Arylmethylene heterocyclic compounds as Kv1.3 potassium SHAKER channel blockers

Abstract

Compounds of formula I() or pharmaceutically acceptable salts thereof are described, wherein substituents are defined herein. Pharmaceutical compositions comprising the same and methods of using the same are also described.

Description

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

[0002] This patent disclosure contains copyrighted material. The copyright holder does not object to the reproduction by fax of the patent document or patent disclosure appearing in the U.S. Patent and Trademark Office's patent documents or records, but otherwise reserves all and all copyright rights.

[0003] Incorporated as a reference

[0004] All references to this document are incorporated herein by reference in their entirety. Invention Field

[0005] This invention relates primarily to the field of pharmaceutical science. More specifically, this invention relates to compounds and compositions that can be used as pharmaceuticals as potassium channel blockers.

[0006] background

[0007] Voltage-gated Kv1.3 potassium (K + Kv1.3 channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, and modulate a wide range of physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal stress. Kv1.3 channels can modulate membrane potential and thus indirectly affect calcium signaling in human effector memory T cells. Effector memory T cells are mediators for several conditions, including multiple sclerosis, type 1 diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. Upon activation, effector memory T cells increase Kv1.3 channel expression. In human B cells, immature and early memory B cells express low levels of Kv1.3 channels when inactive. In contrast, class-switching memory B cells express high levels of Kv1.3 channels. Furthermore, Kv1.3 channels promote calcium homeostasis required for cell activation, gene transcription, and proliferation, regulated by T-cell receptors (Panyi, G. et al., 2004). Trends Immunol. (565-569). Blocking and inhibitory activities of Kv1.3 channels in effector memory T cells, such as calcium signaling, cytokine production (interferon-γ, interleukin-2) and cell proliferation.

[0008] Autoimmune diseases are a family of disorders resulting from tissue damage caused by an invasion from the body's own immune system. These diseases may affect a single organ, as in multiple sclerosis and type 2 diabetes, or may involve multiple organs, as in rheumatoid arthritis and systemic lupus erythematosus. Treatment is often palliative, employing anti-inflammatory and immunosuppressive drugs, which can have serious side effects. The need for more effective therapies has led to research into drugs that can selectively inhibit the function of effector memory T cells (known to be involved in the etiology of autoimmune diseases). These inhibitors are thought to alleviate the symptoms of autoimmune diseases without weakening the protective immune response. Effector memory T cells (TEMs) express a large number of Kv1.3 channels and depend on the function of these channels. In vivo, Kv1.3 channel blockers paralyze TEMs at immune sites and prevent their reactivation in inflamed tissues. Kv1.3 channel blockers do not affect the motility of immature and central memory T cells within lymph nodes. Inhibiting the function of these cells by selectively blocking Kv1.3 channels offers the possibility of effective therapies for autoimmune diseases with minimal side effects.

[0009] Multiple sclerosis (MS) is caused by autoimmune damage to the central nervous system (CNS). Symptoms include muscle weakness and paralysis, which severely impact patients' quality of life. MS progresses rapidly and unpredictably, ultimately leading to death. Kv1.3 channels are also highly expressed in autoreactive effector memory T cells from 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 channel blockers.

[0010] Compounds that are selective Kv1.3 channel blockers are therefore potential therapeutic agents as immunosuppressants or modulators of the immune system. Kv1.3 channels are also considered therapeutic targets for the treatment of obesity and for improving peripheral insulin selectivity in patients with type 2 diabetes. These compounds may also be used to prevent transplant rejection and to treat immunological (e.g., autoimmune) and inflammatory disorders.

[0011] Tubulointerstitial fibrosis (TURF) is a progressive deposit of connective tissue in the renal parenchyma, leading to deterioration of renal function and participating 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 can promote their proliferation, leading to excessive stimulation of chronic inflammation and cellular immunity, which is involved in the underlying pathology of these kidney diseases and is a promoting factor in the development of TURF. Inhibition of lymphocyte Kv1.3 channel currents prevents the proliferation of renal lymphocytes and mitigates the development of renal fibrosis (Kazama I. et al., 2015). Mediators Inflamm. , 1-12).

[0012] Kv1.3 channels also play a role in gastrointestinal disorders including inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease. Ulcerative colitis is a chronic IBD characterized by excessive T-cell infiltration and cytokine production. Ulcerative colitis can impair quality of life and lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8-positive T cells in the inflamed mucosa of UC patients are associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are considered to act 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-TNF-α agents, are insufficient for many patients (Hansen LK et al., 2014). J. Crohns Colitis Crohn's disease (1378-1391) is a type of IBD that can affect any part of the gastrointestinal tract. Because it is caused by a T-cell-driven process triggered by normally safe bacteria, Crohn's disease is considered a result of enteritis. Therefore, Kv1.3 channel inhibition may be used to treat Crohn's disease.

[0013] In addition to T cells, Kv1.3 channels are also expressed in microglia, where they are involved in the production of inflammatory cytokines and nitric oxide and participate in microglial-regulated neuronal death. In humans, strong Kv1.3 channel expression has been found in microglia of the frontal cortex in patients with Alzheimer's disease and in CD68 cells in multiple sclerosis brain injury. + On the cellular level, it has been shown that Kv1.3 channel blockers may be able to preferentially target detrimental pro-inflammatory microglial function. Kv1.3 channels are expressed on activated microglial cells in the brains of infarcted rodents and humans. Higher Kv1.3 channel current densities were observed in acutely isolated microglial cells from the infarcted hemisphere, rather than in microglial cells isolated from the contralateral hemisphere in a mouse model of stroke (Chen YJ et al., 2017). Ann. Clin. Transl. Neurol. , 147-161).

[0014] The expression of Kv1.3 channels is increased in microglia of the human Alzheimer's disease brain, suggesting that Kv1.3 channels are pathologically relevant microglia targets in Alzheimer's disease (Rangaraju S. et al., 2015). J. Alzheimers Dis (797-808). Soluble AβO improves microglial Kv1.3 channel activity. Kv1.3 channels are required for AβO-induced pro-inflammatory activation and neurotoxicity in microglia. Kv1.3 channel expression / activation 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.

[0015] Kv1.3 channel blockers can also be used to alleviate symptoms of cardiovascular diseases, such as ischemic stroke, where activated microglia significantly promote secondary dilation of the infarct.

[0016] Kv1.3 channel expression is associated with the control of proliferation, apoptosis, and cell survival in multiple cell types. These processes are crucial for cancer development. 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 Opinion. Ther. Targets (101-105). Therefore, inhibitors of the Kv1.3 channel may be used as anticancer agents.

[0017] A number of peptide toxins with multiple disulfide bonds from spiders, scorpions, and sea anemones are known to block Kv1.3 channels. Several selective and effective peptide inhibitors of Kv1.3 channels have been developed. The synthetic derivative of carpet anemone toxin (SHK), containing the unnatural amino acid shk-186, is the most potent peptide toxin. Shk has shown efficacy in preclinical models and is currently in a Phase I clinical trial for the treatment of psoriasis. Shk has been able to inhibit the proliferation of TEM cells in animal models of multiple sclerosis, resulting in improved condition. Unfortunately, Shk also binds to closely associated Kv1.3 channel subtypes found in the CNS and heart. Selective inhibitors of Kv1.3 channels are needed to avoid potential cardiotoxicity and neurotoxicity. Furthermore, small peptides such as shk-186 are rapidly cleared from the body after administration, leading to short circulating half-lives and frequent administration events. Therefore, there is a need to develop selective Kv1.3 channel inhibitors with long-lasting effects for the treatment of chronic inflammatory diseases.

[0018] Therefore, there is still a need to develop new Kv1.3 channel blockers as pharmaceutical agents. Invention Overview

[0020] On one hand, a structure having formula I (which can be used as a potassium channel blocker) is described. Compounds of formula I, wherein various substituents are defined herein. The compounds of formula I described herein can block Kv1.3 potassium (K + These compounds are 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 can be used to treat conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and treatment methods have numerous clinical applications, including as pharmaceutically active agents and for the treatment of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, kidney diseases, or combinations thereof.

[0021] On one hand, compounds of formula I or their pharmaceutically acceptable salts are described.

[0022]

[0023] in

[0024] Each occurrence of Y is independently C(R4)2, NR4, O, S, SO, SO2 or SO(=NR)2. a );

[0025] Z is OR a ;

[0026] X1 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0027] X2 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0028] Each occurrence of X3 is independently H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0029] R1 and R2 are each independently H, alkyl, or (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 ;

[0030] Each occurrence of R4 is independently of H, halogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, 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 a 5- or 6-membered heterocycle containing 1-3 heteroatoms each selected from N, O and S with optional substitutions;

[0031] Or two R4s together form an optionally substituted carbocyclic ring, saturated heterocyclic ring, or heteroaryl group containing 0-3 heteroatoms each selected from N, O, and S;

[0032] Each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0033] R a and R b Each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, haloalkyl, halocycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or alternatively, R a and R b Together with the nitrogen atoms to which they are attached, they form optionally substituted heterocycles, the heterocycles comprising the nitrogen atoms and 0-3 additional heteroatoms each selected from N, O and S;

[0034] Where valence permits, the alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups in X1, X2, X3, R1, R2, R4, R6, and R7 may, where applicable, be optionally substituted by 1 to 4 substituents, each independently selected from the following: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 oxygenation;

[0035] As long as the valence allows, each occurrence of n1 is an independent integer between 0 and 4;

[0036] Each occurrence of n3 is an independent integer between 0 and 4; and

[0037] Each occurrence of n4 is independently 0, 1, or 2.

[0038] In any of the embodiments described herein, the structural portion Having structure , , or .

[0039] In any of the embodiments described herein, Y is C(R4)2.

[0040] In any of the embodiments described herein, Y is NR4.

[0041] In any of the embodiments described herein, Y is 0.

[0042] In any of the embodiments described herein, Y is S, SO, SO2, or SO (=NR). a ).

[0043] In any of the embodiments described herein, Y is NR4, CMeR4, or CHR4.

[0044] In any of the embodiments described herein, the structural portion Having structure .

[0045] In any of the embodiments described herein, the structural portion Having structure .

[0046] In any of the embodiments described herein, the structural portion Having structure ;where R x It is R4.

[0047] In any of the embodiments described herein, the structural portion Having structure ;where R x It is R4.

[0048] In any of the embodiments described herein, R1 and R2 are each independently H or alkyl.

[0049] In any of the embodiments described herein, R1 and R2 are each independently H or Me.

[0050] In any of the embodiments described herein, R1 and R2 are each independently H, (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 .

[0051] In any of the embodiments described herein, R1 and R2 are each independently H, CH2OH, CH2NH2, or CONH2.

[0052] In any of the embodiments described herein, at least one occurrence of R4 is independently (CR6R7). n3 OR a (CR6R7) n3 NR a R b (CR6R7) n3 SO2R a (CR6R7) n3 NR a (C=O)R bOr (CR6R7) n3 (C=O)NR a R b .

[0053] In any of the embodiments described herein, at least one occurrence of R4 is independently (CR6R7). n3 NR a (C=O)R b Or (CR6R7) n3 (C=O)NR a R b .

[0054] In any of the embodiments described herein, R4 appears once or more as (CR6R7). n3 OR a Or (CR6R7) n3 NR a R b .

[0055] In any of the embodiments described herein, one or more occurrences of R4 constitute OR. a NR a R b -CH2OR a -CH2NR a R b -CH2CH2OR a or -CH2CH2NR a R b .

[0056] In any of the embodiments described herein, R4 appears at least once as an optionally substituted 5- or 6-membered heterocycle containing 1 to 3 heteroatoms each selected from N, O and S.

[0057] In any of the embodiments described herein, the two R4 atoms together form an optionally substituted carbocyclic, saturated heterocyclic, or heteroaryl group containing 0-3 heteroatoms each selected from N, O, and S.

[0058] In any of the embodiments described herein, R4 appears at least once in the form of CH2OH, CH2NH2, .

[0059] In any of the embodiments described herein, R4 occurs at least once as a heterocycle selected from the following:

[0060]

[0061] Where the valence allows, the heterocycle is optionally converted by an alkyl group, OH group, oxo group, or (C=O)C group. 1-4 Alkyl substitution.

[0062] In any of the embodiments described herein, R4 appears at least once as H, alkyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, CF3, OCF3, OR a (CR6R7) n3 OR a Or oxygenation.

[0063] In any of the embodiments described herein, R4 occurs at least once as (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 .

[0064] In any of the embodiments described herein, at least one occurrence of R4 is independently H or an alkyl group.

[0065] In any of the embodiments described herein, the two R4 groups together with the carbon atoms to which they are attached form a 3- to 7-membered optionally substituted carbocyclic or heterocyclic ring.

[0066] In any of the embodiments described herein, the two R4 groups together with the two carbon atoms to which they are attached form a fused bicyclic system having the following structure: , where A is a 3-7 member, optionally substituted carbocyclic, saturated heterocyclic, or heteroaryl group.

[0067] In any of the embodiments described herein, structural primitives Having structure .

[0068] In any of the embodiments described herein, each occurrence of R6 and R7 is independently H or alkyl.

[0069] In any of the embodiments described herein, Z is OH or OMe.

[0070] In any of the embodiments described herein, Z is OH.

[0071] In any of the embodiments described herein, X1 is H, CN, halogen, fluoroalkyl, or alkyl.

[0072] In any of the embodiments described herein, X1 is H, CN, Cl, Br, Me, or CF3.

[0073] In any of the embodiments described herein, X1 is H or Cl.

[0074] In any of the embodiments described herein, X2 is H, CN, halogen, fluoroalkyl, or alkyl.

[0075] In any of the embodiments described herein, X2 is H, CN, Cl, Br, Me, or CF3.

[0076] In any of the embodiments described herein, X2 is H or Cl.

[0077] In any of the embodiments described herein, X3 is H, halogen, CN, alkyl, or haloalkyl.

[0078] In any of the embodiments described herein, X3 is H, Cl, Br, Me, or CF3.

[0079] In any of the embodiments described herein, X3 is H or Cl.

[0080] In any of the embodiments described herein, the structural portion Having structure .

[0081] In any of the embodiments described herein, n1 is 0, 1, 2, or 3.

[0082] In any of the embodiments described herein, each occurrence of n3 is independently 0, 1, or 2.

[0083] In any of the embodiments described herein, n4 is 1 or 2.

[0084] In any of the embodiments described herein, R a or Rb It appears at least once independently as H, alkyl, cycloalkyl, saturated heterocyclic, aryl or heteroaryl.

[0085] In any of the embodiments described herein, R a or R b The at least one occurrence of the substance is independently H, Me, Et, Pr, or a heterocycle selected from the following:

[0086]

[0087] Where the valence allows, the heterocycle is optionally converted by an alkyl group, OH group, oxo group, or (C=O)C group. 1-4 Alkyl substitution.

[0088] In any of the embodiments described herein, R a and R b Together with the nitrogen atoms attached to them, they form optionally substituted heterocycles, which contain the nitrogen atoms and 0-3 additional heteroatoms each selected from N, O and S.

[0089] In any of the embodiments described herein, the compound is selected from compounds 1-66 shown in Table 1.

[0090] 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.

[0091] In another aspect, methods for treating conditions in mammals in need are described, including administering to mammals a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any one of the embodiments described herein, wherein the condition is selected from cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0092] In any of the embodiments described herein, the immunological disorder is transplant rejection or an autoimmune disease.

[0093] In any of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0094] In any of the embodiments described herein, the central nervous system (CNS) disorder is Alzheimer's disease.

[0095] In any of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

[0096] In any of the embodiments described herein, the gastrointestinal disorder is inflammatory bowel disease.

[0097] In any of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0098] In any of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0099] In any of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0100] In any of the embodiments described herein, the condition is selected from 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.

[0101] In any of the embodiments described herein, the mammal class is human.

[0102] In another aspect, methods for blocking Kv1.3 potassium channels in desired mammals are described, comprising administering to the mammals a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any of the embodiments described herein.

[0103] In any of the embodiments described herein, the mammal class is human.

[0104] Any embodiment disclosed herein may be suitably combined with any other embodiment disclosed herein. Combinations of any embodiment disclosed herein with any other embodiment disclosed herein are expressly contemplated. Specifically, the selection of one or more embodiments for a substituent may be suitably combined with the selection of one or more particular embodiments for any other substituent. Such combinations may be made in any one or more embodiments of the application described herein or in any of the formulas described herein. Invention Details

[0106] definition

[0107] The following are definitions of terms used in this application specification. Unless otherwise stated, the initial definitions provided herein for groups or terms apply individually or as part of another group throughout this application specification. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0108] The term "alkyl" (and "alk") refers to a straight-chain or branched alkane (hydrocarbon) group containing 1-12 carbon atoms, preferably 1-6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. The term "(C 1- "C4) alkyl" refers to a straight-chain or branched alkane (hydrocarbon) group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group that is substituted at any possible link by one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., monohalogen substituents or polyhalogen substituents, in the latter case forming a group such as CF3 or an alkyl group carrying CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR 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 NR bC(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c Together with the N atoms that are optionally bonded to them, they form heterocycles; and R e Each occurrence of the group is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. In some embodiments, the group itself, such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic, and aryl, can be optionally substituted.

[0109] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group comprising 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary examples of such groups include vinyl or allyl. The term "C2-C6 alkenyl" refers to a straight-chain or branched hydrocarbon group comprising 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl, etc. E )-But-2-enyl, ( Z )-But-2-enyl, 2-methyl-( E )-But-2-enyl, 2-methyl-( Z )-But-2-enyl, 2,3-dimethyl-but-2-enyl, ( Z )-pent-2-enyl, ( E )-pent-1-enyl, ( Z )-hex-1-enyl, ( E )-pent-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)-Hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group that is substituted at any possible connection point by one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, haloalkyl (i.e., alkyl groups carrying monohalogen or polyhalogen substituents, such as CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R.b and R c Together with the N atoms that are optionally bonded to them, they form heterocycles; and R e Each occurrence of the substance is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substitutions can be optionally substituted.

[0110] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary examples of such groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, pent-1-alkynyl, pent-2-alkynyl, hex-1-alkynyl, hex-2-alkynyl, and hex-3-alkynyl. "Substituted alkynyl" refers to an alkynyl group that is substituted at any possible linking point by one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., monohalogen or polyhalogen substituents, in the latter case forming a group such as CF3 or an alkyl group carrying CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR dS(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c Together with the N atoms that are optionally bonded to them, they form heterocycles; and R e Each occurrence of the substance is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substitutions can be optionally substituted.

[0111] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings, each ring having 3 to 8 carbons. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group whose junctions are substituted by one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., monohalogen or polyhalogen substituents, in the latter case forming a group such as CF3 or an alkyl group carrying CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R aC(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c Together with the N atoms that are arbitrarily bonded to them, they form heterocycles; R e Each occurrence of the is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents can be optionally substituted themselves. Exemplary substituents also include spiro-linked or fused-ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents can be optionally substituted themselves.

[0112] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group comprising 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group in which one or more substituents, preferably 1 to 4 substituents, are substituted at any possible connection point. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., monohalogen or polyhalogen substituents, in the latter case forming a group such as CF3 or an alkyl group carrying CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R eS(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c Together with the N atoms that are optionally bonded to them, they form heterocycles; and R e Each occurrence of the is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents can be optionally substituted themselves. Exemplary substituents also include spiro-linked or fused-ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents can be optionally substituted themselves.

[0113] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, particularly a monocyclic or bicyclic group, such as phenyl, biphenyl, or naphthyl. In cases containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be single-point connected (e.g., biphenyl) or fused (e.g., naphthyl, phenanthryl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, wherein two adjacent aromatic rings share two common carbon atoms. "Substituted aryl" refers to an aryl group that is substituted at any possible connection point by one or more substituents, preferably one to three substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., monohalogen or polyhalogen substituents, in the latter case forming a group such as CF3 or an alkyl group carrying CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R aor NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c Together with the N atoms that are optionally bonded to them, they form heterocycles; and R e Each occurrence of the substituent is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents can be optionally substituted themselves. Exemplary substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl groups, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents can be optionally substituted themselves.

[0114] 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 some embodiments, the number of ring atoms in the heteroaryl ring and / or aryl ring is used to specify the size of the aryl or heteroaryl ring in the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a five-membered heteroaryl group is linked to a six-membered aryl group. Other combinations and ring sizes may be specified similarly.

[0115] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group comprising one to four rings, each with three to eight carbon atoms, or a cyclic aromatic hydrocarbon group having one to five aromatic rings, particularly monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. The term "carbocycle" includes cycloalkyl, cycloalkenyl, cycloynyl, and aryl groups as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group that is substituted at any possible connection point by 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 cycloynyl, and substituted aryl groups. Exemplary substituents also include spiro-linked or fused cyclic substituents at any possible one or more connection points, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents themselves can be optionally substituted.

[0116] The terms "heterocycle" and "heterocyclic" refer to a fully saturated, partially or fully unsaturated, aromatic (i.e., "heteroaryl") cyclic group (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) having at least one heteroatom in a ring containing at least one carbon atom. Each ring of the heterocyclic group can be independently saturated, partially or fully unsaturated. Each ring of a heterocyclic group containing a heteroatom can have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group carrying a quaternary nitrogen atom and thus being positively charged). The heterocyclic group can be attached to any heteroatom or carbon atom of the ring or ring system to the rest of the molecule. Exemplary monocyclic heterocyclic groups include azahexacyclic butyl, pyrrolyl, pyrroleyl, pyrazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolyl, oxazolinyl, oxazolinyl, isoxazolinyl, isoxazolinyl, thiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, isothiazolyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazine, 2-oxo Piperazinyl, 2-oxopiperidinyl, 2-oxopyrrolyl, 2-oxoazazyl, azazyl, hexahydrodiazazyl, 4-piperidinoneyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothiopheneyl, etc. Exemplary bicyclic heterocyclic groups include indoleyl, indolinyl, isoyindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothiapheneyl, benzo[ d [1,3]dioxacyclopentenyl, dihydro-2H-benzo[ b [1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxanedienyl, quininecycloyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indazine, benzofuranyl, benzofuranyl, dihydrobenzo[ d Oxazole, cronidone, coumarin, benzopyranyl, cyclopyridinyl, quinoxalinyl, indazole, pyrrolopyridinyl, furanopyridinyl (e.g., furano[2,3-c]pyridinyl, furano[3,2-b]pyridinyl or furano[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinazolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazole, benzoindolyl, phenanthrolinyl, acridine, phenanthidine, xanthonyl, etc.

[0117] "Substituted heterocycle" (e.g., "substituted heteroaryl") refers to a heterocycle or heterocyclic group whose junctions are substituted by one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., monohalogen or polyhalogen substituents, in the latter case forming a group such as CF3 or an alkyl group carrying CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R aEach occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c Together with the N atoms that are optionally bonded to them, they form heterocycles; and R e Each occurrence of the substituent is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents can be optionally substituted themselves. Exemplary substituents also include spiro-linked or fused-ring substituents at any possible connection point, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents can be optionally substituted themselves.

[0118] The term "oxo" refers to Substituent groups can be attached to carbocyclic or heterocyclic atoms. When an oxo-substituent group is attached to a carbocyclic atom of an aromatic group (e.g., aryl or heteroaryl), the bonds on the aromatic ring can be rearranged to meet the required valence. For example, pyridine with a 2-oxo-substituent group can have a structure... It also includes its tautomer forms. .

[0119] 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, isopropylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, etc.

[0120] The term "dialkylamino" refers to a group having the structure -NRR', wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic as defined herein. R and R' may be the same or different in the dialkylamino moiety. Examples of dialkylamino groups include, but are limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)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, etc. In some embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, azacyclopropane, pyrrolyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0121] The term "halogen" or "halogenated" refers to chlorine, bromine, fluorine, or iodine.

[0122] The term "substituted" refers to a molecule, a molecular part, or a substituent group (e.g., alkyl group). 、 Embodiments in which cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl groups, or any other groups disclosed herein, are substituted at any possible linking point with one or more substituents, preferably 1 to 6 substituents, where valence permits. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., monohalogen substituents or polyhalogen substituents, in the latter case forming groups such as CF3 or alkyl groups carrying CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)Ra C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c Together with the N atoms that are optionally bonded to them, they form heterocycles; and R e Each occurrence of the group is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aryl. In the exemplary substituents described above, groups such as alkyl, cycloalkyl, alkenyl, ynyl, cycloalkenyl, heterocyclic, and aryl can themselves be optionally substituted. The term "optionally substituted" refers to a molecule, a molecular portion, or a substituent group (e.g., alkyl) where the substituent group is alkyl. 、 Embodiments in which cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl groups or any other groups disclosed herein may or may not be substituted by one or more of the substituents described above.

[0123] Unless otherwise stated, it is assumed that any heteroatom having a non-valenced valence has a hydrogen atom that is sufficient to satisfy the valence.

[0124] The compounds of the present invention can form salts, which are also within the scope of the present invention. Unless otherwise stated, references to the compounds of the present invention are understood to include references to their salts. As used herein, the term "salt" means an acidic and / or basic salt formed with inorganic and / or organic acids and bases. Furthermore, when the compounds of the present invention comprise both a basic moiety (e.g., but not limited to pyridine or imidazole) and an acidic moiety (e.g., but not limited to carboxylic acids), zwitterions ("internal salts") can be formed and included within the term "salt" as used herein. Although other salts are also useful, pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, for example, in the separation or purification steps that may be used in the preparation process. Salts of the compounds of the present invention can be formed, for example, by reacting the compounds described herein with a certain amount of an acid or base (e.g., an equivalent) in, for example, a salt precipitation medium or an aqueous medium, followed by lyophilization.

[0125] The compounds of the present invention contain a basic moiety, such as, but not limited to, an amine, pyridine, or an imidazole ring, which can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (e.g., those formed with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucono-p-ethyl, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromates, hydroiodates, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, and naphthalenesulfonates (e.g., 2-naphthalenesulfonate). Nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those that form with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates, such as tosylates, undecanoates, etc.

[0126] The compounds of the present invention containing an acidic moiety, such as, but not limited to, phenol or carboxylic acids, can form salts with a variety of organic and inorganic bases. Exemplary basic 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 formed with organic bases (e.g., organic amines) such as benzathines, dicyclohexylamine, hydrabamines (formed with N,N-bis(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide).

[0127] Prodrugs and solvates of the compounds of the present invention are also considered herein. As used herein, the term "prodrug" refers to a compound that, upon administration to a subject, undergoes a metabolic or chemical transformation 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.

[0128] The compounds of the present invention and their salts or solvates may exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are considered part of the invention herein. As used herein, any descriptive structure of a compound includes its tautomeric form.

[0129] All stereoisomers of the compounds of the present invention (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomers and diastereomers, are contemplated within the scope of the invention. The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers with specific activities), or may be mixed, for example, as racemates or with all other or other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. Racemate forms may be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. The individual optical isomers may be obtained from the racemate by any suitable method, including but not limited to conventional methods, such as forming a salt with an optically active acid followed by crystallization.

[0130] The compounds of the present invention, after their preparation, are preferably isolated and purified to obtain a composition containing an amount equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% by weight of the compound (“substantially pure” compound), which is then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also considered part of the present invention herein.

[0131] All configurational isomers of the compounds of this invention are considered, whether in mixtures or in pure or substantially pure form. The definition of compounds of this invention includes cis( Z ) and trans ( E ) olefin isomers, and cis and trans isomers of cyclic hydrocarbons or heterocycles.

[0132] Throughout the specification, its groups and substituents can be selected to provide stable moieties and compounds.

[0133] This document describes the definitions of specific functional groups and chemical terms in more detail. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, Handbook of Chemistry and Physics The 75th edition, identified by its inner cover, and the specific functional groups are generally as defined therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0134] Certain compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof falling within the scope of this 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 this invention.

[0135] According to the present invention, mixtures of isomers comprising any ratio of multiple isomers can be used. For example, 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 considered in the present invention when only two isomers are mixed. Those skilled in the art will readily understand that similar ratios are expected for more complex mixtures of isomers.

[0136] This invention also includes isotopically labeled compounds that are identical to those disclosed herein, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, […]. 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. All compounds of the present invention, or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates, comprising the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those doped with radioactive isotopes such as… 3 H and 14 Those of C can be used for drug and / or substrate tissue distribution determination. Tritium-based... 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (e.g., deuterium, i.e., 2 H) Substitution can provide certain therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in certain situations. Isotope-labeled compounds can typically be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents by performing the procedures disclosed in the following schemes and / or examples.

[0137] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by chiral derivatization, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric isomer is then resolved by fractional crystallization or chromatographic means known in the art, and the pure enantiomer is subsequently recovered.

[0138] It should be understood that compounds described herein can be substituted with any number of substituents or functional portions. Generally, the term "substituted" refers to the substitution of a hydrogen group in a given structure with the group of a particular substituent, regardless of whether it is preceded by the term "optionally" and the substituent included in the formula of the invention. When more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituents at each position can be the same or different. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For the purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds that satisfy the heteroatom valence as described herein. Furthermore, the invention is not intended to be limited in any way by the permissible substituents of organic compounds. The combinations of substituents and variables contemplated in this invention are preferably those that result in the formation of stable compounds that can be used to treat, for example, proliferative disorders. As used herein, the term "stable" preferably refers to a compound that has sufficient stability to allow for manufacture and that maintains its integrity for a period of time sufficient to be detected and preferably for the purposes detailed herein.

[0139] As used herein, the term “cancer” and the equivalent “tumor” refer to a condition in which abnormal replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant. Cancer 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; kidney (renal) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other cancers and sarcomas. Cancer can be primary or metastatic. Diseases other than cancer may be associated with mutational alterations in components of the Ras signaling pathway, and the compounds disclosed herein may be used to treat these non-cancer diseases. Such non-cancerous conditions may include: neurofibromatosis; panther syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; Cardio-facio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformations—arteriovenous malformations.

[0140] As used herein, "effective amount" means any amount necessary or sufficient to achieve or promote a desired outcome. In some cases, effective amount is therapeutically effective amount. Therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application can vary depending on factors such as the disease or condition being treated, the specific agent administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can determine the effective amount of a particular agent empirically without excessive experimentation.

[0141] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammal class. 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, domesticated animals, and undomesticated animals.

[0142] compound

[0143] Novel compounds as Kv1.3 potassium channel blockers are described. The applicant has found, surprisingly, that the disclosed compounds exhibit potent Kv1.3 potassium channel inhibitory properties. Furthermore, the applicant has found, surprisingly, that the disclosed compounds selectively block Kv1.3 potassium channels without blocking hERG channels, thus possessing the desired cardiovascular safety characteristics.

[0144] On one hand, compounds of formula I or their pharmaceutically acceptable salts are described.

[0145]

[0146] in

[0147] Each occurrence of Y is independently C(R4)2, NR4, O, S, SO, SO2 or SO(=NR)2. a );

[0148] Z is OR a ;

[0149] X1 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0150] X2 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0151] Each occurrence of X3 is independently H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0152] R1 and R2 are each independently H, alkyl, or (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 ;

[0153] Each occurrence of R4 is independently of H, halogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, 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 a 5- or 6-membered heterocycle containing 1-3 heteroatoms each selected from N, O and S with optional substitutions;

[0154] Or two R4s together form an optionally substituted carbocyclic ring, saturated heterocyclic ring, or heteroaryl group containing 0-3 heteroatoms each selected from N, O, and S;

[0155] Each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0156] Ra and R b Each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, haloalkyl, halocycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or alternatively, R a and R b Together with the nitrogen atoms to which they are attached, they form optionally substituted heterocycles, the heterocycles comprising the nitrogen atoms and 0-3 additional heteroatoms each selected from N, O and S;

[0157] Where valence permits, the alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 1 to 4 substituents, each independently selected from the following: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 And oxygenation;

[0158] As long as the valence allows, each occurrence of n1 is an independent integer between 0 and 4;

[0159] Each occurrence of n3 is an independent integer between 0 and 4; and

[0160] Each occurrence of n4 is independently 0, 1, or 2.

[0161] In some implementations, n1 is an integer from 1 to 4. In some implementations, n1 is an integer from 1 to 3. In some implementations, n1 is 1 or 2. In some implementations, n1 is 1. In some implementations, n1 is 0.

[0162] In some implementations, n3 is an integer from 0 to 4. In some implementations, n3 is an integer from 1 to 3. In some implementations, n3 is 0. In some implementations, n3 is 1 or 2. In some implementations, n3 is 1.

[0163] In some implementations, n4 is an integer between 0 and 2. In some implementations, n4 is 0. In some implementations, n4 is 2. In some implementations, n4 is 1.

[0164] In some implementation schemes, the structural portion Having structure The various substituents are defined herein. In some embodiments, the structural portion Having structure In some implementations, the structural portion Having structure In some implementations, the structural portion Having structure In some implementations, the structural portion Having structure .

[0165] In some embodiments, Y is C(R4)2. In other embodiments, Y is NR4. In still other embodiments, Y is 0. In yet other embodiments, Y is S, SO, SO2, 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.

[0166] In some implementation schemes, the structural portion Having structure In other implementations, the structural portion Having structure In other implementation schemes, the structural portion Having structure ;where R x R4. In some specific implementations, the structural portion Having structure In some specific implementations, the structural portion Having structure .

[0167] In some implementation schemes, the structural portion Having structure ;where R x R4. In some specific implementations, the structural portion Having structure In some specific implementations, the structural portion Having structure In some specific implementations, the structural portion Having structure .

[0168] In some embodiments, R1 and R2 are each H or an alkyl group. In some embodiments, both R1 and R2 are H. In some embodiments, R1 and R2 are alkyl groups, such as Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In some embodiments, R1 and R2 are H and an alkyl group, respectively.

[0169] In some implementations, R1 and R2 appear at least once in the form of (CR6R7). n3 OR a Or (CR6R7) n3 NR a R b In some implementations, R1 and R2 appear at least once as H.

[0170] In some implementations, R1 and R2 are independently H, (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 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 H and Me.

[0171] In some implementations, at least one occurrence of R4 is independently (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 implementations, at least one occurrence of R4 is independently (CR6R7). n3 NR a(C=O)R b Or (CR6R7) n3 (C=O)NR a R b In some implementations, at least one occurrence of R4 is independently (CR6R7). n3 OR a Or (CR6R7) n3 NR a R b In some implementations, at least one occurrence of R4 independently constitutes OR. a NR 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, R4 appears at least once as CH2NH2, In other specific embodiments, R4 appears at least once in the form of CH2OH, CH2NH2, .

[0172] In other embodiments, R4 occurs at least once as an optionally substituted 4-, 5-, or 6-membered heterocycle containing 1 to 3 heteroatoms each selected from N, O, and S. In a further embodiment, R4 occurs at least once as a heterocycle selected from:

[0173]

[0174] Where the valence allows, the heterocycle is optionally converted by an alkyl group, OH group, oxo group, or (C=O)C group. 1-4 Alkyl substitution. In a further embodiment, the two R4s together form an optionally substituted carbocyclic, saturated heterocyclic, or heteroaryl group containing 0-3 heteroatoms each selected from N, O, and S.

[0175] In some embodiments, R4 appears at least once as H, alkyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, CF3, OCF3, OR a (CR6R7) n3 OR a Or oxidative oxidation. In some embodiments, R4 occurs at least once as (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 .

[0176] In some specific embodiments, R4 appears at least once as 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) n3SO2NR a R b (CR6R7) n3 SO2R a Oxygenated or (CR6R7) n3 (C=O)NR a R b In some embodiments, R4 occurs at least once independently as H or an alkyl group.

[0177] In some specific implementations, R4 is H, halogen, alkyl, or OR. a NR a R b Or oxidized. 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, NNEt2, or oxidized. In yet another specific embodiment, R4 appears at least once as H, halogen, alkyl, OH, NH2, CN, CF3, OCF3, CONH2, CONHMe2, or CONMe2.

[0178] In other embodiments, the two R4 groups together with the two carbon atoms to which they are attached form a fused bicyclic system having the following structure: Where A is a 3-7 member, optionally substituted carbocyclic, saturated heterocyclic, or heteroaryl group. In some embodiments, the structural unit... Having structure .

[0179] In some embodiments, each occurrence of R6 and R7 is independently H or an alkyl group. In some specific embodiments, CR6R7 is CH2, CHMe, CMe2, CHEt, or CEt2. In some specific embodiments, CR6R7 is CH2.

[0180] In some implementations, Z stands for OR a In some implementations, Z is OH or OMe. In some implementations, Z is OH.

[0181] In some embodiments, X1 is H, a halogen, CN, an alkyl group, a haloalkyl group, a cycloalkyl group, or a halocycloalkyl group. In any embodiment described herein, X1 can be H, a halogen, a fluoroalkyl group, or an alkyl group. In some embodiments, X1 is H or a halogen. In other embodiments, X1 is a fluoroalkyl group or an alkyl group. In other embodiments, X1 is a cycloalkyl group. 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.

[0182] In some embodiments, X2 is H, a halogen, CN, an alkyl group, a haloalkyl group, a cycloalkyl group, or a halocycloalkyl group. In any embodiment described herein, X2 can be H, a halogen, a fluoroalkyl group, or an alkyl group. In some embodiments, X2 is H or a halogen. In other embodiments, X2 is a fluoroalkyl group or an alkyl group. In other embodiments, X2 is a cycloalkyl group. 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.

[0183] In some embodiments, each occurrence of X3 is independently H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In any of the embodiments described herein, X3 can be H, halogen, fluoroalkyl, or alkyl. In some embodiments, X3 is H or halogen. In other embodiments, X3 is fluoroalkyl 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.

[0184] In some implementation schemes, the structural portion Having structure .

[0185] In some implementations, Z is OH or OMe. In some implementations, Z is OH.

[0186] In any of the embodiments described herein, R a or R bAt least once, it independently consists of H or an optionally substituted alkyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl group. In some embodiments, R... a or R b The occurrence of at least one of these independently is H, Me, Et, Pr, or Bu. In some implementations, R a or R b At least one occurrence of the substance is independently selected from the following heterocycles:

[0187]

[0188] Where the valence allows, the heterocycle is optionally converted by an alkyl group, OH group, oxo group, or (C=O)C group. 1-4 Alkyl substitution.

[0189] In some implementation schemes, R a and R b Together with the nitrogen atom to which they are attached, they form optionally substituted heterocycles, which contain the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

[0190] In some embodiments, the compound of formula I is selected from compounds 1-66 shown in Table 1 below.

[0191] abbreviation

[0192] ACN Acetonitrile Boc tert-butoxycarbonyl DCE dichloroethane DCM dichloromethane DIBAL-H Diisobutylaluminum hydride DMF dimethylformamide EA Ethyl acetate HATU -[(dimethylamino)(3-1,2,3-triazolo(4,4-b)pyridin-3-yloxy)methylene]-methylmethylammonium hexafluorophosphate LDA Lithium diisopropylaminodimethylamine PE petroleum ether PMHS polymethylhydrosiloxane TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran

[0193] Preparation method

[0194] The following are general synthetic schemes for producing 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 produce the compounds disclosed herein. Different methods will be apparent to a person skilled in the art. Furthermore, the various steps in the synthesis may be performed in an alternating order or sequence to obtain the desired compound. All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrative and not limiting to the preparation of some of the starting materials and compounds disclosed herein.

[0195] The following embodiments 1-3 describe synthetic routes that can be used to synthesize the compounds of the present invention, such as compounds having the structure of Formula I or precursors thereof. Those skilled in the art will envision various modifications to these methods to obtain results similar to those of the present invention given below. In the following embodiments, the synthetic routes are described using compounds having the structure of Formula I or precursors thereof as examples. The general synthetic routes described in embodiments 1-3 and the examples described in the Examples section below illustrate methods for preparing the compounds described herein.

[0196] Compounds I-1 and I-3 shown in Scheme 1 below can be prepared and / or are commercially available by any method known in the art. The substituents shown in Scheme 1 are defined herein. Compounds disclosed herein where R1 and R2 are H can be prepared 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 such as TEA in a solvent such as ACN. The reductive amination of aryl aldehyde I-2a with cyclic amine I-3 can be carried out with a reducing agent such as sodium triacetoxyborohydride in a solvent such as DCE, or using PMHS and tin chloride in a solvent such as methanol. For compounds disclosed herein where Z is OH, the reductive amination step does not require a protecting group. For compounds disclosed herein where R4 contains an amino group, the amine can be protected with a protecting group such as Boc or trifluoroacetamide. Any other amine protecting group known in the art can be used. The protecting group is then removed after the reductive amination step.

[0197]

[0198] Compounds I-2c and I-3 as shown in Scheme 2 below can be prepared and / or are commercially available by any method known in the art. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as an OH protecting group. 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 reacting it with a Grignard reagent R1MgBr. The resulting alcohol I-5 is then converted to bromide I-6 using a brominating agent such as phosphorus tribromide. I-6 reacts with cyclic amine I-3 in the presence of a base such as potassium carbonate in a solvent such as DMF to give I-4c (Scheme 2). In some embodiments, this method can also be used for compounds in which both R1 and R2 are H.

[0199]

[0200] Compounds I-1b and I-3, as shown in Scheme 3 below, can be prepared and / or are commercially available by any method known in the art. As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as an OH protecting group. 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. Phenol I-1b reacts with ethyl glyoxylate in a Lewis acid such as titanium tetrachloride in a solvent such as DCM to give alcohol I-5b. The phenolic group in I-5b is then selectively protected, for example, as an ether such as methyl or allyl ether I-5c. I-5c is converted to bromide I-6b in a solvent such as DCM using a brominating agent such as phosphorus tribromide. The reaction of I-6b with amine I-3 provides I-4d. The ester group in I-4d can be converted into various R1 groups, such as amide, hydroxymethyl, or aminomethyl, using methods known in the art. Optionally, the protecting group PG can be removed to provide a compound of formula I.

[0201]

[0202] The reactions described in Schemes 1-3 above can be carried out in suitable solvents. 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 to 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 cold bath at temperatures below room temperature, such as 0, -10, -20, -30, -40, -50, -78, or -90 °C. The reaction can be carried out by removing the solvent or partitioning the organic solvent phase with one or more aqueous phases, each aqueous phase optionally containing NaCl, NaHCO3, or NH4Cl. The solvent in the organic phase can be removed by vacuum evaporation, and the resulting residue can be purified using silica gel column chromatography or HPLC.

[0203] Pharmaceutical Composition

[0204] 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.

[0205] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from the compounds of Formula I described herein, and a pharmaceutically acceptable carrier or diluent.

[0206] In some embodiments, the composition is in the form of a hydrate, a solvate, or a pharmaceutically acceptable salt. The composition may be administered to the subject via any suitable route of administration, including but not limited to oral and parenteral administration.

[0207] As used herein, the phrase “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, relating to the carrying or transport of the subject pharmaceutical agent from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation and harmless 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; 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 glycerol, 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; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. The term "carrier" refers to an organic or inorganic component, natural or synthetic, to which an active ingredient is bound to facilitate application. The components of the pharmaceutical composition can also be mixed with the compounds of the present invention, and mixed with each other, in a manner that does not significantly impair the desired efficacy.

[0208] As described above, certain embodiments of the pharmaceutical preparations of the present invention can be provided in the form of pharmaceutically acceptable salts. In this regard, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic acid addition salt of the compounds of the present invention. These salts can be prepared in situ during the final separation and purification of the compounds of the present invention, or by reacting the purified free base form of the present invention with a suitable organic or inorganic acid and separating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylformate, methanesulfonate, glucono-p-ethyl, lacturonate, and laurylsulfonate, etc. (See, for example, Berge et al., (1977) "Pharmaceutical Salts") J. Pharm. Sci.66:1-19.

[0209] Pharmaceutically acceptable salts of the subject compound include conventional non-toxic salts or quaternary ammonium salts of the compound, such as those derived from non-toxic organic or inorganic acids. Examples of conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, butionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionic acid, etc.

[0210] In other cases, the compounds of the present invention may contain one or more acidic functional groups, and thus be capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic base addition salt of the compounds of the present invention. These salts can also be prepared in situ during the final separation and purification of the compounds, or by reacting the purified compound in its purified free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al., supra.).

[0211] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polybutane copolymers, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0212] The formulations of the present invention include those suitable for oral, nasal, topical (including oral and sublingual), rectal, vaginal, and / or parenteral administration. The formulations can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Typically, in 100%, this amount is from about 1% to about 99%, preferably from about 5% to about 70%, and most preferably from about 10% to about 30% of the active ingredient.

[0213] Methods for preparing these formulations or compositions include the step of combining the compounds of the present invention with a carrier and optionally one or more auxiliary components. Typically, formulations are prepared by uniformly and tightly combining the compounds of the present invention with a liquid carrier or a finely chopped solid carrier, or both, and then, if desired, shaping the product.

[0214] Formulations of the present invention suitable for oral administration may be in the form of capsules, sachets, pills, tablets, lozenges (using a flavoring base, typically sucrose and gum arabic or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as sugar lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as large pills, licks, or pastes.

[0215] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration of the present invention, 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 silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; and humectants. Examples of active ingredients include: glycerin; disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, sodium carbonate, and sodium starch glycolate; solution blockers such as paraffin; absorption enhancers such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glyceryl monostearate, and polyethylene oxide-polybutane copolymers; absorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose (lactose or milk sugars) and high molecular weight polyethylene glycol.

[0216] Tablets can be prepared by compression or molding, optionally using one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxybutyl methyl cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0217] The pharmaceutical compositions of the present invention, in tablet and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated to provide a slow or controlled release of the active ingredient therein, for example using varying proportions of hydroxybutyl methylcellulose to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacterial trap filter, or by the addition of a sterilizing agent in the form of a sterile solid composition, which may be dissolved immediately in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain a light-blocking agent and may be compositions in which they optionally release the active ingredient in a delayed manner only or preferably in a specific portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. If suitable, the active ingredient may also be in a microencapsulated form with one or more of the excipients described above.

[0218] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isobutanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butanediol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitol and mixtures thereof. Furthermore, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, may be used to dissolve the compounds.

[0219] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aromatizers and preservatives.

[0220] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0221] The dosage forms for topical or transdermal administration of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds can be mixed under aseptic conditions with pharmaceutically acceptable carriers and any preservatives, buffers, or propellants that may be required.

[0222] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0223] In addition to the compounds of this invention, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Aerosols may additionally contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and butane.

[0224] Transdermal patches offer the added advantage of controlled delivery of the compounds of the present invention to the body. This dosage form can be prepared by dissolving or dispersing the agent in a suitable medium. Absorption enhancers can also be used to increase the flux of the agents of the present invention through the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0225] Ophthalmic preparations, eye ointments, powders, solutions, etc., are also considered to be within the scope of this invention.

[0226] The pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more of the compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions prior to use, wherein may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0227] In some cases, to prolong the effect of a drug, it is necessary to slow its absorption from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The rate of drug absorption depends on its dissolution rate, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of parenteral administration can be achieved by dissolving or suspending the drug in an oil-based medium. One strategy for long-acting depot injection involves using polyethylene oxide-polypropylene oxide copolymers, where the medium is fluid at room temperature and solidifies at body temperature.

[0228] Injectable, long-acting formulations are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolic acid. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Long-acting injectable formulations can also be prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0229] When the compounds of the present invention are given to humans and animals as drugs, they may be given on their own or as a pharmaceutical composition 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.

[0230] The compounds and pharmaceutical compositions of the present invention can be used for combination therapy, i.e., the compounds and pharmaceutical compositions can be administered simultaneously, before, or after one or more other desired treatments or medical procedures. The specific combination of therapies (therapies or procedures) employed in the combination regimen will take into account the compatibility of the desired therapies and / or procedures and the desired therapeutic effect to be achieved. It should also be understood that the therapies employed can achieve the desired effect on the same obstacle (e.g., the compounds of the present invention can be administered simultaneously with another anticancer agent).

[0231] The compounds of this invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. These compounds can be used to treat arthritis conditions in mammals (e.g., humans, livestock, and domesticated animals), racehorses, birds, lizards, and any other organisms that can tolerate the compounds.

[0232] The present invention also provides a pharmaceutical package or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical composition of the present invention. Optionally associated with such containers may be a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, reflecting the approval of the manufacturing, using, or selling agency for human administration.

[0233] Dosing to subjects

[0234] In another aspect, the present invention provides a method for treating a condition in mammals in need, the method comprising administering to the mammal a therapeutically effective amount of at least one compound selected from compounds of formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0235] In some implementation schemes, the cancer is selected from bile duct 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, kidney (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

[0236] In some implementations, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy. In some implementations, the gastrointestinal disorder is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis.

[0237] In some implementations, the immunological disorder is transplant rejection or an autoimmune disease (such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type 1 diabetes). In some implementations, the central nervous system (CNS) disorder is Alzheimer's disease.

[0238] In some implementations, the metabolic disorder is obesity or type II diabetes. In some implementations, the cardiovascular disorder is ischemic stroke. In some implementations, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0239] In some implementations, the mammal class is defined as humans.

[0240] In some implementations, the condition is selected from 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.

[0241] In another aspect, methods for blocking Kv1.3 potassium channels in desired mammals are described, including administering a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof to the mammal.

[0242] In some embodiments, the compounds described herein selectively block Kv 1.3 potassium channels and have 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 hERG channels and therefore possess the desired cardiovascular safety properties.

[0243] Some aspects of the present invention relate to administering an effective amount of the composition to a subject to achieve a specific outcome. The small molecule compositions useful according to the method of the invention can therefore be formulated in any manner suitable for pharmaceutical use.

[0244] The formulations of the present invention are administered in a pharmaceutically acceptable solution, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optional other therapeutic ingredients.

[0245] For therapeutic use, an effective amount of the compound may be administered to the subject in any manner that allows the compound to be taken up by suitable target cells. The "administration" of the pharmaceutical composition of the present invention may be accomplished in any manner known to those skilled in the art. Specific routes of administration include, but are not limited to, oral, transdermal (e.g., via patch), parenteral (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, rectal, vaginal, etc.). Injection may be a single bolus infusion or a continuous infusion.

[0246] For example, pharmaceutical compositions according to the invention are typically administered intravenously, intramuscularly, or otherwise parenterally. They can also be administered via nasal application, inhalation, topical administration, oral administration, or as implants, and even rectal or vaginal use is possible. Suitable liquid or solid pharmaceutical formulations are, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, coated, coated on microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation in the skin, or dried onto a sharp object for dipping into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or formulations having sustained release of the active compound, in which excipients and additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers are typically used as described above. The pharmaceutical compositions are suitable for a variety of drug delivery systems. For a brief review of the drug delivery methods of the invention, see Langer R (1990). Science 249:1527-33, which are incorporated in this article for reference.

[0247] The concentration of compounds included in the compositions used in the methods of the present invention can range from about 1 nM to about 100 M. The effective dose is believed to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0248] 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. For the treatment of a patient, different dosages may be required depending on the activity of the compound, the route of administration, the purpose of administration (i.e., prophylactic or therapeutic), the nature and severity of the disorder, the patient's age, and weight. Administration of a given dose can be achieved either by a single dose in the form of a single dosage unit or by a single dose in the form of several smaller dosage units. The invention also considers repeated and multiple administrations at specific intervals of days, weeks, or months.

[0249] The composition may be administered either as is (pure) or as a pharmaceutically acceptable salt. When used in medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be conveniently used to prepare their 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. Furthermore, such salts may be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts of a carboxylic acid group.

[0250] Suitable buffers include: acetic acid and its salt (1-2% w / v); citric acid and its salt (1-3% w / v); boric acid and its salt (0.5-2.5% w / v); and phosphoric acid and its salt (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).

[0251] Compositions suitable for parenteral administration conveniently include sterile aqueous formulations that are isotonic with the recipient's blood. Acceptable mediators and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile mineral or non-mineral oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid can be used to prepare injectable formulations. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc., administration can be... Remington's Pharmaceutical Sciences Found at Mack Publishing Company, Easton, PA.

[0252] The compounds that can be used in this invention can be delivered in the form of a mixture of more than two such compounds. In addition to the combination of compounds, the mixture may also include one or more adjuvants.

[0253] Multiple routes of administration are available. The specific mode of administration chosen depends, of course, on the specific compound selected, the age and general health of the subject, the specific condition being treated, and the dosage required for therapeutic efficacy. Generally, the method of the present invention can be implemented using any medically acceptable route of administration, meaning any method that produces an effective level of response without causing clinically unacceptable side effects. Preferred routes of administration have been discussed above.

[0254] This composition can be readily available in unit dosage forms and can be prepared by any method well-known in the pharmaceutical field. All methods involve the step of binding the compound with a carrier constituting one or more auxiliary components. Generally, the composition is prepared by uniformly and tightly binding the compound with a liquid carrier, a fine-particle solid carrier, or both, and then, if desired, shaping the product.

[0255] Other delivery systems may include timed-release, delayed-release, or sustained-release delivery systems. Such systems can avoid repeated administration of compounds, increasing convenience for subjects 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-glycolic acid), copolyoxalate, polycaprolactone, polyesteramide, polyorthoester, polyhydroxybutyrate, and polyanhydride. Microcapsules containing the aforementioned polymers of a drug are described, for example, in U.S. Patent No. 5,075,109. Delivery systems also include non-polymer systems, which are: lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids, or neutral fats such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings; tablets using conventional adhesives and excipients; partially fused implants, etc. Specific examples include, but are not limited to: (a) erosion systems in which the agents of the present invention are contained in a matrix-bound form, 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 component permeates from the polymer at a controlled rate, as described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. Furthermore, pump-based hardware delivery systems can be used, some of which are suitable for implantation.

[0256] Efficacy determination of Kv1.3 potassium channel blockers

[0257] In some embodiments, the activity of the compounds described herein against Kv1.3 potassium channels is tested. In some embodiments, the electrophysiological activity of the compounds described herein against Kv1.3 potassium channels is tested. In some embodiments, the hERG electrophysiological activity of the compounds described herein is tested.

[0258] equivalent

[0259] The representative embodiments described below are intended to help illustrate the invention and are not intended to, nor should they be construed as, limiting the scope of the invention. In fact, various modifications to the 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 entirety of this document, including the following embodiments and the scientific and patent references cited herein. It should also be understood that the contents of those cited references are incorporated herein by reference to aid in the illustration of the technical situation. The following embodiments contain important additional information, examples, and guidance applicable to the practice of various embodiments of the invention and their equivalents. Example

[0260] Examples 1-2 describe the various intermediates used in the synthesis of the representative Formula I compounds disclosed herein.

[0261] Example 1. Intermediate 1 (4,5-Dichloro-2-hydroxybenzaldehyde)

[0262]

[0263] Step a:

[0264] Hexamethylenetetramine (47.50 g, 337.40 mmol) was added to a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol) in methanesulfonic acid (35 mL) at room temperature. The reaction solution was stirred at 110 °C for 30 min. The reaction solution was cooled to room temperature and quenched with water (500 mL). The resulting solution was extracted with DCM (3 x 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / DCM (10 / 1) to obtain intermediate 1 (4,5-dichloro-2-hydroxybenzaldehyde) (13.50 g, 23%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.98 (s, 1H), 9.85 (s, 1H), 7.66 (s, 1H), 7.16 (s, 1H).

[0265] Example 2. Intermediate 2 (1-(bromomethyl)-4,5-dichloro-2-methoxybenzene)

[0266]

[0267] Step a:

[0268] CH3I (11.10 g, 78.53 mmol) was added 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. The mixture was stirred at 30 °C for 2 h. The reaction was diluted with water (500 mL). The mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 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 with PE / EA (5 / 1) elution to obtain 4,5-dichloro-2-methoxybenzaldehyde (10.30 g, 96%) as a grayish-white solid: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H).

[0269] Step b:

[0270] To a solution of 4,5-dichloro-2-methoxybenzaldehyde (5.00 g, 24.39 mmol) in EtOH (40 mL) and THF (5 mL) at room temperature, NaBH4 (1.80 g, 48.88 mmol) was added. After stirring at room temperature for 1 h, the resulting solution was quenched with water (1 mL) at room temperature and diluted with a cosolvent of EA (80 mL) and water (100 mL). The separated aqueous layer was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (3 x 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (4,5-dichloro-2-methoxyphenyl)methanol (5.0 g, crude substance) as a pale yellow solid, which was used in subsequent steps without further purification.

[0271] Step c:

[0272] PBr3 (13.10 g, 48.30 mmol) was added to a stirred solution of (4,5-dichloro-2-methoxyphenyl)methanol (5.00 g, 24.15 mmol) in CH2Cl2 (40 mL) at room temperature. After stirring for 1 h at room temperature, the resulting solution was quenched with water (80 mL). The aqueous layer was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (3 x 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (4 / 1) elution to obtain intermediate 2 (1-(bromomethyl)-4,5-dichloro-2-methoxybenzene) (5.00 g, 69%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.37 (s, 1H), 6.93 (s, 1H), 4.42 (s, 2H), 3.86 (s, 3H).

[0273] Examples 3-28 describe the synthesis of representative Formula I compounds disclosed herein.

[0274] Example 3. Compound 2 ((1-(4,5-dichloro-2-hydroxybenzyl)piperidine-2,4-diyl)diethanol) Compound 1 (1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-2-carboxylic acid methyl ester)

[0275]

[0276] Step a:

[0277] PtO2 (10 mg, 10%) was added to a solution of methyl 4-(hydroxymethyl)pyridine-2-carboxylate (0.10 g, 0.60 mmol) in MeOH (5 mL) at room temperature under a nitrogen atmosphere. The mixture was degassed three times with hydrogen. The reaction mixture was stirred for 16 h at room temperature under a hydrogen atmosphere (5 atm). 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 reversed-phase chromatography by elution with 40% ACN / water containing 20 mM NH4HCO3. A faster eluent was obtained as a pale yellow oil form of piperidine-2,4-dimethyldiethanol (0.2 g, 20%): against C7H 15 NO2 [M +H] + Calculated LCMS (ESI): 146, measured value: 146;

[0278] A slower eluent was obtained as a pale yellow oil of methyl 4-(hydroxymethyl)piperidine-2-carboxylate (0.30 g, 30%): against C8H 15 NO3 [M + H] + Calculated LCMS (ESI): 174, measured value: 174;

[0279] Step b:

[0280] Intermediate 2 (0.50 g, 1.85 mmol) was added to a mixture of piperidine-2,4-diyldiethanol (0.35 g, 2.04 mmol) and K₂CO₃ (0.51 g, 3.70 mmol) in DMF (3 mL) at room temperature. The reaction mixture was heated 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 x 50 mL). The combined organic layers were washed with brine (3 x 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 by elution with DCM / MeOH (10 / 1) to obtain (1-(4,5-dichloro-2-methoxybenzyl)piperidine-2,4-diyl)diethanol (0.17 g, 28%) as a pale yellow oil: against C 15 H 21 Cl2NO3 [M + H] + Calculated LCMS (ESI): 334, 336 (3:2), measured value 334, 336 (3:2).

[0281] Step c:

[0282] BBr3 (0.56 g, 2.24 mmol) was added to a solution of (1-(4,5-dichloro-2-methoxybenzyl)piperidine-2,4-diyl)diethanol (0.15 g, 0.45 mmol) in DCM (1 mL) at room temperature. After stirring for 1 h at room temperature, the resulting mixture was quenched with saturated NaHCO3 aqueous solution (10 mL) at room temperature and extracted with DCM / MeOH (10 / 1) (5 x 10 mL) as a co-solvent. The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 60% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 7.44 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 2 ((1-(4,5-dichloro-2-hydroxybenzyl)piperidine-2,4-diyl)diethanol) (26 mg, 18%) as a grayish-white solid: against C 14 H 19 Cl2NO3 [M + H] + Calculated LCMS (ESI): 320, 322 (3:2); Measured values: 320, 322 (3:2); 1 H NMR (300 MHz, CD3OD) δ 7.15 (s, 1H), 6.85 (s, 1H), 4.44 (d, J = 14.4Hz, 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).

[0283] Step b':

[0284] At room temperature, methyl 4-(hydroxymethyl)piperidin-2-carboxylate (71 mg, 0.41 mmol) and K₂CO₃ (0.15 g, 1.11 mmol) in DMF (3 mL) were added to a mixture of methyl 4-(hydroxymethyl)piperidin-2-carboxylate (71 mg, 0.41 mmol) and K₂CO₃ (0.15 g, 1.11 mmol) in DMF (3 mL). 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 x 20 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 TLC (PE / EA 2 / 1) to obtain methyl 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(hydroxymethyl)piperidin-2-carboxylate (89 mg, 66%) as an off-white solid: against C 16 H 21 Cl2NO4 [M + H] + Calculated LCMS (ESI): 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 = 9.4Hz, 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':

[0286] BBr3 (0.43 g, 1.72 mol) was added dropwise 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) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched with water (10 mL) and the pH was adjusted to 7 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EA (3 x 20 mL). The combined organic layers were then 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 under the following conditions: column: XBridge C 18OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 80% B over 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 obtain compound 1 (methyl 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-2-carboxylate) (40 mg, 39%) as a grayish-white solid: against C 15 H 19 Cl2NO4 [M + H] + Calculated LCMS (ESI): 348, 350 (3:2); Measured values: 348, 350 (3:2); 1 H NMR (400 MHz, CD3OD) δ7.34 (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).

[0287] Example 4. Compound 3 (2-((4-amino-4-(aminomethyl)piperidin-1-yl)methyl)-4,5-dichlorophenol)

[0288]

[0289] Step a:

[0290] 2,2,2-trifluoroacetic anhydride (0.55 g, 2.62 mmol) was added to a stirred solution of tert-butyl 4-amino-4-(aminomethyl)piperidine-1-carboxylate (0.20 g, 0.87 mmol) and Et3N (0.44 g, 4.36 mmol) in DCM (4 mL) at room temperature. The reaction solution was stirred at room temperature for 1 h. The reaction mixture was quenched with water (30 mL) and 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 reversed-phase chromatography with 40% ACN / water (with 0.05% TFA) to obtain tert-butyl 4-(2,2,2-trifluoroacetamido)-4-[(2,2,2-trifluoroacetamido)methyl]piperidine-1-carboxylate (0.32 g, 78%) as a grayish-white solid: against C 15 H 21 F6N3O4 [M + H] + Calculated LCMS (ESI): 422, measured value: 422; 1 H NMR (300 MHz, DMSO-) d 6) 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- d 6) δ -73.75.

[0291] Step b:

[0292] TFA (1 mL) was added to a stirred solution of 0.32 g (0.76 mmol) of 4-(2,2,2-trifluoroacetamido)-4-[(2,2,2-trifluoroacetamido)methyl]piperidine-1-carboxylic acid tert-butyl ester (DCM) in 1 mL at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was concentrated under reduced pressure to obtain 2,2,2-trifluoro- N -[[4-(2,2,2-trifluoroacetamido)piperidin-4-yl]methyl]acetamide (0.12 g, crude substance): targeting C10 H 13 F6N3O2 [M + H] + Calculated LCMS (ESI): 322, measured value: 322.

[0293] Step c:

[0294] At room temperature, 2,2,2-trifluoro- N A stirred solution of 4-[[4-(trifluoroacetamyl)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 to HOAc (25 mg, 0.42 mmol) and NaBH(OAc)3 (0.24 g, 1.14 mmol). After stirring at room temperature for 2 h, the resulting mixture was quenched with water (10 mL) and extracted with EA (3 x 30 mL). The combined organic layers were then 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 TLC by elution with PE / EA (3 / 1) to obtain a light yellow solid. N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(trifluoroacetamido)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide (63 mg, 27%): for C 17 H 17 Cl2F6N3O3 [M + H] + Calculated LCMS (ESI): 496, 498 (3:2); Measured values: 496, 498 (3:2); 1 H NMR (300 MHz, DMSO- d 6) 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- d 6) δ -73.84, 74.00.

[0295] Step d:

[0296] At room temperature 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) was stirred and then added to a saturated aqueous solution of NaOH (2 mL). The reaction solution was stirred at room temperature for 2 h. The solution was then subjected to HCl aqueous solution (1... N The resulting solution was adjusted to pH 7 and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: X Bridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B over 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 obtain compound 3 (2-((4-amino-4-(aminomethyl)piperidin-1-yl)methyl)-4,5-dichlorophenol) (25.8 mg, 50%) as a grayish-white solid: against C 13 H 19 Cl2N3O [M + H] + Calculated LCMS (ESI): 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.

[0297] Example 5. Compound 4 (2-[2-amino-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]-4,5-dichlorophenol)

[0298]

[0299] Step a:

[0300] NaOH (32 mg, 0.80 mmol) was added 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 H₂O (0.2 mL) at room temperature. The reaction solution was stirred at room temperature for 16 h. The resulting solution was concentrated under reduced pressure to obtain sodium 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetate (0.10 g, crude substance) as a pale yellow solid, which was used directly in the following steps without further purification: for C 15 H 19 Cl2NO4 [M + H] + The calculated LCMS (ESI) is 348, 350 (3:2), and the measured value is 348, 350 (3:2).

[0301] Step b:

[0302] HATU (49 mg, 0.57 mmol), NH4Cl (31 mg, 0.57 mmol), and Et3N (58 mg, 0.57 mmol) were added 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) at room temperature. The reaction solution was stirred at room temperature for 16 h. 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 reversed-phase chromatography with elution of 33% ACN / water (with 0.05% TFA) to obtain 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetamide (50 mg, 45%) as a grayish-white solid: against C 15 H 20 Cl2N2O3 [M + H] + The calculated LCMS (ESI) is 347, 349 (3:2), and the measured value is 347, 349 (3:2).

[0303] Step c:

[0304] BH3·THF (0.75 mL, 0.75 mmol, 1 M in THF) was added 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. The reaction solution was heated 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 reversed-phase chromatography using 37% ACN / water (with 0.05% TFA) to obtain [1-[2-amino-1-(4,5-dichloro-2-methoxyphenyl)ethyl]piperidin-4-yl]methanol (70 mg, 47%) as a colorless oil: against C 15 H 22 Cl2N2O2 [M + H] + Calculated LCMS (ESI): 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 = 5.2Hz, 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).

[0305] Step d:

[0306] BBr3 (0.36 g, 1.44 mmol) was added 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) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with water (1 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 65% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 6.67 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 4 (2-[2-amino-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]-4,5-dichlorophenol) (14.1 mg, 17%) as a grayish-white solid: against C 14 H 20 Cl2N2O2 [M + H] + Calculated LCMS (ESI): 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).

[0307] Example 6. Compound 5 (2-[[4-(aminomethyl)-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol)

[0308]

[0309] Step a:

[0310] At room temperature 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) was added to a stirred solution of 2 mL MeOH with 0.5 mL of saturated aqueous NaOH solution. The reaction solution was stirred at room temperature for 2 h. The solution was then reacted with an aqueous HCl solution (1... NThe resulting solution was adjusted to pH 7 and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column, 100 Å, 10 µm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B over 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 obtain compound 5 (2-[[4-(aminomethyl)-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol) (38 mg, 67%) as a pale yellow solid: against C 14 H 20 Cl2N2O2 [M + H] + Calculated LCMS (ESI): 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).

[0311] Example 7. Compound 6 (4,5-dichloro-2-[[4-(hydroxymethyl)-4-[(pyrrolidin-1-yl)carbonyl]piperidin-1-yl]methyl]phenol)

[0312]

[0313] Step a:

[0314] TFA (2 mL) was added 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) at room temperature. After stirring at room temperature for 1 h, the resulting solution was concentrated under reduced pressure. The residue was diluted with water (10 mL) and the pH was adjusted to 7 with a saturated aqueous solution of K2CO3. 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 obtain 4-(hydroxymethyl)piperidine-4-carboxynitrile (0.10 g, crude substance) as a yellow oil, which was used in the following steps without further purification: for C7H12 N2O [M + H] + Calculated LCMS (ESI): 141, measured value: 141.

[0315] Step b:

[0316] HOAc (85 mg, 1.43 mmol) and NaBH(OAc)3 (0.90 g, 4.28 mmol) were added to a stirred solution of 4-(hydroxymethyl)piperidin-4-carboxynitrile (0.20 g, 1.43 mmol) and intermediate 1 (0.27 g, 1.43 mmol) in MeOH (3.5 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (2 / 3) to obtain 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-carboxynitrile (0.20 g, 60%) as a yellow solid. 14 H 16 Cl2N2O2 [M + H] + Calculated LCMS (ESI): 315, 317 (3:2); Measured values: 315, 317 (3:2); 1 H 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).

[0317] Step c:

[0318] 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carboxynitrile (0.15 g, 0.48 mmol) was stirred at 80 °C in an aqueous solution of HCl (3 mL, 12 mL). N The solution was incubated for 2 hours. After cooling to room temperature, the resulting solution was concentrated under reduced pressure to obtain 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carboxylic acid (0.12 g, crude substance) as a pale yellow solid, which was used in the following steps without further purification: for C 14 H 17 Cl2NO4[M + H] +Calculated LCMS (ESI): 334, 336 (3:2), measured value 334, 336 (3:2).

[0319] Step d:

[0320] Pyrrolidine (51 mg, 0.72 mmol), HATU (0.27 g, 0.72 mmol), and Et3N (0.11 g, 1.08 mmol) were added to a stirred solution of 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-carboxylic acid (0.12 g, 0.36 mmol) in DMF (3 mL) at room temperature. The reaction solution was stirred at room temperature for 16 h. The resulting solution was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column 100 Å, 10 μm, 19 mm x 250 mm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 80% B over 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 obtain compound 6 (4,5-dichloro-2-[[4-(hydroxymethyl)-4-[(pyrrolidine-1-yl)carbonyl]piperidin-1-yl]methyl]phenol) (24.1 mg, 16%) as a grayish-white solid: against C 18 H 24 Cl2N2O3 [M + H] + Calculated LCMS (ESI): 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).

[0321] Example 8. Compound 7 ( N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)prop-2-enamide)

[0322]

[0323] Step a:

[0324] Acrylonitrile chloride (11 mg, 0.12 mmol) was added to a stirred solution of 2-[[4-(aminomethyl)-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol (38 mg, 0.12 mmol) and Et3N (18 mg, 0.18 mmol) in DCM (2 mL) under a nitrogen atmosphere at room temperature. The reaction solution was stirred at room temperature for 1.5 h. The resulting solution was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: X Bridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 7.84 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 7 as a grayish-white solid. N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)prop-2-enamide) (8.6 mg, 19%): for C 17 H 22 Cl2N2O3 [M + H] + Calculated LCMS (ESI): 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).

[0325] Example 9. Compound 8 ( N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)acetamide)

[0326]

[0327] Step a:

[0328] Acetic anhydride (65 mg, 0.63 mmol) was added 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) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 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 over 9 min; Detector: UV 254 / 210 nm; Retention time: 7.85 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 8 as a grayish-white solid. N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)acetamide) (60 mg, 27%): for C 15 H 20 Cl2N2O3 [M +H] + Calculated LCMS (ESI): 347, 349 (3:2); Measured values: 347, 349 (3:2); 1 H NMR (400MHz, 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).

[0329] Example 10. Compound 9 (4-(aminomethyl)-1-[(4,5-dichloro-2-hydroxyphenyl)methyl]piperidine-4-ol trifluoroacetic acid)

[0330]

[0331] Step a:

[0332] Under a nitrogen atmosphere at room temperature, tert-butyl trifluoroacetate (2.00 g, 8.68 mmol) and Et3N (1.32 g, 13.04 mmol) were added dropwise to a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (2.00 g, 8.68 mmol) in DCM (20 mL). The reaction solution was stirred for 3 h under a nitrogen atmosphere at room temperature. The resulting solution was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with saturated aqueous solution of NaHCO3 (2 x 50 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl 4-hydroxy-4-[(trifluoroacetamyl)methyl]piperidine-1-carboxylate (2.65 g, crude substance) as a pale yellow solid. 13 H 21 F3N2O4 [M + H] + Calculated LCMS (ESI): 327, measured value: 327; 1 H NMR (300 MHz, DMSO- d 6) 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).

[0333] Step b:

[0334] A solution of tert-butyl 4-hydroxy-4-[(trifluoroacetamyl)methyl]piperidine-1-carboxylate (1.30 g, 3.98 mmol) in DCM (6 mL) and TFA (3 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with water (20 mL) at room temperature and alkalized to pH 7-8 with saturated aqueous NaHCO3 solution. The resulting solution was concentrated under reduced pressure to obtain a crude product. The crude product was ground 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 obtain 2,2,2-trifluoro- N -[(4-hydroxypiperidin-4-yl)methyl]acetamide (1.40 g, crude material): targeting C8H 13 F3N2O2 [M + H] + Calculated LCMS (ESI): 227, measured value: 227.

[0335] Step c:

[0336] To 2,2,2-trifluoro-N A solution of -[(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 to NaBH(OAc)3 (0.76 g, 3.52 mmol). The reaction solution was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting solution was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with DCM / MeOH (20 / 1) to obtain a yellow semi-solid. N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)-2,2,2-trifluoroacetamide (0.10 g, 22%): targeting C 15 H 17 Cl2F3N2O3 [M + H] + Calculated LCMS (ESI): 401, 403 (3:2); Measured values: 401, 403 (3:2); 1 H 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).

[0337] Step d:

[0338] At room temperature N A solution of 1-([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) was added to NaOH (0.10 g, 2.50 mmol). After stirring at room temperature for 2 h, the resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water (with 0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 60% B over 8 min; Detector: 210 / 254 nm; Retention time: 6 min. Fractions containing the desired product were collected and concentrated under reduced pressure to obtain compound 9 (4-(aminomethyl)-1-[(4,5-dichloro-2-hydroxyphenyl)methyl]piperidine-4-ol trifluoroacetic acid) (17 mg, 16%) as a purple solid. 13 H 18 Cl2N2O2 [M + H] + Calculated LCMS (ESI): 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.

[0339] 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)

[0340]

[0341] Step a:

[0342] Intermediate 2 (0.50 g, 1.85 mmol) was added 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) 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 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC by elution with PE / EA (4 / 1) to obtain 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidin-4-one (0.40 g, 59%) as a colorless oil: against C 19 H 19 Cl2NO2 [M + H] + Calculated LCMS (ESI): 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).

[0343] Step b:

[0344] Under a nitrogen atmosphere at room temperature, 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. 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 h. The reaction was quenched with water (20 mL) 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. The residue was purified by preparative TLC by elution with PE / EA (5 / 1) to obtain (4) as a grayish-white solid. E )-1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(methoxymethylene)-2-phenylpiperidine (0.40 g, 92%): targeting C 21 H 23 Cl2NO2 [M + H] + Calculated LCMS (ESI): 392, 394 (3:2), measured value 392, 394 (3:2).

[0345] Step c:

[0346] At room temperature to (4 E A solution of 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(methoxymethylene)-2-phenylpiperidine (0.40 g, 1.02 mmol) in THF (4 mL) was added to an aqueous solution of HCl (1 mL, 6 mL). N The reaction mixture was stirred at room temperature for 4 h. The resulting mixture was neutralized to pH 7 with a saturated aqueous solution of 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 obtain 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidine-4-carboxaldehyde (0.35 g, crude material) as a yellow oil, which was used directly in the following steps without further purification: for C 20 H 21 Cl2NO2 [M +H] + Calculated LCMS (ESI): 378, 380 (3:2), measured values: 378, 380 (3:2).

[0347] Step d:

[0348] NaBH4 (70 mg, 1.85 mmol) was added to a solution of 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidin-4-carboxaldehyde (0.35 g, 0.93 mmol) in MeOH (2 mL) / THF (5 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was quenched with water (30 mL) and extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (1-(4,5-dichloro-2-methoxybenzyl)-2-phenylpiperidin-4-yl)methanol (0.28 g, crude) as a yellow oil, which was used directly in the following steps without further purification: for C 20 H 23 Cl2NO2[M + H] + Calculated LCMS (ESI): 380, 382 (3:2), measured values: 380, 382 (3:2).

[0349] Step e:

[0350] BBr3 (1.00 g, 4.00 mmol) was added 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) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and neutralized to pH >7 with a saturated aqueous solution of NaHCO3. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Xbridge C 18 OBD preparative column: 100 Å, 10 µm, 19 mm x 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 over 9 min; Detector: UV 254 / 210 nm; Retention times: 7.44 min and 7.68 min.

[0351] The rapidly eluting isomer was obtained as a grayish-white solid, compound 11 (4,5-dichloro-2-(((2R,4R)-rel-4-(hydroxymethyl)-2-phenylpiperidin-1-yl)methyl)phenol) (3.0 mg, 2%): targeting C 19 H 21 Cl2NO2[M + H]+ Calculated LCMS (ESI): 366, 368 (3:2); Measured values: 366, 368 (3:2); 1 H NMR (300 MHz, DMSO-) d 6) 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).

[0352] The slower-eluting isomer was obtained as a grayish-white solid of compound 10 (4,5-dichloro-2-(((2S,4R)-rel-4-(hydroxymethyl)-2-phenylpiperidin-1-yl)methyl)phenol) (16.9 mg, 9%): against C 19 H 21 Cl2NO2[M + H] + Calculated LCMS (ESI): 366, 368 (3:2); Measured values: 366, 368 (3:2); 1 H NMR (300 MHz, DMSO-) d 6) 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).

[0353] Example 12. Compound 12 ( N -[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]acetamide)

[0354]

[0355] Step a:

[0356] Ac₂O (91 mg, 0.89 mmol) was added 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) at room temperature. The reaction solution was stirred at room temperature for 3 h. Then, NaOH (0.10 g, 2.50 mmol) and H₂O (1 mL) were added to the reaction solution. The resulting mixture was stirred at room temperature for another 3 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 50% B over 16 min; Detector: UV 254 / 210 nm; Retention time: 9.65 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 12 as a grayish-white solid. N -[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]acetamide (49.1 mg, 48%): for C 15 H 20 Cl2N2O3 [M+ H] + Calculated LCMS (ESI): 347, 349 (3:2); Measured values: 347, 349 (3:2); 1 H NMR (300MHz, 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).

[0357] Example 13. Compound 13 ( N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide)

[0358]

[0359] Step a:

[0360] Et3N (0.25 g, 2.46 mmol) was added to a stirred solution of 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) at room temperature. The resulting solution was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to obtain 4-(hydroxymethyl)-4-((2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate (0.2 g, crude product) as a yellow oil, which was used directly in the following steps without further purification: for C 14 H 23 F3N2O4 [M + H] + Calculated LCMS (ESI): 341, measured value: 341.

[0361] Step b:

[0362] TFA (1 mL) was added to a stirred solution of 0.20 g (0.58 mmol) of 4-(hydroxymethyl)-4-((2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.58 mmol) in DCM (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to obtain 2,2,2-trifluoro- N -((4-(hydroxymethyl)piperidin-4-yl)methyl)acetamide (0.2 g, crude product), which was used directly in the following steps without further purification: for C9H 15 F3N2O2 [M + H] + Calculated LCMS (ESI): 241, measured value: 241.

[0363] Step c:

[0364] At room temperature, 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) were stirred and HOAc (3 mg, 0.04 mmol) was added. The resulting solution was stirred at room temperature for 1 h. NaBH(OAc)3 (0.29 g, 1.35 mmol) was added to the stirred solution at room temperature under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) at room temperature and extracted with EA (5 x 30 mL). The combined organic layers were washed with brine (2 x 25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residues were purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column: 100 Å, 10 µm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B to 90% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 8-10 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 13 as a grayish-white solid. N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide) (82 mg, 43%): for C 16 H 19 Cl2F3N2O3 [M + H] + Calculated LCMS (ESI): 415, 417 (3:2); Measured values: 415, 417 (3:2); 1 H NMR (400 MHz, DMSO- d 6) 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).

[0365] Example 14. Compound 14 (2-[[4-amino-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol)

[0366]

[0367] Step a:

[0368] Under a nitrogen atmosphere at room temperature, intermediate 1 (0.23 g, 1.20 mmol), HOAc (60 mg, 1.00 mmol), and... N A stirred solution of tert-butyl 4-[4-(hydroxymethyl)piperidin-4-yl]carbamate (0.29 g, 1.00 mmol) in MeOH (5 mL) was added to NaBH(OAc)3 (0.64 g, 3.00 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 30 min 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 x 20 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution with EA to obtain a yellow oil. N -[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]tert-butyl carbamate (0.10 g, 25%): for C 18 H 26 Cl2N2O4 [M + H] + Calculated LCMS (ESI): 405, 407 (3:2); Measured 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).

[0369] Step b:

[0370] At room temperature NTFA (2 mL) was added to a stirred solution of 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]carbamate tert-butyl ester (0.10 g, 0.25 mmol) in DCM (2 mL). The resulting mixture was stirred for 1 h under ambient atmosphere and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 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 over 9 min; Detector: UV 254 / 210 nm; Retention time: 7.41 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 14 (2-[[4-amino-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol) (29.3 mg, 39%) as a grayish-white solid: against C 13 H 18 Cl2N2O2 [M + H] + Calculated LCMS (ESI): 305, 307 (3:2); Measured 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).

[0371] Example 15. Compound 15 (4,5-dichloro-2-[2-hydroxy-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol)

[0372]

[0373] Step a:

[0374] TiCl4 (1.20 g, 6.33 mmol) was added dropwise to a stirred solution of 3,4-dichlorophenol (1.00 g, 6.13 mmol) in DCM (10 mL) under an argon atmosphere at -30 °C. After stirring at -30 °C for 30 min, a solution of 2-oxoethyl acetate (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 a saturated aqueous solution of NH4Cl (2 mL) at room temperature and diluted with a cosolvent of EA (50 mL) and water (50 mL). The separated aqueous solution was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using DCM / EA (6 / 1) elution to obtain ethyl 2-(4,5-dichloro-2-hydroxyphenyl)-2-hydroxyacetate (0.60 g, 31%) as a pale yellow semi-solid: against C 10 H 10 Cl2O4[M - 1] + Calculated LCMS (ESI) 263, 265 (3:2), measured values ​​263, 265 (3:2); 1 H NMR (400 MHz, DMSO- d 6) 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).

[0375] Step b:

[0376] K₂CO₃ (0.21 g, 1.51 mmol) and MeI (0.32 g, 2.26 mmol) were added to a stirred solution of ethyl 2-(4,5-dichloro-2-hydroxyphenyl)-2-hydroxyacetate (0.20 g, 0.75 mmol) in DMF (2 mL) at room temperature. The reaction mixture was heated to 40 °C and stirred for 1 h. The resulting mixture was diluted with EA (20 mL) and water (20 mL). The separated aqueous layer was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (5 x 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 by elution with PE / EA (5 / 1) to obtain ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-hydroxyacetate (0.15 g, 64%) as a colorless oil. 1 H NMR (300 MHz, DMSO- d 6) 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).

[0377] Step c:

[0378] PBr3 (0.62 g, 2.29 mmol) was added dropwise to a stirred solution of ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-hydroxyacetate (0.16 g, 0.57 mmol) in DCM (2 mL) at room temperature. The reaction solution was stirred at room temperature for 3 h. The resulting solution was quenched with water (20 mL) at room temperature and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (5 x 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 by elution with PE / EA (9 / 1) to obtain ethyl 2-bromo-2-(4,5-dichloro-2-methoxyphenyl)acetate (0.15 g, 65%) as a pale yellow oil. 1 H 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 = 7.1Hz, 3H).

[0379] Step d:

[0380] At room temperature, piperidin-4-ylmethanol (76 mg, 0.66 mmol) and K₂CO₃ (0.12 g, 0.88 mmol) were added 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). The reaction mixture was heated 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 separated aqueous layer was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (5 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain ethyl 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]acetate (0.15 g, crude substance) as a pale yellow oil: against C 17 H 23 Cl2NO4[M + H] + Calculated LCMS (ESI): 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).

[0381] Step e:

[0382] DIBAL-H (2.2 mL, 2.21 mmol, 1 M in toluene) was added 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) at 0 °C under an argon atmosphere. The reaction solution was stirred at 0 °C for 1 h under an argon atmosphere. The resulting solution was quenched with water (20 mL) at 0 °C and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]ethane-1-ol (0.10 g, crude) as a pale yellow oil, which was used in the following steps without further purification: for C 15 H 21 Cl2NO3 [M + H] ＋ Calculated LCMS (ESI): 334, 335 (3:2), measured values: 334, 335 (3:2).

[0383] Step f:

[0384] BBr3 (0.34 g, 1.35 mmol) was added to a stirred solution of 2-(4,5-dichloro-2-methoxyphenyl)-2-[4-(hydroxymethyl)piperidin-1-yl]ethane-1-ol (0.10 g, 0.30 mmol) in DCM (2 mL) at room temperature. The reaction solution was stirred at room temperature for 5 h. The resulting mixture was quenched with water (1 mL) at 0 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 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 over 9 min; Detector: UV 254 / 210 nm; Retention time: 6.55 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 15 (4,5-dichloro-2-[2-hydroxy-1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol) (20 mg, 20%) as a grayish-white solid: against C 14 H 19 Cl2NO3 [M + H] +Calculated LCMS (ESI): 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).

[0385] Example 16. Compound 16 (2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dimethylphenol)

[0386]

[0387] Step a:

[0388] HOAc (40 mg, 0.67 mmol) and NaBH(OAc)3 (0.42 g, 2.00 mmol) were added 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) under a nitrogen atmosphere at room temperature. After stirring for 2 h under a nitrogen atmosphere at room temperature, the resulting mixture was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 55% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 8.15 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 16 (2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dimethylphenol) (25 mg, 15%) as a grayish-white solid: [Target C] 15 H 23 NO2 [M + H]+ Calculated LCMS (ESI): 250, measured value: 250; 1 H NMR (400 MHz, DMSO-) d 6) 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).

[0389] Example 17. Compound 17 (5-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4-methylphenol)

[0390]

[0391] Step a:

[0392] BH3 (6 mL, 6.00 mmol, 1 M in THF) was added dropwise to a stirred solution of 5-bromo-4-chloro-2-hydroxybenzoic acid (0.50 g, 1.99 mmol) in THF (10 mL) under a nitrogen atmosphere at 0 °C. The reaction solution was then warmed to room temperature and stirred for 1 h under a nitrogen atmosphere. The resulting solution was quenched with water (30 mL) at 0 °C and 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 to obtain 4-bromo-5-chloro-2-(hydroxymethyl)phenol (0.33 g, 69%) as a grayish-white solid: against C7H6BrClO2 [M - H] + Calculated LCMS (ESI): 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).

[0393] Step b:

[0394] MeI (0.60 g, 4.22 mmol) was added dropwise 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) 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 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 silica gel column chromatography by elution with PE / EA (15 / 1) to obtain (5-bromo-4-chloro-2-methoxyphenyl)methanol (0.20 g, 56%) as a grayish-white solid. 1 H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 6.99 (s, 1H), 4.66 (s, 2H), 3.90 (s, 3H).

[0395] Step c:

[0396] PBr3 (0.43 g, 1.58 mmol) was added to a stirred solution of (5-bromo-4-chloro-2-methoxyphenyl)methanol (0.20 g, 0.79 mmol) in DCM (3.5 mL) 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 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 to obtain 1-bromo-5-(bromomethyl)-2-chloro-4-methoxyphenyl (0.20 g, 80%) as a grayish-white solid, which was used directly in the following steps without further purification: 1 HNMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 6.97 (s, 1H), 5.06 (s, 2H), 3.90 (s, 3H).

[0397] Step d:

[0398] At room temperature, piperidin-4-ylmethanol (0.13 g, 1.13 mmol) was added 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). The reaction mixture was heated 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 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 silica gel column chromatography by elution with DCM / MeOH (15 / 1) to obtain [1-[(5-bromo-4-chloro-2-methoxyphenyl)methyl]piperidin-4-yl]methanol (0.13 g, 49%) as a grayish-white solid: against C 14 H 19 BrClNO2 [M + H] + Calculated LCMS (ESI): 348, 350, 352 (2:3:1), measured values: 348, 350, 352 (2:3:1).

[0399] Step e:

[0400] Pd(dppf)Cl2 (54 mg, 0.07 mmol) was added 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 K2CO3 (0.23 g, 1.67 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) at room temperature. The reaction mixture was degassed three times with nitrogen. The reaction mixture was then heated to 80 °C and stirred for 2.5 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was quenched with water (20 mL) and 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 silica gel column chromatography with DCM / MeOH (10 / 1) elution to obtain [1-[(4-chloro-2-methoxy-5-methylphenyl)methyl]piperidin-4-yl]methanol (72 mg, 68%) as a brown solid: against C 15 H 22 ClNO2 [M + H] +Calculated LCMS (ESI): 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, 1H), 2.30 (s, 3H), 1.85-1.23 (m, 5H).

[0401] Step f:

[0402] BBr3 (0.25 g, 1.01 mmol) was added 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) at room temperature. After stirring for 2.5 h at room temperature, the resulting mixture was quenched with water (8 mL) at room temperature and the pH was adjusted to 7 with saturated aqueous NaHCO3 solution. 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 under the following conditions: column: X Bridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B to 90% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 8.17 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 17 (5-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-4-methylphenol) (16 mg, 23%) as a grayish-white solid: against C 14 H 20 ClNO2 [M + H] + Calculated LCMS (ESI): 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).

[0403] Example 18. Compound 18 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]propyl]phenol)

[0404]

[0405] Step a:

[0406] Magnesium bromo(ethyl)magnesium (0.6 mL, 1.74 mmol, 3 M in diethyl ether) was added to a stirred solution of intermediate 1 (0.15 g, 0.79 mmol) in THF (3 mL) under a nitrogen atmosphere at room temperature. After stirring for 2 h under a nitrogen atmosphere at room temperature, the resulting solution was quenched with water (30 mL) at 0 °C and extracted with EA (3 x 35 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 to obtain 2-(1-bromopropyl)-4,5-dichlorophenol (72 mg, crude substance) as a grayish-white solid, which was used directly in the following steps without further purification: targeting C9H 10 Cl2O2 [M - H] + Calculated LCMS (ESI): 219, 221 (3:2), measured values: 219, 221 (3:2).

[0407] Step b:

[0408] PBr3 (0.49 g, 1.81 mmol) was added to a stirred solution of 4,5-dichloro-2-(1-hydroxypropyl)phenol (0.20 g, 0.90 mmol) in DCM (3 mL) at room temperature under a nitrogen atmosphere. After stirring for 2 h at room temperature under a nitrogen atmosphere, the resulting solution was quenched with water (30 mL) and extracted with EA (3 x 45 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 7.50 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain 2-(1-bromopropyl)-4,5-dichlorophenol (70 mg, 32% for two steps) as a grayish-white solid: against C9H9BrCl2O [M-H]. + Calculated LCMS (ESI): 281, 283, 285 (2 : 3 : 1), measured values: 281, 283, 285 (2 : 3 : 1).

[0409] Step c:

[0410] To a stirred mixture of 2-(1-bromopropyl)-4,5-dichlorophenol (70 mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.49 mmol) in DMF (3 mL), piperidin-4-ylmethanol (28 mg, 0.25 mmol) was added at room temperature. After stirring at room temperature for 2 h, 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 under the following conditions: column: XBridge C 18 OBD preparative column, 100 Å, 5 µm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B over 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 obtain compound 18 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]propyl]phenol) (18 mg, 21%) as a grayish-white solid: against C 15 H 21 Cl2NO2 [M + H] + Calculated LCMS (ESI): 318, 320 (3:2); Measured values: 318, 320 (3:2); 1 H NMR (300 MHz, DMSO-d 6) 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).

[0411] Example 19. Compound 19 (4-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-5-methylphenol)

[0412]

[0413] Step a:

[0414] DIBAL-H (12.5 mL, 12.46 mmol, 1 M in toluene) was added dropwise to a stirred solution of methyl 5-chloro-2-hydroxy-4-methylbenzoate (0.50 g, 2.49 mmol) in THF (15 mL) 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 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with PE / EA (5 / 1) to obtain 4-chloro-2-(hydroxymethyl)-5-methylphenol (0.35 g, 67%) as a grayish-white solid: against C₈H₉ClO₂ [M⁻¹]. - Calculated LCMS (ESI): 171, 173 (3:1); Measured values: 171, 173 (3:1); 1 H NMR (300 MHz, CDCl3)δ 7.00 (s, 1H), 6.77 (s, 1H), 4.81 (s, 2H), 2.31 (s, 3H).

[0415] Step b:

[0416] PBr3 (1.10 g, 4.06 mmol) was added dropwise to a stirred solution of 4-chloro-2-(hydroxymethyl)-5-methylphenol (0.35 g, 2.03 mmol) in DCM (10 mL) under a nitrogen atmosphere at 0 °C. After stirring at 0 °C for 2 h under a nitrogen atmosphere, the resulting solution was quenched with water (30 mL) at 0 °C and extracted with EA (3 x 70 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(bromomethyl)-4-chloro-5-methylphenol (0.35 g, crude) as a yellow oil, which was used directly in the following steps without further purification: for C8H8BrClO [M - H] + Calculated LCMS (ESI): 233, 235, 237 (2:3:1), measured values: 233, 235, 237 (2:3:1).

[0417] Step c:

[0418] 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), piperidin-4-ylmethanol (0.26 g, 2.23 mmol) was added at room temperature. The reaction mixture was heated to 40 °C and stirred for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: X Bridge C 18 OBD preparative column: 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 60% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 8.50 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 19 (4-chloro-2-[[4-(hydroxymethyl)piperidin-1-yl]methyl]-5-methylphenol) (25 mg, 6% in two steps) as a grayish-white solid: [Target C] 14 H 20 ClNO2 [M + H] +Calculated LCMS (ESI): 270, 272 (3:1); Measured values: 270, 272 (3:1); 1 H NMR (300 MHz, DMSO- d 6) 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).

[0419] Example 20. Compound 21 ( N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)acetamide)

[0420]

[0421] Step a:

[0422] Acetic anhydride (84 mg, 0.82 mmol) was added to a stirred solution of 4-(aminomethyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.82 mmol) and Et3N (0.25 g, 2.46 mmol) in DCM (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure to obtain 4-(acetamidomethyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (0.30 g, crude product), which was used in the following steps without further purification: for C 14 H 26 N₂O₄ [M + H] + Calculated LCMS (ESI): 287, measured value: 287.

[0423] Step b:

[0424] TFA (1 mL) was added to a stirred solution of tert-butyl 4-(acetamidomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.30 g, 1.05 mmol) in DCM (1 mL) at room temperature. The reaction solution was stirred at room temperature for 30 min. The resulting solution was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and neutralized to pH 8 with a saturated aqueous solution of 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 obtain N -((4-(hydroxymethyl)piperidin-4-yl)methyl)acetamide (0.12 g, crude product), which was used directly in the following steps without further purification: for C9H 18 N₂O₂ [M + H] + Calculated LCMS (ESI): 187, measured value: 187.

[0425] Step c:

[0426] At room temperature under a nitrogen atmosphere N A stirred solution of 4-[[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 to HOAc (35 mg, 0.6 mmol) and NaBH(OAc)3. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting solution was quenched with water (5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column: 100 Å, 10 µm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 80% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 8.14 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 21 as a grayish-white solid. N -([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)acetamide) (97 mg, 46%): for C 16 H 22 Cl2N2O3 [M + H] +Calculated LCMS (ESI): 361, 363 (3:2); Measured values: 361, 363 (3:2); 1 H NMR (400 MHz, DMSO- d 6 ) 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).

[0427] Example 21. Compound 23 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]-3-methylbutyl]phenol)

[0428]

[0429] Step a:

[0430] Magnesium bromo(2-methylpropyl)magnesium (0.6 mL, 1.14 mmol, 2 M in diethyl ether) was added to a stirred solution of intermediate 1 (0.10 g, 0.52 mmol) in THF (2 mL) 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 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 4,5-dichloro-2-(1-hydroxy-3-methylbutyl)phenol (0.14 g, crude) as a yellow oil, which was used directly in the following steps without further purification: [The text abruptly ends here, so the translation stops here as well.] 11 H 14 Cl2O2 [M - H] + Calculated LCMS (ESI): 247, 249 (3:2), measured value 247, 249 (3:2).

[0431] Step b:

[0432] PBr3 (0.30 g, 1.12 mmol) was added to a stirred solution of 4,5-dichloro-2-(1-hydroxy-3-methylbutyl)phenol (0.14 g, crude) in DCM (2 mL) at room temperature under a nitrogen atmosphere. The reaction solution was stirred for 2 h at room temperature under a nitrogen atmosphere. 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 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(1-bromo-3-methylbutyl)-4,5-dichlorophenol (0.18 g, crude) as a yellow oil, which was used in the following steps without further purification: for C 11 H 13 BrCl2O [M - H] + Calculated LCMS (ESI): 309, 311, 313 (2:3:1), measured values: 309, 311, 313 (2:3:1).

[0433] Step c:

[0434] To a stirred solution of 2-(1-bromo-3-methylbutyl)-4,5-dichlorophenol (0.18 g, 0.58 mmol) in DMF (1 mL), piperidin-4-ylmethanol (0.13 g, 1.15 mmol) and K₂CO₃ (0.16 g, 1.15 mmol) were added at room temperature. After stirring for 2 h at room temperature, the resulting mixture was diluted with water (20 mL) at room temperature and extracted with EA (5 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C 18 OBD preparative column 100 Å, 10 μm, 19 mm x 250 mm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 80% B over 9 min; Detector: UV 254 / 210 nm; Retention time: 8.14 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 23 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]-3-methylbutyl]phenol) (10 mg, 5% in three steps): against C 17 H 25 Cl2NO2 [M + H]+ Calculated LCMS (ESI): 346, 348 (3:2); Measured values: 346, 348 (3:2); 1 H NMR (400 MHz, DMSO- d 6) 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).

[0435] Example 22. Compound 28 (2-(1-(4,5-dichloro-2-hydroxybenzyl)piperidin-4-yl)acetic acid)

[0436]

[0437] Step a:

[0438] HOAc (62 mg, 1.03 mmol) and NaBH(OAc)3 (0.66 g, 3.12 mmol) were added 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) under a nitrogen atmosphere at room temperature. After stirring for 2 h under a nitrogen atmosphere at room temperature, the resulting solution was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (7 / 1) to obtain methyl 2-(1-(4,5-dichloro-2-hydroxybenzyl)piperidin-4-yl)acetate (0.19 g, 55%) as a light brown solid. 15 H 19 Cl2NO3 [M + H] + Calculated LCMS (ESI): 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).

[0439] Step b:

[0440] NaOH (0.11 g, 2.75 mmol) was added 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) at room temperature. The reaction solution was stirred at room temperature for 2 h. The solution was then passed through an aqueous solution of HCl (1... N Adjust the pH of the resulting solution to 7-8. Concentrate the mixture under reduced pressure. Purify the residue by preparative HPLC under the following conditions: Column: Sunfire preparative C1450 HPLC. 18 OBD column, 10 μm, 19 x 250 mm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 16% B to 43% B over 9 min; detector: UV 254 / 210 nm; retention time: 7.52. Fractions containing the desired product were collected and concentrated under reduced pressure to obtain compound 28 as a colorless viscous oil: 2-(1-(4,5-dichloro-2-hydroxybenzyl)piperidin-4-yl)acetic acid trifluoroacetic acid (24.7 mg, 14%): against C 14 H 17 Cl2NO3 [M + H] + Calculated LCMS (ESI): 318, 320 (3:2); Measured values: 318, 320 (3:2); 1 H NMR (400 MHz, CD3OD) δ7.58 (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).

[0441] Example 23. Compound 29 (4,5-dichloro-2-(((2) S 4 S )-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol) and compound 24 (4,5-dichloro-2-(((2 R 4 S )-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol)

[0442]

[0443] Step a:

[0444] NaBH4 (79 mg, 2.09 mmol) was added to a stirred solution of intermediate 1 (0.20 g, 1.05 mmol) in EtOH (10 mL) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 30 min under a nitrogen atmosphere at 0 °C. The resulting mixture was quenched with water (10 mL) and 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 to obtain 4,5-dichloro-2-(hydroxymethyl)phenol (0.20 g, crude) as a grayish-white solid, which was used directly in the following steps without further purification: against C7H6Cl2O2 [M - H] - Calculated LCMS (ESI): 191, 193 (3:2), Measured values: 191, 193 (3:2).

[0445] Step b:

[0446] PBr3 (0.56 g, 2.07 mmol) was added dropwise to a stirred solution of 4,5-dichloro-2-(hydroxymethyl)phenol (0.20 g, 1.04 mmol) in DCM (10 mL) under a nitrogen atmosphere at room temperature. The reaction solution was stirred for 30 min under a nitrogen atmosphere at room temperature. The resulting solution was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(bromomethyl)-4,5-dichlorophenol (0.20 g, crude) as a dark gray oil, which was used directly in the following steps without further purification: against C7H5BrCl2O [M - H] -Calculated LCMS (ESI): 253, 255, 257 (2:3:1), measured values: 253, 255, 257 (2:3:1).

[0447] Step c:

[0448] At room temperature, 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 to (2-methylpiperidin-4-yl)methanol (0.15 g, 1.17 mmol). 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 under the following conditions: column: X Bridge C 18 OBD preparative 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 over 9 min; Detector: UV 254 / 210 nm; Retention time: Rt1: 8.10 min, Rt2: 8.60 min.

[0449] The rapidly eluting isomer was obtained as compound 29 (4,5-dichloro-2-(((2)) S 4 S )-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol) (90 mg, 37%): for C 14 H 19 Cl2NO2[M + H] + Calculated LCMS (ESI): 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).

[0450] The slower-eluting isomer was obtained as a pale yellow solid, compound 24 (4,5-dichloro-2-(((2) R 4 S )-rel-4-(hydroxymethyl)-2-methylpiperidin-1-yl)methyl)phenol) (6.5 mg, 3%): for C 14 H 19 Cl2NO2[M + H] + Calculated LCMS (ESI): 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).

[0451] Example 24. Compound 46 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol)

[0452]

[0453] Step a:

[0454] MeMgBr (9 mL, 9.00 mmol, 1 M in THF) was added to a stirred solution of 4,5-dichloro-2-methoxybenzaldehyde (1.50 g, 7.32 mmol) in THF (50 mL) at 0 °C under a nitrogen atmosphere. The reaction solution was warmed to room temperature and stirred for 1 h under a nitrogen atmosphere. The resulting solution was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with PE / EA (5 / 1) to obtain 1-(4,5-dichloro-2-methoxyphenyl)ethane-1-ol (1.40 g, 87%) as a grayish-white solid.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).

[0455] Step b:

[0456] PBr3 (1.22 g, 4.52 mmol) was added dropwise to a stirred solution of 1-(4,5-dichloro-2-methoxyphenyl)ethane-1-ol (0.50 g, 2.26 mmol) in DCM (10 mL) at room temperature. After stirring for 15 min at room temperature, the resulting solution was quenched with water (10 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 1-(1-bromoethyl)-4,5-dichloro-2-methoxyphenyl (0.50 g, crude) as a pale yellow oil, which was used directly in the following steps without further purification: 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 6.96 (s, 1H), 5.55 (q, J = 7.0Hz, 1H), 3.90 (s, 3H), 2.01 (d, J = 7.0 Hz, 3H).

[0457] Step c:

[0458] At room temperature, piperidin-4-ylmethanol (0.12 g, 1.06 mmol) was added 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). The reaction mixture was heated to 40 °C and stirred for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: X Bridge C 18OBD preparative 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: 40% B to 80% B over 8 min; Detector: UV 210 nm; Retention time: 7.57 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain [1-[1-(4,5-dichloro-2-methoxyphenyl)ethyl]piperidin-4-yl]methanol (0.10 g, 43%) as a grayish-white solid. (Target C) 15 H 21 Cl2NO2 [M + H] + Calculated LCMS (ESI): 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).

[0459] Step d:

[0460] BBr3 (1.65 g, 6.60 mmol) was added 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) at room temperature. After stirring at room temperature for 2 h, the resulting mixture was quenched with ice water (10 mL) and then neutralized to pH 7–8 with a saturated aqueous solution of NaHCO3. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: X Bridge C 18OBD preparative 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: 42% B to 50% B over 12 min; Detector: UV 210 nm; Retention time: 8.60 min. Fractions containing the desired product were collected and concentrated under reduced pressure to obtain compound 46 (4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol) (250 mg, 37%) as a grayish-white solid: against C 14 H 19 Cl2NO2 [M + H] + Calculated LCMS (ESI): 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).

[0461] Example 25. Compound 54 (1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carboxynitrile)

[0462]

[0463] Step a:

[0464] LDA (2.85 mL, 5.71 mmol, 2 M in THF) was added dropwise to a stirred solution of tert-butyl 4-cyanopiperidinium-1-carboxylate (1.00 g, 4.76 mmol) in THF (8 mL) under an argon atmosphere at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. Then, paraformaldehyde (0.17 g, 5.71 mmol) was added to the solution. The resulting mixture was warmed to room temperature and stirred for 1 h under an argon atmosphere. The resulting solution was quenched with a saturated aqueous solution of NH4Cl (2 mL) at -78 °C and diluted with water (50 mL). The aqueous layer was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (3 / 1) elution to obtain tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (0.60 g, 42%) as a grayish-white semi-solid: against C 12 H 20 N₂O₃ [M + H] + Calculated LCMS (ESI): 241, measured value: 241; 1 H NMR (300 MHz, CDCl3) δ 4.37-4.01 (m, 2H), 3.64 (s, 2H), 3.14-2.91 (m, 2H), 1.99-1.83 (m, 2H), 1.51-1.28 (m, 11H).

[0465] Step b:

[0466] TFA (2 mL) was added to a stirred solution of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (0.20 g, 0.83 mmol) in DCM (2 mL) at room temperature. After stirring at room temperature for 1 h, the resulting solution was concentrated under reduced pressure. The residue was dissolved in water (10 mL), and the pH was adjusted to 8 with a saturated aqueous solution of K₂CO₃. The aqueous layer was extracted with DCM (10 x 20 mL). The combined organic layers were dried over anhydrous K₂CO₃ and filtered. The filtrate was concentrated under reduced pressure to obtain 4-(hydroxymethyl)piperidine-4-carboxynitrile (0.10 g, crude substance) as a yellow oil, which was used directly in the following steps without further purification.

[0467] Step c:

[0468] 4-(hydroxymethyl)piperidin-4-carboxynitrile (73 mg, 0.52 mmol), HOAc (31 mg, 0.52 mmol), and NaBH(OAc)3 (0.33 g, 1.57 mmol) were added to a stirred solution of intermediate 1 (0.10 g, 0.52 mmol) in DCE (3 mL) at room temperature. After stirring at room temperature for 3 h, the resulting mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 19 x 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 over 9 min; detector: UV 210 nm; retention time: 8.23 ​​min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 54 (1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carboxynitrile) (24 mg, 14%) as a grayish-white solid: against C 14 H 16 Cl2N2O2 [M + H] + Calculated LCMS (ESI) 315, 317 (3:2), measured values ​​315, 317 (3:2); 1 H NMR (300 MHz, DMSO- d 6)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).

[0469] Example 26. Compound 60 (4,5-dibromo-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol)

[0470]

[0471] Step a:

[0472] To a Biotage 20 mL vial equipped with a magnetic stir bar, 4-piperidinemethanol (53.9 μL, 300 μL) was added to a solution of 4,5-dibromo-2-hydroxybenzaldehyde (80.0 mg, 286 μL) 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 μL) was added dropwise to the reaction mixture, followed by the fractional addition of NaBH(OAc)3 (78.4 mg, 372 μL). The reaction was stirred overnight from 0 °C to room temperature. The reaction was quenched by adding NaOH 1N dropwise at 0 °C (5 mL) while transferring the mixture to an Erlenmeyer flask and stirring for another 30 minutes. The reaction mixture was then diluted with DCM (40 mL) and a saturated solution of NaHCO3 (20 mL) was added to the two-phase mixture. The mixture was then transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted with DCM (3 x 20 mL). The organic layer was then washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and evaporated to dryness. The crude solid was then purified by rapid chromatography using 30–100% EA / hexane. The resulting white solid fraction was then dissolved in a mixture of ACN / water (40:60) and lyophilized to obtain compound 60 (4,5-dibromo-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol) (61.4 mg, 48%) as a white solid. (The last sentence appears to be incomplete and possibly refers to a specific concentration of C.) 13 H 17 Br2NO2 [M] + Calculated LCMS (ESI): 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).

[0473] Example 27. Compound 63 ((1-(4,5-dibromo-2-hydroxybenzyl)piperidin-4-yl)(pyrrolidine-1-yl)methyl ketone)

[0474]

[0475] Step a:

[0476] Add 4-piperidinyl(1-pyrrolyl) methyl ketone hydrochloride (656 mg, 3.0 mmol), Et3N (0.42 mL, 3.0 mmol), and dibromosalicylic acid aldehyde (663 mg, 3.3 mmol) to a Biotage 20 mL vial equipped with a magnetic stir bar. Dissolve the reagents in anhydrous THF (10 mL) and stir the solution at room temperature for 4 hours. Cool the solution to 0 °C and add AcOH (0.35 mL, 6.0 mmol) dropwise. Then, add NaBH(OAc)3 (1.27 g, 6.0 mmol) fractionally and allow the reaction to proceed overnight from 0 °C to room temperature with stirring. Quench the reaction by adding 0.5 N HCl (10 mL) at 0 °C and stir for another 30 minutes. Dilute the reaction with DCM (40 mL) and add a saturated solution of NaHCO3 (30 mL) to the two-phase mixture. Transfer the two-phase mixture 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 and washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and evaporated to dryness. The resulting gel was then purified by rapid chromatography using a gradient from 60% EA / hexane to 10% MeOH / EA. The product was further purified by reversed-phase chromatography (C-18 column) using a gradient from 5-100% ACN / H2O. The desired fractions were combined and lyophilized to obtain compound 63 (1-(4,5-dibromo-2-hydroxybenzyl)piperidin-4-yl)(pyrrolidine-1-yl) methyl ketone) (35.2 mg, 6.6%) as a white solid. 17 H 22 Br2N2O2 [M+ H] + Calculated LCMS (ESI): 444.0 / 446.0 (1:2), Measured values: 444.8 / 446.8, 351 (1:2) 1 HNMR (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).

[0477] Example 28. Compound 65 (4,5-dichloro-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol)

[0478]

[0479] Step a:

[0480] NaBH(OAc)3 (0.32 g, 1.51 mmol) was added 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) at room temperature under a nitrogen atmosphere. After stirring for 3 h at room temperature under a nitrogen atmosphere, the reaction mixture was quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by preparative HPLC under the following conditions: column: XBridge Prep C 18 OBD column 190 mm x 150 mm, 5 μm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40% B to 55% B over 7 min; detector: UV 254 / 220 nm; retention time: 6.33 min. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 65 (4,5-dichloro-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol) (34 mg, 22%) as a grayish-white solid: against C 13 H 17 Cl2NO2 [M + H] + Calculated LCMS (ESI): 290, 292 (3:2); Measured values: 290, 292 (3:2); 1 H NMR (400 MHz, DMSO) d6 + 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 = 11.2Hz, 2H), 1.40-1.36 (m, 1H), 1.17 (q, J = 8.0 Hz, 2H).

[0481] The compounds in Table 1a below are prepared in a manner similar to that described for compound 65, starting with 4,5-dichloro-2-hydroxybenzaldehyde and the corresponding amine (which is prepared as described herein or is available from commercial sources).

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489] Example 29. Evaluation of the activity of Kv1.3 potassium channel blocker

[0490] This assay was used to evaluate the activity of the disclosed compounds as Kv1.3 potassium channel blockers.

[0491] Cell culture

[0492] 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 in a 5% CO2-humidified incubator at 37 °C.

[0493] solution

[0494] Cells were immersed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, and 10 mM HEPES; the pH was adjusted to 7.4 with NaOH; 295–305 mOsm. An internal solution containing 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES was used; the pH was adjusted to 7.2 with KOH; 285 mOsm. All compounds were dissolved in DMSO at 30 mM. The compound stock solutions were freshly diluted with the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 µM, 3 µM, 10 µM, 30 µM, and 100 µM. The highest concentration of DMSO (0.3%) was 100 µM.

[0495] Voltage Protocol

[0496] Current was induced by applying a depolarization pulse ranging from -90 mV (holding potential) to +40 mV over 100 ms (applied at a frequency of 0.1 Hz). The control (no compound) pulse train and the compound pulse trains for each applied compound concentration consisted of 20 pulses. A 10-second interruption was used between pulse trains (see Table A below).

[0497] Table A. Voltage Protocol

[0498]

[0499] Patch clamp recording and compound application

[0500] Whole-cell current recording and compound application were performed using the automated patch-clamp platform Patchliner (Nanion Technologies GmbH). An EPC 10 patch-clamp amplifier (HEKA Elektronik Dr. Schulze GmbH) and Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) were used for data acquisition. Data was acquired at 10 kHz without filtering. Passive leakage current was subtracted online using the P / 4 procedure (HEKA Elektronik Dr. Schulze GmbH). Increasing compound concentrations were continuously applied to the same cells without washout. The total compound incubation time before the next pulse train did not exceed 10 seconds. Peak current suppression was observed during compound equilibration.

[0501] Data Analysis

[0502] AUC and peak values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). To determine IC... 50 The last single pulse in the pulse train corresponding to a given compound concentration was used. The AUC and peak values ​​obtained with the compound present were normalized to the control values ​​without the compound. Origin (OridinLab) was used, IC50... 50 It was derived from data fitted to the Hill equation: I 化合物 / I 对照 =(100-A) / (1 + ([compound] / IC) 50 )nH)+A, where IC 50 The value is the concentration at which the current is suppressed to half of its maximum value, [compound] is the concentration of the compound applied, A is the fraction of the current not blocked, and nH is the Hill coefficient.

[0503] Example 30. Evaluation of hERG activity

[0504] This analysis was used to evaluate the inhibitory activity of the disclosed compounds on the hERG channel.

[0505] hERG electrophysiology

[0506] This assay was used to evaluate the inhibitory activity of the disclosed compounds against hERG channels.

[0507] Cell culture

[0508] CHO-K1 cells stably expressing hERG were grown in Ham's F-12 medium containing glutamine, which included 10% heat-inactivated FBS, 1% penicillin / streptomycin, hygromycin (100 µg / ml), and G418 (100 µg / ml). Cells were then grown in culture flasks in an incubator moistened with 5% CO2 at 37°C.

[0509] solution

[0510] Cells were immersed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, and 10 mM HEPES; the pH was adjusted to 7.4 with NaOH; 295–305 mOsm. An internal solution containing 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES was used; the pH was adjusted to 7.2 with KOH; 285 mOsm. All compounds were dissolved in DMSO at 30 mM. The compound stock solutions were freshly diluted with the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 µM, 3 µM, 10 µM, 30 µM, and 100 µM. The highest concentration of DMSO (0.3%) was 100 µM.

[0511] Voltage Protocol

[0512] The voltage protocol (see Table B) was designed to simulate voltage changes during a cardiac action potential, with a 300 ms depolarization to +20 mV (similar to the plateau phase of a cardiac action potential), a 300 ms repolarization to -50 mV (inducing tail current), and a final step reaching a hold potential of -80 mV. The pulse frequency was 0.3 Hz. The control (no compound) pulse train and the compound pulse trains for each applied compound concentration contained 70 pulses.

[0513] Table B. hERG Voltage Protocol

[0514] .

[0515] Patch clamp recording and compound application

[0516] Whole-cell current recording and compound application were performed using the automated patch-clamp platform Patchliner (Nanion). An EPC 10 patch-clamp amplifier (HEKA) along with Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) was used for data acquisition. Data was sampled at 10 kHz without filtering. Increasing compound concentrations were continuously applied to the same cells without inter-cell flushing.

[0517] Data Analysis

[0518] AUC and peak values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). To determine IC... 50The last single pulse in the pulse train corresponding to a given compound concentration was used. The AUC and peak values ​​obtained with the compound present were normalized to the control values ​​without the compound. Origin (OridinLab) was used, IC50... 50 It was derived from data fitted to the Hill equation: I 化合物 / I 对照 =(100-A) / (1 + ([compound] / IC) 50 )nH)+A, where IC 50 The current suppression is half the maximum concentration, [compound] is the applied compound concentration, A is the unblocked current fraction, and nH is the Hill coefficient.

[0519] Table 1 provides an overview of the inhibitory activities of certain selected compounds on Kv1.3 potassium channels and hERG channels.

[0520] Table 1. IC50 of some example compounds for Kv1.3 potassium channels and hERG channels 50 (µM) value

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528] *Not tested.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in Each occurrence of Y is independently C(R4)2, NR4, or O; Structural parts Having structure R1 and R2 are each independently H, C1-C6 alkyl, or (CR6R7). n3 OR a Or (CR6R7) n3 NR a R b ; Each occurrence of R4 is independently of H, halogen, C1-C6 alkyl, C3-C7 cycloalkyl, halo-C1-C6 alkyl, halo-C3-C7 cycloalkyl, 3- to 7-membered saturated heterocycle, phenyl, 3- to 7-membered 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 a 5- or 6-membered heterocycle containing 1-3 heteroatoms each selected from N, O and S; Or two R4s together form a 3 to 7-membered carbon ring, a 3 to 7-membered saturated heterocycle, or a 3 to 7-membered heteroaryl group, which contains 0 to 3 heteroatoms each selected from N, O and S; Each occurrence of R6 and R7 is independently H; R a and R b Each occurrence of is independently H, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, halo-C1-C6 alkyl, halo-C3-C7 cycloalkyl, 3- to 7-membered saturated heterocycle, phenyl, or 3- to 7-membered heteroaryl; or alternatively, R a and R b Together with the nitrogen atoms to which they are attached, they form 3 to 7-membered heterocycles, the heterocycles containing the nitrogen atoms and 0 to 3 other heteroatoms each selected from N, O and S; Where valence permits, the C1-C6 alkyl, C3-C7 cycloalkyl, 3- to 7-membered carbon ring, 3- to 7-membered heterocycle, phenyl, and 3- to 7-membered heteroaryl groups in R1, R2, and R4 may, where applicable, be optionally substituted by 1 to 4 substituents, each independently selected from the following: C1-C6 alkyl, C3-C7 cycloalkyl, halo-C3-C7 cycloalkyl, halo-C1-C6 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 oxygenation; As long as the valence allows, each occurrence of n1 is an independent integer between 0 and 3; Each occurrence of n3 is an independent integer between 0 and 3; and Each occurrence of n4 is independently 0, 1, 2, or 3. Compound of formula I is not 4-chloro-5-methyl-2-[(piperidin-1-yl)methyl]phenol.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural moiety... It has (a) structure or (b) Structure or (c) Structure Where R x R4; or (d) Structure Where R x It is R4.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently: (a) H or C1-C6 alkyl; or (b) H or Me; or (c)H、(CR6R7) n3 OR a Or (CR6R7) n3 NR a R b ;or (d)H, CH2OH or CH2NH2.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein... (a) R4 occurs at least once independently as (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 ;or (b) The occurrence of R4 at least once is independently (CR6R7). n3 NR a (C=O)R b Or (CR6R7) n3 (C=O)NR a R b ;or (c) One or more occurrences of R4 constitute (CR6R7) n3 OR a Or (CR6R7) n3 NR a R b ;or (d) One or more occurrences of R4 constitute OR a NR a R b -CH2OR a -CH2NR a R b -CH2CH2OR a or -CH2CH2NR a R b ;or (e) R4 occurs at least once as a 5- or 6-membered heterocycle, said heterocycle containing 1-3 heteroatoms each selected from N, O, and S; or (f) Two R4 atoms together form a 3- to 7-membered carbon ring, a 3- to 7-membered saturated heterocycle, or a 3- to 7-membered heteroaryl group containing 0-3 heteroatoms selected from N, O, and S; or (g) R4 appears at least once in the form of CH2OH, CH2NH2, (h) R4 appears at least once in a 3- to 7-membered heterocycle selected from the following: Where the valence allows, the 3 to 7-membered heterocycle is optionally replaced by a C1-C6 alkyl group, OH, oxo group, or (C=O)C. 1-4 Alkyl substitution; or (i) R4 appears at least once as H, C1-C6 alkyl, C3-C7 cycloalkyl, 3- to 7-membered saturated heterocycle, phenyl, 3- to 7-membered heteroaryl, CN, CF3, OCF3, OR a (CR6R7) n3 OR a Or oxygenation; or (j) The 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 ;or (k)R4 occurs at least once independently of H or C1-C6 alkyl; or (l) The two R4 groups together with the carbon atoms they are attached to form 3-7 membered carbon rings or heterocycles.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the two R4 groups together with the two carbon atoms to which they are attached form a fused bicyclic system having the following structure: Where A is a 3-7 membered carbon ring, a saturated heterocycle, or a heteroaryl group.

6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structural motif Having structure 7. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein n1 is 0, 1, 2 or 3.

8. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein each occurrence of n3 is independently 0, 1 or 2.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n4 is 1 or 2.

10. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein... (a)R a or R b At least once, it independently consists of H, C1-C6 alkyl, C3-C7 cycloalkyl, 3- to 7-membered saturated heterocycle, phenyl, or 3- to 7-membered heteroaryl; or (b)R a Or R b It appears at least once independently as H, Me, Et, Pr or a 3- to 7-membered heterocycle selected from the following: Where the valence allows, the 3 to 7-membered heterocycle is optionally replaced by a C1-C6 alkyl group, OH, oxo group, or (C=O)C. 1-4 Alkyl substitution; or (c)R a and R b Together with the nitrogen atoms to which they are attached, they form 3 to 7-membered heterocycles, which contain the nitrogen atoms and 0 to 3 additional heteroatoms each selected from N, O and S.

11. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the following compounds 12. A pharmaceutical composition comprising at least one compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising at least one compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent.

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