells or tissues It is a law, i) The cell or tissue and any one of the above

[36] to

[39] to

[42] contacting the compound with a radiolabel or a pharma- ceutically acceptable salt thereof; and ii) imaging the cell or tissue with an imaging technique. The method includes:

[52] A method for imaging histone deacetylase (HDAC) enzymes in a subject, comprising: i) administering to the subject a radiolabel according to any one of the above

[36] to

[39] to

[42] administering a compound or a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique; The method includes:

[53] Abnormal expression of histone deacetylase (HDAC) enzymes or 1. A method for imaging a disease associated with abnormal activity, comprising: i) administering to the subject a radiolabel according to any one of the above

[36] to

[39] to

[42] administering a compound or a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique; The method includes:

[54] Abnormal expression of histone deacetylase (HDAC) enzymes or 1. A method for monitoring the treatment of a disease associated with abnormal activity, comprising: i) imaging said object with an imaging technique; ii) administering to the subject a compound according to any one of the above [1] to

[42] or a pharmaceutical formulation thereof; administering a therapeutically effective amount of a therapeutically acceptable salt thereof; iii) imaging the object with an imaging technique; and iv) comparing the image of step i) with the image of step iii); The method includes:

[55] The imaging techniques include single photon emission computed tomography, positron emission tomography, CT imaging, computed tomography, computed tomography imaging Positron emission tomography, consisting of positron emission tomography with magnetic resonance imaging The method according to any one of the above

[50] to

[54] , wherein the method is selected from the group consisting of

[56] The imaging technique is positron emission tomography imaging, 2. The method according to any one of claims 1 to 11, wherein the method is a

[57] The method according to any one of

[0051] to

[56] above, wherein the histone deacetylase (HDAC) enzyme is HDAC6.

[58] A method for imaging the brain of a subject, comprising: i) administering to the subject a radiolabel according to any one of the above

[36] to

[39] to

[42] administering a compound or a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique; The method includes:

[59] A method of treating a disease in a subject in need thereof, comprising administering to the subject The compound according to any one of the above [1] to

[42] or a pharma- ceutically acceptable salt thereof. The method comprises administering a therapeutically effective amount of the compound to a patient suffering from a disease, such as cancer, a disease of the central nervous system, or an inflammatory disease. Autoimmune diseases.

[60] The method according to

[59] above, wherein the disease is cancer.

[61] The method according to

[59] or

[60] above, wherein the cancer comprises a solid tumor.

[62] The cancer is selected from the group consisting of glioma, glioblastoma, and non-small cell lung cancer. The method according to any one of the above

[59] to

[61] .

[63] The method according to

[59] or

[60] above, wherein the cancer is a blood cancer.

[64] The above-mentioned

[63] , wherein the blood cancer is selected from the group consisting of leukemia and lymphoma. The method described above.

[65] The cancer may be caused by abnormal expression or abnormalities of histone deacetylase (HDAC) enzymes. The method according to any one of the above

[59] to

[64] , which is associated with activity.

[66] The cancer is associated with aberrant expression or activity of HDAC6. A method according to any one of claims 1 to 64.

[67] The method according to

[59] above, wherein the disease is a disease of the central nervous system.

[68] The central nervous system disease includes a neurodegenerative disease, Method of posting.

[69] The method according to

[59] or

[67] above, wherein the central nervous system disease is depression. .

[70] The central nervous system diseases include schizophrenia, bipolar disorder, Alzheimer's disease, and The method according to any one of claims 59 to 67, wherein the disease is selected from the group consisting of Huntington's disease.

[71] The method according to any one of

[59] ,

[68] or

[0070] above, wherein the central nervous system disease further comprises depression.

[72] The above central nervous system diseases are caused by abnormalities in the histone deacetylase (HDAC) enzymes. Any one of the above

[59] or

[67] to

[71] , which is associated with expression or abnormal activity The method according to claim 5.

[73] The above central nervous system diseases are associated with abnormal expression or activity of HDAC6. The method according to any one of the above

[59] or

[67] to

[71] ,

[74] The method according to

[59] above, wherein the disease is an inflammatory autoimmune disease.

[75] The inflammatory autoimmune diseases are caused by abnormalities in the histone deacetylase (HDAC) enzymes. The method according to

[74] above, wherein the gene is associated with abnormal expression or activity.

[76] The inflammatory autoimmune disease is associated with abnormal expression or activity of HDAC6. The method according to any one of the above

[59] ,

[74] or

[75] ,

[77] The method according to any one of the above-mentioned

[0049] to

[58] , wherein about 0.1% to about 5% of the administered compound passes through the blood-brain barrier.

[78] The administered compound has a brain:plasma ratio of at least about 1:1 to at least about 5. The method according to any one of the above

[49] to

[58] , wherein the ratio is 0:1.

[79] A method of treating cancer in a subject, comprising: i) the cancer is characterized by aberrant activity or expression of histone deacetylase (HDAC) enzymes; Identifying as being associated with; and ii) administering to the subject a compound according to any one of the above [1] to

[42] or a pharmaceutical formulation thereof; administering a therapeutically effective amount of a therapeutically acceptable salt thereof The method includes:

[80] A method for treating a central nervous system disorder in a subject, comprising: i) the central nervous system disorder is characterized by abnormal activity of histone deacetylase (HDAC) enzymes; or associated with abnormal expression; and ii) administering to the subject a compound according to any one of the above [1] to

[42] or a pharmaceutical formulation thereof; administering a therapeutically effective amount of a therapeutically acceptable salt thereof The method includes:

[81] A method of treating an inflammatory autoimmune disease in a subject, comprising: i) the inflammatory autoimmune disease is caused by abnormal activity of histone deacetylase (HDAC) enzymes; Identifying the genetic material as being associated with sexual or abnormal expression; and ii) administering to the subject a compound according to any one of the above [1] to

[42] or a pharmaceutical formulation thereof; administering a therapeutically effective amount of a therapeutically acceptable salt thereof The method includes:

[82] The method described in any one of

[0079] to

[81] above, wherein the histone deacetylase (HDAC) enzyme is HDAC6.

Claims

1. Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, X １ is -N(R Ｎ )- or -CH(R Ｃ )—wherein X ２ is CR ２ or N; X ３ is CR ３ or N; R Ｎ is H, C １～６ Alkyl, and C １～６ haloalkyl; R Ｃ is H, C １～６ Alkyl, and C １～６ haloalkyl; L １ is a bond or C １～６ is an alkylene group; L ２ is a bond or C １～６ is an alkylene group; R １ is C １～６ Alkyl, C １～６ Alkoxy, C ３～１０ Cycloalkyl, and C ６～１０ aryl, ３～１０ Cycloalkyl and C ６～１ ０ Each aryl is C １～６ one or two independently selected from alkyl and halo; and optionally substituted with a group R ２ , R ３ , R ４ , and R ５ are each independently H, C １～６ Alkyl, halo, and C １～６ haloalkyl A compound or a pharma- ceutically acceptable salt thereof.

2. X １ -N(R Ｎ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, 。

3. R Ｎ is selected from the group consisting of H and methyl; and pharma- ceutically acceptable salts thereof.

4. X １ is -CH(R Ｃ )- or a pharma- ceutically acceptable salt thereof. salt.

5. R ｃ is H; or a pharma- ceutically acceptable salt thereof.

6. L １ is a bond, or a pharma- ceutically acceptable salt thereof. Salt to be used.

7. L １ is C １～６ The compound according to any one of claims 1 to 5, which is an alkylene group, and pharma- ceutically acceptable salts thereof.

8. L １ Any one of claims 1 to 5, wherein is selected from the group consisting of methylene and propylene.

3. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

9. L ２ is a bond, or a pharma- ceutically acceptable salt thereof. Salt to be used.

10. L ２ is methylene, Acceptable salts.

11. R １ is one or two independently selected C １～３ Optionally substituted with alkyl groups C ６～１０ The compound according to any one of claims 1 to 10, which is cycloalkyl. or a pharma- ceutically acceptable salt thereof.

12. R １ are cyclohexyl, adamantyl, norbornyl, and 6,6-dimethylbis(cyclohexyl). Any one of claims 1 to 10, wherein the compound is selected from the group consisting of 2[3.1.1]heptanyl. or a pharma- ceutically acceptable salt thereof.

13. R １ The compound according to any one of claims 1 to 12, wherein is adamantyl.

14. X ２ is N, or a pharma- ceutically acceptable salt thereof, of the compound according to any one of claims 1 to 13. Salt to be used.

15. X ２ is CR ２ The compound according to any one of claims 1 to 13, Acceptable salts.

16. R ２ is H or F, A pharma- ceutically acceptable salt of

17. R ２ is F, A commercially acceptable salt.

18. X ３ is N, or a pharma- ceutically acceptable salt thereof, of the compound according to any one of claims 1 to 17. Salt to be used.

19. X ３ is CR ３ The compound according to any one of claims 1 to 17, Acceptable salts.

20. R ３ is H or F, A pharma- ceutically acceptable salt of

21. R ３ is H, A commercially acceptable salt.

22. X ２ and X ３ Each of the formulas is N. and pharma- ceutically acceptable salts thereof.

23. X ２ is CR ２ And X ３ is CR ３ According to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

24. R ２ is F and R ３ Any one of claims 1 to 13, 15 or 19, wherein or a pharma- ceutically acceptable salt thereof.

25. R ４ is H or CF ３ The compound or drug thereof according to any one of claims 1 to 24, A physiologically acceptable salt.

26. R ４ is H, or a pharma- ceutically acceptable salt thereof, of the compound according to any one of claims 1 to 24. Salt to be used.

27. R ５ is H or CF ３ The compound or drug thereof according to any one of claims 1 to 26, A physiologically acceptable salt.

28. R ５ is H, or a pharma- ceutically acceptable salt thereof, of the compound according to any one of claims 1 to 26. Salt to be used.

29. R ２ is F and R ３ , R ４ , and R ５ Each of claims 1 to 13 is H.

24. The compound according to any one of claims 5, 19 and 23, or a pharma- ceutically acceptable salt thereof.

30. X １ is -N(R Ｎ )- or -CH ２ - and X ２ is CR ２ or N; X ３ is CR ３ or N; R Ｎ is selected from the group consisting of H and methyl; L １ is a bond or C １～３ is an alkylene group; L ２ is a bond or methylene; R １ is C ６～１０ cycloalkyl and phenyl, ６～ １０ Cycloalkyl and phenyl are each C １～３ independently selected from alkyl and halo optionally substituted with one or two groups selected from R ２ is selected from the group consisting of H and halo; R ３ , R ４ , and R ５ are H, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

31. X １ is -N(R Ｎ )- or -CH ２ - and X ２ is CR ２ or N; X ３ is CR ３ or N; R Ｎ is selected from the group consisting of H and methyl; L １ is a bond or is selected from the group consisting of methylene and propylene; L ２ is a bond or methylene; R １ is C ６～１０ cycloalkyl and phenyl, ６～ １０ Cycloalkyl and phenyl are each C １～３ independently selected from alkyl and halo optionally substituted with one or two groups selected from R ２ is selected from the group consisting of H and halo; R ３ , R ４ , and R ５ are H, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

32. The compound of formula I has formula II: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

33. The compound of formula I has formula III: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

34. The compound of formula I has the formula IV: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

35. The compound of formula I has formula V: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

36. The compound or pharma- ceutically acceptable salt thereof comprises at least one radioisotope.

36. The compound according to any one of 1 to 35, or a pharma- ceutically acceptable salt thereof.

37. The compound or a pharma- ceutically acceptable salt thereof is １１ C and １８ Selected from the group consisting of F A compound according to any one of claims 1 to 35, comprising at least one radioisotope. and a pharma- ceutically acceptable salt thereof.

38. The compound or pharma- ceutically acceptable salt thereof comprises at least one １８ Contains F radioisotope, 36. The compound according to any one of claims 1 to 35, or a pharma- ceutically acceptable salt thereof.

39. The compound of formula I has the formula VI: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof. The compound according to claim 1,

40. The compound of formula I is 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof. Compound.

41. The compound of formula I is 【Chemistry 8】 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof. 。

42. The compound of formula I is 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof. 。

43. A compound according to any one of claims 1 to 42 or a pharma- ceutically acceptable salt thereof and at least and at least one pharma- ceutical composition comprising the compound of formula (I) and at least one pharma- ceutical acceptable carrier.

44. 1. A method for inhibiting the activity of a histone deacetylase (HDAC) enzyme, comprising: C enzyme and a compound according to any one of claims 1 to 42 or a pharma- ceutically acceptable salt thereof. The method of claim 1, further comprising contacting said

45. Inhibiting the activity of histone deacetylase (HDAC) enzymes inhibits the activity of said histone deacetylases.

45. The method of claim 44, comprising deregulating an acetate (HDAC) enzyme.

46. 44 or 4, wherein the histone deacetylase (HDAC) enzyme is HDAC6.

5. The method according to claim 5.

47. The compounds include HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, HDAC12, HDAC13, HDAC14, HDAC15, HDAC16, HDAC17, HDAC18, HDAC19, HDAC20, HDAC21, HDAC22, HDAC23, HDAC24, HDAC25, HDAC26, HDAC2 HDAC6 out of HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11 The method of any one of claims 44 to 46, wherein one or more are selectively inhibited.

48. The method according to any one of claims 44 to 47, wherein the method is an in vitro method. 。

49. The method according to any one of claims 44 to 47, wherein the method is an in vivo method.

50. 1. A method of imaging an object, comprising: i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42 or administering a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique. The method includes:

51. A method for imaging histone deacetylase (HDAC) enzymes in cells or tissues. hand, i) the cell or tissue and a radiolabeled compound according to any one of claims 36 to 39 to 42 or a pharma- ceutically acceptable salt thereof; and ii) imaging the cell or tissue with an imaging technique. The method includes:

52. 1. A method for imaging histone deacetylase (HDAC) enzymes in a subject, comprising: i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42 or administering a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique. The method includes:

53. Abnormal expression or activity of histone deacetylase (HDAC) enzymes in a subject.

1. A method for imaging a gender-related disorder, comprising: i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42 or administering a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique. The method includes:

54. Abnormal expression or activity of histone deacetylase (HDAC) enzymes in a subject.

1. A method for monitoring treatment of a gender-related disease, comprising: i) imaging said object with an imaging technique; ii) administering to said subject a compound according to any one of claims 1 to 42 or a pharma- ceutical acceptable salt thereof. administering a therapeutically effective amount of an acceptable salt; iii) imaging the object with an imaging technique; and iv) comparing the image of step i) with the image of step iii). The method includes:

55. The imaging techniques include single photon emission computed tomography, positron emission tomography imaging, , Computed Tomography, Positron with Computed Tomography Imaging positron emission tomography with magnetic resonance imaging; and positron emission tomography with magnetic resonance imaging. The method according to any one of claims 50 to 54, wherein

56. Any of claims 50 to 54, wherein the imaging technique is positron emission tomography imaging. The method according to any one of claims 1 to 5.

57. 57. The histone deacetylase (HDAC) enzyme of claims 51 to 56 is HDAC6.

2. The method according to claim 1 .

58. 1. A method of imaging the brain of a subject, comprising: i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42 or administering a pharma- ceutically acceptable salt thereof; and ii) imaging the object using an imaging technique. The method includes:

59. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutic agent as claimed in claim 1. A therapeutically effective amount of a compound according to any one of claims 1 to 42 or a pharma- ceutically acceptable salt thereof. and the disease is selected from the group consisting of cancer, diseases of the central nervous system, and inflammatory autoimmune diseases. The method of claim 1, wherein the

60. 60. The method of claim 59, wherein the disease is cancer.

61. 61. The method of claim 59 or 60, wherein the cancer comprises a solid tumor.

62. 5. The method of claim 4, wherein the cancer is selected from the group consisting of glioma, glioblastoma, and non-small cell lung cancer.

9. The method of any one of claims 9 to 61.

63. 61. The method of claim 59 or 60, wherein the cancer is a hematological cancer.

64. 64. The method of claim 63, wherein the hematological cancer is selected from the group consisting of leukemia and lymphoma. Law.

65. The cancer is associated with aberrant expression or activity of histone deacetylase (HDAC) enzymes. The method according to any one of claims 59 to 64.

66. The cancer is associated with aberrant expression or activity of HDAC6. The method according to any one of claims 1 to 5.

67. 60. The method of claim 59, wherein the disease is a disease of the central nervous system.

68. 68. The method of claim 59 or 67, wherein the disease of the central nervous system comprises a neurodegenerative disease.

69. 68. The method of claim 59 or 67, wherein the central nervous system disorder is depression.

70. The central nervous system diseases include schizophrenia, bipolar disorder, Alzheimer's disease, and Huntington's disease.

68. The method of claim 59 or 67, wherein the compound is selected from the group consisting of: Tonkin's disease.

71. 71. Any one of claims 59, 68 or 70, wherein the central nervous system disorder further comprises depression. The method according to

72. The central nervous system disease is caused by abnormal expression of histone deacetylase (HDAC) enzymes or 72. The method of any one of claims 59 or 67-71, which is associated with an abnormal activity.

73. The central nervous system disease is associated with abnormal expression or activity of HDAC6. The method according to any one of claims 59 or 67 to 71.

74. 60. The method of claim 59, wherein the disease is an inflammatory autoimmune disease.

75. The inflammatory autoimmune diseases are caused by the abnormal expression or function of histone deacetylase (HDAC) enzymes. is associated with an abnormal activity.

76. The inflammatory autoimmune disease is associated with abnormal expression or activity of HDAC6.

76. The method of any one of claims 59, 74 or 75.

77. 49-5, wherein about 0.1% to about 5% of the administered compound crosses the blood-brain barrier.

9. The method according to any one of claims 8 to 9.

78. The administered compound provides a brain:plasma ratio of at least about 1:1 to at least about 50:

1. The method according to any one of claims 49 to 58.

79. 1. A method of treating cancer in a subject, comprising: i) the cancer is characterized by aberrant activity or expression of histone deacetylase (HDAC) enzymes; Identifying the person as being associated with ii) administering to said subject a compound according to any one of claims 1 to 42 or a pharma- ceutical acceptable salt thereof. administering a therapeutically effective amount of an acceptable salt; The method includes:

80. 1. A method of treating a central nervous system disorder in a subject, comprising: i) the central nervous system disorder is characterized by abnormal activity of histone deacetylase (HDAC) enzymes; or associated with abnormal expression; and ii) administering to said subject a compound according to any one of claims 1 to 42 or a pharma- ceutical acceptable salt thereof. administering a therapeutically effective amount of an acceptable salt; The method includes:

81. 1. A method of treating an inflammatory autoimmune disease in a subject, comprising: i) the inflammatory autoimmune disease is characterized by abnormal activity of histone deacetylase (HDAC) enzymes; Identifying the genetic material as being associated with sexual or abnormal expression; and ii) administering to said subject a compound according to any one of claims 1 to 42 or a pharma- ceutical acceptable salt thereof. administering a therapeutically effective amount of an acceptable salt; The method includes:

82. Claims 79-81, wherein the histone deacetylase (HDAC) enzyme is HDAC6.

2. The method according to claim 1 .

Images