Arylmethylene heterocycles as Kv1.3 potassium shaker channel blockers

Abstract

Compounds of Formula I (I), or pharmaceutically acceptable salts thereof, are described, wherein the substituents are as defined herein. Pharmaceutical compositions containing the compounds and methods of using them are also described. [Formula 1] TIFF2022551198000129.tif4151

Description

[Technical Field]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 911,652, filed October 7, 2019, the entire contents of which are incorporated herein by reference.

[0002] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction of the patent document or the patent disclosure, as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights whatsoever.

[0003] Incorporation by Reference All documents cited herein are incorporated by reference in their entirety.

[0004] The present invention relates generally to the field of pharmacology. More specifically, the present invention relates to compounds and compositions useful as pharmaceuticals as potassium channel blockers. [Background technology]

[0005] Voltage-gated Kv1.3 potassium (K +Kv1.3 channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, regulating numerous physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kv1.3 channels regulate membrane potential, thereby indirectly affecting calcium signaling in human effector memory T cells. Effector memory T cells are mediators of several conditions, including multiple sclerosis, type 1 diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. Upon activation, effector memory T cells increase their expression of Kv1.3 channels. Among human B cells, naive and early memory B cells express low numbers of Kv1.3 channels when resting. In contrast, class-switched memory B cells express high numbers of Kv1.3 channels. Furthermore, Kv1.3 channels promote calcium homeostasis, which is necessary for T cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G., et al., 2004, Trends Immunol., 565-569). Blockade of Kv1.3 channels in effector memory T cells suppresses activities such as calcium signaling, cytokine production (interferon-gamma, interleukin-2), and cell proliferation.

[0006] Autoimmune diseases are a family of disorders resulting from tissue damage caused by attacks from the body's own immune system. Such diseases can affect a single organ, as in multiple sclerosis and type 1 diabetes, or can involve multiple organs, as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatment is generally palliative, using anti-inflammatory and immunosuppressive drugs that can have severe side effects. The need for more effective treatments has led to the search for drugs that can selectively inhibit the function of effector memory T cells, which are known to be involved in the pathogenesis of autoimmune diseases. It is believed that these inhibitors can ameliorate autoimmune disease symptoms without compromising protective immune responses. Effector memory T cells (TEMs) express numerous Kv1.3 channels and depend on these channels for their function. In vivo, Kv1.3 channel blockers paralyze TEMs at sites of inflammation and prevent their reactivation in inflamed tissues. Kv1.3 channel blockers do not affect the motility of naive and central memory T cells within lymph nodes. Inhibition of the function of these cells by selectively blocking Kv1.3 channels offers the potential for effective treatment of autoimmune diseases with minimal side effects.

[0007] Multiple sclerosis (MS) is caused by autoimmune damage to the central nervous system (CNS). Symptoms include muscle weakness and paralysis, which severely impact the quality of life for patients. MS progresses rapidly, unpredictably, and ultimately leads to death. Kv1.3 channels are also highly expressed in autoreactive effector memory T cells of MS patients (Wulff H., et al., 2003, J. Clin. Invest., 1703-1713; Rus H., et al., 2005, PNAS, 11094-11099). Animal models of multiple sclerosis have been successfully treated using Kv1.3 channel blockers.

[0008] Therefore, the compound that is selective Kv1.3 channel blocker is a potential therapeutic agent as immunosuppressant or immune system modulator.Kv1.3 channel is also considered as a therapeutic target for treating obesity and enhancing peripheral insulin sensitivity in patients with type 2 diabetes.These compounds can also be used to prevent transplant rejection and treat immunological (for example, autoimmune) and inflammatory disorders.

[0009] Tubulointerstitial fibrosis (TIF) is a progressive connective tissue deposition in the renal parenchyma that leads to the deterioration of renal function. It is involved in the pathology of chronic kidney disease, chronic renal failure, nephritis, and glomerular inflammation, and is a common cause of end-stage renal failure. Overexpression of Kv1.3 channels in lymphocytes is involved in the underlying pathology of these kidney diseases and can promote proliferation, leading to chronic inflammation and excessive stimulation of cell-mediated immunity, which are contributing factors in the progression of tubulointerstitial fibrosis. Inhibition of lymphocyte Kv1.3 channel currents suppresses renal lymphocyte proliferation and ameliorates the progression of renal fibrosis (Kazama I., et al., 2015, Mediators Inflamm., 1-12).

[0010] Kv1.3 channels also play a role in gastroenterological disorders, including inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease. UC is a chronic IBD characterized by excessive T cell infiltration and cytokine production. UC can impair quality of life and lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8 T cells in the inflamed mucosa of UC patients have been associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are thought to serve as a marker of disease activity, and pharmacological blockade may constitute a novel immunosuppressive strategy in UC. Current treatment regimens for UC, including corticosteroids, salicylates, and anti-TNFα agents, are insufficient for many patients (Hansen LK, et al., 2014, J. Crohn's Colitis, 1378-1391). Crohn's disease is a type of IBD that can affect any part of the digestive tract. Crohn's disease is thought to be the result of intestinal inflammation caused by a T cell-driven process that is usually initiated by harmless bacteria. Therefore, Kv1.3 channel inhibition can be used to treat Crohn's disease.

[0011] In addition to T cells, Kv1.3 channels are also expressed in microglia, where they are involved in inflammatory cytokine and nitric oxide production and microglia-mediated neuronal death. In humans, strong Kv1.3 channel expression is found in microglia in the frontal cortex of patients with Alzheimer's disease and in CD68 in multiple sclerosis brain lesions. + It has been observed in cells. It has been suggested that Kv1.3 channel blockers can preferentially target detrimental pro-inflammatory microglial function. Kv1.3 channels are expressed on activated microglia in infarcted rodent and human brains. Higher Kv1.3 channel current density is observed in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere in a mouse model of stroke (Chen YJ, et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

[0012] Kv1.3 channel expression is elevated in microglia in human Alzheimer's disease brains, suggesting that Kv1.3 channels are a pathologically relevant microglial target in Alzheimer's disease (Rangaraju S., et al., 2015, J. Alzheimers Dis., 797-808). Soluble AβOs enhance microglial Kv1.3 channel activity. Kv1.3 channels are required for AβO-induced microglial proinflammatory activation and neurotoxicity. Kv1.3 channel expression / activity is upregulated in transgenic Alzheimer's disease animals and human Alzheimer's disease brains. Pharmacological targeting of microglial Kv1.3 channels can affect hippocampal synaptic plasticity and reduce amyloid deposition in APP / PS1 mice. Therefore, Kv1.3 channels may be a therapeutic target for Alzheimer's disease.

[0013] Kv1.3 channel blockers may also be useful in ameliorating pathology in cardiovascular disorders such as ischemic stroke, where activated microglia contribute significantly to the subsequent expansion of the infarct.

[0014] Kv1.3 channel expression is associated with the regulation of proliferation, apoptosis, and cell survival in multiple cell types. These processes are crucial for cancer progression. In this context, Kv1.3 channels located in the inner mitochondrial membrane can interact with the apoptosis regulator Bax (Serrano-Albarras, A., et al., 2018, Expert Opin. Ther. Targets, 101-105). Therefore, inhibitors of Kv1.3 channels can be used as anticancer drugs.

[0015] Several peptide toxins with multiple disulfide bonds derived from spiders, scorpions, and sea anemones are known to block Kv1.3 channels. A few selective and potent peptide inhibitors of Kv1.3 channels have been developed. A synthetic derivative of stichodactyla toxin (shk) with an unnatural amino acid (shk-186) is the most advanced peptide toxin. Shk has demonstrated efficacy in preclinical models and is currently in phase I clinical trials for the treatment of psoriasis. Shk can suppress TEM cell proliferation and result in improvement in animal models of multiple sclerosis. Unfortunately, Shk also binds to closely related Kvi channel subtypes found in the CNS and heart. To avoid potential cardiotoxicity and neurotoxicity, selective Kv1.3 channel inhibitors are needed. Furthermore, small peptides such as shk-186 are rapidly eliminated from the body after administration, resulting in short circulatory half-lives and frequent dosing events. Therefore, there is a need for the development of long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases. Summary of the Invention [Problem to be solved by the invention]

[0016] Therefore, there remains a need for the development of novel Kv1.3 channel blockers as pharmaceutical agents. [Means for solving the problem]

[0017] In one aspect, the structure of Formula I:

[0018] [ka] ) wherein the various substituents are defined herein. Compounds of formula I described herein are useful as potassium channel blockers having the formula: +) channels and can be used to treat a variety of conditions. Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have several clinical uses, including as pharmaceutically active agents and in methods of treating cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, renal disease, or a combination thereof.

[0019] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof

[0020] [ka] (In the formula, Each occurrence of Y is independently C(R4)2, NR4, O, S, SO, SO2, or SO(=NR a ) and; Z is OR a and; X1 is H, halogen, CN, alkyl, alkyl halide, cycloalkyl, or cycloalkyl halide; X2 is H, halogen, CN, alkyl, alkyl halide, cycloalkyl, or cycloalkyl halide; each occurrence of X3 is independently H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl; R1 and R2 are each independently H, alkyl, (CR6R7) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 (C=O)NR b R a , or (CR6R7) n3 NR b (C=O)R a and; Each occurrence of R4 is independently H, halogen, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, oxo, (C=O)R b , (C=O)OR b , (CR6R7) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 SO2R a , (CR6R7) n3 SO2NR a R b , (CR6R7) n3 NR a SO2R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 (C=O)NR a R b , (CR6R7) n3 NR a (C=O)NR a R b , (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b or an optionally substituted 5- or 6-membered heterocycle containing 1 to 3 heteroatoms, each selected from the group consisting of N, O, and S; or two R4 taken together form an optionally substituted carbocycle, saturated heterocycle, or heteroaryl, each containing 0-3 heteroatoms selected from the group consisting of N, O, and S; each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R a and R beach occurrence of is independently H, alkyl, alkenyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; Where applicable, the alkyl, cycloalkyl, carbocycle, heterocycle, aryl, and heteroaryl of X1, X2, X3, R1, R2, R4, R6, and R7 may, where valences permit, be alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, (CR a R b ) n3 OR a , (CR a R b ) n3 NR a R b , (CR a R b ) n3 NR a (C=O)R b , (CR a R b ) n3 (C=O)NR a R b optionally substituted with 1 to 4 substituents independently selected from the group consisting of: each occurrence of n1 is independently, where valence allows, an integer from 0 to 4; each occurrence of n3 is independently an integer from 0 to 4; each occurrence of n4 is independently 0, 1, or 2) is described.

[0021] In any one of the embodiments described herein, the structural moiety

[0022] [ka] but,

[0023] [ka] It has the following structure.

[0024] In any one of the embodiments described herein, Y is C(R4)2.

[0025] In any one of the embodiments described herein, Y is NR4.

[0026] In any one of the embodiments described herein, Y is O.

[0027] In any one of the embodiments described herein, Y is S, SO, SO, or SO(=NR a )

[0028] In any one of the embodiments described herein, Y is NR4, CMeR4, or CHR4.

[0029] In any one of the embodiments described herein, the structural moiety

[0030] [ka] but,

[0031] [ka] It has the following structure.

[0032] In any one of the embodiments described herein, the structural moiety

[0033] [ka] but,

[0034] [ka] It has the following structure.

[0035] In any one of the embodiments described herein, the structural moiety

[0036] [ka] but,

[0037] [ka] (In the formula, R x is R4).

[0038] In any one of the embodiments described herein, the structural moiety

[0039] [ka] but,

[0040] [ka] (In the formula, R x is R4).

[0041] In any one of the embodiments described herein, R1 and R2 are each independently H or alkyl.

[0042] In any one of the embodiments described herein, R1 and R2 are each independently H or Me.

[0043] In any one of the embodiments described herein, R and R are each independently H, (CR R ) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3(C=O)NR b R a , or (CR6R7) n3 NR b (C=O)R a is.

[0044] In any one of the embodiments described herein, R1 and R2 are each independently H, CH2OH, CH2NH2, or CONH2.

[0045] In any one of the embodiments described herein, at least one occurrence of R4 is independently selected from the group consisting of (CR6R7) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 SO2R a , (CR6R7) n3 NR a (C=O)R b , or (CR6R7) n3 (C=O)NR a R b is.

[0046] In any one of the embodiments described herein, at least one occurrence of R4 is independently selected from the group consisting of (CR6R7) n3 NR a (C=O)R b or (CR6R7) n3 (C=O)NR a R b is.

[0047] In any one of the embodiments described herein, one or more occurrences of R4 are (CR6R7) n3 OR a , or (CR6R7) n3 NR a R b is.

[0048] In any one of the embodiments described herein, one or more occurrences of R4 are selected from the group consisting of OR a , N.R. a Rb , -CH2OR a , -CH2NR a R b , -CH2CH2OR a , or -CH2CH2NR a R b is.

[0049] In any one of the embodiments described herein, at least one occurrence of R4 is an optionally substituted 5- or 6-membered heterocycle containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.

[0050] In any one of the embodiments described herein, two R4 taken together form an optionally substituted carbocycle, saturated heterocycle, or heteroaryl, each containing 0-3 heteroatoms selected from the group consisting of N, O, and S.

[0051] In any one of the embodiments described herein, at least one occurrence of R4 is selected from the group consisting of CH2OH, CH2NH2,

[0052] [ka] is.

[0053] In any one of the embodiments described herein, at least one occurrence of R4 is

[0054] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 Optionally substituted with alkyl.

[0055] In any one of the embodiments described herein, at least one occurrence of R4 is selected from the group consisting of H, alkyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, CF3, OCF3, OR a , (CR6R7) n3 OR a , or oxo.

[0056] In any one of the embodiments described herein, at least one occurrence of R4 is (C=O)R b , (C=O)OR b , SO2R a , (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a SO2R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 NR a (C=O)NR a R b , or (CR6R7) n3 (C=O)NR a R b is.

[0057] In any one of the embodiments described herein, at least one occurrence of R4 is independently H or alkyl.

[0058] In any one of the embodiments described herein, two R groups together with the carbon atoms to which they are attached form a 3- to 7-membered optionally substituted carbocyclic or heterocyclic ring.

[0059] In any one of the embodiments described herein, the two R groups together with the two carbon atoms to which they are attached form:

[0060] [ka] where A is a 3- to 7-membered optionally substituted carbocycle, saturated heterocycle, or heteroaryl.

[0061] In any one of the embodiments described herein, the structural motif

[0062] [ka] but

[0063] [ka] It has the following structure.

[0064] In any one of the embodiments described herein, each occurrence of R6 and R7 is independently H or alkyl.

[0065] In any one of the embodiments described herein, Z is OH or OMe.

[0066] In any one of the embodiments described herein, Z is OH.

[0067] In any one of the embodiments described herein, X 1 is H, CN, halogen, fluorinated alkyl, or alkyl.

[0068] In any one of the embodiments described herein, X1 is H, CN, Cl, Br, Me, or CF3.

[0069] In any one of the embodiments described herein, X 1 is H or Cl.

[0070] In any one of the embodiments described herein, X2 is H, CN, halogen, fluorinated alkyl, or alkyl.

[0071] In any one of the embodiments described herein, X2 is H, CN, Cl, Br, Me, or CF3.

[0072] In any one of the embodiments described herein, X2 is H or Cl.

[0073] In any one of the embodiments described herein, X3 is H, halogen, CN, alkyl, or alkyl halide.

[0074] In any one of the embodiments described herein, X3 is H, Cl, Br, Me, or CF3.

[0075] In any one of the embodiments described herein, X3 is H or Cl.

[0076] In any one of the embodiments described herein, the structural moiety

[0077] [ka] but,

[0078] [ka] It has the following structure.

[0079] In any one of the embodiments described herein, n1 is 0, 1, 2, or 3.

[0080] In any one of the embodiments described herein, each occurrence of n3 is independently 0, 1, or 2.

[0081] In any one of the embodiments described herein, n4 is 1 or 2.

[0082] In any one of the embodiments described herein, R a or R b At least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

[0083] In any one of the embodiments described herein, R a or R b at least one occurrence of independently is H, Me, Et, Pr, or

[0084] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 Optionally substituted with alkyl.

[0085] In any one of the embodiments described herein, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0086] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 1-66 shown in Table 1.

[0087] In another aspect, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0088] In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, comprising the step of administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0089] In any one of the embodiments described herein, the immunological disorder is transplant rejection or an autoimmune disease.

[0090] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0091] In any one of the embodiments described herein, the central nervous system (CNS) disorder is Alzheimer's disease.

[0092] In any one of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

[0093] In any one of the embodiments described herein, the gastroenterological disorder is inflammatory bowel disease.

[0094] In any one of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0095] In any one of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0096] In any one of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0097] In any one of the embodiments described herein, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0098] In any one of the embodiments described herein, the mammalian species is human.

[0099] In yet another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof.

[0100] In any one of the embodiments described herein, the mammalian species is human.

[0101] Any one of the embodiments disclosed herein can be appropriately combined with any other embodiment disclosed herein.The combination of any one of the embodiments disclosed herein with any other embodiment disclosed herein is expressly contemplated.In particular, the selection of one or more embodiments for a certain substituent can be appropriately combined with the selection of one or more specific embodiments for any other substituent.Such combinations can be made with any one or more embodiments of the application described herein or any formula described herein. DETAILED DESCRIPTION OF THE INVENTION

[0102] definition The following are definitions of terms used herein. Unless otherwise specified, the initial definition provided for a group or term herein applies to that group or term throughout the specification, whether individually or as part of another group. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0103] The terms "alkyl" and "alk" refer to straight- or branched-chain alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "(C1-C4) alkyl" refers to straight- or branched-chain alkane (hydrocarbon) groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e, S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0104] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term "C2-C6 alkenyl" includes ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-penta- "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as (Z)-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hexa-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group having a single halogen substituent or multiple halogen substituents, such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d, C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents themselves can be optionally substituted.

[0105] The term "alkynyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary such groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, etc. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NRb R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents themselves can be optionally substituted.

[0106] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF3 or CCl3, in the latter case), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2Re , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R eis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0107] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl), cyano, nitro, oxo (i.e., ═O), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NRb R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0108] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, such as phenyl, biphenyl, or naphthyl, particularly a monocyclic or bicyclic group. When containing two or more aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be linked at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, in which two adjacent aromatic rings share two carbon atoms. "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably one to three substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF3 or CCl3, in the latter case), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. dS(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0109] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups linked by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group linked by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, the number of ring atoms in the heteroaryl and / or aryl ring is used to specify the aryl or heteroaryl ring size of the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be specified similarly.

[0110] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring, or a cyclic aromatic hydrocarbon group having one to five aromatic rings, such as phenyl, biphenyl, or naphthyl, particularly a monocyclic or bicyclic group. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl, as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves may be optionally substituted.

[0111] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated, cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems), including aromatic (i.e., "heteroaryl") groups, having at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heterocyclic group can independently be saturated, or partially or fully unsaturated. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, with the nitrogen and sulfur heteroatoms optionally being oxidized and the nitrogen heteroatom optionally being quaternized. (The term "heteroarylium" refers to a heteroaryl group bearing a quaternized nitrogen atom, thus carrying a positive charge.) A heterocyclic group can be attached to the remainder of the molecule at any heteroatom or carbon atom in the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, Examples of aryl include 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, Included are benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0112] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2Re , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R eis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0113] The term "oxo" refers to a ring that may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring.

[0114] [ka] When an oxo substituent is attached to a carbon ring atom on an aromatic group, such as an aryl or heteroaryl, the bonds on the aromatic ring can be rearranged to meet valence requirements. For example, a pyridine with a 2-oxo substituent is

[0115] [ka] may have the structure

[0116] [ka] Also included are the tautomeric forms thereof:

[0117] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0118] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined herein. R and R' can be the same or different dialkylamino moieties. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure can be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0119] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0120] The term "substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) is substituted with one or more substituents, preferably 1 to 6 substituents, at any available point of attachment, where valence allows. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl), in the latter case, cyano, nitro, oxo (i.e., ═O), CF, OCF, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. bC(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In the above exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be optionally substituted. The term "optionally substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) may or may not be substituted with one or more of the substituents described above.

[0121] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0122] The compounds of the present invention can form salts that are also within the scope of the present invention. Reference to a compound of the present invention is understood to include reference to its salts, unless otherwise indicated. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, when a compound of the present invention contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and are included in the term "salt" as used herein. Although pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts are also useful, for example, in isolation or purification steps that may be used during preparation. Salts of the compounds of the present invention can be formed, for example, by reacting a compound described herein with, for example, an equivalent amount of acid or base in a medium such as a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0123] Compounds of the present invention that contain a basic moiety, such as, but not limited to, an amine or a pyridine or imidazole ring, can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetate (such as those formed with acetic acid or a trihaloacetic acid, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, and the like. Salts include sulfonates (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0124] Compounds of the present invention that contain an acidic moiety, such as, but not limited to, a phenol or a carboxylic acid, can form salts with a variety of organic and inorganic bases. Exemplary base salts include ammonium salts, alkali metal salts, such as sodium, lithium, and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, t-butylamine, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl chloride, bromide, and iodide, lauryl, myristyl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0125] Prodrugs and solvates of the compounds of the present invention are also contemplated herein.The term "prodrug" as used herein refers to a compound that, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to produce the compounds of the present invention, or their salts and / or solvates.Solvates of the compounds of the present invention include, for example, hydrates.

[0126] The compounds of the present invention, and their salts or solvates, may exist in their tautomeric form (e.g., as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of a compound includes its tautomeric form.

[0127] All stereoisomers of the present compounds, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbon atoms on various substituents), are contemplated within the scope of the present invention. Individual stereoisomers of the present compounds may be, for example, substantially free of other isomers (e.g., as pure or substantially pure optical isomers having the specified activity), e.g., as racemates, or admixed with all other or selected stereoisomers. Chiral centers of the present invention may have the S or R configuration as defined by the 1974 Recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation, or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by any suitable method, including, but not limited to, conventional methods such as, for example, salt formation with an optically active acid followed by crystallization.

[0128] After preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 90% by weight or more, e.g., 95% by weight or more, 99% by weight or more of the compound (a "substantially pure" compound), which are then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also contemplated herein as part of the present invention.

[0129] All configurational isomers of the compounds of the invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds of the invention encompasses both cis (Z) and trans (E) alkene isomers, as well as both cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0130] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0131] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0132] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0133] Isomeric mixtures containing any of a variety of isomer ratios can be utilized by the present invention. For example, when combining only two isomers, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0134] The present invention also includes isotopically labeled compounds that are identical to the compounds disclosed herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, that contain the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g., 3 H and 14 Those in which a radioactive isotope, such as 1C, is incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavy isotopes such as H can confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following the procedures disclosed in the following schemes and / or examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0135] For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with an asymmetric auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0136] It is understood that the compounds described herein can be substituted with any number of substituents or functional moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, and whether the substituent is included in the formula of the invention, refers to the replacement of a hydrogen radical in a given structure with the radical of the specified substituent. When more than one position in any given structure can be substituted with more than one substituent selected from the specified group, the substituents can be the same or different at all positions. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful, for example, in the treatment of proliferative disorders. As used herein, the term "stable" refers to compounds that preferably have sufficient stability to permit manufacture and maintain compound integrity for a period of time sufficient to be detected, preferably to be useful for the purposes detailed herein.

[0137] As used herein, the terms "cancer," and equivalently, "tumor," refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant. Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. Cancer can be primary or metastatic. Because diseases other than cancer can be associated with mutational changes in components of the Ras signaling pathway, the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases may include neurofibromatosis; Leopard syndrome; Noonan syndrome; Regius syndrome; Costello syndrome; cardio-facial-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arteriovenous malformation.

[0138] As used herein, "effective amount" refers to any amount that is necessary or sufficient to achieve or promote a desired outcome.In some instances, an effective amount is a therapeutically effective amount.A therapeutically effective amount is any amount that is necessary or sufficient to promote or achieve a desired biological response in a subject.The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the specific drug being administered, the size of the subject, or the severity of the disease or condition.Those skilled in the art can empirically determine the effective amount of a particular drug without undue experimentation.

[0139] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including, but not limited to, non-human primates, laboratory animals, livestock, racehorses, domestic animals, and non-domestic animals.

[0140] compound Novel compounds are described as Kv1.3 potassium channel blockers. Applicants have surprisingly discovered that the compounds disclosed herein exhibit potent Kv1.3 potassium channel inhibitory properties. Furthermore, applicants have surprisingly discovered that the compounds disclosed herein selectively block Kv1.3 potassium channels and do not block hERG channels, and therefore have desirable cardiovascular safety profiles.

[0141] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is

[0142] [ka] (In the formula, Each occurrence of Y is independently C(R4)2, NR4, O, S, SO, SO2, or SO(=NR a ) and; Z is OR a and; X1 is H, halogen, CN, alkyl, alkyl halide, cycloalkyl, or cycloalkyl halide; X2 is H, halogen, CN, alkyl, alkyl halide, cycloalkyl, or cycloalkyl halide; each occurrence of X3 is independently H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl; R1 and R2 are each independently H, alkyl, (CR6R7) n3 OR a , (CR6R7) n3 NR a R b, (CR6R7) n3 (C=O)NR b R a , or (CR6R7) n3 NR b (C=O)R a and; Each occurrence of R4 is independently H, halogen, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, oxo, (C=O)R b , (C=O)OR b , (CR6R7) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 SO2R a , (CR6R7) n3 SO2NR a R b , (CR6R7) n3 NR a SO2R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 (C=O)NR a R b , (CR6R7) n3 NR a (C=O)NR a R b , (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b or an optionally substituted 5- or 6-membered heterocycle containing 1 to 3 heteroatoms, each selected from the group consisting of N, O, and S; or two R4 taken together form an optionally substituted carbocycle, saturated heterocycle, or heteroaryl, each containing 0-3 heteroatoms selected from the group consisting of N, O, and S; each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R a and R b each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; Alkyl, cycloalkyl, carbocycle, heterocycle, aryl, and heteroaryl are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, (CR6R7) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 (C=O)NR a R b optionally substituted with 1 to 4 substituents independently selected from the group consisting of: each occurrence of n1 is independently, where valence allows, an integer from 0 to 4; each occurrence of n3 is independently an integer from 0 to 4; each occurrence of n4 is independently 0, 1, or 2) is described.

[0143] In some embodiments, n1 is an integer from 1 to 4. In some embodiments, n1 is an integer from 1 to 3. In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 1. In some embodiments, n1 is 0.

[0144] In some embodiments, n3 is an integer from 0 to 4. In some embodiments, n3 is an integer from 1 to 3. In some embodiments, n3 is 0. In some embodiments, n3 is 1 or 2. In some embodiments, n3 is 1.

[0145] In some embodiments, n4 is an integer from 0 to 2. In some embodiments, n4 is 0. In some embodiments, n4 is 2. In some embodiments, n4 is 1.

[0146] In some embodiments, the structural moiety

[0147] [ka] but,

[0148] [ka] wherein the various substituents are defined herein. In some embodiments, the structural moiety

[0149] [ka] but,

[0150] [ka] In some embodiments, the structural moiety

[0151] [ka] but,

[0152] [ka] In some embodiments, the structural moiety

[0153] [ka] but,

[0154] [ka] In some embodiments, the structural moiety

[0155] [ka] but,

[0156] [ka] It has the following structure.

[0157] In some embodiments, Y is C(R). In other embodiments, Y is NR. In still other embodiments, Y is O. In still other embodiments, Y is S, SO, SO, or SO(=NR a ). In some specific embodiments, Y is NR4, CMeR4, or CHR4. In some specific embodiments, Y is NH. In some specific embodiments, Y is CH2.

[0158] In some embodiments, the structural moiety

[0159] [ka] but,

[0160] [ka] In another embodiment, the structural moiety

[0161] [ka] but,

[0162] [ka] In yet another embodiment, the structural moiety

[0163] [ka] but,

[0164] [ka] (In the formula, R x is R4). In some specific embodiments, the structural moiety

[0165] [ka] but,

[0166] [ka] In some specific embodiments, the structural moiety

[0167] [ka] but,

[0168] [ka] It has the following structure.

[0169] In some embodiments, the structural moiety

[0170] [ka] but,

[0171] [ka] (In the formula, R xis R4). In some specific embodiments, the structural moiety

[0172] [ka] but,

[0173] [ka] In some specific embodiments, the structural moiety

[0174] [ka] but,

[0175] [ka] In some specific embodiments, the structural moiety

[0176] [ka] but,

[0177] [ka] It has the following structure.

[0178] In some embodiments, R1 and R2 are each H or alkyl. In some embodiments, R1 and R2 are both H. In some embodiments, R1 and R2 are alkyl, such as Me, Et, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl. In some embodiments, R1 and R2 are each H and alkyl.

[0179] In some embodiments, at least one occurrence of R1 and R2 is (CR6R7) n3 OR a , or (CR6R7) n3 NRa R b In some embodiments, at least one occurrence of R and R is H.

[0180] In some embodiments, R and R are each independently H, (CRR) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 (C=O)NR b R a , or (CR6R7) n3 NR b (C=O)R a In some specific embodiments, R1 and R2 are each independently H, Me, CH2OH, CH2NH2, CONH2, CONHMe2, CONMe2, NH(CO)Me, or NMe(CO)Me. In some embodiments, R1 and R2 are each independently H, CH2OH, CH2NH2, or CONH2. In other embodiments, R1 and R2 are each independently selected from the group consisting of H and Me.

[0181] In some embodiments, at least one occurrence of R4 is independently selected from the group consisting of (CR6R7) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 SO2R a , (CR6R7) n3 NR a (C=O)R b , or (CR6R7) n3 (C=O)NR a R b In some embodiments, at least one occurrence of R4 is independently: (CR6R7) n3 NR a (C=O)R b or (CR6R7) n3 (C=O)NR a R bIn some embodiments, at least one occurrence of R4 is independently: (CR6R7) n3 OR a or (CR6R7) n3 NR a R b In some embodiments, at least one occurrence of R4 is independently OR a , N.R. a R b , -CH2OR a , -CH2NR a R b , -CH2CH2OR a , or -CH2CH2NR a R b In some specific embodiments, R4 is NH2, CH2NH2, CH2CH2NH2, CONH2, CONHMe2, CONMe2, NH(CO)Me, NMe(CO)Me, CH2CONH2, CH2CONHMe2, CH2CONMe2, CH2NH(CO)Me, or CH2NMe(CO)Me. In other specific embodiments, at least one occurrence of R4 is CH2NH2,

[0182] [ka] In other specific embodiments, at least one occurrence of R4 is CH2OH, CH2NH2,

[0183] [ka] is.

[0184] In still other embodiments, at least one occurrence of R4 is an optionally substituted 4-, 5-, or 6-membered heterocycle containing 1-3 heteroatoms each selected from the group consisting of N, O, and S. In further embodiments, at least one occurrence of R4 is

[0185] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 In a further embodiment, two R4 are taken together to form an optionally substituted carbocycle, saturated heterocycle, or heteroaryl, each containing 0-3 heteroatoms selected from the group consisting of N, O, and S.

[0186] In some embodiments, at least one occurrence of R is selected from H, alkyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, CF, OCF, OR a , (CR6R7) n3 OR a or oxo. In some embodiments, at least one occurrence of R is (C=O)R b , (C=O)OR b , SO2R a , (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a SO2R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 NR a (C=O)NR a R b , or (CR6R7) n3 (C=O)NR a R b is.

[0187] In some specific embodiments, at least one occurrence of R4 is H, halogen, alkyl, OH, NH2, CN, CF3, OCF3, CONH2, CONHMe2, or CONMe2. In some specific embodiments, R4 is H, halogen, alkyl, cycloalkyl, CN, CF3, OR a , (CR6R7) n3 OR a , (C=O)OR b , (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 SO2NR a R b , (CR6R7) n3 SO2R a , oxo, or (CR6R7) n3 (C=O)NR a R b In some embodiments, at least one occurrence of R4 is independently H or alkyl.

[0188] In some specific embodiments, R4 is H, halogen, alkyl, OR a , N.R. a R b , or oxo. In other specific embodiments, R4 is H, F, Cl, Br, Me, Et, Pr, iso-Pr, Bu, iso-Bu, sec-Bu, or tert-Bu. In other specific embodiments, R4 is OH, NH2, NHMe, NMe2, NHEt, NMeEt, NEt2, or oxo. In yet other specific embodiments, at least one occurrence of R4 is H, halogen, alkyl, OH, NH2, CN, CF3, OCF3, CONH2, CONHMe2, or CONMe2.

[0189] In other embodiments, the two R groups, together with the two carbon atoms to which they are attached, form:

[0190] [ka] wherein A is a 3- to 7-membered optionally substituted carbocycle, saturated heterocycle, or heteroaryl. In some embodiments, the structural motif

[0191] [ka] but,

[0192] [ka] It has the following structure.

[0193] In some embodiments, each occurrence of R and R is independently H or alkyl. In some specific embodiments, CR R is CH, CHMe, CMe, CHEt, or CEt. In some specific embodiments, CR R is CH.

[0194] In some embodiments, Z is OR a In some embodiments, Z is OH, or OMe. In some embodiments, Z is OH.

[0195] In some embodiments, X1 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In any one of the embodiments described herein, X1 can be H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X1 is H or halogen. In other embodiments, X1 is fluorinated alkyl or alkyl. In other embodiments, X1 is cycloalkyl. In some embodiments, X1 is H, F, Cl, Br, Me, or CF3. In some embodiments, X1 is H, F, or Cl. In some embodiments, X1 is F or Cl. In some embodiments, X1 is H or Cl. In some embodiments, X1 is F. In some embodiments, X1 is CF3.

[0196] In some embodiments, X2 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In any one of the embodiments described herein, X2 can be H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X2 is H or halogen. In other embodiments, X2 is fluorinated alkyl or alkyl. In other embodiments, X2 is cycloalkyl. In some embodiments, X2 is H, F, Cl, Br, Me, or CF3. In some embodiments, X2 is H, F, or Cl. In some embodiments, X2 is F or Cl. In some embodiments, X2 is H or Cl. In some embodiments, X2 is F. In some embodiments, X2 is CF3.

[0197] In some embodiments, each occurrence of X3 is independently H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In any one of the embodiments described herein, X3 can be H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X3 is H or halogen. In other embodiments, X3 is fluorinated alkyl or alkyl. In other embodiments, X3 is cycloalkyl. In some embodiments, X3 is H, F, Cl, Br, Me, or CF3. In some embodiments, X3 is H, F, or Cl. In some embodiments, X3 is F or Cl. In some embodiments, X3 is H or Cl. In some embodiments, X3 is F. In some embodiments, X3 is CF3.

[0198] In some embodiments, the structural moiety

[0199] [ka] but,

[0200] [ka] It has the following structure.

[0201] In some embodiments, Z is OH or OMe. In some embodiments, Z is OH.

[0202] In any one of the embodiments described herein, R a or R b is independently H or an optionally substituted alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. a or R b is independently H, Me, Et, Pr, or Bu. a or R b At least one occurrence of independently

[0203] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 Optionally substituted with alkyl.

[0204] In some embodiments, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0205] In some embodiments, the compound of formula I is selected from the group consisting of compounds 1-66 shown in Table 1 below.

[0206] [Table 1]

[0207] Preparation method The following are general synthetic schemes for preparing the compounds of the present invention. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Furthermore, various steps of the synthesis can be performed in an alternative sequence or order to obtain the desired compound. All documents cited herein are incorporated by reference in their entirety. For example, the following reactions are illustrative, but not limiting, of the preparation of some of the starting materials and compounds disclosed herein.

[0208] Schemes 1-3 below describe synthetic routes that can be used to synthesize compounds of the present invention, such as compounds having the structure of Formula I, or precursors thereof. Various modifications of these methods to achieve results similar to those of the present invention provided below may occur to those skilled in the art. In the following embodiments, synthetic routes are described using compounds having the structure of Formula I, or precursors thereof, as examples. The general synthetic routes described in Schemes 1-3, and the examples provided in the Examples section below, illustrate methods used to prepare the compounds described herein.

[0209] As shown in Scheme 1 immediately below, compounds I-1 and I-3 can be prepared by any method known in the art and / or are commercially available. The substituents shown in Scheme 1 are defined herein. Compounds disclosed herein in which R1 and R2 are H can be made by reductive amination of aryl aldehyde I-2a with cyclic amine I-3 to give compound I-4a (Scheme 1). If not commercially available, aldehyde I-2a can be obtained by formylation of substituted benzene I-1 with paraformaldehyde, magnesium chloride, and a base (e.g., TEA) in a solvent (e.g., ACN). Reductive amination of aryl aldehyde I-2a with cyclic amine I-3 can be carried out using a reducing agent (e.g., sodium triacetoxyborohydride) in a solvent (e.g., DCE) or PMHS and tin chloride in a solvent (e.g., methanol). For compounds disclosed herein in which Z is OH, no protecting group is required for the reductive amination step. For compounds disclosed herein in which R4 contains an amino group, the amine may be protected with a protecting group, such as Boc or trifluoroacetamide. Any other protecting group for amines known in the art can be used. The protecting group is then removed after the reductive amination step.

[0210] [ka]

[0211] As shown in Scheme 2 immediately below, compounds I-2c and I-3 can be prepared by any method known in the art and / or are commercially available. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. The substituents shown in Scheme 2 are defined herein. Compounds disclosed herein in which R1 is an alkyl group can be prepared from benzaldehyde I-2c by reaction with the Grignard reagent R1MgBr. The resulting alcohol I-5 is then converted to bromide I-6 using a brominating agent, such as phosphorus tribromide. Reaction of I-6 with cyclic amine I-3 in a solvent (e.g., DMF) in the presence of a base (e.g., potassium carbonate) provides I-4c (Scheme 2). In some embodiments, this method can also be used for compounds in which R1 and R2 are both H.

[0212] [ka] As shown in Scheme 3 immediately below, compounds I-1b and I-3 can be prepared by any method known in the art and / or are commercially available. As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. The substituents shown in Scheme 3 are defined herein. Compounds disclosed herein in which R1 is a functional group can be synthesized from phenol I-1b, as shown in Scheme 3. Reaction of phenol I-1b with ethyl glyoxalate in a solvent (e.g., DCM) in the presence of a Lewis acid (e.g., titanium tetrachloride) provides alcohol I-5b. The phenol group of I-5b is then selectively protected, for example, as an ether, such as a methyl or allyl ether I-5c. I-5c is converted to bromide I-6b using a brominating agent (e.g., phosphorus tribromide) in a solvent (e.g., DCM). I-6b is reacted with amine I-3 to give I-4d. The ester group of I-4d can be converted to various R groups, such as amide, hydroxymethyl, or aminomethyl, using methods known in the art. The protecting group PG can optionally be removed to give compounds of formula I.

[0213] [ka]

[0214] The reactions described above in Schemes 1-3 can be carried out in a suitable solvent. Suitable solvents include, but are not limited to, ACN, methanol, ethanol, DCM, DMF, THF, MTBE, or toluene. The reactions described in Schemes 1-3 can be carried out under an inert atmosphere, such as nitrogen or argon, or in a sealed tube. The reaction mixture can be heated in a microwave or at an elevated temperature. Suitable elevated temperatures include, but are not limited to, 40, 50, 60, 80, 90, 100, 110, 120 °C or higher, or the reflux / boiling temperature of the solvent used. Alternatively, the reaction mixture can be cooled in a cooling bath at a temperature below room temperature, such as 0, -10, -20, -30, -40, -50, -78, or -90 °C. The reaction can be worked up by removing the solvent or by partitioning the organic solvent phase with one or more aqueous phases, each optionally containing NaCl, NaHCO3, or NHCl. The solvent of the organic phase can be removed by low vacuum evaporation and the resulting residue can be purified using a silica gel column or HPLC.

[0215] Pharmaceutical Composition The present invention also provides pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0216] In yet another aspect, the present invention provides pharmaceutical compositions comprising at least one compound selected from the group consisting of compounds of formula I described herein and a pharmaceutically acceptable carrier or diluent.

[0217] In certain embodiments, the composition is in the form of a hydrate, solvate, or pharmaceutically acceptable salt. The composition can be administered to a subject by any suitable route of administration, including, but not limited to, oral and parenteral.

[0218] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the pharmaceutical agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as butylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical preparations.The term "carrier" refers to a natural or synthetic organic or inorganic ingredient that combines with active ingredients to facilitate application. The components of the pharmaceutical compositions also are capable of being co-mingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0219] As noted above, certain embodiments of the pharmaceutical agent may be provided in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" in this context refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compounds of the present invention in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. (See, e.g., Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0220] Pharmaceutically acceptable salts of the present compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, and the like; and salts prepared from organic acids such as acetate, butyonic acid, succinate, glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, palmitate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalate, isothionic acid, and the like.

[0221] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, e.g., Berge et al., supra.)

[0222] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0223] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0224] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0225] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as an active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0226] In the solid dosage forms of the present invention for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; agar, calcium carbonate, potato, etc. Disintegrating agents such as maize or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymers; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type can also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0227] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxybutylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0228] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxybutylmethylcellulose, other polymer matrices, liposomes, and / or microspheres that provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents into the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of implant compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0229] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage form may contain solubilizers and emulsifiers, such as inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, can be used to solubilize the compound.

[0230] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0231] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0232] Dosage forms for topical or transdermal administration of a compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0233] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0234] Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example, butane and butane.

[0235] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the drug in a suitable medium.Absorption enhancers can also be used to increase the flux of the drug of the present invention across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0236] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0237] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0238] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections to prolong the drug's effect. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the drug depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle. One strategy for depot injection involves the use of polyethylene oxide-polypropylene oxide copolymers, whose vehicles are fluid at room temperature but solidify at body temperature.

[0239] Injectable depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0240] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be given as they are or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0241] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, that is, the compounds and pharmaceutical compositions can be administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures.The specific combination of treatments (therapeutic agents or procedures) used in combination regimen will take into account the compatibility of desired therapeutic agents and / or procedures and the desired therapeutic effect achieved.It will also be understood that the treatments used can achieve the desired effect for the same disorder (for example, the compounds of the present invention can be administered simultaneously with another anticancer drug).

[0242] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds can be used to treat arthritic conditions in mammals (e.g., humans, livestock and domestic animals), racehorses, birds, lizards, and any other organisms that can tolerate the compounds.

[0243] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, optionally accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, reflecting approval by the agency of the manufacture, use, or sale for human administration.

[0244] Administration to subjects In yet another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of a compound selected from the group consisting of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and renal diseases.

[0245] In some embodiments, the cancer is selected from the group consisting of biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasia, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

[0246] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy. In some embodiments, the gastroenterological disorder is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis.

[0247] In some embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes). In some embodiments, the central nervous system (CNS) disorder is Alzheimer's disease.

[0248] In some embodiments, the metabolic disorder is obesity or type II diabetes. In some embodiments, the cardiovascular disorder is ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0249] In some embodiments, the mammalian species is human.

[0250] In some embodiments, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0251] In yet another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the compounds described herein are selective in blocking the Kv1.3 potassium channel with minimal or no off-target inhibitory activity against other potassium channels, or against calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channel, and therefore have a desirable cardiovascular safety profile.

[0253] Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a particular outcome. Accordingly, small molecule compositions useful according to the methods of the invention can be formulated in any manner suitable for pharmaceutical use.

[0254] The formulations of the present invention are administered in pharmaceutically acceptable solutions which may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0255] For use in treatment, an effective amount of the compound can be administered to a subject by any method that allows the compound to be taken up by appropriate target cells.The "administration" of the pharmaceutical composition of the present invention can be achieved by any means known to those skilled in the art.Specific administration routes include, but are not limited to, oral, transdermal (for example, via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.).Injection can be bolus or continuous infusion.

[0256] For example, pharmaceutical compositions according to the present invention are often administered intravenously, intramuscularly, or by other parenteral means. They can also be administered intranasally, by inhalation, topically, orally, or as an implant, and even rectally or vaginally. Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, cochleated, coated on fine gold particles, contained in liposomes, nebulized, aerosolized, pellets for implantation in the skin, or dried on a sharp object for scratching into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with extended release of active compounds, in which excipients and additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers are commonly used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief overview of this method for drug delivery, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference.

[0257] The concentration of the compound contained in the composition used in the method of the present invention can range from about 1 nM to about 100 μM. An effective dose is believed to be in the range of about 100 picomoles / kg to about 100 micromoles / kg.

[0258] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders and suppositories. To treat a patient, different dosages may be required depending on the activity of the compound, the method of administration, the purpose of administration (i.e., preventive or therapeutic), the nature and severity of the disorder, and the age and weight of the patient. The administration of a given dose can be carried out by both single administration in the form of individual dosage units or several smaller dosage units. Repeated doses and multiple administrations at specific daily, weekly or monthly intervals are also contemplated by the present invention.

[0259] The composition can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. For medical use, the salt should be pharmaceutically acceptable, although non-pharmaceutically acceptable salts can be conveniently used to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. These salts can also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0260] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0261] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations that can be isotonic with the recipient's blood. Acceptable vehicles and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed, or non-mineral oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid have found use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous administration, etc. can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0262] The compounds useful in the present invention may be delivered in a mixture of three or more such compounds, which may further include one or more adjuvants in addition to the combination of compounds.

[0263] A variety of administration routes are available.The specific mode selected will naturally depend on the specific compound selected, the age and general health condition of the subject, the specific condition to be treated, and the dosage required for therapeutic effectiveness.The method of the present invention can be carried out using any medically acceptable administration mode, which generally means any mode that produces an effective level of response without causing clinically unacceptable adverse effects.Preferred administration modes are discussed above.

[0264] Composition can be conveniently provided in unit dosage form, and can be prepared by any method well known in the field of pharmacy.All methods comprise the step of associating compound with carrier that constitutes one or more accessory components.Generally, composition is prepared by associating compound with liquid carrier, finely divided solid carrier, or both, uniformly and intimately, and then, if necessary, shaping product.

[0265] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems. Such systems can avoid repeated administration of the compound, increasing convenience for patients and physicians. Many types of release delivery systems are available and known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Drug-containing microcapsules of these polymers are described, for example, in U.S. Pat. No. 5,075,109. Delivery systems also include non-polymeric systems, such as lipids containing sterols, such as cholesterol, cholesterol esters, and fatty acids or neutral lipids, e.g., mono-, di-, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; and partially fused implants. Specific examples include, but are not limited to, (a) erosion systems in which the agents of the invention are contained within a matrix, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusion systems in which the active ingredient permeates through a polymer at a controlled rate, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. Additionally, pump-based hardware delivery systems, some of which are adapted for implantation, can be used.

[0266] Assay for efficacy of Kv1.3 potassium channel blockers In some embodiments, the compound described herein is tested for its activity against Kv1.3 potassium channel.In some embodiments, the compound described herein is tested for its Kv1.3 potassium channel electrophysiology.In some embodiments, the compound described herein is tested for its hERG electrophysiology.

[0267] equivalent The following representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the present invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the complete contents of this document, including the following examples, and with reference to the scientific and patent literature cited herein. It should be further understood that the contents of these cited references are incorporated herein by reference to help illustrate the prior art. The following examples contain important additional information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof. [Example]

[0268] Examples 1-2 describe various intermediates used in the synthesis of representative compounds of Formula I disclosed herein.

[0269] [Example 1] Intermediate 1 (4,5-dichloro-2-hydroxybenzaldehyde)

[0270] [ka]

[0271] Step A: To a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol) in methanesulfonic acid (35 mL) was added hexamethylenetetramine (47.50 g, 337.40 mmol) at room temperature. The reaction solution was stirred at 110° C. for 30 minutes. The reaction solution was cooled to room temperature and quenched with water (500 mL). The resulting solution was extracted with DCM (3×500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / DCM (10 / 1) to give intermediate 1 (4,5-dichloro-2-hydroxybenzaldehyde) as a yellow solid (13.50 g, 23%): 1H NMR (400 MHz, CDCl3) δ 10.98 (s, 1H), 9.85 (s, 1H), 7.66 (s, 1H), 7.16 (s, 1H).

[0272] [Example 2] Intermediate 2 (1-(bromomethyl)-4,5-dichloro-2-methoxybenzene)

[0273] [ka]

[0274] Step A: To a stirred solution of intermediate 1 (4,5-dichloro-2-hydroxybenzaldehyde) (10.00 g, 52.35 mmol) and K2CO3 (21.70 g, 157.06 mmol) in DMF (100 mL) at room temperature was added CHCl (11.10 g, 78.53 mmol). The resulting mixture was stirred at 30 °C for 2 h. The reaction was diluted with water (500 mL). The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 4,5-dichloro-2-methoxybenzaldehyde as an off-white solid (10.30 g, 96%): 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H).

[0275] Step B: To a solution of 4,5-dichloro-2-methoxybenzaldehyde (5.00 g, 24.39 mmol) in EtOH (40 mL) and THF (5 mL) was added NaBH (1.80 g, 48.88 mmol) at room temperature. After stirring at room temperature for 1 h, the resulting solution was quenched with water (1 mL) and diluted with a cosolvent of EA (80 mL) and water (100 mL) at room temperature. The isolated aqueous layer was extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (3 × 80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (4,5-dichloro-2-methoxyphenyl)methanol as a pale yellow solid (5.0 g, crude), which was used in the next step without further purification.

[0276] Step C: To a stirred solution of (4,5-dichloro-2-methoxyphenyl)methanol (5.00 g, 24.15 mmol) in CHCl (40 mL) was added PBr (13.10 g, 48.30 mmol) at room temperature. After stirring at room temperature for 1 h, the resulting solution was quenched with water (80 mL). The aqueous layer was extracted with EA (3×80 mL). The combined organic layers were washed with brine (3×80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give intermediate 2 (1-(bromomethyl)-4,5-dichloro-2-methoxybenzene) as a pale yellow oil (5.00 g, 69%): H NMR (300 MHz, CDCl) δ 7.37 (s, 1H), 6.93 (s, 1H), 4.42 (s, 2H), 3.86 (s, 3H).

[0277] Examples 3-28 describe the synthesis of representative compounds of Formula I disclosed herein.

[0278] [Example 3] Compound 2 ((1-(4,5-dichloro-2-hydroxybenzyl)piperidine-2,4-diyl)dimethanol) Compound 1 (Methyl 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-2-carboxylate)

[0279] [ka]

[0280] Step A: To a solution of methyl 4-(hydroxymethyl)pyridine-2-carboxylate (0.10 g, 0.60 mmol) in MeOH (5 mL) was added PtO2 (10 mg, 10%) under nitrogen atmosphere at room temperature. The mixture was degassed with hydrogen three times. The mixture was stirred under hydrogen atmosphere (5 atm) at room temperature for 16 hours. The mixture was filtered. The filter cake was washed with MeOH (2 x 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN in water containing 20 mM NH4HCO3. The faster eluent was obtained as piperidine-2,4-diyldimethanol (0.2 g, 20%) as a pale yellow oil: LCMS (ESI) CH 15 NO2[M + H] + Calculated value: 146, measured value 146;

[0281] The slower eluting material was obtained as methyl 4-(hydroxymethyl)piperidine-2-carboxylate as a pale yellow oil (0.30 g, 30%): LCMS (ESI) C8H 15 NO3[M + H] + Calculated value: 174, measured value 174;

[0282] Step B: To a mixture of piperidine-2,4-diyldimethanol (0.35 g, 2.04 mmol) and K2CO3 (0.51 g, 3.70 mmol) in DMF (3 mL) was added intermediate 2 (0.50 g, 1.85 mmol) at room temperature. The reaction mixture was warmed to 45 °C and stirred for 2 h. After cooling to room temperature, the resulting mixture was diluted with water (20 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give (1-(4,5-dichloro-2-methoxybenzyl)piperidine-2,4-diyl)dimethanol as a pale yellow oil (0.17 g, 28%): LCMS (ESI) C 15 H 21 Cl2NO3[M + H]+ Calculated values: 334, 336 (3:2), measured values: 334, 336 (3:2).

[0283] Step C: To a solution of (1-(4,5-dichloro-2-methoxybenzyl)piperidine-2,4-diyl)dimethanol (0.15 g, 0.45 mmol) in DCM (1 mL) was added BBr (0.56 g, 2.24 mmol) at room temperature. After stirring at room temperature for 1 hour, the resulting mixture was quenched with saturated aqueous NaHCO (10 mL) at room temperature and extracted with a co-solvent of DCM / MeOH (10 / 1) (5 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: Water with 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 60% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 7.44 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 2 ((1-(4,5-dichloro-2-hydroxybenzyl)piperidine-2,4-diyl)dimethanol) as an off-white solid (26 mg, 18%): LCMS (ESI) C 14 H 19 Cl2NO3[M + H] + Calculated values: 320, 322 (3 : 2), measured values ​​320, 322 (3 : 2); 1H NMR (300 MHz, CD3OD) δ 7.15 (s, 1H), 6.85 (s, 1H), 4.44 (d, J = 14.4 Hz, 1H), 3.82 (dd, J = 11.9, 4.0 Hz, 1H), 3.61 (dd, J = 11.8, 3.7 Hz, 1H), 3.39 (d, J = 6.1 Hz, 2H), 3.22-3.20 (m, 1H), 3.01-2.88 (m, 1H), 2.48-2.25 (m, 1H), 2.24-2.04 (m, 1H), 1.84-1.51 (m, 3H), 1.37-1.04 (m, 2H).

[0284] Step b': To a mixture of methyl 4-(hydroxymethyl)piperidine-2-carboxylate (71 mg, 0.41 mmol) and K2CO3 (0.15 g, 1.11 mmol) in DMF (3 mL) was added 1-(bromomethyl)-4,5-dichloro-2-methoxybenzene (0.10 g, 0.37 mmol) at room temperature. The reaction mixture was stirred at 45 °C for 3 h. The resulting mixture was poured into water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA2 / 1) to give methyl 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(hydroxymethyl)piperidine-2-carboxylate as an off-white solid (89 mg, 66%): LCMS (ESI) C 16 H 21 Cl2NO4[M + H] + Calculated values: 362, 364 (3 : 2), measured values ​​362, 364 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 6.92 (s, 1H), 3.77 (d, J = 9.4 Hz, 6H), 3.64-3.45 (m, 4H), 3.12-3.02 (m, 1H), 2.14-1.98 (m, 2H), 1.74-1.43 (m, 5H).

[0285] Step c': To a stirred solution of methyl 1-(4,5-dichloro-2-methoxybenzyl)-4-(hydroxymethyl)piperidine-2-carboxylate (0.10 g, 0.29 mmol) in DCM (2 mL) was added dropwise BBr (0.43 g, 1.72 mol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. The resulting mixture was quenched with water (10 mL), and the pH was adjusted to 7 with saturated aqueous NaHCO solution. The aqueous layer was extracted with EA (3 × 20 mL). The combined organic layers were then washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water with 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 80% B in 9 min; detector: UV 254 / 210 nm; retention time: 8.14 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 1 (methyl 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-2-carboxylate) as an off-white solid (40 mg, 39%): LCMS (ESI) C 15 H 19 Cl2NO4[M + H] + Calculated values: 348, 350 (3 : 2), measured values ​​348, 350 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.34 (s, 1H), 6.98 (s, 1H), 4.04 (d, J = 13.2 Hz, 1H), 3.82 (s, 3H), 3.77-3.65 (m, 1H), 3.54-3.33 (m, 3H), 3.22-3.20 (m, 1H), 2.46 (s, 1H), 2.16 (d, J = 10.4 Hz, 1H), 1.80 (d, J = 10.4 Hz, 1H), 1.70 (s, 1H), 1.47-1.33 (m, 2H).

[0286] [Example 4] Compound 3 (2-((4-amino-4-(aminomethyl)piperidin-1-yl)methyl)-4,5-dichlorophenol)

[0287] [ka]

[0288] Step A: To a stirred solution of tert-butyl 4-amino-4-(aminomethyl)piperidine-1-carboxylate (0.20 g, 0.87 mmol) and EtN (0.44 g, 4.36 mmol) in DCM (4 mL) was added 2,2,2-trifluoroacetic anhydride (0.55 g, 2.62 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 40% ACN in water (+0.05% TFA) to give tert-butyl 4-(2,2,2-trifluoroacetamido)-4-[(2,2,2-trifluoroacetamido)methyl]piperidine-1-carboxylate as an off-white solid (0.32 g, 78%): LCMS (ESI) C 15 H 21 F6N3O4[M + H] + Calculated value: 422, measured value 422;1 H NMR (300 MHz, DMSO-d6) δ 9.47 (t, J = 6.3 Hz, 1H), 8.64 (s, 1H), 3.65 (d, J = 13.8 Hz, 2H), 3.46 (d, J = 6.2 Hz, 2H), 2.91-2.68 (m, 2H), 2.54-2.48 (m, 2H), 2.15 (d, J = 13.7 Hz, 2H), 1.35 (s, 9H); 19 F NMR (282 MHz, DMSO-d6) δ -73.75.

[0289] Step B: To a stirred solution of tert-butyl 4-(2,2,2-trifluoroacetamido)-4-[(2,2,2-trifluoroacetamido)methyl]piperidine-1-carboxylate (0.32 g, 0.76 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give 2,2,2-trifluoro-N-[[4-(2,2,2-trifluoroacetamido)piperidin-4-yl]methyl]acetamide as a colorless oil (0.12 g, crude): LCMS (ESI) C 10 H 13 F6N3O2[M + H] + Calculated value: 322, Measured value: 322.

[0290] Step C: To a stirred solution of 2,2,2-trifluoro-N-[[4-(trifluoroacetamido)piperidin-4-yl]methyl]acetamide (0.12 g, 0.38 mmol) and Intermediate 1 (87 mg, 0.46 mmol) in MeOH (2 mL) was added HOAc (25 mg, 0.42 mmol) and NaBH(OAc) (0.24 g, 1.14 mmol) at room temperature. After stirring at room temperature for 2 hours, the resulting mixture was quenched with water (10 mL) and extracted with EA (3 × 30 mL). The combined organic layer was then washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (3 / 1) to give N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(trifluoroacetamido)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide as a pale yellow solid (63 mg, 27%): LCMS (ESI) C 17 H 17 Cl2F6N3O3[M + H] + Calculated values: 496, 498 (3 : 2), measured values: 496, 498 (3 : 2); 1 H NMR (300 MHz, DMSO-d6) δ 9.45 (d, J = 5.9 Hz, 1H), 8.56 (s, 1H), 7.36 (s, 1H), 6.90 (s, 1H), 3.56 (s, 2H), 3.15 (s, 2H), 2.67-2.54 (m, 2H), 2.29-2.00 (m, 4H), 1.61-1.42 (m, 2H); 19 F NMR (282 MHz, DMSO-d6) δ-73.84, 74.00.

[0291] Step D: To a stirred solution of N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(trifluoroacetamido)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide (63 mg, 0.13 mmol) in MeOH (2 mL) at room temperature was added saturated aqueous NaOH (2 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was adjusted to pH 7 with aqueous HCl (1N) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column, 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water with 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 80% B in 9 min; detector: UV 254 / 210 nm; retention time: 7.74 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 3 (2-((4-amino-4-(aminomethyl)piperidin-1-yl)methyl)-4,5-dichlorophenol) as an off-white solid (25.8 mg, 50%): LCMS (ESI) C 13 H 19 Cl2N3O [M + H] + Calculated values: 304, 306 (3 : 2), measured values ​​304, 306 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.56 (s, 1H), 7.09 (s, 1H), 4.30 (s, 2H), 3.58-3.38 (m, 4H), 3.12-2.96 (m, 2H), 2.15-1.97 (m, 4H); 19 F NMR (376 MHz, CD3OD) δ -77.20.

[0292] [Example 5] Compound 4 (2-[2-amino-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]-4,5-dichlorophenol)

[0293] [ka]

[0294] Step A: To a stirred solution of ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetate (Example 15, Step D) (0.15 g, 0.40 mmol) in MeOH (1 mL) and HO (0.2 mL) at room temperature was added NaOH (32 mg, 0.80 mmol). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure to give sodium 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetate as a pale yellow solid (0.10 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 15 H 19 Cl2NO4[M + H] + Calculated values: 348, 350 (3:2), measured values: 348, 350 (3:2).

[0295] Step B: To a stirred solution of sodium 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetate (0.10 g, 0.29 mmol) in DMF (3 mL) was added HATU (49 mg, 0.57 mmol), NH4Cl (31 mg, 0.57 mmol), and Et3N (58 mg, 0.57 mmol) at room temperature. The reaction solution was stirred at room temperature for 16 hours. The resulting solution was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. 。 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 33% ACN in water (+0.05% TFA) to give 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetamide as an off-white solid (50 mg, 45%): LCMS (ESI) C 15 H 20 Cl2N2O3[M + H] +Calculated values: 347, 349 (3:2), measured values: 347, 349 (3:2).

[0296] Step C: To a stirred solution of 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetamide (0.13 g, 0.37 mmol) in THF (2 mL) under an argon atmosphere at 0 °C, BH3·THF (0.75 mL, 0.75 mmol, 1 M in THF) was added. The reaction solution was warmed to 70 °C and stirred for 3 h. After cooling to room temperature, the resulting solution was quenched with water (1 mL) at room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 37% ACN in water (+0.05% TFA) to afford [1-[2-amino-1-(4,5-dichloro-2-methoxyphenyl)ethyl]piperidin-4-yl]methanol as a colorless oil (70 mg, 47%): LCMS (ESI) C 15 H 22 Cl2N2O2[M + H] + Calculated values: 333, 335 (3 : 2), measured values: 333, 335 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.65 (s, 1H), 7.41 (s, 1H), 3.95 (s, 3H), 3.87-3.74 (m, 1H), 3.73-3.50 (m, 2H), 3.42 (d, J = 5.2 Hz, 2H), 2.93-2.75 (m, 1H), 2.71-2.65 (m, 1H), 1.98-1.87 (m, 2H), 1.74-1.43 (m, 3H), 1.33-1.18 (m, 1H), 1.01-0.79 (m, 1H).

[0297] Step D: To a stirred solution of [1-[2-amino-1-(4,5-dichloro-2-methoxyphenyl)ethyl]piperidin-4-yl]methanol (80 mg, 0.24 mmol) in DCM (3 mL) was added BBr3 (0.36 g, 1.44 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with water (1 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 65% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 6.67 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 4 (2-[2-amino-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]-4,5-dichlorophenol) as an off-white solid (14.1 mg, 17%): LCMS (ESI) C 14 H 20 Cl2N2O2[M + H] + Calculated values: 319, 321 (3 : 2), measured values ​​319, 321 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.23 (s, 1H), 6.92 (s, 1H), 3.71-3.66 (m, 1H), 3.45-3.38 (m, 2H), 3.24-3.14 (m, 2H), 3.07-2.92 (m, 2H), 2.23 (t, J = 11.5 Hz, 1H), 2.14-2.03 (m, 1H), 1.88-1.72 (m, 2H), 1.55-1.48 (m, 1H), 1.38-1.23 (m, 2H).

[0298] [Example 6] Compound 5 (2-[[4-(aminomethyl)-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol)

[0299] [ka]

[0300] Step A: To a stirred solution of N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide) (Compound 13, Example 13) (66 mg, 0.16 mmol) in MeOH (2 mL) at room temperature was added saturated aqueous NaOH (0.5 mL). The reaction solution was stirred at room temperature for 2 hours. The pH of the resulting solution was adjusted to 7 with aqueous HCl (1N) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column, 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.44 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 5 (2-[[4-(aminomethyl)-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol) as a pale yellow solid (38 mg, 67%): LCMS (ESI) C 14 H 20 Cl2N2O2[M + H] + Calculated values: 319, 321 (3 : 2), measured values ​​319, 321 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.19 (s, 1H), 6.86 (s, 1H), 3.71 (s, 2H), 3.53 (s, 2H), 2.72 (s, 2H), 2.65-2.56 (m, 4H), 1.59-1.50 (m, 4H).

[0301] [Example 7] Compound 6 (4,5-dichloro-2-[[4-(hydroxymethyl)-4-[(pyrrolidin-1-yl)carbonyl]piperidin-1-yl]methyl]phenol)

[0302] [ka]

[0303] Step A: To a solution of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (Example 25, step a) (0.20 g, 0.83 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. After stirring at room temperature for 1 hour, the resulting solution was concentrated under reduced pressure. The residue was diluted with water (10 mL), and the pH value was adjusted to 7 with saturated aqueous K2CO3 solution. The aqueous layer was extracted with DCM (10 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 4-(hydroxymethyl)piperidine-4-carbonitrile as a yellow oil (0.10 g, crude), which was used in the next step without further purification: LCMS (ESI) C7H 12 NO [M + H] + Calculated value: 141, Measured value: 141.

[0304] Step B: To a stirred solution of 4-(hydroxymethyl)piperidine-4-carbonitrile (0.20 g, 1.43 mmol) and Intermediate 1 (0.27 g, 1.43 mmol) in MeOH (3.5 mL) was added HOAc (85 mg, 1.43 mmol) and NaBH(OAc) (0.90 g, 4.28 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 3) to give 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carbonitrile as a yellow solid (0.20 g, 60%): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated values: 315, 317 (3 : 2), measured values ​​315, 317 (3 : 2); 1H NMR (300 MHz, CDCl3) δ 7.07 (s, 1H), 6.89 (s, 1H), 3.72 (s, 2H), 3.60 (s, 2H), 3.07-2.97 (m, 2H), 2.54-2.39 (m, 3H), 2.08-1.96 (m, 2H), 1.72-1.56 (m, 2H).

[0305] Step C: A solution of 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carbonitrile (0.15 g, 0.48 mmol) in aqueous HCl (3 mL, 12 N) was stirred at 80° C. for 2 hours. After cooling to room temperature, the resulting solution was concentrated under reduced pressure to give 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carboxylic acid as a pale yellow solid (0.12 g, crude), which was used in the next step without further purification: LCMS (ESI) C 14 H 17 Cl2NO4[M + H] + Calculated values: 334, 336 (3:2), measured values: 334, 336 (3:2).

[0306] Step D: To a stirred solution of 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carboxylic acid (0.12 g, 0.36 mmol) in DMF (3 mL) was added pyrrolidine (51 mg, 0.72 mmol), HATU (0.27 g, 0.72 mmol), and EtN (0.11 g, 1.08 mmol) at room temperature. The reaction solution was stirred at room temperature for 16 hours. The resulting solution was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH₄HCO₃, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.28 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 6 (4,5-dichloro-2-[[4-(hydroxymethyl)-4-[(pyrrolidin-1-yl)carbonyl]piperidin-1-yl]methyl]phenol) as an off-white solid (24.1 mg, 16%): LCMS (ESI) C 18 H 24 Cl2N2O3[M + H] + Calculated values: 387, 389 (3 : 2), measured values ​​387, 389 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.18 (s, 1H), 6.86 (s, 1H), 3.89-3.42 (m, 8H), 2.82-2.78 (m, 2H), 2.40-2.32 (m, 4H), 2.04-1.88 (m, 4H), 1.66-1.57 (t, J = 11.5 Hz, 2H).

[0307] [Example 8] Compound 7 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)prop-2-enamide)

[0308] [ka]

[0309] Step A: To a stirred solution of 2-[[4-(aminomethyl)-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol (38 mg, 0.12 mmol) and EtN (18 mg, 0.18 mmol) in DCM (2 mL) was added prop-2-enoyl chloride (11 mg, 0.12 mmol) at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 1.5 hours. The resulting solution was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water with 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 80% B in 9 min; detector: UV 254 / 210 nm; retention time: 7.84 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 7 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)prop-2-enamide) as an off-white solid (8.6 mg, 19%): LCMS (ESI) C 17 H 22 Cl2N2O3[M + H] + Calculated values: 373, 375 (3 : 2), measured values: 373, 375 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.19 (s, 1H), 6.86 (s, 1H), 6.33-6.24 (m, 2H), 5.71-5.63 (m, 1H), 3.73 (s, 2H), 3.32 (s, 4H), 2.62-2.58 (m, 4H), 1.60-1.49 (m, 4H).

[0310] [Example 9] Compound 8 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)acetamide)

[0311] [ka]

[0312] Step A: To a mixture of 4-(aminomethyl)-1-[(4,5-dichloro-2-hydroxyphenyl)methyl]piperidin-4-ol (0.19 g, 0.62 mmol) and NaOH (49 mg, 1.24 mmol) in EtOH (4 mL) was added acetic anhydride (65 mg, 0.63 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 38% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 7.85 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 8 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)acetamide) as an off-white solid (60 mg, 27%): LCMS (ESI) C 15 H 20 Cl2N2O3[M + H] + Calculated values: 347, 349 (3 : 2), measured values: 347, 349 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.22 (s, 1H), 6.88 (s, 1H), 3.74 (s, 2H), 3.24 (s, 2H), 2.74 (d, J = 11.7 Hz, 2H), 2.58 (t, J = 10.8 Hz, 2H), 2.00 (s, 3H), 1.71-157 (m, 4H).

[0313] [Example 10] Compound 9 (4-(aminomethyl)-1-[(4,5-dichloro-2-hydroxyphenyl)methyl]piperidin-4-ol trifluoroacetic acid)

[0314] [ka]

[0315] Step A: To a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (2.00 g, 8.68 mmol) in DCM (20 mL) was added trifluoroacetyl 2,2,2-trifluoroacetate (1.83 g, 8.71 mmol) and EtN (1.32 g, 13.04 mmol) dropwise at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting solution was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO (2 × 50 mL). The organic phase was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 4-hydroxy-4-[(trifluoroacetamido)methyl]piperidine-1-carboxylate as a pale yellow solid (2.65 g, crude): LCMS (ESI) C 13 H 21 F3N2O4[M + H] + Calculated value: 327, measured value 327; 1 H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 4.67 (s, 1H), 3.70-3.61 (m, 2H), 3.18 (d, J = 6.2 Hz, 2H), 3.03 (s, 2H), 1.38 (s, 13H).

[0316] Step B: A solution of tert-butyl 4-hydroxy-4-[(trifluoroacetamido)methyl]piperidine-1-carboxylate (1.30 g, 3.98 mmol) in DCM (6 mL) and TFA (3 mL) was stirred at room temperature for 1 h. The resulting solution was diluted with water (20 mL) at room temperature and basified to pH 7-8 with saturated aqueous NaHCO3. The resulting solution was concentrated under reduced pressure to give the crude product. The crude product was triturated with MeOH (50 mL). The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to give 2,2,2-trifluoro-N-[(4-hydroxypiperidin-4-yl)methyl]acetamide as a colorless oil (1.40 g, crude): LCMS (ESI) CH 13 F3N2O2[M + H] + Calculated value: 227, Measured value: 227.

[0317] Step C: To a solution of 2,2,2-trifluoro-N-[(4-hydroxypiperidin-4-yl)methyl]acetamide (0.27 g, 1.19 mmol), HOAc (72 mg, 1.20 mmol), and Intermediate 1 (0.23 g, 1.21 mmol) in MeOH (10 mL) was added NaBH(OAc) (0.76 g, 3.52 mmol) at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting solution was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20 / 1) to give N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)-2,2,2-trifluoroacetamide as a yellow semi-solid (0.10 g, 22%): LCMS (ESI) C 15 H 17 Cl2F3N2O3[M + H] + Calculated values: 401, 403 (3 : 2), measured values: 401, 403 (3 : 2); 1H NMR (300 MHz, CD3OD) δ 7.37 (s, 1H), 6.96 (s, 1H), 3.99 (s, 2H), 3.28 (d, J = 1.6 Hz, 2H), 3.13-2.87 (m, 4H), 1.89-1.61 (m, 4H).

[0318] Step D: To a solution of N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)-2,2,2-trifluoroacetamide (0.10 g, 0.25 mmol) in EtOH (2 mL) and water (1 mL) at room temperature was added NaOH (0.10 g, 2.50 mmol). After stirring at room temperature for 2 hours, the resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 60% B in 8 min; Detector: 210 / 254 nm; Retention time: 6 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 9 (4-(aminomethyl)-1-[(4,5-dichloro-2-hydroxyphenyl)methyl]piperidin-4-ol trifluoroacetate) as a purple solid (17 mg, 16%): LCMS (ESI) C 13 H 18 Cl2N2O2[M + H] + Calculated values: 305, 307 (3 : 2), measured values: 305, 307 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 1H), 7.10 (s, 1H), 4.35 (s, 2H), 3.42 (d, J = 15.6 Hz, 4H), 3.00 (s, 2H), 1.93 (s, 4H); 19 F NMR (376 MHz, CD3OD) δ -76.98.

[0319] [Example 11] Compound 11 (4,5-dichloro-2-(((2R,4R)-rel-4-(hydroxymethyl)-2-phenylpiperidin-1-yl)methyl)phenol) and Compound 10 (4,5-dichloro-2-(((2S,4R)-rel-4-(hydroxymethyl)-2-phenylpiperidin-1-yl)methyl)phenol)

[0320] [ka]

[0321] Step A: To a mixture of 2-phenylpiperidin-4-one (0.49 g, 2.78 mmol) and K2CO3 (0.51 g, 3.70 mmol) in DMF (8 mL) was added intermediate 2 (0.50 g, 1.85 mmol) at room temperature. The reaction mixture was warmed to 40 °C and stirred for 16 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (4 / 1) to give 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidin-4-one as a colorless oil (0.40 g, 59%): LCMS (ESI) C 19 H 19 Cl2NO2[M + H] + Calculated values: 364, 366 (3 : 2), measured values: 364, 366 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.45-7.29 (m, 5H), 6.87 (s, 1H), 3.75 (s, 3H), 3.65 (dd, J = 10.9, 3.8 Hz, 1H), 3.52 (d, J = 14.9 Hz, 1H), 3.20 (d, J = 14.8 Hz, 2H), 2.78-2.61 (m, 2H), 2.55 (d, J = 14.5 Hz, 1H), 2.46-2.31 (m, 2H).

[0322] Step B: To a mixture of methoxymethyltriphenylphosphonium chloride (1.08 g, 3.29 mmol) in THF (15 mL, 185.14 mmol) was added t-BuOK (0.37 g, 3.29 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Then, a solution of 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidin-4-one (0.40 g, 1.10 mmol) in THF (2 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (5 / 1) to give (4E)-1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(methoxymethylidene)-2-phenylpiperidine as an off-white solid (0.40 g, 92%): LCMS (ESI) C 21 H 23 Cl2NO2[M + H] + Calculated values: 392, 394 (3:2), measured values: 392, 394 (3:2).

[0323] Step C: To a solution of (4E)-1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(methoxymethylidene)-2-phenylpiperidine (0.40 g, 1.02 mmol) in THF (4 mL) was added aqueous HCl (1 mL, 6N) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was neutralized to pH 7 with saturated aqueous NaHCO3 and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidine-4-carbaldehyde as a yellow oil (0.35 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C20 H 21 Cl2NO2[M + H] + Calculated values: 378, 380 (3:2), measured values: 378, 380 (3:2).

[0324] Step D: To a solution of 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidine-4-carbaldehyde (0.35 g, 0.93 mmol) in MeOH (2 mL) in THF (5 mL) was added NaBH (70 mg, 1.85 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (30 mL) and extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (1-(4,5-dichloro-2-methoxybenzyl)-2-phenylpiperidin-4-yl)methanol as a yellow oil (0.28 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 20 H 23 Cl2NO2[M + H] + Calculated values: 380, 382 (3:2), measured values: 380, 382 (3:2).

[0325] Step E: To a solution of [1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidin-4-yl]methanol (0.19 g, 0.50 mmol) in DCM (1 mL) was added BBr3 (1.00 g, 4.00 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and neutralized to pH > 7 with saturated aqueous NaHCO3. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Xbridge C 18OBD Prep column 100Å, 10 μm, 19 mm × 250 mm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 ml / min; gradient: 20% B to 70% B in 9 min; detector: UV 254 / 210 nm; retention times: 7.44 min and 7.68 min.

[0326] The faster eluting isomer was obtained as compound 11 (4,5-dichloro-2-(((2R,4R)-rel-4-(hydroxymethyl)-2-phenylpiperidin-1-yl)methyl)phenol) as an off-white solid (3.0 mg, 2%): LCMS (ESI) C 19 H 21 Cl2NO2[M + H] + Calculated values: 366, 368 (3 : 2), measured values ​​366, 368 (3 : 2); 1 H NMR (300 MHz, DMSO-d6) δ 7.39-7.31 (m, 5H), 7.26-7.21 (m, 1H), 6.90 (s, 1H), 4.53 (s, 1H), 3.55-3.32 (m, 4H), 3.21-3.16 (m, 1H), 2.73-2.65 (m, 1H), 2.30-2.26 (m, 1H), 1.91-1.76 (m, 5H).

[0327] The slower eluting isomer was obtained as compound 10 (4,5-dichloro-2-(((2S,4R)-rel-4-(hydroxymethyl)-2-phenylpiperidin-1-yl)methyl)phenol) as an off-white solid (16.9 mg, 9%): LCMS (ESI) C 19 H 21 Cl2NO2[M + H] + Calculated values: 366, 368 (3 : 2), measured values ​​366, 368 (3 : 2); 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.31 (m, 5H), 7.26-7.21 (m, 1H), 6.90 (s, 1H), 4.46 (s, 1H), 3.46 (d, J = 15.0 Hz, 1H), 3.41-3.20 (m, 3H), 3.10 (d, J = 15.0 Hz, 1H), 2.95 (d, J = 11.4 Hz, 1H), 2.13-2.01 (m, 1H), 1.80-1.50 (m, 3H), 1.38-1.20 (m, 2H).

[0328] [Example 12] Compound 12 (N-[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]acetamide)

[0329] [ka]

[0330] Step A: To a stirred solution of 2-((4-amino-4-(hydroxymethyl)piperidin-1-yl)methyl)-4,5-dichlorophenol (Compound 14, Example 14) (0.12 g, 0.30 mmol) in DCM (5 mL) was added AcO (91 mg, 0.89 mmol) at room temperature. The reaction solution was stirred at room temperature for 3 hours. NaOH (0.10 g, 2.50 mmol) and HO (1 mL) were then added to the reaction solution. The resulting mixture was stirred at room temperature for an additional 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 50% B in 16 min; Detector: UV 254 / 210 nm; Retention time: 9.65 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 12 (N-[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]acetamide) as an off-white solid (49.1 mg, 48%): LCMS (ESI) C 15 H 20 Cl2N2O3[M + H] + Calculated values: 347, 349 (3 : 2), measured values: 347, 349 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.19 (s, 1H), 6.86 (s, 1H), 3.67 (d, J = 9.4 Hz, 4H), 2.74 (d, J = 12.0 Hz, 2H), 2.39 (t, J = 11.3 Hz, 2H), 2.20 (d, J = 14.2 Hz, 2H), 1.96 (s, 3H), 1.73-1.57 (m, 2H).

[0331] [Example 13] Compound 13 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide)

[0332] [ka]

[0333] Step A: To a stirred solution of tert-butyl 4-(aminomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.20 g, 0.82 mmol) and 2,2,2-trifluoroacetic anhydride (0.17 g, 0.82 mmol) in DCM (2 mL) was added EtN (0.25 g, 2.46 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give tert-butyl 4-(hydroxymethyl)-4-((2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate as a yellow oil (0.2 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 14 H 23 F3N2O4[M + H] + Calculated value: 341, Measured value: 341.

[0334] Step B: To a stirred solution of tert-butyl 4-(hydroxymethyl)-4-((2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate (0.20 g, 0.58 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give 2,2,2-trifluoro-N-((4-(hydroxymethyl)piperidin-4-yl)methyl)acetamide as a yellow oil (0.2 g, crude), which was used directly in the next step without further purification: LCMS (ESI) CH 15 F3N2O2[M + H] + Calculated value: 241, Measured value: 241.

[0335] Step C: To a stirred solution of 2,2,2-trifluoro-N-[[4-(hydroxymethyl)piperidin-4-yl]methyl]acetamide (0.11 g, 0.45 mmol) and Intermediate 1 (86 mg, 0.45 mmol) in MeOH (1 mL) was added HOAc (3 mg, 0.04 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 hour. To the stirred solution, NaBH(OAc) (0.29 g, 1.35 mmol) was added at room temperature under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL) at room temperature and extracted with EA (5 × 30 mL). The combined organic layers were washed with brine (2 × 25 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: 20 mmol / L NH4HCO3 in water, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B to 90% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.10 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 13 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide) as an off-white solid (82 mg, 43%): LCMS (ESI) C 16 H 19 Cl2F3N2O3[M + H] + Calculated values: 415, 417 (3 : 2), measured values: 415, 417 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.39 (s, 1H), 6.98 (s, 1H), 4.70 (br, 1H), 3.72 (s, 2H), 3.30 (s, 2H), 3.25 (d, J = 6.0 Hz, 2H), 2. 28-2.50 (m, 4H), 1.61-1.55 (m, 2H), 1.47-1.30 (m, 2H).

[0336] [Example 14] Compound 14 (2-[[4-amino-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol)

[0337] [ka]

[0338] Step A: To a stirred solution of Intermediate 1 (0.23 g, 1.20 mmol), HOAc (60 mg, 1.00 mmol), and tert-butyl-N-[4-(hydroxymethyl)piperidin-4-yl]carbamate (0.29 g, 1.00 mmol) in MeOH (5 mL) was added NaBH(OAc) (0.64 g, 3.00 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes and then quenched with water (5 mL). The mixture was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with water (3 × 20 mL). The organic phase was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give tert-butyl-N-[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]carbamate as a yellow oil (0.10 g, 25%): LCMS (ESI) C 18 H 26 Cl2N2O4[M + H] + Calculated value of: 405, 407 (3 : 2), Actual values ​​405, 407 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.23 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 1.9 Hz, 1H), 3.74 (s, 2H), 3.61 (s, 2H), 2.80 (d, J = 11.8 Hz, 2H), 2.45 (t, J = 11.8 Hz, 2H), 2.12 (d, J = 13.9 Hz, 2H), 1.73-1.62 (m, 2H), 1.45 (s, 9H).

[0339] Step B: To a stirred solution of tert-butyl-N-[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]carbamate (0.10 g, 0.25 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 70% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 7.41 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 14 (2-[[4-amino-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol) as an off-white solid (29.3 mg, 39%): LCMS (ESI) C 13 H 18 Cl2N2O2[M + H] + Calculated value of: 305, 307 (3 : 2), Actual values ​​305, 307 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.18 (s, 1H), 6.85 (s, 1H), 3.72 (s, 2H), 3.38 (s, 2H), 2.68-2.55 (m, 4H), 1.71-1.65 (m, 2H), 1.57-1.47 (m, 2H).

[0340] [Example 15] Compound 15 (4,5-dichloro-2-[2-hydroxy-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol)

[0341] [ka]

[0342] Step A: To a stirred solution of 3,4-dichlorophenol (1.00 g, 6.13 mmol) in DCM (10 mL) was added TiCl (1.20 g, 6.33 mmol) dropwise under an argon atmosphere at −30°C. After stirring at −30°C for 30 min, a solution of ethyl 2-oxoacetate (1.50 g, 7.35 mmol, 50% in toluene) in DCM (5 mL) was added dropwise to the mixture. After the addition, the resulting mixture was warmed to room temperature and stirred for an additional 16 h under an argon atmosphere. The resulting solution was quenched with saturated aqueous NH Cl (2 mL) at room temperature and diluted with a cosolvent of EA (50 mL) and water (50 mL). The isolated aqueous solution was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na SO , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / EA (6 / 1) to give ethyl 2-(4,5-dichloro-2-hydroxyphenyl)-2-hydroxyacetate as a pale yellow semi-solid (0.60 g, 31%): LCMS (ESI) C 10 H 10 Cl2O4[M - 1] + Calculated values ​​263, 265 (3 : 2), measured values ​​263, 265 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.43 (s, 1H), 6.99 (s, 1H), 6.13 (d, J = 8.0 Hz, 1H), 5.22 (s, 1H), 4.16-4.00 (m, 2H), 1.22-1.09 (m, 3H).

[0343] Step B: To a stirred solution of ethyl 2-(4,5-dichloro-2-hydroxyphenyl)-2-hydroxyacetate (0.20 g, 0.75 mmol) in DMF (2 mL) was added K2CO3 (0.21 g, 1.51 mmol) and MeI (0.32 g, 2.26 mmol) at room temperature. The reaction mixture was warmed to 40 °C and stirred for 1 h. The resulting mixture was diluted with EA (20 mL) and water (20 mL). The isolated aqueous layer was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (5 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-hydroxyacetate as a colorless oil (0.15 g, 64%): 1 H NMR (300 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.29 (s, 1H), 6.22 (d, J = 6.2 Hz, 1H), 5.21 (d, J = 5.9 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H).

[0344] Step C: To a stirred solution of ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-hydroxyacetate (0.16 g, 0.57 mmol) in DCM (2 mL) was added PBr (0.62 g, 2.29 mmol) dropwise at room temperature. The reaction solution was stirred at room temperature for 3 hours. The resulting solution was quenched with water (20 mL) at room temperature and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (5 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (9 / 1) to give ethyl 2-bromo-2-(4,5-dichloro-2-methoxyphenyl)acetate as a pale yellow oil (0.15 g, 65%): 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.11 (s, 1H), 5.70 (s, 1H), 4.25 (q, J = 7.5 Hz, 2H), 3.85 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0345] Step D: To a stirred solution of ethyl 2-bromo-2-(4,5-dichloro-2-methoxyphenyl)acetate (0.15 g, 0.44 mmol) in DMF (2 mL) was added piperidin-4-ylmethanol (76 mg, 0.66 mmol) and K2CO3 (0.12 g, 0.88 mmol) at room temperature. The reaction mixture was warmed to 40 °C and stirred for 2 h. The resulting mixture was diluted with a cosolvent of EA (20 mL) and water (20 mL). The isolated aqueous layer was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (5 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetate as a pale yellow oil (0.15 g, crude): LCMS (ESI) C 17 H 23 Cl2NO4[M + H] + Calculated values: 376, 378 (3 : 2), measured values ​​376, 378 (3 : 2); 1 H NMR (300 MHz, CDCl3) 7.59 (s, 1H), 6.95 (s, 1H), 4.52 (s, 1H), 4.18 (q, J = 9.0, 2H), 3.81 (s, 3H), 3.52 (d, J = 7.1 Hz, 2H), 3.10-2.98 (m, 2H), 2.37-2.02 (m, 2H), 1.81-1.61 (m, 2H) 1.60-1.40 (m, 3H), 1.24 (q, J = 7.2 Hz, 3H).

[0346] Step E: To a stirred solution of ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetate (0.14 g, 0.37 mmol) in THF (2 mL) was added DIBAL-H (2.2 mL, 2.21 mmol, 1 M in toluene) at 0° C. under an argon atmosphere. The reaction solution was stirred at 0° C. under an argon atmosphere for 1 h. The resulting solution was quenched with water (20 mL) at 0° C. and extracted with EA (3×20 mL). The combined organic layers were washed with brine (3×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]ethan-1-ol as a pale yellow oil (0.10 g, crude), which was used in the next step without further purification: LCMS (ESI) C 15 H 21 Cl2NO3[M + H] + Calculated values: 334, 335 (3:2), measured values: 334, 335 (3:2).

[0347] Step F: To a stirred solution of 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]ethan-1-ol (0.10 g, 0.30 mmol) in DCM (2 mL) was added BBr (0.34 g, 1.35 mmol) at room temperature. The reaction solution was stirred at room temperature for 5 hours. The resulting mixture was quenched with water (1 mL) at 0 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 90% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 6.55 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 15 (4,5-dichloro-2-[2-hydroxy-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol) as an off-white solid (20 mg, 20%): LCMS (ESI) C 14 H 19 Cl2NO3[M + H] + Calculated values: 320, 322 (3 : 2), measured values ​​320, 322 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.24 (s, 1H), 6.86 (s, 1H), 4.00-3.87 (m, 2H), 3.63 (t, J = 4.8 Hz, 1H), 3.43 (d, J = 6.3 Hz, 2H), 3.33-3.28 (m, 1H), 3.07-2.98 (m, 1H), 2.40 -2.29 (m, 2H), 1.92-1.76 (m, 2H), 1.57 (s, 1H), 1.40-1.23 (m, 2H).

[0348] [Example 16] Compound 16 (2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dimethylphenol)

[0349] [ka]

[0350] Step A: To a stirred solution of 2-hydroxy-4,5-dimethylbenzaldehyde (0.10 g, 0.67 mmol) and piperidin-4-ylmethanol (77 mg, 0.67 mmol) in MeOH (3 mL) was added HOAc (40 mg, 0.67 mmol) and NaBH(OAc) (0.42 g, 2.00 mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 2 hours under a nitrogen atmosphere, the resulting mixture was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: 20 mmol / L NH4HCO3 in water, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 55% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.15 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 16 (2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dimethylphenol) as an off-white solid (25 mg, 15%): LCMS (ESI) C 15 H 23 NO2[M + H] + Calculated value: 250, measured value 250; 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (br, 1H), 6.78 (s, 1H), 6.51 (s, 1H), 4.44 (br, 1H), 3.55 (s, 2H), 3.26 (d, J = 6.2 Hz, 2H), 2.88 (d, J = 11.7, 2H), 2.10 (d, J = 11.5 Hz, 6H), 1.99 (td, J = 11.6, 2.5 Hz, 2H), 1.73-1.63 (m, 2H), 1.45-1.35 (m, 1H), 1.21-1.05 (m, 2H).

[0351] [Example 17] Compound 17 (5-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4-methylphenol)

[0352] [ka]

[0353] Step A: To a stirred solution of 5-bromo-4-chloro-2-hydroxybenzoic acid (0.50 g, 1.99 mmol) in THF (10 mL) was added BH (6 mL, 6.00 mmol, 1 M in THF) dropwise at 0 °C under a nitrogen atmosphere. The reaction solution was then warmed to room temperature and stirred under a nitrogen atmosphere for 1 h. The resulting solution was quenched with water (30 mL) at 0 °C and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 4-bromo-5-chloro-2-(hydroxymethyl)phenol as an off-white solid (0.33 g, 69%): LCMS (ESI) C7H6BrClO2[M - H] + Calculated values: 235, 237, 239 (2 : 3 : 1), measured values: 235, 237, 239 (2 : 3 : 1); 1 H NMR (300 MHz, CDCl3) δ 7.34 (s, 1H), 6.89 (s, 1H), 4.69 (s, 2H).

[0354] Step B: To a stirred mixture of 4-bromo-5-chloro-2-(hydroxymethyl)phenol (0.33 g, 1.41 mmol) and K2CO3 (0.39 g, 2.81 mmol) in DMF (3.5 mL) was added dropwise MeI (0.60 g, 4.22 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (15 / 1) to give (5-bromo-4-chloro-2-methoxyphenyl)methanol as an off-white solid (0.20 g, 56%): 1 H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 6.99 (s, 1H), 4.66 (s, 2H), 3.90 (s, 3H).

[0355] Step C: To a stirred solution of (5-bromo-4-chloro-2-methoxyphenyl)methanol (0.20 g, 0.79 mmol) in DCM (3.5 mL) was added PBr (0.43 g, 1.58 mmol) under a nitrogen atmosphere at 25 °C. After stirring at 25 °C for 1 h, the resulting solution was quenched with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 1-bromo-5-(bromomethyl)-2-chloro-4-methoxybenzene as an off-white solid (0.20 g, 80%), which was used directly in the next step without further purification: 1 H NMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 6.97 (s, 1H), 5.06 (s, 2H), 3.90 (s, 3H).

[0356] Step D: To a mixture of 1-bromo-5-(bromomethyl)-2-chloro-4-methoxybenzene (0.20 g, 0.76 mmol) and K2CO3 (0.21 g, 1.51 mmol) in DMF (2.5 mL) was added piperidin-4-ylmethanol (0.13 g, 1.13 mmol) at room temperature. The reaction mixture was warmed to 40 °C and stirred for 1.5 h. After cooling to room temperature, the resulting mixture was diluted with water (20 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (15 / 1) to give [1-[(5-bromo-4-chloro-2-methoxyphenyl)methyl]piperidin-4-yl]methanol as an off-white solid (0.13 g, 49%): LCMS (ESI) C 14 H 19 BrClNO2[M + H] + Calculated values: 348, 350, 352 (2:3:1), measured values: 348, 350, 352 (2:3:1).

[0357] Step E: To a mixture of [1-[(5-bromo-4-chloro-2-methoxyphenyl)methyl]piperidin-4-yl]methanol (0.13 g, 0.37 mmol), methylboronic acid (66 mg, 1.11 mmol), and KCO (0.23 g, 1.67 mmol) in 1,4-dioxane (4 mL) and HO (1 mL) was added Pd(dppf)Cl (54 mg, 0.07 mmol) at room temperature. The reaction mixture was degassed with nitrogen three times. The reaction mixture was then warmed to 80 °C and stirred under a nitrogen atmosphere for 2.5 h. After cooling to room temperature, the resulting mixture was quenched with water (20 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give [1-[(4-chloro-2-methoxy-5-methylphenyl)methyl]piperidin-4-yl]methanol as a brown solid (72 mg, 68%): LCMS (ESI) C 15 H 22 ClNO2[M + H] + Calculated values: 284, 286 (3 : 1), measured values: 284, 286 (3 : 1); 1 H NMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 6.91 (s, 1H), 4.07 (s, 2H), 3.79 (s, 3H), 3.55-3.49 (m, 3H), 3.31 (s, 2H), 2.49 (s, 1 H), 2.30 (s, 3H), 1.85-1.23 (m, 5H).

[0358] Step F: To a stirred solution of [1-[(4-chloro-2-methoxy-5-methylphenyl)methyl]piperidin-4-yl]methanol (72 mg, 0.25 mmol) in DCM (2.5 mL) was added BBr3 (0.25 g, 1.01 mmol) at room temperature. After stirring at room temperature for 2.5 h, the resulting mixture was quenched with water (8 mL) at room temperature, and the pH value was adjusted to 7 with saturated aqueous NaHCO3. The aqueous layer was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH₄HCO₃, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B to 90% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.17 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 17 (5-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4-methylphenol) as an off-white solid (16 mg, 23%): LCMS (ESI) C 14 H 20 ClNO2[M + H] + Calculated values: 270, 272 (3 : 1), measured values: 270, 272 (3 : 1); 1 H NMR (300 MHz, CD3OD) δ 6.93 (s, 1H), 6.73 (s, 1H), 3.69 (s, 2H), 3.42 (d, J = 6.3 Hz, 2H), 3.04 (d, J = 11.4 Hz, 2H), 2.23 (s, 3H), 2.21-2.15 (m, 2H), 1.82 (d, J = 13.2 Hz, 2H), 1.60-1.49 (m, 1H), 1.35-1.22 (m, 2H).

[0359] [Example 18] Compound 18 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]propyl]phenol)

[0360] [ka]

[0361] Step A: To a stirred solution of intermediate 1 (0.15 g, 0.79 mmol) in THF (3 mL) was added bromo(ethyl)magnesium (0.6 mL, 1.74 mmol, 3 M in ether) at room temperature under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 2 h, the resulting solution was quenched with water (30 mL) at 0 °C and extracted with EA (3 × 35 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 2-(1-bromopropyl)-4,5-dichlorophenol as an off-white solid (72 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) CH 10 Cl2O2[M - H] + Calculated values: 219, 221 (3:2), measured values: 219, 221 (3:2).

[0362] Step B: To a stirred solution of 4,5-dichloro-2-(1-hydroxypropyl)phenol (0.20 g, 0.90 mmol) in DCM (3 mL) was added PBr (0.49 g, 1.81 mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 2 hours, the resulting solution was quenched with water (30 mL) and extracted with EA (3 × 45 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18OBD Prep column, 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH₄HCO₃, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 7.50 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 2-(1-bromopropyl)-4,5-dichlorophenol as an off-white solid (70 mg, 32% over two steps): LCMS (ESI) C₈H₈BrCl₂O [M - H] + Calculated values: 281, 283, 285 (2:3:1), measured values: 281, 283, 285 (2:3:1).

[0363] Step C: To a stirred solution of 2-(1-bromopropyl)-4,5-dichlorophenol (70 mg, 0.25 mmol) and K2CO3 (69 mg, 0.49 mmol) in DMF (3 mL) was added piperidin-4-ylmethanol (28 mg, 0.25 mmol) at room temperature. After stirring at room temperature for 2 hours, the resulting mixture was diluted with water (20 mL) and extracted with EA (5 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 7.54 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 18 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]propyl]phenol) as an off-white solid (18 mg, 21%): LCMS (ESI) C 15 H 21 Cl2NO2[M + H] + Calculated values: 318, 320 (3 : 2), measured values ​​318, 320 (3 : 2); 1H NMR (300 MHz, DMSO-d6) δ 7.24 (s, 1H), 6.90 (s, 1H), 3.60-3.52 (m, 1H), 3.21 (d, J = 6.1 Hz, 2H), 3.06 (d, J = 11.5 Hz, 1H), 2.84 (d, J = 11.5 Hz, 1H), 2.09-1.89 (m, 2H), 1.89-1.52 (m, 4H), 1.43-1.34 (m, 1H), 1.26-1.01 (m, 2H), 0.68 (t, J = 7.3 Hz, 3H).

[0364] [Example 19] Compound 19 (4-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-5-methylphenol)

[0365] [ka]

[0366] Step A: To a stirred solution of methyl 5-chloro-2-hydroxy-4-methylbenzoate (0.50 g, 2.49 mmol) in THF (15 mL) was added dropwise DIBAL-H (12.5 mL, 12.46 mmol, 1 M in toluene) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred under a nitrogen atmosphere at 0 °C for 2 h. The reaction mixture was quenched with water (50 mL) at 0 °C and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 4-chloro-2-(hydroxymethyl)-5-methylphenol as an off-white solid (0.35 g, 67%): LCMS (ESI) C8H9ClO2[M - 1] - Calculated values: 171, 173 (3 : 1), measured values: 171, 173 (3 : 1); 1H NMR (300 MHz, CDCl3) δ 7.00 (s, 1H), 6.77 (s, 1H), 4.81 (s, 2H), 2.31 (s, 3H).

[0367] Step B: To a stirred solution of 4-chloro-2-(hydroxymethyl)-5-methylphenol (0.35 g, 2.03 mmol) in DCM (10 mL) was added PBr (1.10 g, 4.06 mmol) dropwise under nitrogen at 0 °C. After stirring at 0 °C for 2 h under nitrogen at 0 °C, the resulting solution was quenched with water (30 mL) at 0 °C and extracted with EA (3 × 70 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 2-(bromomethyl)-4-chloro-5-methylphenol as a yellow oil (0.35 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C8H8BrClO [M - H] + Calculated values: 233, 235, 237 (2:3:1), measured values: 233, 235, 237 (2:3:1).

[0368] Step C: To a stirred mixture of 2-(bromomethyl)-4-chloro-5-methylphenol (0.35 g, 1.49 mmol) and K2CO3 (0.41 g, 2.97 mmol) in ACN (15 mL) was added piperidin-4-ylmethanol (0.26 g, 2.23 mmol) at room temperature. The reaction mixture was warmed to 40 °C and stirred for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 60% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.50 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 19 (4-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-5-methylphenol) as an off-white solid (25 mg, 6% overall for 2 steps): LCMS (ESI) C 14 H 20 ClNO2[M + H] + Calculated values: 270, 272 (3 : 1), measured values: 270, 272 (3 : 1); 1 H NMR (300 MHz, DMSO-d6) δ 7.06 (s, 1H), 6.67 (s, 1H), 3.56 (s, 2H), 3.23 (d, J = 6.2 Hz, 2H), 2.84 (d, J = 11.2 Hz, 2H), 2.19 (s, 3H), 2.00 (m, J = 11.2, 2.4 Hz, 2H), 1.65 (d, J = 13.0 Hz, 2H), 1.35 (d, J = 11.2 Hz, 1H), 1.22-0.98 (m, 2H).

[0369] [Example 20] Compound 21 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)acetamide)

[0370] [ka]

[0371] Step A: To a stirred solution of tert-butyl 4-(aminomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.20 g, 0.82 mmol) and EtN (0.25 g, 2.46 mmol) in DCM (1 mL) was added acetic anhydride (84 mg, 0.82 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give tert-butyl 4-(acetamidomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.30 g, crude), which was used in the next step without further purification: LCMS (ESI) C 14 H 26 N2O4[M + H] + Calculated value: 287, Measured value: 287.

[0372] Step B: To a stirred solution of tert-butyl 4-(acetamidomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.30 g, 1.05 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. The reaction solution was stirred at room temperature for 30 minutes. The resulting solution was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and neutralized to pH 8 with saturated aqueous NaHCO3. The aqueous layer was extracted with EA (10 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give N-((4-(hydroxymethyl)piperidin-4-yl)methyl)acetamide (0.12 g, crude), which was used in the next step without further purification: LCMS (ESI) C9H 18 N2O2[M + H] + Calculated value: 187, Measured value: 187.

[0373] Step C: To a stirred solution of N-[[4-(hydroxymethyl)piperidin-4-yl]methyl]acetamide (0.12 g, 0.58 mmol) and Intermediate 1 (0.11 g, 0.58 mmol) in MeOH (1 mL) was added HOAc (35 mg, 0.6 mmol) and NaBH(OAc)3 at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting solution was quenched with water (5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm × 250 mm; Mobile Phase A: 20 mmol / L NH4HCO3 in water, Mobile Phase B: ACN; Flow Rate: 20 mL / min; Gradient: 30% B to 80% B in 9 min; Detector: UV 254 / 210 nm; Retention Time: 8.14 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 21 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)acetamide) as an off-white solid (97 mg, 46%): LCMS (ESI) C 16 H 22 Cl2N2O3[M + H] + Calculated values: 361, 363 (3 : 2), measured values ​​361, 363 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 7.89-7.76 (m, 1H), 7.34 (s, 1H), 6.95 (s, 1H), 4.94-4.29 (m, 1H).3.64 (s, 2H), 3.07 (d, J = 6.3 Hz, 2H), 2.49-2.40 (m, 4H), 1.86 (s, 3H), 1.47-1.26 (m, 4H).

[0374] [Example 21] Compound 23 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]-3-methylbutyl]phenol)

[0375] [ka]

[0376] Step A: To a stirred solution of intermediate 1 (0.10 g, 0.52 mmol) in THF (2 mL) was added bromo(2-methylpropyl)magnesium (0.6 mL, 1.14 mmol, 2 M in ether) at room temperature under a nitrogen atmosphere. After stirring for 1 h, the resulting solution was quenched with water (20 mL) and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 4,5-dichloro-2-(1-hydroxy-3-methylbutyl)phenol as a yellow oil (0.14 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 11 H 14 Cl2O2[M - H] + Calculated values: 247, 249 (3:2), measured values: 247, 249 (3:2).

[0377] Step B: To a stirred solution of 4,5-dichloro-2-(1-hydroxy-3-methylbutyl)phenol (0.14 g, crude) in DCM (2 mL) was added PBr (0.30 g, 1.12 mmol) at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting solution was quenched with water (20 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 2-(1-bromo-3-methylbutyl)-4,5-dichlorophenol as a yellow oil (0.18 g, crude), which was used in the next step without further purification: LCMS (ESI) C 11 H 13 BrClO [M - H] + Calculated values: 309, 311, 313 (2:3:1), measured values: 309, 311, 313 (2:3:1).

[0378] Step C: To a stirred solution of 2-(1-bromo-3-methylbutyl)-4,5-dichlorophenol (0.18 g, 0.58 mmol) in DMF (1 mL) was added piperidin-4-ylmethanol (0.13 g, 1.15 mmol) and K2CO3 (0.16 g, 1.15 mmol) at room temperature. After stirring at room temperature for 2 hours, the resulting mixture was diluted with water (20 mL) at room temperature and extracted with EA (5 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: 20 mmol / L NH4HCO3 in water, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 80% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.14 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 23 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]-3-methylbutyl]phenol) as an off-white solid (10 mg, 5% overall for 3 steps): LCMS (ESI) C 17 H 25 Cl2NO2[M + H] + Calculated values: 346, 348 (3 : 2), measured values: 346, 348 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 7.25 (s, 1H), 6.96 (s, 1H), 4.39 (br, 1H), 3.83-3.76 (m, 1H), 3.22 (d, J = 6.1 Hz, 2H), 3.00 (d, J = 11.5 Hz, 1H), 2.83 (d, J = 11.5 Hz, 1H), 1.98-1.89 (m, 2H), 1.78-1.60 (m, 3H), 1.57-1.48 (m, 1H), 1.43-1.23 (m, 2H), 1.19-0.99 (m, 2H), 0.92-0.82 (m, 6H).

[0379] [Example 22] Compound 28 (2-(1-(4,5-dichloro-2-hydroxybenzyl)piperidin-4-yl)acetic acid)

[0380] [ka]

[0381] Step A: To a stirred solution of methyl 2-(piperidin-4-yl)acetate (0.25 g, 1.29 mmol) and Intermediate 1 (0.20 g, 1.05 mmol) in MeOH (3 mL) was added HOAc (62 mg, 1.03 mmol) and NaBH(OAc) (0.66 g, 3.12 mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 2 hours under a nitrogen atmosphere, the resulting solution was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (7 / 1) to give methyl 2-(1-(4,5-dichloro-2-hydroxybenzyl)piperidin-4-yl)acetate as a light brown solid (0.19 g, 55%): LCMS (ESI) C 15 H 19 Cl2NO3[M + H] + Calculated values: 332, 334 (3 : 2), measured values ​​332, 334 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 0.9 Hz, 1H), 6.94 (s, 1H), 3.69 (s, 3H), 3.67 (s, 2H), 3.00 (d, J = 11.7 Hz, 2H), 2.29 (d, J = 6.9 Hz, 2H), 2.24-2.13 (m, 2H), 1.96-1.75 (m, 3H), 1.44-1.31 (m, 2H).

[0382] Step B: To a stirred solution of methyl 2-[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]piperidin-4-yl]acetate (0.19 g, 0.57 mmol) in MeOH (4 mL) and water (2 mL) was added NaOH (0.11 g, 2.75 mmol) at room temperature. The reaction solution was stirred at room temperature for 2 hours. The pH of the resulting solution was adjusted to 7-8 with aqueous HCl (1N). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Sunfire Prep C 18 OBD column, 10 μm, 19 × 250 mm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 16% B to 43% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 7.52. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 282-(1-(4,5-dichloro-2-hydroxybenzyl)piperidin-4-yl)acetic acid trifluoroacetic acid as a colorless viscous oil (24.7 mg, 14%): LCMS (ESI) C 14 H 17 Cl2NO3[M + H] + Calculated values: 318, 320 (3 : 2), measured values ​​318, 320 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 1H), 7.12 (s, 1H), 4.27 (s, 2H), 3.58-3.49 (m, 2H), 3.30 (s, 1H), 3.14-3.04 (m, 2H), 2.31 (d, J = 6.5 Hz, 2H), 2.14-2.00 (m, 2H), 1.53 (m, 2H).

[0383] [Example 23] Compound 29 (4,5-dichloro-2-(((2S,4S)-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol) and Compound 24 (4,5-dichloro-2-(((2R,4S)-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol)

[0384] [ka]

[0385] Step A: To a stirred solution of intermediate 1 (0.20 g, 1.05 mmol) in EtOH (10 mL) was added NaBH (79 mg, 2.09 mmol) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. The resulting mixture was quenched with water (10 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 4,5-dichloro-2-(hydroxymethyl)phenol as an off-white solid (0.20 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C7H6Cl2O2 [M - H] - Calculated values: 191, 193 (3:2), measured values: 191, 193 (3:2).

[0386] Step B: To a stirred solution of 4,5-dichloro-2-(hydroxymethyl)phenol (0.20 g, 1.04 mmol) in DCM (10 mL) was added PBr (0.56 g, 2.07 mmol) dropwise at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The resulting solution was quenched with water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 2-(bromomethyl)-4,5-dichlorophenol as a dark gray oil (0.20 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C7H5BrCl2O [M - H] - Calculated values: 253, 255, 257 (2:3:1), measured values: 253, 255, 257 (2:3:1).

[0387] Step C: To a mixture of 2-(bromomethyl)-4,5-dichlorophenol (0.20 g, 0.78 mmol) and K2CO3 (0.22 g, 1.56 mmol) in ACN (10 mL) was added (2-methylpiperidin-4-yl)methanol (0.15 g, 1.17 mmol) at room temperature. The reaction mixture was warmed to 40 °C and stirred for 1 h. After cooling to room temperature, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column, 100 Å, 10 μm, 19 mm x 250 mm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 43% B to 65% B in 9 min; detector: UV 254 / 210 nm; retention times: Rt1: 8.10 min, Rt2: 8.60 min.

[0388] The faster eluting isomer was obtained as compound 29 (4,5-dichloro-2-(((2S,4S)-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol) as a pale yellow solid (90 mg, 37%): LCMS (ESI) C 14 H 19 Cl2NO2[M + H] + Calculated values: 304, 306 (3 : 2), measured values ​​304, 306 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.12 (s, 1H), 6.79 (s, 1H), 4.33 (d, J = 14.7 Hz, 1H), 3.46-3.29 (m, 3H), 3.05-2.84 (m, 1H), 2.55-2.30 (m, 1H), 2.17 (td, J = 12.4, 2.6 Hz, 1H), 1.86-1.49 (m, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.33-0.97 (m, 2H).

[0389] The slower eluting isomer was obtained as compound 24 (4,5-dichloro-2-(((2R,4S)-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol) as a pale yellow solid (6.5 mg, 3%): LCMS (ESI) C 14 H 19 Cl2NO2[M + H] + Calculated values: 304, 306 (3 : 2), measured values ​​304, 306 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.15 (s, 1H), 6.79 (s, 1H), 3.84 (d, J = 2.0 Hz, 2H), 3.38 (d, J = 6.2 Hz, 2H), 3.27-3.13 (m, 1H), 2.79-2.59 (m, 2H), 1.92-1.61 (m, 3H), 1.50 (m, 1H), 1.38-1.18 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H).

[0390] [Example 24] Compound 46 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol)

[0391] [ka]

[0392] Step A: To a stirred solution of 4,5-dichloro-2-methoxybenzaldehyde (1.50 g, 7.32 mmol) in THF (50 mL) was added MeMgBr (9 mL, 9.00 mmol, 1 M in THF) at 0° C. under a nitrogen atmosphere. The reaction solution was warmed to room temperature and stirred under a nitrogen atmosphere for 1 h. The resulting solution was quenched with water (50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 1-(4,5-dichloro-2-methoxyphenyl)ethan-1-ol as an off-white solid (1.40 g, 87%): 1 H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 0.7 Hz, 1H), 6.91 (s, 1H), 5.03 (q, J = 6.3 Hz, 1H), 3.82 (s, 3H), 1.43 (d, J = 6.5 Hz, 3H).

[0393] Step B: To a stirred solution of 1-(4,5-dichloro-2-methoxyphenyl)ethan-1-ol (0.50 g, 2.26 mmol) in DCM (10 mL) was added PBr (1.22 g, 4.52 mmol) dropwise at room temperature. After stirring at room temperature for 15 min, the resulting solution was quenched with water (10 mL) and extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 1-(1-bromoethyl)-4,5-dichloro-2-methoxybenzene as a pale yellow oil (0.50 g, crude), which was used directly in the next step without further purification: 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 6.96 (s, 1H), 5.55 (q, J = 7.0 Hz, 1H), 3.90 (s, 3H), 2.01 (d, J = 7.0 Hz, 3H).

[0394] Step C: To a stirred mixture of 1-(1-bromoethyl)-4,5-dichloro-2-methoxybenzene (0.12 g, 1.06 mmol) and K2CO3 (0.19 g, 1.41 mmol) in ACN (10 mL) was added piperidin-4-ylmethanol (0.12 g, 1.06 mmol) at room temperature. The reaction mixture was warmed to 40 °C and stirred for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 10 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 80% B in 8 min; Detector: UV 210 nm; Retention time: 7.57 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give [1-[1-(4,5-dichloro-2-methoxyphenyl)ethyl]piperidin-4-yl]methanol as an off-white solid (0.10 g, 43%): LCMS (ESI) C 15 H 21 Cl2NO2[M + H] + Calculated values: 318, 320 (3 : 2), measured values ​​318, 320 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.94 (s, 1H), 3.90-3.78 (m, 1H), 3.82 (s, 3H), 3.51 (d, J = 6.3 Hz, 2H), 3.18 (d, J = 11.1 Hz, 1H), 2.82 (d, J = 11.4 Hz, 1H), 1.99 (t, J = 10.3 Hz, 1H), 1.89-1.73 (m, 2H), 1.65 (d, J = 13.1 Hz, 1H), 1.48-1.40 (m, 1H), 1.37-1.10 (m, 5H).

[0395] Step D: To a stirred solution of [1-[1-(4,5-dichloro-2-methoxyphenyl)ethyl]piperidin-4-yl]methanol (0.70 g, 2.20 mmol) in DCM (20 mL) was added BBr3 (1.65 g, 6.60 mmol) at room temperature. After stirring at room temperature for 2 hours, the resulting mixture was quenched with ice water (10 mL) and then neutralized to pH 7-8 with saturated aqueous NaHCO3. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water with 10 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 42% B to 50% B in 12 min; Detector: UV 210 nm; Retention time: 8.60 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 46 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol) as an off-white solid (250 mg, 37%): LCMS (ESI) C 14 H 19 Cl2NO2[M + H] + Calculated values: 304, 306 (3 : 2), measured values ​​304, 306 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.07 (s, 1H), 6.93 (s, 1H), 3.84 (s, 1H), 3.52 (d, J = 6.3 Hz, 2H), 3.05 (d, J = 11.5 Hz, 2H), 2.38 (t, J = 11.6 Hz, 1H), 2.18 (t, J = 11.6 Hz, 1H), 1.85 (d, J = 13.2 Hz, 2H), 1.47-1.23 (m, 6H).

[0396] [Example 25] Compound 54 (1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carbonitrile)

[0397] [ka]

[0398] Step A: To a stirred solution of tert-butyl 4-cyanopiperidine-1-carboxylate (1.00 g, 4.76 mmol) in THF (8 mL) was added dropwise LDA (2.85 mL, 5.71 mmol, 2 M in THF) at −78° C. under an argon atmosphere. The reaction mixture was stirred at −78° C. for 1 h. Paraformaldehyde (0.17 g, 5.71 mmol) was then added to the solution. The resulting mixture was warmed to room temperature and stirred under an argon atmosphere for 1 h. The resulting solution was quenched with saturated aqueous NH4Cl (2 mL) at −78° C. and diluted with water (50 mL). The aqueous layer was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate as an off-white semi-solid (0.60 g, 42%): LCMS (ESI) C 12 H 20 N2O3[M + H] + Calculated value: 241, measured value 241; 1 H NMR (300 MHz, CDCl3) δ4.37-4.01 (m, 2H), 3.64 (s, 2H), 3.14-2.91 (m, 2H), 1.99-1.83 (m, 2H), 1.51-1.28 (m, 11H).

[0399] Step B: To a stirred solution of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (0.20 g, 0.83 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. After stirring at room temperature for 1 hour, the resulting solution was concentrated under reduced pressure. The residue was dissolved in water (10 mL), and the pH value was adjusted to 8 with saturated aqueous K2CO3 solution. The aqueous layer was extracted with DCM (10 × 20 mL). The combined organic layers were dried over anhydrous K2CO3 and filtered. The filtrate was concentrated under reduced pressure to give 4-(hydroxymethyl)piperidine-4-carbonitrile as a yellow oil (0.10 g, crude), which was used directly in the next step without further purification.

[0400] Step C: To a stirred solution of intermediate 1 (0.10 g, 0.52 mmol) in DCE (3 mL) was added 4-(hydroxymethyl)piperidine-4-carbonitrile (73 mg, 0.52 mmol), HOAc (31 mg, 0.52 mmol), and NaBH(OAc) (0.33 g, 1.57 mmol) at room temperature. After stirring at room temperature for 3 hours, the resulting mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column 19 × 250 mm, 10 μm; Mobile phase A: water containing 10 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 78% B in 9 min; Detector: UV 210 nm; Retention time: 8.23 ​​min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 54 (1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carbonitrile) as an off-white solid (24 mg, 14%): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated values ​​315, 317 (3 : 2), measured values ​​315, 317 (3 : 2); 1H NMR (300 MHz, DMSO-d6) δ 10.7 (br, 1H), 7.33 (s, 1H), 6.94 (s, 1H), 5.39 (s, 1H), 3.54 (s, 2H), 3.43 (s, 2H), 2.93-2.76 (m, 2H), 2.28-2.06 (m, 2H), 1.90-1.69 (m, 2H), 1.62-1.39 (m, 2H).

[0401] [Example 26] Compound 60 (4,5-dibromo-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol)

[0402] [ka]

[0403] Step A: In a 20 mL Biotage vial equipped with a magnetic stir bar, 4-piperidinemethanol (53.9 μL, 300 μmol) was added to a solution of 4,5-dibromo-2-hydroxybenzaldehyde (80.0 mg, 286 μmol) in anhydrous THF (2 mL). The solution was stirred at room temperature for 3 hours. The solution was cooled to 0°C, and AcOH (20 mL, 372 μmol) was added dropwise to the reaction, followed by the addition of NaBH(OAc)3 (78.4 mg, 372 μmol) in small portions. The reaction was allowed to stir from 0°C to room temperature overnight. The reaction was quenched by the dropwise addition of NaOH 1N at 0°C (5 mL) while transferring to an Erlenmeyer, where it was further stirred for 30 minutes. The reaction was then diluted with DCM (40 mL), and saturated aqueous NaHCO3 (20 mL) was added to the biphasic mixture, which was then transferred to an extraction funnel. The layers were separated, and the aqueous layer was extracted with DCM (3 × 20 mL). The organic layer was then washed with brine (2 × 30 mL), dried over NaSO, filtered, and evaporated to dryness. The resulting crude solid was then purified by flash chromatography using 30-100% EA in hexanes. The resulting white solid was then partially dissolved in a mixture of ACN / water (40:60) and lyophilized to give compound 60 (4,5-dibromo-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol) (61.4 mg, 48%) as a white solid. LCMS (ESI) C 13 H 17 Br2NO2[M] + Calculated value: 377.0 / 379.0 (1:2), Measured value [M + H] + : 378.0 / 380.0 (1 : 2). 1 H NMR (500 MHz, DMSO) δ 7.44 (s, 1H), 7.07 (s, 1H), 3.59 (s, 2H), 3.25 (d, J = 6.3 Hz, 2H), 2.86 (d, J = 11.7 Hz, 2H), 2.04 (td, J = 11.8, 2.3 Hz, 2H), 1.68 (dd, J = 12.7, 1.5 Hz, 2H), 1.46 - 1.34 (m, 1H), 1.14 (qd, J = 12.5, 3.8 Hz, 2H).

[0404] [Example 27] Compound 63 ((1-(4,5-dibromo-2-hydroxybenzyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone)

[0405] [ka]

[0406] Step A: To a 20 mL Biotage vial equipped with a magnetic stir bar was added 4-piperidinyl(1-pyrrolidinyl)methanone hydrochloride (656 mg, 3.0 mmol), EtN (0.42 mL, 3.0 mmol), and dibromosalicaldehyde (663 mg, 3.3 mmol). The reagents were dissolved in anhydrous THF (10 mL), and the solution was stirred at room temperature for 4 h. The solution was cooled to 0 °C, and AcOH (0.35 mL, 6.0 mmol) was added dropwise. NaBH(OAc) (1.27 g, 6.0 mmol) was then added in small portions, and the reaction was stirred from 0 °C to room temperature overnight. The reaction was quenched at 0 °C by the addition of HCl 0.5 N (10 mL) and stirred for another 30 min. The reaction was then diluted with DCM (40 mL), and saturated aqueous NaHCO3 (30 mL) was added to the biphasic mixture. The biphasic mixture was transferred to an extraction funnel. The layers were separated, and the aqueous layer was extracted with DCM (3 x 20 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and evaporated to dryness. The resulting gum was then purified by flash chromatography using a gradient of 60% EA to 10% MeOH / EA in hexanes. The product was repurified by reverse phase (C-18 column) using a gradient of 5-100% ACN / H2O. The desired fractions were combined and lyophilized to give compound 63 (1-(4,5-dibromo-2-hydroxybenzyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone) as a white solid (35.2 mg, 6.6%). LCMS (ESI) C 17 H 22 Br2N2O2[M + H]+ Calculated value: 444.0 / 446.0 (1:2), Measured value: 444.8 / 446.8, 351 (1:2) 1 H NMR (400 MHz, cdcl3) δ 7.17 (s, 1H), 7.10 (s, 1H), 3.63 (d, J = 9.1 Hz, 2H), 3.46 (t, J = 6.8 Hz, 4H), 3.04 (d, J = 11.8 Hz, 2H), 2.41 (t, J = 10.9 Hz, 1H), 2.15 (s, 2H), 2.02 - 1.91 (m, 3H), 1.91 - 1.81 (m, 3H), 1.81-1.73 (m, 2H).

[0407] [Example 28] Compound 65 (4,5-dichloro-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol)

[0408] [ka]

[0409] Step A: To a solution of piperidin-4-ylmethanol (63 mg, 0.55 mmol), Intermediate 1 (0.10 g, 0.53 mmol), and acetic acid (30 mg, 0.50 mmol) in DCE (3 mL) was added NaBH(OAc) (0.32 g, 1.51 mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 3 hours under a nitrogen atmosphere, the reaction mixture was quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layer was washed with brine (2 × 30 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Prep C 18OBD column 190 mm × 150 mm, 5 μm; mobile phase A: water with 10 mmol / L NH₄HCO₃, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40% B to 55% B in 7 min; detector: UV 254 / 220 nm; retention time: 6.33 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 65 (4,5-dichloro-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol) as an off-white solid (34 mg, 22%): LCMS (ESI) C 13 H 17 Cl2NO2[M + H] + Calculated values: 290, 292 (3 : 2), measured values: 290, 292 (3 : 2); 1 H NMR (400 MHz, DMSOd6+ D2O) δ 7.32 (s, 1H), 6.93 (s, 1H), 3.61 (s, 2H), 3.25 (d, J = 6.4 Hz, 2H), 2.84 (d, J = 11.2 Hz, 2H), 2.04 (t, J = 9.6 Hz, 2H), 1.69 (d, J = 11.2 Hz, 2H), 1.40-1.36 (m, 1H), 1.17 (q, J = 8.0 Hz, 2H).

[0410] The compounds listed below in Table 1a were prepared in a manner similar to that described for compound 65, starting from 4,5-dichloro-2-hydroxy-benzaldehyde and the corresponding amine, prepared as described herein or available from commercial sources.

[0411] [Table 2-1]

[0412] [Table 2-2]

[0413] [Table 2-3]

[0414] [Table 2-4]

[0415] [Table 2-5]

[0416] [Table 2-6]

[0417] [Example 29] Evaluation of Kv1.3 potassium channel blocker activity This assay was used to evaluate the activity of the disclosed compounds as Kv1.3 potassium channel blockers.

[0418] cell culture CHO-K1 cells stably expressing Kv1.3 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, and G418 (500 μg / ml). Cells were grown in culture flasks at 37°C in a humidified incubator with 5% CO2.

[0419] solution Cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM MgCl, 5 mM glucose, and 10 mM HEPES; pH was adjusted to 7.4 with NaOH; pH was 295–305 mOsm. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES; pH was adjusted to 7.2 with KOH; pH was 285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted in the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. A maximum content of DMSO (0.3%) was present in the 100 μM solution.

[0420] Voltage Protocol Currents were elicited by applying 100 ms depolarizing pulses from -90 mV (holding potential) to +40 mV at a frequency of 0.1 Hz. Control (no compound) and compound pulse trains applied for each compound concentration contained 20 pulses. A 10 second break was used between pulse trains (see Table A below).

[0421] [Table 3]

[0422] Patch clamp recording and compound application Whole-cell current recording and compound application were enabled by means of the automated patch-clamp platform Patchliner (Nanion Technologies GmbH). An EPC10 patch-clamp amplifier (HEKA Elektronik Dr. Schulze GmbH) was used for data acquisition with Patchmaster software (HEKA Elektronik Dr. Schulze GmbH). Data were sampled at 10 kHz without filtering. Passive leak currents were subtracted online using the P / 4 procedure (HEKA Elektronik Dr. Schulze GmbH). Increasing compound concentrations were applied consecutively to the same cell without washout. The total compound incubation time before the next pulse train was less than 10 seconds. Inhibition of peak currents was observed during compound equilibration.

[0423] Data analysis AUC and peak values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). 50 The last single pulse in the pulse train corresponding to a given compound concentration was used to determine the IC. The resulting AUC and peak values ​​in the presence of compound were normalized to the control values ​​in the absence of compound. Origin (OridinLab) was used to determine the IC. 50 The Hill formula: compound / I control =(100-A) / (1+([Compound] / IC 50 )nH)+A(where, IC 50 Values ​​are derived from data fitting to (where [compound] is the concentration at which current inhibition was half-maximal, A is the fraction of unblocked current, and nH is the Hill coefficient).

[0424] [Example 30] Assessment of hERG activity This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0425] hERG electrophysiology This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0426] cell culture CHO-K1 cells stably expressing hERG were grown in Ham's F-12 medium containing 10% heat-inactivated FBS, 1% penicillin / streptomycin, hygromycin (100 μg / ml), and glutamine containing G418 (100 μg / ml). Cells were grown in culture flasks at 37°C in a humidified incubator with 5% CO2.

[0427] solution Cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM MgCl, 5 mM glucose, and 10 mM HEPES; pH was adjusted to 7.4 with NaOH; pH was 295–305 mOsm. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES; pH was adjusted to 7.2 with KOH; pH was 285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted in the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. A maximum content of DMSO (0.3%) was present in the 100 μM solution.

[0428] Voltage Protocol The voltage protocol (see Table B) was designed to simulate the voltage changes during a cardiac action potential, with a 300 ms depolarization to +20 mV (similar to the plateau phase of the cardiac action potential), a 300 ms repolarization to -50 mV (to induce tail current), and a final step to a holding potential of -80 mV. The pulse frequency was 0.3 Hz. The control (no compound) and compound pulse trains applied for each compound concentration contained 70 pulses.

[0429] [Table 4]

[0430] Patch clamp recording and compound application Whole-cell current recording and compound application were made possible by means of the automated patch clamp platform Patchliner (Nanion). An EPC10 patch clamp amplifier (HEKA) was used for data collection with Patchmaster software (HEKA Elektronik Dr. Schulze GmbH). Data were sampled at 10 kHz without filtering. Increasing compound concentrations were applied consecutively to the same cell without washout in between.

[0431] Data analysis AUC and peak values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). 50 The last single pulse in the pulse train corresponding to a given compound concentration was used to determine the IC. The resulting AUC and peak values ​​in the presence of compound were normalized to the control values ​​in the absence of compound. Origin (OridinLab) was used to determine the IC. 50 The Hill formula: compound / I control =(100-A) / (1+([Compound] / IC 50 )nH)+A(where, IC 50 where A is the concentration at which current inhibition was half-maximal, [compound] is the applied compound concentration, A is the fraction of unblocked current, and nH is the Hill coefficient.

[0432] Table 1 provides a summary of the inhibitory activity of certain selected compounds against the Kv1.3 potassium channel and the hERG channel.

[0433] [Table 5-1]

[0434] Table 5-2

[0435] Table 5-3

[0436] Table 5-4

[0437] Table 5-5

[0438] Table 5-6

[0439] Table 5-7 The present application also relates to the following aspects: (1) A compound of formula I or a pharmaceutically acceptable salt thereof

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Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof 【Chemistry 1】 During the ceremony, structural part 【Chemistry 2】 but, (a) 【Transformation 3】 or (b) 【Chemistry 4】 or 【Transformation 5】 or having the structure 【Transformation 6】 ; having the structure: Said structural part 【Transformation 7】 but, 【Transformation 8】 having the structure R １ and R ２ are each independently H, alkyl, (CR ６ R ７ ) ｎ３ OR ａ , (CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ (C=O)NR ｂ R ａ , or (CR ６ R ７ ) ｎ３ NR ｂ (C=O)R ａ and R ４ each occurrence independently represents H, halogen, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, oxo, (C=O)R ｂ , (C=O)OR ｂ , (CR ６ R ７ ) ｎ３ OR ａ , (CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ SO ２ R ａ , (CR ６ R ７ ) ｎ３ SO ２ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ SO ２ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ (C=O)R ｂ , (CR ６ R ７ ) ｎ３ (C=O)NR ａ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ (C=O)NR ａ R ｂ , (C=O)(CR ６ R ７ ) ｎ３ OR ｂ , (C=O)(CR ６ R ７ ) ｎ３ NR ａ R ｂ or an optionally substituted 5- or 6-membered heterocycle containing 1 to 3 heteroatoms, each selected from the group consisting of N, O, and S; Or two R's ４ taken together form an optionally substituted cycloalkyl, saturated heterocycle, or heteroaryl, each containing 0-1 heteroatoms selected from the group consisting of N, O, and S; R ６ and R ７ each occurrence is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ａ and R ｂ each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R ａ and R ｂ together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; If applicable, R １ , R ２ , R ４ , R ６ , and R ７ The alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl of the formula (I) are, when valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, (CR ａ R ｂ ) ｎ３ OR ａ , (CR ａ R ｂ ) ｎ３ NR ａ R ｂ , (CR ａ R ｂ ) ｎ３ NR ａ (C=O)R ｂ , (CR ａ R ｂ ) ｎ３ (C=O)NR ａ R ｂ and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: n １ each occurrence is independently 1, 2, 3, or 4, where valence allows; n ３ each occurrence of is independently an integer from 0 to 4), However, the compounds mentioned above exclude compounds represented by the following structural formula: 【Chemistry 9】 。

2. R １ and R ２ are each independently, (a) H or alkyl; (b) is H or Me; (c) H, (CR ６ R ７ ) ｎ３ OR ａ , (CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ (C=O)NR ｂ R ａ , or (CR ６ R ７ ) ｎ３ NR ｂ (C=O)R ａ or (d) H, CH ２ OH, CH ２ NH ２ , or CONH ２ That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. (a) R ４ At least one occurrence of independently ６ R ７ ) ｎ３ OR ａ , (CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ SO ２ R ａ , (CR ６ R ７ ) ｎ３ NR ａ (C=O)R ｂ , or (CR ６ R ７ ) ｎ３ (C=O)NR ａ R ｂ Or (b) R ４ At least one occurrence of independently ６ R ７ ) ｎ３ NR ａ (C=O)R ｂ or (CR ６ R ７ ) ｎ３ (C=O)NR ａ R ｂ Or (c) R ４ One or more occurrences of (CR ６ R ７ ) ｎ３ OR ａ or (CR ６ R ７ ) ｎ３ NR ａ R ｂ Or (d) R ４ One or more occurrences of OR ａ , N.R. ａ R ｂ , -CH ２ OR ａ , -CH ２ NR ａ R ｂ , -CH ２ CH ２ OR ａ , or -CH ２ CH ２ NR ａ R ｂ Or (e) R ４ is an optionally substituted 5- or 6-membered heterocycle containing 1 to 3 heteroatoms each selected from the group consisting of N, O, and S; (f) Two R ４ taken together form an optionally substituted cycloalkyl, saturated heterocycle, or heteroaryl, each containing 0-1 heteroatoms selected from the group consisting of N, O, and S; (g) R ４ At least one occurrence of CH ２ OH, CH ２ NH ２ , 【Chemistry 10】 Or (h) R ４ At least one occurrence of 【Chemistry 11】 wherein said heterocycle, when valences permit, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C １～４ optionally substituted with alkyl; (i) R ４ is H, alkyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, CF ３ , OCF ３ , OR ａ , (CR ６ R ７ ) ｎ３ OR ａ , or oxo, (j) R ４ At least one occurrence of is (C=O)R ｂ , (C=O)OR ｂ , S.O. ２ R ａ , (C=O)(CR ６ R ７ ) ｎ３ OR ｂ , (C=O)(CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ SO ２ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ (C=O)R ｂ , (CR ６ R ７ ) ｎ３ NR ａ (C=O)NR ａ R ｂ , or (CR ６ R ７ ) ｎ３ (C=O)NR ａ R ｂ Or (k) R ４ is independently H or alkyl; or (l) Two R's ４ groups taken together with the carbon atom to which they are attached form a 3- to 7-membered optionally substituted cycloalkyl or heterocycle; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R ６ and R ７ 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each occurrence of is independently H or alkyl.

5. n １ 4. The compound of claim 1, wherein R is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

6. n ３ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each occurrence of is independently 0, 1, or 2.

7. (a) R ａ or R ｂ is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; (b) R ａ or R ｂ at least one occurrence of is independently H, Me, Et, Pr, or 【Chemistry 12】 wherein said heterocycle, when valences permit, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C １～４ optionally substituted with alkyl, or (c) R ａ and R ｂ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. A compound selected from the group consisting of the compounds shown below, or a pharmaceutically acceptable salt thereof. 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】

9. 10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

10. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

11. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in a method of treating a condition in a mammalian species in need thereof, comprising: the method comprises the step of administering to the mammalian species a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a renal disease; Optionally, said condition is: (a) an immunological disorder that is transplant rejection or an autoimmune disease, wherein said autoimmune disease is optionally rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes; (b) a central nervous system (CNS) disorder that is Alzheimer's disease; (c) an inflammatory disorder that is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy; (d) the gastroenterological disorder is inflammatory bowel disease; (e) a metabolic disorder that is obesity or type II diabetes; (f) cardiovascular disorder, which is ischemic stroke; (g) kidney disease that is chronic kidney disease, nephritis, or chronic renal failure; or (h) is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof, and optionally said mammalian species is human; Pharmaceutical compositions.

12. A selective Kv1.3 channel blocker comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof: 【Chemistry 17】 。

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