Aryl heterobicyclic compounds as Kv1.3 potassium Shaker channel blockers

Abstract

Describes a compound of formula I () or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined herein. Also described are pharmaceutical compositions comprising them and methods of using them.

Description

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 911,642, filed on October 7, 2019, the entire content of which is incorporated herein by reference in its entirety.

[0002] This patent disclosure contains copyrighted material. The copyright owner does not object to the facsimile reproduction of the patent document or patent disclosure as it appears in the Patent and Trademark Office patent files or records, but reserves all other copyrights in all other respects.

[0003] Incorporation by reference

[0004] All documents cited herein are incorporated herein by reference in their entirety. Field of the Invention

[0005] The present invention generally relates to the field of pharmaceutical sciences. More specifically, the present invention relates to compounds and compositions that can be used as drugs as potassium channel blockers.

[0006] Background

[0007] Voltage-gated Kv1.3 potassium (K + ) channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, and regulate a large number of physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kv1.3 channels can regulate the membrane potential and thereby indirectly affect calcium signaling in human effector memory T cells. Effector memory T cells are mediators of several conditions, including multiple sclerosis, type I diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. After activation, effector memory T cells increase the expression of Kv1.3 channels. In human B cells, naive and early memory B cells express a small amount of Kv1.3 channels at rest. In contrast, class-switched memory B cells express a large amount of Kv1.3 channels. In addition, Kv1.3 channels promote the calcium homeostasis required for T-cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G., et al., 2004, Trends Immunol. , 565-569). Blockade of Kv1.3 channels in effector memory T cells inhibits activities such as calcium signaling, cytokine production (interferon-γ, interleukin 2), and cell proliferation.

[0008] Autoimmune diseases are a group of disorders caused by tissue damage resulting from the attack of the body's own immune system. Such disorders may affect a single organ, as in multiple sclerosis and type I diabetes, or may involve multiple organs, as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatment is usually palliative, using anti-inflammatory and immunosuppressive drugs, which may have severe side effects. The need for more effective therapies has led to the search for drugs that can selectively inhibit the function of effector memory T cells, which are known to be involved in the etiology of autoimmune diseases. These inhibitors are thought to be able to improve the symptoms of autoimmune diseases without compromising the protective immune response. Effector memory T cells (TEM) express a large amount of Kv1.3 channels and rely on these channels to perform their functions. In vivo, Kv1.3 channel blockers paralyze TEM at the site of inflammation and prevent them from reactivating in the inflamed tissue. Kv1.3 channel blockers do not affect the movement of naive and central memory T cells within lymph nodes. Inhibiting the function of these cells by selectively blocking Kv1.3 channels provides the possibility of effectively treating 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 affect the quality of life of patients. MS progresses rapidly and unpredictably and ultimately leads 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 Kv1.3 channel blockers.

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

[0011] Renal tubulointerstitial fibrosis is the progressive deposition of connective tissue in the renal parenchyma, leading to the deterioration of renal function and involving 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 the Kv1.3 channel in lymphocytes can promote their proliferation, leading to chronic inflammation and overstimulation of cellular immunity, which are involved in the underlying pathology of these renal diseases and are contributing factors to the progression of renal tubulointerstitial fibrosis. Inhibition of the lymphocyte Kv1.3 channel current inhibits the proliferation of renal lymphocytes and improves the progression of renal fibrosis (Kazama I., et al., 2015, Mediators Inflamm. , 1-12).

[0012] The Kv1.3 channel also plays a role in gastroenterological disorders, including inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease. UC is a chronic IBD characterized by excessive T cell infiltration and cytokine production. UC impairs quality of life and can lead to life-threatening complications. High Kv1.3 channel levels in CD4 and CD8 positive T cells in the inflamed mucosa of UC patients have been associated with the production of pro-inflammatory compounds in active UC. The Kv1.3 channel is thought to act as a marker of disease activity, and pharmacological blockade may constitute a new immunosuppressive strategy in UC. Current UC treatment regimens, including corticosteroids, salicylates, and anti-TNF-α agents, are insufficient for many patients (Hansen L.K., et al., 2014, J. Crohns Colitis , 1378-1391). Crohn's disease is a type of IBD that can affect any part of the gastrointestinal tract. Crohn's disease is thought to be the result of intestinal inflammation caused by a T cell-driven process triggered by normally harmless bacteria. Therefore, Kv1.3 channel inhibition can be used to treat Crohn's disease.

[0013] In addition to T cells, the Kv1.3 channel is also expressed in microglia, where the channel is involved in the production of inflammatory cytokines and nitric oxide and in microglia-mediated neuronal killing. In humans, it has been found in microglia in the frontal cortex of Alzheimer's disease patients and in CD68 in multiple sclerosis brain lesions +Strong Kv1.3 channel expression has been found on cells. It has been shown that Kv1.3 channel blockers may be able to preferentially target the harmful pro-inflammatory microglial functions. Kv1.3 channels are expressed on activated microglia in infarcted rodent and human brains. Higher Kv1.3 channel current density was observed in microglia acutely isolated from infarcted cerebral hemispheres than in microglia isolated from the contralateral cerebral hemispheres of a mouse model of stroke (Chen Y.J., et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

[0014] Expression of Kv1.3 channels is elevated in microglia of the human Alzheimer's disease brain, indicating that Kv1.3 channels are pathologically relevant microglial targets in Alzheimer's disease (Rangaraju S., et al.,2015, J. Alzheimers Dis ., 797-808). Soluble AβO enhances microglial Kv1.3 channel activity. AβO-induced microglial pro-inflammatory activation and neurotoxicity require Kv1.3 channels. Kv1.3 channel expression / activity is upregulated in transgenic Alzheimer's disease animals and human Alzheimer's disease brains. Pharmacological targeting of microglial Kv1.3 channels can affect hippocampal synaptic plasticity and reduce amyloid deposition in APP / PS1 mice. Thus, Kv1.3 channels may be therapeutic targets for Alzheimer's disease.

[0015] Kv1.3 channel blockers can also be used to improve the pathology of cardiovascular disorders such as ischemic stroke, in which activated microglia significantly contribute to secondary expansion of infarction.

[0016] Kv1.3 channel expression is associated with controlling the proliferation, apoptosis, and cell survival of multiple cell types. These processes are crucial for cancer progression. In this context, Kv1.3 channels located in the inner mitochondrial membrane can interact with the apoptosis regulator Bax (Serrano-Albarras, A., et al., 2018, Expert Opin. Ther. Targets , 101-105). Thus, inhibitors of Kv1.3 channels can be used as anti-cancer agents.

[0017] Many peptide toxins with multiple disulfide bonds from spiders, scorpions, and anemones are known to block the Kv1.3 channel. Some selective and potent peptide inhibitors of the Kv1.3 channel have been developed. A synthetic derivative of an anemone (Stichodactyla) toxin (Shk) containing a non-natural amino acid (Shk-186) is the most advanced peptide toxin. Shk has shown efficacy in preclinical models and is currently in a Phase I clinical trial for the treatment of psoriasis. Shk can inhibit the proliferation of TEM cells and produce improved conditions in animal models of multiple sclerosis. Unfortunately, Shk also binds to closely related Kvi channel subtypes found in the CNS and heart. Selective inhibitors of the Kv1.3 channel are needed to avoid potential cardiac and neurotoxicity. In addition, small peptides such as Shk-186 are rapidly cleared from the body after administration, resulting in a short circulatory half-life and frequent dosing events. Therefore, there is a need to develop long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases.

[0018] Therefore, there remains a need to develop new Kv1.3 channel blockers as pharmaceutical agents. Summary of the Invention

[0020] In one aspect, compounds having the structure of Formula I that can be used as potassium channel blockers are described wherein various substituents are defined herein. The compounds of Formula I described herein can block the Kv1.3 potassium (K + ) channels and are useful for treating a variety of disease 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 many clinical applications, including as pharmaceutically active agents and methods for treating cancer, immunological disorders, CNS disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, kidney diseases, or combinations thereof.

[0021] In one aspect, compounds of Formula I or pharmaceutically acceptable salts thereof are described

[0022]

[0023] wherein

[0024] Y is independently C(R2)2 or NR1 each occurrence;

[0025] Z is OR a ;

[0026] X1 is H, halogen, or alkyl;

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

[0028] X3 is H, halogen, CN, alkyl, cycloalkyl, halocycloalkyl or haloalkyl;

[0029] Alternatively, X1 and X2 together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered aryl group;

[0030] Alternatively, X2 and X3 together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered aryl group;

[0031] Each occurrence of R1 is H, alkyl, cycloalkyl, heteroalkyl or cycloheteroalkyl;

[0032] Each occurrence of R2 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl or NR a R b ;

[0033] R3 is H, alkyl or halogen;

[0034] R4 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl or NR a R b ;

[0035] Each occurrence of R5 is H, halogen, OR6 or alkyl, wherein each R5 may be attached to any of the carbocyclic atoms of ;

[0036] Alternatively, R1 and R4 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;

[0037] Alternatively, R2 and R4 together with the carbon and nitrogen atoms to which they are attached respectively form an optionally substituted heterocycle;

[0038] R a and R b Each occurrence is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl or heteroaryl; alternatively, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle comprising the nitrogen atom and 0 - 3 additional heteroatoms each independently selected from N, O and S;

[0039] Where applicable, in X1, X2, X3, R1, R2, R3, R4, R5, R a or R bThe alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl therein are each independently and optionally substituted with 1 - 4 substituents, and the substituents are each independently selected from alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, CN, OR6, -(CH2) 1-2 OR6, N(R6)2, (C=O)R6, (C=O)N(R6)2, NR6(C=O)R6, and oxo, where valence permits;

[0040] Each occurrence of R6 is independently H, alkyl, or a heterocycle optionally substituted with alkyl; alternatively, two R6 groups together with the nitrogen atom to which they are attached form a heterocycle, which is optionally substituted with alkyl and includes the nitrogen atom and 0 - 3 additional heteroatoms each independently selected from N, O, and S;

[0041] n1 is an integer from 0 - 1;

[0042] n2 is an integer from 0 - 2; and

[0043] n3 is an integer from 0 - 2.

[0044] In any of the embodiments described herein, the structural moiety has the structure , , or .

[0045] In any of the embodiments described herein, the structural moiety has the structure or .

[0046] In any of the embodiments described herein, the structural moiety has the structure , , or .

[0047] In any of the embodiments described herein, the structural moiety has the structure , , or .

[0048] In any of the embodiments described herein, the structural moiety has the structure , , , or .

[0049] In any of the embodiments described herein, the structural part has a structure .

[0050] In any of the embodiments described herein, at least one of R1, R2, and R4 is H, alkyl, or cycloalkyl.

[0051] In any of the embodiments described herein, at least one of R1, R2, and R4 is H, Me, Et, n- Pr, iso- Pr, n- Bu, sec- Bu or tert- Bu.

[0052] In any of the embodiments described herein, at least one of R2 and R4 is alkyl or cycloalkyl, each optionally substituted by one or more OR6, N(R6)2, or -(CH2) 1-2 OR6.

[0053] In any of the embodiments described herein, at least one of R2 and R4 is , , , , , , or .

[0054] In any of the embodiments described herein, R2 appears at least once as Me, Et, , , , , , , , , or .

[0055] In any of the embodiments described herein, at least one of R2 and R4 is , , , , , , , , or .

[0056] In any of the embodiments described herein, at least one of R1, R2, and R4 is heteroalkyl or cycloheteroalkyl.

[0057] In any of the embodiments described herein, at least one of R2 and R4 is NR a R b .

[0058] In any of the embodiments described herein, R a and R b are each independently H, alkyl, or cycloalkyl.

[0059] In any of the embodiments described herein, at least one of R2 and R4 is NH2, NHMe, or NHMe2.

[0060] In any of the embodiments described herein, at least one of R2 and R4 is cycloheteroalkyl optionally substituted with one or more alkyl groups.

[0061] In any of the embodiments described herein, at least one of R2 and R4 is , , , , , or .

[0062] In any of the embodiments described herein, R1 and R4 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle; or wherein R2 and R4 together with the carbon and nitrogen atoms to which they are attached respectively form an optionally substituted heterocycle.

[0063] In any of the embodiments described herein, the structural moiety has the structure , or .

[0064] In any of the embodiments described herein, the structural moiety has the structure , , or .

[0065] In any of the embodiments described herein, R5 occurs at least once as H or alkyl.

[0066] In any of the embodiments described herein, R5 occurs at least once as halogen or OH.

[0067] In any of the embodiments described herein, n3 is 0 or 1.

[0068] In any of the embodiments described herein, Z is OH, OMe, OEt, OPr or OBu.

[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, halogen or Me.

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

[0073] In any of the embodiments described herein, X2 is H, halogen, fluoroalkyl or alkyl.

[0074] In any of the embodiments described herein, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl or CF3.

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

[0076] In any of the embodiments described herein, X3 is H, halogen, fluoroalkyl or alkyl.

[0077] In any of the embodiments described herein, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl or CF3.

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

[0079] In any of the embodiments described herein, R3 is H, Me, Et, Pr, F, Cl or Br.

[0080] In any of the embodiments described herein, R3 is H.

[0081] In any of the embodiments described herein, R3 is Me, Et or Pr.

[0082] In any of the embodiments described herein, R3 is F, Cl or Br.

[0083] In any of the embodiments described herein, the structural moiety has the structure , , , , , , or .

[0084] In any of the embodiments described herein, the compound has the structure of formula II’ or II:

[0085]

[0086]

[0087] wherein R 3’ is independently H, halogen or alkyl; and

[0088] n4 is an integer from 0 - 3.

[0089] In any of the embodiments described herein, n4 is 0, 1 or 2.

[0090] In any of the embodiments described herein, n4 is 0.

[0091] In any of the embodiments described herein, R 3’ is H or alkyl.

[0092] In any of the embodiments described herein, R 3’ is halogen.

[0093] In any of the embodiments described herein, R a or R b when occurring at least once is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl or heteroaryl.

[0094] In any of the embodiments described herein, R a or R b when occurring at least once is independently H, Me, Et, Pr or a heterocycle selected from: ,

[0095] and ; wherein the heterocycle is optionally substituted with alkyl, OH, oxo or (C=O)C 1-4 alkyl, where valency permits.

[0096] In any of the embodiments described herein, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle comprising the nitrogen atom and 0 - 3 additional heteroatoms each independently selected from N, O and S.

[0097] In any of the embodiments described herein, the compound is selected from Compounds 1-70 as shown in Table 1.

[0098] In another aspect, a pharmaceutical composition is described that comprises at least one compound according to any of the embodiments described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0099] In another aspect, a method of treating a condition in a mammalian species in need thereof is described that comprises administering to the mammalian species a therapeutically effective amount of at least one compound according to any of the embodiments described herein or a pharmaceutically acceptable salt thereof, wherein the condition is selected from cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0100] In any of the embodiments described herein, the immunological disorder is transplant rejection or an autoimmune disease.

[0101] In any of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0102] In any of the embodiments described herein, the central nervous system disorder is Alzheimer's disease.

[0103] In any of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neuropathy.

[0104] In any of the embodiments described herein, the gastrointestinal disorder is inflammatory bowel disease.

[0105] In any of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0106] In any of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0107] In any of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0108] 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 neuropathies, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0109] In any of the embodiments described herein, the mammalian species is a human.

[0110] In another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, which comprises administering to the mammalian species a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any of the embodiments described herein.

[0111] In any of the embodiments described herein, the mammalian species is a human.

[0112] Any of the embodiments disclosed herein can be suitably combined with any other embodiment disclosed herein. Combinations of any of the embodiments disclosed herein with any other embodiment disclosed herein are expressly contemplated. Specifically, the selection of one or more embodiments of one substituent can be suitably combined with the selection of one or more specific embodiments of any other substituent. Such combinations can be made in any one or more embodiments of the applications described herein or in any of the formulas described herein. Detailed Description of the Invention

[0114] Definitions

[0115] The following are definitions of terms used in this specification. Unless otherwise indicated, the initial definitions provided for the groups or terms herein apply to the groups or terms used throughout this specification, either alone or as part of another group. 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.

[0116] The terms "alkyl" and "alk" refer to straight-chain or branched-chain alkane (hydrocarbon) groups containing from 1 to 12 carbon atoms, preferably from 1 to 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, and the like. The term "(C 1-"C4) alkyl" refers to a straight 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 substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or alkyl with 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 a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , Rc and R d Each occurrence is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c Optionally forms a heterocycle together with the N to which they are attached, and R e Each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In certain embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl themselves may optionally be substituted.

[0117] The term "heteroalkyl" refers to a straight-chain or branched-chain alkyl group which preferably has 2 to 12 carbons, more preferably 2 to 10 carbons in the chain, and in which one or more have been replaced by heteroatoms selected from S, O, P and N. Exemplary heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, etc. The group may be a terminal group or a bridging group.

[0118] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include vinyl or allyl. The term "C2-C6 alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl, ( 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)-hexa-1,3-dienyl. "Substituted alkenyl" refers to alkenyl substituted at any available point of attachment with 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 with a single halogen substituent or multiple halogen substituents such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , 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 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or said Rb and R c optionally form a heterocycle together with the N to which they are bonded; and R e is, each occurrence independently, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. The exemplary substituents themselves may be optionally substituted.

[0119] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl or hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl substituted at any available point of attachment with 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., a single halogen substituent or multiple halogen substituents, in the latter case forming groups such as CF3 or an alkyl with 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 , NRd 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 wherein R a is, each occurrence independently, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b 、R c and R d are, each occurrence independently, hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c optionally form a heterocycle together with the N to which they are attached; and R e is, each occurrence independently, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. The exemplary substituents themselves may be optionally substituted.

[0120] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl substituted at any available attachment point with 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., a single halogen substituent or multiple halogen substituents, in the latter case forming groups such as CF3 or an alkyl with 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 , wherein R a is, each time it appears independently, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d are, each time they appear independently, hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c optionally form a heterocycle together with the N to which they are attached; and R e is, each time it appears independently, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. The exemplary substituents themselves may be optionally substituted. Exemplary substituents also include spiro-linked or fused cyclic substituents, especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycles (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycles or fused aryl, wherein the foregoing cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0121] The term "heterocycloalkyl" or "cycloheteroalkyl" refers to a saturated or partially saturated monocyclic, bicyclic or polycyclic ring which contains at least one heteroatom selected from nitrogen, sulfur and oxygen, preferably 1 to 3 heteroatoms, in at least one ring. Each ring is preferably 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholino, 1,3-diazepanyl, 1,4-diazepanyl, 1,4-oxazepanyl and 1,4-oxathiepanyl. The groups may be terminal groups or bridging groups.

[0122] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon radical containing 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 substituted by one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halogen substituents, forming a group such as CF in the latter case or with CCl alkyl), cyano, nitro, oxo (i.e., =O), CF , OCF , 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 a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , Rc and R d Each occurrence is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c optionally forms a heterocycle together with the N to which they are attached; and R e Each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. The exemplary substituents themselves may be optionally substituted. Exemplary substituents also include spiro-linked or fused cyclic substituents, especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycles (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycles or fused aryl, where the foregoing cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0123] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. In the case of containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl may be linked at a single point (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, where two adjacent aromatic rings have two common carbon atoms. "Substituted aryl" refers to aryl substituted at any available attachment point by one or more substituents, preferably 1 to 3 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming groups such as CF3 or an alkyl with 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 bR 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 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or said R b and R c Together with the N to which they are bound, they optionally form a heterocyclic ring; and R e Each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. The exemplary substituents themselves may be optionally substituted. Exemplary substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0124] The term "biaryl" refers to two aryls connected by a single bond. The term "biaryl" refers to two heteroaryls connected by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl and an aryl connected by a single bond, and the term "aryl-heteroaryl" refers to an aryl and a heteroaryl connected by a single bond. In certain embodiments, the size of the aryl or heteroaryl ring in the substituent is described using the number of ring atoms in the heteroaryl and / or aryl ring. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is connected to a 6-membered aryl. Other combinations and ring sizes can be described similarly.

[0125] The term "carbocycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic aromatic hydrocarbon group with 1 to 5 aromatic rings, particularly a monocyclic or bicyclic group such as phenyl, biphenyl or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl defined above. The term "substituted carbocycle" refers to a carbocyclic group substituted by one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl and substituted aryl. Exemplary substituents also include spiro-linked or fused cyclic substituents at any available attachment point, in particular spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the foregoing cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0126] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or completely unsaturated (including aromatic (i.e., "heteroaryl")) cyclic groups (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 at least one ring containing carbon atoms. Each ring of the heterocyclic group can independently be saturated, or partially or completely unsaturated. Each ring of the heterocyclic group containing heteroatoms can have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. (The term "heteroarylium" refers to a heteroaryl group with a quaternary nitrogen atom and thus a positive charge). The heterocyclic group can be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperid ... -oxopyrrolodinyl, 2-oxoazepine, azepine, hexahydrodiazepine, 4-piperidone, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazine, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothiphenyl, etc. Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothiophenyl, benzo[ d[1,3]Dioxolyl, dihydro-2H-benzo b [1,4]oxazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, benzofurazanyl, dihydrobenzo d oxazolyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furanopyridinyl (such as furano[2,3-c]pyridinyl, furano[3,2-b]pyridinyl or furano[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0127] "Substituted heterocycle" and "substituted heterocyclic" (such as "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted at any available attachment point with 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., a single halogen substituent or multiple halogen substituents, in the latter case forming groups such as CF3 or an alkyl group with 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 、NRb 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 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c Together with the N to which they are bound, they optionally form a heterocyclic ring; and R e Each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. The exemplary substituent itself can be optionally substituted. Exemplary substituents also include spirals connected or fused cyclic substituents at any available attachment point, particularly spiral cycloalkyl, spiral cycloalkenyl, spiral heterocycle (not including heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves can be optionally substituted.

[0128] The term "oxo" refers to Substituents can be attached to carbon ring atoms on a carbocyclic or heterocyclic ring. When an oxo substituent is attached to a carbon ring atom on an aromatic group (e.g., aryl or heteroaryl), the bonds on the aromatic ring may be rearranged to satisfy valence requirements. For example, pyridine with a 2-oxo substituent may have The structure of .

[0129] The term "alkylamino" refers to a group having the structure -NHR', wherein R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0130] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined herein. R and R' may be the same or different in the dialkylamino moiety. Examples of dialkylamino include, but are not 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, and the like. In certain 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, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0131] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0132] The term "substituted" refers to embodiments in which a molecule, moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl or any other group disclosed herein) is substituted at any available attachment point with one or more substituents, preferably 1 to 6 substituents, where valence allows. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming groups such as CF3 or an alkyl bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, 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 , wherein R a is, each time it appears independently, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d are, each time they appear independently, hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; and R e is, each time it appears independently, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In the foregoing exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl themselves may optionally be substituted. The term "optionally substituted" refers to embodiments in which a molecule, moiety or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl or any other group disclosed herein) may or may not be substituted by one or more of the foregoing substituents.

[0133] Unless otherwise specified, any heteroatom having an unsatisfied valence is assumed to have hydrogen atoms sufficient to satisfy the valence.

[0134] The compounds of the present invention can form salts which are also within the scope of the present invention. References to the compounds of the present invention are understood to include references to their salts, unless otherwise indicated. As used herein, the term "salt" refers to acid addition salts and / or base salts formed with inorganic and / or organic acids and bases. Additionally, when a compound of the present invention contains both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, phenol or carboxylic acid), zwitterions ("inner salts") can be formed and are included in the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts can also be used, for example, in separation or purification steps that may be employed during the preparation process. The salts of the compounds of the present invention can be formed, for example, by reacting the compounds described herein with an amount (such as an equivalent amount) of an acid or base in a medium (such as a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0135] Compounds of the present invention containing a basic moiety (such as, but not limited to, an amine or a pyridine or imidazole ring) can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates (such as tosylates), undecanoates, etc.

[0136] The compounds of the present invention containing acidic moieties such as, but not limited to, phenol or carboxylic acid can form salts with a variety of organic and inorganic bases. Exemplary base salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts formed with organic bases (e.g., organic amines) such as benzathine penicillin, dicyclohexylamine, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, 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), etc.

[0137] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. As used herein, the term "prodrug" refers to a compound that, upon administration to a subject, is chemically transformed by a metabolic or chemical process to produce the compound of the present invention or its salt and / or solvate. Solvates of the compounds of the present invention include, for example, hydrates.

[0138] The compounds of the present invention and their salts or solvates can exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted compound structure includes its tautomeric forms.

[0139] All stereoisomers of the compounds of the present invention (e.g., those which may exist due to asymmetric carbons on different substituents), including enantiomeric and diastereomeric forms, are contemplated within the scope of the present invention. A single stereoisomer of a compound of the present invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be mixed, e.g., as a racemate or mixed with all other or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. Racemic forms can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. A single optical isomer can be obtained from a racemate by any suitable method, including but not limited to conventional methods such as, for example, formation of salts with optically active acids followed by crystallization.

[0140] After its preparation, the compound of the present invention is preferably isolated and purified to obtain a composition containing the compound in an amount equal to or greater than 90% by weight, e.g., equal to or greater than 95%, equal to or greater than 99% (“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.

[0141] All configurational isomers of the compounds of the present invention are contemplated, whether in the form of mixtures or in pure or substantially pure form. The definition of the compounds of the present invention includes cis (Z) and trans (E) alkene isomers as well as cis and trans isomers of cyclic hydrocarbons or heterocycles.

[0142] Throughout this specification, groups and their substituents may be chosen to provide stable moieties and compounds.

[0143] The definitions of specific functional groups and chemical terms are described in more detail herein. For the purposes of the present invention, chemical elements are identified according to the Periodic Table (CAS version, Handbook of Chemistry and Physics , 75th Edition, inside front cover), and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito (1999), the entire content of which is incorporated herein by reference.

[0144] Certain compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures and other mixtures thereof, all of which fall within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are intended to be included in the present invention.

[0145] Isomer mixtures containing any of the various isomer ratios can be utilized in accordance with the present invention. For example, in the case of combining only two isomers, the present invention contemplates all 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. Those of ordinary skill in the art will readily recognize similar ratios for more complex isomer mixtures.

[0146] The present invention also includes isotopically labeled compounds which are identical to the compounds disclosed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention containing the foregoing isotopes and / or other isotopes of other atoms, or their enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts or solvates are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and / or substrate tissue distribution assays. Because of their ease of preparation and detectability, tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred. In addition, use of heavier isotopes (such as deuterium, i.e., 2H) Substitution can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and may thus be preferred in certain instances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the following schemes and / or examples, substituting an isotopically labeled reagent for a non-isotopically labeled reagent that is readily available.

[0147] For example, if a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the separated diastereomeric mixture is obtained and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in cases where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, and the diastereomers thus formed are then resolved by fractional crystallization or chromatographic means well known in the art, and the pure enantiomer is subsequently recovered.

[0148] It should be understood that the compounds described herein can be substituted by any number of substituents or functional moieties. In general, the term "substituted" (whether or not preceded by the term "optionally") and the substituents contained in the formulas of the invention refer to the replacement of a hydrogen group in a given structure with a group of the designated substituents. When more than one position in any given structure can be substituted by more than one substituent selected from the designated group, the substituents at each position can be the same or different. The term "substituted" as used herein is contemplated to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For the purposes of the present invention, heteroatoms (such as nitrogen) can have hydrogen substituents and / or any permissible substituents of the organic compounds described herein, provided that the valency of the heteroatom is satisfied. Additionally, the present invention is not intended to be limited in any way by the permissible substituents of organic compounds. Combinations of substituents and variables contemplated by the present invention are preferably those that result in the formation of stable compounds, which can be used, for example, in the treatment of proliferative disorders. The term "stable" as used herein preferably refers to a compound that has sufficient stability to allow for its manufacture and maintains the integrity of the compound over a period of time sufficient to be detected and preferably over a period of time sufficient to be useful for the purposes detailed herein.

[0149] As used herein, the terms "cancer" and the equivalent term "tumor" refer to a condition in which abnormally replicating cells of host origin are present in a subject in a detectable amount. Cancer can be malignant or non-malignant cancer. Cancers or tumors include, but are not limited to: biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. Cancer can be primary or metastatic. Diseases other than cancer may be associated with mutant alterations in components of the Ras signaling pathway, and the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases can include: neurofibromatosis; Leopard Syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; cardio-facio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arteriovenous malformation.

[0150] As used herein, "effective amount" means any amount necessary or sufficient to achieve or facilitate a desired result. In some cases, an effective amount is a therapeutically effective amount. A 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 particular agent being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without undue experimentation.

[0151] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including, but not limited to, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals.

[0152] Compound

[0153] Novel compounds are described as Kv1.3 potassium channel blockers. The applicants have surprisingly found that the compounds disclosed herein exhibit potent Kv1.3 potassium channel inhibitory properties. Additionally, the applicants have surprisingly found that the compounds disclosed herein selectively block the Kv1.3 potassium channel and do not block the hERG channel, and thus have a desirable cardiovascular safety profile.

[0154] In one aspect, a compound of formula I or a pharmaceutically acceptable salt thereof is described,

[0155]

[0156] wherein

[0157] Y is independently C(R2)2 or NR1 each occurrence;

[0158] Z is OR a ;

[0159] X1 is H, halogen or alkyl;

[0160] X2 is H, halogen, CN, alkyl, cycloalkyl, halocycloalkyl or haloalkyl;

[0161] X3 is H, halogen, CN, alkyl, cycloalkyl, halocycloalkyl or haloalkyl;

[0162] Alternatively, X1 and X2 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl;

[0163] Alternatively, X2 and X3 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl;

[0164] R1 is H, alkyl, cycloalkyl, heteroalkyl or cycloheteroalkyl each occurrence;

[0165] R2 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl or NR a R b ;

[0166] R3 is H, alkyl or halogen;

[0167] R4 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl or NR a R b ;

[0168] R5 is H, halogen, OR6 or alkyl each occurrence, wherein each R5 can be attached to any of the carbocyclic atoms of;

[0169] Alternatively, R1 and R4 and the nitrogen atom to which they are attached together form an optionally substituted heterocycle;

[0170] Alternatively, R2 and R4 and the carbon and nitrogen atoms to which they are attached respectively form an optionally substituted heterocycle;

[0171] R a and R b are independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl or heteroaryl each occurrence; alternatively, Ra and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle comprising said nitrogen atom and 0 - 3 additional heteroatoms each independently selected from N, O, and S;

[0172] where applicable, the alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl in X1, X2, X3, R1, R2, R3, R4, R5, R a or R b are each independently and optionally substituted with 1 - 4 substituents each independently selected from alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, CN, OR6, -(CH2) 1-2 OR6, N(R6)2, (C=O)R6, (C=O)N(R6)2, NR6(C=O)R6, and oxo, where valency permits;

[0173] R6 is each occurrence independently H, alkyl, or a heterocycle optionally substituted with alkyl; or, two R6 groups together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with alkyl and comprising said nitrogen atom and 0 - 3 additional heteroatoms each independently selected from N, O, and S;

[0174] n1 is an integer from 0 - 1;

[0175] n2 is an integer from 0 - 2; and

[0176] n3 is an integer from 0 - 2.

[0177] In certain embodiments, the structural moiety has the structure , , or . In certain embodiments, the structural moiety has the structure . In certain embodiments, the structural moiety has the structure . In certain embodiments, the structural moiety has the structure . In certain embodiments, the structural moiety has the structure .

[0178] In certain embodiments, n1 is 1. In certain embodiments, n1 is 0. In certain embodiments, n2 is an integer from 0 - 2. In certain embodiments, n2 is an integer from 1 - 2. In certain embodiments, n2 is 0. In certain embodiments, n2 is 1 or 2. In certain embodiments, n2 is 2. In certain embodiments, n2 is 1.

[0179] In certain embodiments, Y occurs at least once as C(R2)2. In other embodiments, Y occurs at least once as NR1. In certain embodiments, Yn2 is -C(R2)2. In other embodiments, Yn2 is -NR1-. In still other embodiments, Yn2 is -C(R2)2-C(R2)2-. In still other embodiments, the structural moiety -(C=O)-Y n2 - is -(C=O)-C(R2)2-NR1-. In still other embodiments, the structural moiety -(C=O)-Y n2 - is -(C=O)-NR1-C(R2)2-.

[0180] In certain embodiments, the structural moiety has the structure 、 、 or 。 In certain embodiments, the structural moiety has the structure 、 、 or 。 In certain specific embodiments, the structural moiety has the structure 、 、 、 or 。 In certain specific embodiments, the structural moiety has the structure 。 In certain specific embodiments, the structural moiety has the structure 。 In certain specific embodiments, the structural moiety has the structure 。 In certain specific embodiments, the structural moiety has the structure 。

[0181] In certain embodiments, R1 is H, alkyl, or cycloalkyl. In other embodiments, R1 is heteroalkyl or cycloheteroalkyl.

[0182] In certain embodiments, R2 occurs at least once as H, alkyl, or cycloalkyl. In certain specific embodiments, R2 occurs at least once as H, Me, Et, n- Pr, iso -Pr, n- Bu, sec- Bu or tert-Bu. In other specific embodiments, R2 appears at least once as alkyl or cycloalkyl, each optionally substituted by one or more OR6, N(R6)2 or -(CH2) 1-2 OR6. In certain specific embodiments, R2 appears at least once as , , , , , , or .

[0183] In certain embodiments, R2 appears at least once as Me, Et, , , , , , , , , or .

[0184] In certain embodiments, R2 appears at least once as , , , , , , , , or . In certain specific embodiments, R2 appears at least once as heteroalkyl, cycloheteroalkyl or NR a R b . In certain specific embodiments, R2 appears at least once as NR a R b , such as NH2, NHMe or NHMe2. In certain specific embodiments, R2 is NR a R b and R a is H and R b is alkyl or cycloalkyl. In certain specific embodiments, R2 is NR a R b and R a and R b each of which is alkyl or cycloalkyl. In other embodiments, R2 appears at least once as cycloheteroalkyl optionally substituted by one or more alkyl groups. In certain specific embodiments, R2 is , , , , , or 。

[0185] In certain embodiments, R2 is heteroalkyl. In certain specific embodiments, R2 is an alkyl ether, a secondary alkylamine, a tertiary alkylamine, or an alkyl sulfide, such as -CH2-CH2-OMe, -CH2-CH2-OEt, -CH2-CH2-OPr, -CH2-CH2-SMe, -CH2-CH2-SEt, -CH2-CH2-SPr, -CH2-CH2-NHMe, -CH2-CH2-NMe2, -CH2-CH2-NEtMe, or -CH2-CH2-NEt2. In certain embodiments, R2 is cycloheteroalkyl. Non-limiting examples of cycloheteroalkyl include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholino, 1,3-diazepanyl, 1,4-diazepanyl, 1,4-oxazepanyl, and 1,4-oxathiepanyl.

[0186] In certain embodiments, R4 is H, alkyl, or cycloalkyl. In certain specific embodiments, R4 is H, Me, Et, n-Pr, iso -Pr, n- Bu, sec- Bu or tert- Bu. In other specific embodiments, R4 is an alkyl or cycloalkyl, each optionally substituted with one or more OR6, N(R6)2, or -(CH2) 1-2 OR6 substituents. In certain specific embodiments, R4 is 、 、 、 、 、 、 or 。

[0187] In certain embodiments, R4 is 、 、 、 、 、 、 、 、 or 。In certain specific embodiments, R4 is heteroalkyl, cycloheteroalkyl, or NR a R b 。In certain specific embodiments, R4 is NR a R b ,such as NH2, NHMe, or NHMe2. In certain specific embodiments, R4 is NRa R b and R a is H and R b is alkyl or cycloalkyl. In certain specific embodiments, R4 is NR a R b and R a and R b each of which is alkyl or cycloalkyl. In other embodiments, R4 is a cycloheteroalkyl optionally substituted with one or more alkyl groups. In certain specific embodiments, R4 is , , , , , or .

[0188] In certain embodiments, R4 is heteroalkyl. In certain specific embodiments, R4 is an alkyl ether, a secondary or tertiary alkylamine, or an alkyl sulfide, such as -CH2-CH2-OMe, -CH2-CH2-OEt, -CH2-CH2-OPr, -CH2-CH2-SMe, -CH2-CH2-SEt, -CH2-CH2-SPr, -CH2-CH2-NHMe, -CH2-CH2-NMe2, -CH2-CH2-NEtMe or -CH2-CH2-NEt2. In certain embodiments, R4 is cycloheteroalkyl. Non-limiting examples of cycloheteroalkyl include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholino, 1,3-diazepanyl, 1,4-diazepanyl, 1,4-oxazepanyl and 1,4-oxathiepanyl.

[0189] In other embodiments, R1 and R4 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle. In still other embodiments, R2 and R4 together with the carbon and nitrogen atoms to which they are attached respectively form an optionally substituted heterocycle.

[0190] In certain specific embodiments, the structural moiety has the structure , or . In certain specific embodiments, the structural moiety has the structure , , or . In certain specific embodiments, the structural moiety has the structure or .

[0191] In certain embodiments, R5 occurs at least once as H or alkyl. Non-limiting examples of alkyl include Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In other embodiments, R5 is OR6 or halogen. In certain specific embodiments, R5 is halogen. In certain specific embodiments, R5 is OR6. In certain specific embodiments, R5 is OH. In certain embodiments, n3 is 2. In certain embodiments, n3 is 1. In certain embodiments, n3 is 0.

[0192] In certain embodiments, R6 is H or alkyl. In other embodiments, R6 is an optionally substituted heterocycle. In still other embodiments, two R6 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle that includes the nitrogen atom and 0 - 3 additional heteroatoms each independently selected from N, O, and S.

[0193] In certain embodiments, Z is OR a . In certain embodiments, Z is OH, OMe, OEt, OPr, or OBu. In certain embodiments, Z is OH.

[0194] In certain embodiments, X1 is H, halogen, or alkyl. In any of the embodiments described herein, X1 can be H or halogen. In certain embodiments, X1 is H or alkyl. In other embodiments, X1 is alkyl. In other embodiments, X1 is H. In certain embodiments, X1 is H, F, Cl, Br, or Me. In certain embodiments, X1 is H, F, or Cl. In certain embodiments, X1 is F or Cl. In certain embodiments, X1 is H or Cl. In certain embodiments, X1 is F. In certain embodiments, X1 is Cl. In certain embodiments, X1 is H.

[0195] In certain embodiments, X2 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In any of the embodiments described herein, X2 can be H, halogen, fluoroalkyl, or alkyl. In certain embodiments, X2 is H or halogen. In other embodiments, X2 is fluoroalkyl or alkyl. In other embodiments, X2 is cycloalkyl. In certain embodiments, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In certain embodiments, X2 is H, F, or Cl. In certain embodiments, X2 is F or Cl. In certain embodiments, X2 is H or Cl. In certain embodiments, X2 is F. In certain embodiments, X2 is CF3. In certain embodiments, X2 is CF2Cl. In certain embodiments, X2 is Cl.

[0196] In certain embodiments, X3 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In any of the embodiments described herein, X3 can be H, halogen, fluoroalkyl, or alkyl. In certain embodiments, X3 is H or halogen. In other embodiments, X3 is fluoroalkyl or alkyl. In other embodiments, X3 is cycloalkyl. In certain embodiments, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In certain embodiments, X3 is H, F, or Cl. In certain embodiments, X3 is F or Cl. In certain embodiments, X3 is H or Cl. In certain embodiments, X3 is F. In certain embodiments, X3 is CF3. In certain embodiments, X3 is CF2Cl. In certain embodiments, X3 is Cl.

[0197] In certain embodiments, the structural moiety has the structure , , , , , , or .

[0198] In any of the embodiments described herein, R3 is H, alkyl, or halogen. In certain embodiments, R3 is H or halogen. In certain embodiments, R3 is H, F, Cl, or Br. Non-limiting examples of alkyl include Me, Et, propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.

[0199] In certain embodiments, the compound of formula I has the structure of formula II' or II,

[0200]

[0201] wherein R 3’ is independently H, halogen, or alkyl each time it appears; and n4 is an integer from 0 - 3, and the other substituents are as defined herein.

[0202] In certain embodiments, Z is OR a . In certain embodiments, Z is OH, OMe, OEt, OPr, or OBu. In certain embodiments, Z is OH.

[0203] In certain embodiments, n4 is an integer from 0 - 3. In certain embodiments, n4 is an integer from 1 - 3. In certain embodiments, n4 is 0. In certain embodiments, n4 is 1 or 2. In certain embodiments, n4 is 1. In certain embodiments, R 3’ is H or alkyl. In certain embodiments, R3’ is H. In certain embodiments, R 3’ is alkyl. In certain embodiments, R 3’ is halogen.

[0204] In any of the embodiments described herein, R a or R b in at least one occurrence is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. In certain embodiments, R a or R b in at least one occurrence is independently H, Me, Et, Pr, or Bu. In certain embodiments, R a or R b in at least one occurrence is independently a heterocycle selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , and ; wherein the heterocycle is optionally substituted with alkyl, OH, oxo, or (C=O)C 1-4 alkyl, where valency permits.

[0205] In certain embodiments, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle comprising the nitrogen atom and 0 - 3 additional heteroatoms each independently selected from N, O, and S.

[0206] In certain embodiments, the compounds of formula I are selected from Compounds 1 - 70 as shown in Table 1 below.

[0207] Abbreviations

[0208] ACN Acetonitrile

[0209] Boc tert - Butyloxycarbonyl

[0210] CDI Carbonyl diimidazole

[0211] DCM Dichloromethane

[0212] DIPA Diisopropylamine

[0213] DIPEA N , N -Diisopropylethylamine

[0214] DMAP 4-Dimethylaminopyridine

[0215] DMF Dimethylformamide

[0216] EA Ethyl acetate

[0217] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0218] HATU N -[(Dimethylamino)(3 H -1,2,3-triazolo(4,4- b )pyridin-3-yloxy)methylene]- N -Methylmethanaminium hexafluorophosphate

[0219] HBTU 2-(1 H -Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0220] HOBT 1-Hydroxybenzotriazole

[0221] IPA Isopropyl alcohol

[0222] PE Petroleum ether

[0223] TEA Triethylamine

[0224] TFA Trifluoroacetic acid

[0225] THF Tetrahydrofuran.

[0226] Preparation method

[0227] The following is a general synthetic scheme for preparing the compounds of the present invention. These schemes are exemplary and are not intended to limit the possible techniques that those skilled in the art can use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Additionally, the individual steps in the synthesis can be carried out in alternative orders or sequences to produce the desired compounds. All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrative rather than limiting of the preparation of some of the starting materials and compounds disclosed herein.

[0228] The following Schemes 1-6 describe synthetic routes that can be used to synthesize the compounds of the present invention (e.g., compounds having the structure of Formula I or their precursors). Those skilled in the art can consider various modifications to these methods to obtain results similar to those of the present invention given below. In the following embodiments, compounds having the structure of Formula I or their precursors are used as examples to describe the synthetic routes. The general synthetic routes described in Schemes 1-6 and the examples described in the Examples section below illustrate methods for preparing the compounds described herein.

[0229] Compounds I-1a and I-2 shown in Scheme 1 below can be prepared by any method known in the art and / or can be commercially available. As shown in Scheme 1, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or other protecting groups known in the art suitable for use as protecting groups for OH or amino groups. Other substituents are defined herein. As shown in Scheme 1, in certain embodiments, the compounds disclosed herein can be synthesized from a suitable substituted bromo- or iodo-benzene I-1a, which is converted to the corresponding boronic acid I-1b as follows: metallated with, for example, n-butyllithium and reacted with a trialkyl borate such as trimethyl borate. The keto ester I-2 is reacted with a base such as lithium hexamethyldisilazide and N -phenyltrifluoromethanesulfonimide to form the enol trifluoromethanesulfonate I-3. The coupling of I-3 with boronic acid I-1b in the presence of a catalyst such as 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium(II) (Pd(dppf)Cl2) yields the cyclic amine I-4. The hydrogenation of I-4 on a catalyst such as platinum oxide yields the saturated cyclic amine ester I-5a. The protecting group in compound I-5a can then be removed to produce a compound of Formula I, and such compounds having a free phenolic OH and / or free nitrogen group can optionally be further converted to other compounds of Formula I using methods known in the art.

[0230]

[0231] Compounds I-1a and I-6, as shown in Scheme 2 below, can be prepared by any method known in the art and / or can be commercially available. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyls, dialkylaminocarbonyl or other protecting groups known in the art suitable for use as protecting groups for OH. Other substituents are defined herein. As shown in Scheme 2, in certain embodiments, the compounds disclosed herein (where n1 = 1) can be prepared by an alternative route. Coupling of iodo- or bromo-benzene I-1a with pyridine borate I-6 in the presence of a palladium catalyst such as Pd(dppf)Cl2 forms 4-aryl pyridine I-7. Hydrogenation of I-7 over a catalyst such as platinum oxide provides 4-aryl piperidine I-5b. The protecting group in compound I-5b can then be removed to produce a compound of formula I, and such compounds having a free phenolic OH and / or free nitrogen group can optionally be further converted to other compounds of formula I using methods known in the art.

[0232]

[0233] As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyls, dialkylaminocarbonyl or other protecting groups known in the art suitable for use as protecting groups for OH. Other substituents are defined herein. As shown in Scheme 3 below, the compounds disclosed herein (where R4 is H or lower alkyl) can be obtained from piperidine esters I-5b or I-5c, which can be obtained from I-5a by selective removal of the protecting group on nitrogen. Coupling of the cyclic amine ester I-5b or I-5c with a suitably protected amino acid using a coupling agent such as EDC / HOBt, HBTU or HATU forms amide I-8. An example of a suitable amine protecting group on nitrogen is tert-butyloxycarbonyl (boc). Removal of the amine protecting group using TFA, followed by heating with a base such as triethylamine in a solvent such as toluene, results in cyclization to diketopiperazine I-9a. Removal of the phenol protecting group gives I-10a.

[0234]

[0235] As shown in Scheme 4, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyls, dialkylaminocarbonyls or additional protecting groups known in the art suitable for use as protecting groups for OH. Other substituents are defined herein. The relevant methods applicable to more complex R4 groups are shown in Scheme 4 below. The amino ester I-5c is reacted with chloroacetyl chloride and a base such as triethylamine to produce chloroacetamide I-11. I-11 is treated with an amine R4NH2 and a base such as triethylamine and heated in a solvent such as ethanol to produce N-substituted diketopiperazine I-9b, which is converted to I-10b by removal of the phenol protecting group.

[0236]

[0237] As shown in Scheme 5, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyls, dialkylaminocarbonyls or additional protecting groups known in the art suitable for use as protecting groups for OH. Other substituents are defined herein. The compounds disclosed herein in which Y is absent or is nitrogen can be synthesized by the methods shown in Scheme 5 below. As shown in Scheme 5, for the compounds disclosed herein in which Y is absent, the amino ester I-5c is reacted with an amine R4NH2 by heating in methanol to provide amide I-12. The amide I-12 is treated with carbonyldiimidazole (CDI) in DMF, causing cyclization to imidazolidinedione I-13. For the compounds disclosed herein in which Y is nitrogen, the reaction of the boc-protected amino ester I-5d with hydrazine hydrate directly produces triazolidinedione I-14. The protecting groups in compounds I-13 and I-14 can then be removed to produce compounds of formula I, and such compounds having a free phenolic OH group can optionally be further converted to other compounds of formula I using methods known in the art.

[0238]

[0239] As shown in Scheme 6, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyls, dialkylaminocarbonyls or additional protecting groups known in the art suitable for use as protecting groups for OH. Other substituents are defined herein. The stereocontrolled synthesis of intermediate 5d to produce the chiral intermediate 5e is shown in Scheme 6 below.

[0240] As shown in Scheme 6, the enantiopure piperidone I-15 can be synthesized from protected L-aspartic acid and maleic acid by the method of Org. Syn. , 2008, 85, 147 and then according to Syn. Lett., the procedure described in 2009, 71 - 74 is converted to enol triflate I - 16 by treatment with trifluoromethanesulfonic anhydride and a base. The enol triflate I - 16 is coupled with boric acid I - 1b using a palladium catalyst such as Pd(dppf)Cl2 to yield I - 17. Hydrogenation of I - 17 over a catalyst such as platinum oxide gives piperidone I - 18, mainly as 2S , 4S an enantiomer, and reduction of the amide using borane methyl sulfide complex provides enantiopure I - 5e, which can be used in the syntheses outlined in Schemes 3, 4, and 5.

[0241]

[0242] The reactions described in Schemes 1 - 6 above can be carried out in a suitable solvent. Suitable solvents include, but are not limited to, acetonitrile, methanol, ethanol, dichloromethane, DMF, THF, MTBE, or toluene. The reactions described in Schemes 1 - 6 can be carried out under an inert atmosphere, for example, under nitrogen or argon, or the reaction can be carried out in a sealed tube. The reaction mixture can be heated in a microwave or heated 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 a temperature below room temperature, such as 0, - 10, - 20, - 30, - 40, - 50, - 78, or - 90 °C. The reaction can be worked up by removing the solvent or 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 evaporation under reduced pressure, and the resulting residue can be purified using a silica gel column or HPLC.

[0243] Pharmaceutical Compositions

[0244] The present invention also provides a pharmaceutical composition comprising at least one compound as described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

[0245] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound and a pharmaceutically acceptable carrier or diluent, wherein the compound is selected from the compounds of formula I as described herein.

[0246] In certain embodiments, the composition is in the form of a hydrate, solvate, or pharmaceutically acceptable salt. The composition can be administered to a subject by any suitable route of administration, including, but not limited to, oral and parenteral.

[0247] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ or body part to another. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; 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; diols such as butylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents 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 compatible substances employed in pharmaceutical formulations. The term "carrier" denotes a natural or synthetic organic or inorganic ingredient with which the active ingredient is combined to facilitate its application. The components of the pharmaceutical composition can also be mixed with the compounds of the present invention and with each other in a manner such that there are no interactions that would substantially impair the desired pharmaceutical efficacy.

[0248] As noted above, certain embodiments of the pharmaceutical agents of the present invention may be provided in the form of pharmaceutically acceptable salts. In this regard, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compound of the present invention in its free base form with a suitable organic or inorganic acid and isolating the salt so formed. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate, etc. (See, e.g., Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.).

[0249] Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, butyric 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc.

[0250] In other instances, the compounds of the invention may contain one or more acidic functional groups and thus be capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic base addition salts of the compounds of the invention. These salts can also be prepared in situ during the final isolation and purification of the compounds, or as follows: separately reacting the purified compound in its free acid form with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include: lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc. Representative organic amines useful for forming base addition salts include: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. See, e.g., Berge et al. (supra).

[0251] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate, magnesium stearate and poly(ethylene oxide)-poly(butylene oxide) copolymers, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the compositions.

[0252] The formulations of the invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the pharmaceutical art. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect. Generally, on a 100% basis, the amount will range from about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 30%.

[0253] The method for preparing these preparations or compositions includes the step of combining the compounds of the present invention with a carrier and optionally one or more auxiliaries. Generally, the preparations are prepared as follows: the compounds of the present invention are uniformly and closely combined with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, the product is shaped.

[0254] The preparations suitable for oral administration according to the present invention can be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored matrix, usually sucrose and gum arabic or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as water-in-oil or oil-in-water liquid emulsions, or as elixirs or syrups, or as troches (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 can also be administered as boluses, pastilles or pastes.

[0255] In the solid dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) of the present invention for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dibasic calcium phosphate) and / or any one of the following substances: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; humectants, such as glycerol; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate and sodium starch glycolate; solution blockers, such as paraffin wax; absorption promoters, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glyceryl monostearate and poly(ethylene oxide)-poly(butylene oxide) 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 coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also include buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugars and high molecular weight polyethylene glycols.

[0256] Tablets can be prepared by compressing or molding, optionally with one or more auxiliaries. Compressed tablets can be prepared using, for example, binders (such as gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0257] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the pharmaceutical formulation art). They may also be formulated to provide slow release or controlled release of the active ingredient therein, using, for example, different proportions of hydroxybutyl methylcellulose (to provide the desired release characteristics), other polymeric matrices, liposomes, and / or microspheres. They may be sterilized as follows: for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may have a composition that releases only the active ingredient, or preferably in certain parts of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in the form of microcapsules, if appropriate, together with one or more of the above excipients.

[0258] 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 forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isobutanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins (e.g., hydroxybutyl-β-cyclodextrin) may be used to solubilize the compounds.

[0259] In addition to the inert diluent, oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives.

[0260] In addition to the active compound, suspensions may also contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0261] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required, under sterile conditions.

[0262] In addition to the active compounds of the present invention, the ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide, or mixtures thereof.

[0263] In addition to the compounds of the present invention, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants (such as chlorofluorocarbons) and volatile unsubstituted hydrocarbons such as butane and isobutane.

[0264] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the pharmaceutical agent in a suitable medium. Penetration enhancers can also be used to increase the flux of the pharmaceutical agent of the present invention through the skin. The rate of such flux can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0265] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated within the scope of the present invention.

[0266] The pharmaceutical compositions of the present invention suitable for parenteral administration include one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions; or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use and which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0267] In certain cases, in order to prolong the action of a drug, it is necessary to slow the absorption of the drug from a subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn can depend on crystal size and polymorph. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle. One strategy for depot injection involves the use of poly(ethylene oxide)-poly(propylene oxide) copolymers where the vehicle is fluid at room temperature and solidifies at body temperature.

[0268] An injectable depot form is prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as poly(lactide - co - glycolide). The drug release rate can be controlled depending on the ratio of the drug to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot - type injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0269] When the compounds of the present invention are administered as drugs to humans and animals, they can be administered per se or as a pharmaceutical composition containing, for example, from 0.1% to 99.5% (more preferably from 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0270] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapy, that is, the compounds and pharmaceutical compositions can be administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. The particular combination of treatments (therapies or procedures) employed in a combination regimen will take into account the compatibility of the desired therapy and / or procedure with the desired therapeutic effect to be achieved. It should also be understood that the treatments employed can achieve the desired effect for the same condition (e.g., the compounds of the present invention can be administered simultaneously with another anti - cancer agent).

[0271] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds can be used to treat arthritic conditions in mammals (e.g., humans, livestock, and domestic animals), racehorses, birds, lizards, and any other organism that can tolerate the compounds.

[0272] The present invention also provides a drug pack or kit that includes one or more containers filled with one or more ingredients of the pharmaceutical composition of the present invention. Optionally, such containers can be accompanied by instructions in a form prescribed by a governmental agency that regulates the manufacture, use, or sale of pharmaceuticals or biological products, which instructions reflect approval by the governmental agency of manufacture, use, or sale for human administration.

[0273] Administering to a subject

[0274] In another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from the 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.

[0275] In certain embodiments, the cancer is selected from the group consisting of: biliary cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasia, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

[0276] In certain embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neuropathy. In certain embodiments, the gastrointestinal disorder is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis.

[0277] In certain embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes). In certain embodiments, the CNS disorder is Alzheimer's disease.

[0278] In certain embodiments, the metabolic disorder is obesity or type II diabetes. In certain embodiments, the cardiovascular disorder is ischemic stroke. In certain embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0279] In certain embodiments, the mammalian species is human.

[0280] In certain embodiments, 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 neuropathies, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0281] In another aspect, a method of blocking the Kv1.3 potassium channel in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

[0282] In certain embodiments, the compounds described herein selectively block the Kv 1.3 potassium channel and have minimal or no off-target inhibitory activity against other potassium channels or against calcium or sodium channels. In certain embodiments, the compounds described herein do not block the hERG channel and thus have a desirable cardiovascular safety profile.

[0283] Certain aspects of the invention relate to administering to a subject an effective amount of a composition to achieve a specific result. Thus, small molecule compositions useful in the methods according to the invention can be formulated in any manner suitable for pharmaceutical use.

[0284] The formulations of the present invention are administered in a pharmaceutically acceptable solution which may routinely contain salts, buffers, preservatives, compatible carriers, adjuvants and optionally other therapeutic ingredients at pharmaceutically acceptable concentrations.

[0285] For therapeutic use, an effective amount of the compound can be administered to a subject by any mode that allows the compound to be taken up by the appropriate target cells. "Administration" of the pharmaceutical compositions of the present invention can be accomplished by any means known to the person skilled in the art. Specific routes of administration include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.) or mucosal (intranasal, intratracheal, inhalation, rectal, vaginal, etc.). The injection can be a bolus injection or a continuous infusion.

[0286] For example, the pharmaceutical compositions according to the present invention are often administered by intravenous, intramuscular or other parenteral means. They can also be administered by intranasal application, inhalation, topical, oral or as an implant; even rectal or vaginal use is possible. Suitable liquid or solid pharmaceutical dosage forms are, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated onto the surface of minute gold particles, contained in liposomes, atomized, aerosols, pellets for implantation into the skin, or dried onto sharp objects to be scraped into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or formulations with extended release of the active compound, in which excipients and additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorants, sweeteners or solubilizers are used as customary as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of existing methods of drug delivery, see Langer R (1990) Science 249:1527 - 33, which is incorporated herein by reference.

[0287] The concentration of the compound included in the compositions for use in the methods of the present invention can range from about 1 nM to about 100 μM. The effective dose is believed to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0288] The pharmaceutical compositions are preferably prepared and administered in dosage units. A liquid dosage unit is a vial or an ampoule for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders, and suppositories. For treating a patient, different dosages may be required, depending on the activity of the compound, the mode of administration, the purpose of administration (i.e., prophylactic or therapeutic), the nature and severity of the condition, the age and weight of the patient. A given dosage can be administered by a single administration in the form of a single dosage unit or several smaller dosage units. The present invention also contemplates repeated and multiple administrations of the dosage at specific intervals separated by days, weeks, or months.

[0289] The compositions can be administered in the form of the compound itself (pure) or as a pharmaceutically acceptable salt thereof. When used in a drug, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can 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. Moreover, such salts can be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts of carboxylic acid groups.

[0290] Suitable buffering agents include: acetic acid and its salts (1-2% w / v); citric acid and its salts (1-3% w / v); boric acid and its salts (0.5-2.5% w / v); and phosphoric acid and its salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v); and thimerosal (0.004-0.02% w / v).

[0291] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations that are isotonic with the recipient's blood. Acceptable vehicles and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild non-volatile mineral oil or non-mineral oil can be employed, including synthetic glycerol monoesters or diesters. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. Formulations of carriers suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc. administration can be found in Remington’s Pharmaceutical Sciences , Mack Publishing Company, Easton, PA.

[0292] The compounds useful in the present invention can be delivered as a mixture of more than two such compounds. In addition to the combination of compounds, the mixture can also include one or more adjuvants.

[0293] Multiple routes of administration are available. Of course, the particular mode selected will depend on the particular compound chosen, the age and general health of the subject, the particular condition being treated and the dosage required for a therapeutic effect. In general, the methods of the invention may be practiced using any medically acceptable mode of administration (meaning any mode that produces an effective level of response and does not cause clinically unacceptable adverse effects). Preferred modes of administration were discussed above.

[0294] The compositions may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. All methods include the step of bringing the compound into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0295] Other delivery systems may include sustained release, delayed release or controlled release delivery systems. Such systems may avoid repeated administration of the compound, thus increasing convenience for the subject and the physician. Many types of release delivery systems are available and are known to those of ordinary skill in the art. They include polymer-based systems such as poly(lactide-co-glycolide), polyorthoesters, polycaprolactone, poly(amidoesters), polyorthoesters, polyhydroxybutyrate and polyanhydrides. Microcapsules of the foregoing polymers containing a drug are described, for example, in U.S. Patent No. 5,075,109. Delivery systems also include non-polymeric systems, which are: lipids, including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as glycerol monoesters, glycerol diesters and glycerol triesters; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; etc. Specific examples include, but are not limited to: (a) erosion systems, in which the agent of the invention is contained in the form within a matrix, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189 and 5,736,152, and (b) diffusion systems, in which the active component permeates from the polymer at a controlled rate, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974 and 5,407,686. Additionally, pump-based hardware delivery systems may be used, some of which are suitable for implantation.

[0296] Assays for determining the effectiveness of Kv1.3 potassium channel blockers

[0297] In certain embodiments, the activity of the compounds described herein against the Kv1.3 potassium channel is tested. In certain embodiments, the Kv1.3 potassium channel electrophysiology of the compounds described herein is tested. In certain embodiments, the hERG electrophysiology of the compounds described herein is tested.

[0298] Equivalent solutions

[0299] The following representative examples are intended to help illustrate the present invention and are not intended, nor should they be construed, to limit the scope of the present invention. In fact, various modifications of the present invention and many other embodiments thereof will become apparent to those skilled in the art from the complete content of this document, including the following examples and references to scientific and patent literature cited herein. It should further be understood that the content of those cited references is incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, illustrations, and guidance applicable to practicing the present invention in its various embodiments and their equivalent solutions. Examples

[0300] Examples 1-5 describe various intermediates for synthesizing the representative compounds of formula I disclosed herein.

[0301] Example 1. Intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) and Intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene)

[0302]

[0303] Step a:

[0304] To a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) at 0 °C under a nitrogen atmosphere, Br2 (98.04 g, 613.49 mmol) was added dropwise. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched at 0 °C with a saturated aqueous Na2S2O3 solution (500 mL). The resulting mixture was extracted with EA (6 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol as a yellow oil (100 g, crude). The crude product was used directly in the next step without further purification.

[0305] Step b:

[0306] At 0 °C, MeI (16.5 mL, 116.05 mmol, 2 equiv) was added dropwise to a crude mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (32 g, 125.04 mmol, 1 equiv) and K2CO3 (54.9 g, 396.87 mmol, 3 equiv) in ACN (210 mL). The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with PE to afford Intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) as a white solid (8.7 g, 25.7%): 1 H NMR (300 MHz, CDCl3) δ 7.40 (dd, J J =9.0, 1.1 Hz, 1H), 6.79 (d, J J = 8.9 Hz, 1H), 3.92 (s, 3H); and Intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene) as a white solid (24.3 g, 71.77%): 1 H NMR (300 MHz, CDCl3) δ 7.64(s, 1H), 6.99 (s, 1H), 3.91 (s, 3H).

[0307] Example 2. Intermediate 3 ((2,3-dichloro-6-methoxyphenyl)boronic acid)

[0308]

[0309] Step a:

[0310] To a stirred solution of 3,4-dichlorophenol (120 g, 0.74 mol) in THF (400 mL) at room temperature under a nitrogen atmosphere was added portionwise NaOH (75 g, 1.88 mol), followed by stirring for 30 min. To this was added N , N -diethylcarbamoyl chloride (150 g, 1.11 mol) over 40 min, followed by stirring for 15 h. The reaction mixture was poured into water (1.5 L) and extracted with PE (2 x 800 mL). The combined organic phases were washed with brine (500 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford N,N-diethylcarbamic acid 3,4-dichlorophenyl ester as a yellow oil (213 g, crude): C 11 H 13 Cl2NO2 [M + H] +LCMS (ESI) calculated value: 262, 264 (3: 2), found value 262, 264 (3: 2); 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.50-3.34 (m, 4H), 1.32-1.17 (m, 6H).

[0311] Step b:

[0312] To a solution of DIPA (32 g, 0.32 mol) in THF (400 mL) was added dropwise at -65 °C under nitrogen atmosphere n -BuLi (131 mL, 0.33 mmol). The obtained mixture is stirred for 1 h. A solution of 3,4-dichlorophenyl N,N-diethylcarbamate (77 g, 0.29 mol) in THF (200 mL) is added dropwise thereto, followed by stirring for 1 h. A solution of I2 (82 g, 0.32 mol) in THF (200 mL) is added dropwise thereto over 1 h. The obtained mixture is stirred for another 30 min at -65 ° C. By adding NH4Cl aqueous solution (300 mL) at room temperature, the reaction is quenched. The obtained mixture is extracted with EA (3 x 400 mL). The combined organic layer is washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. Three additional batches (3 x 77 g 3,4-dichlorophenyl N,N-diethylcarbamate) are reacted, post-processed and then merged with the previous batch. The resulting residue was slurried in PE (500 mL) and then filtered to give 300 g of 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate. The filtrate was purified by silica gel column chromatography and eluted with PE / EA (50 / 1) to give another 75 g of pure product. 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (375 g, 83% over 2 steps) was obtained as an off-white solid: C 11 H 12 Cl2INO3 [M + H] + LCMS (ESI) calculated value: 388,390 (3: 2), found value 388, 390 (3: 2); 11H NMR (400 MHz, CDCl3) δ 7.48 (d, J J = 8.8Hz, 1H), 7.08 (d, J J = 8.8 Hz, 1H), 3.55 (q, J = 7.2 Hz, 2H), 3.42 (q, J = 7.1Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0313] Step c:

[0314] To a stirred solution of 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (200 g, 0.52 mol) in EtOH (1.50 L) at room temperature was added NaOH (165 g, 4.1 mol). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ice water (1.5 L). Then the mixture was acidified to pH = 3 with aqueous HCl (6 N). The resulting mixture was extracted with EA (3 x 1 L). The combined organic layers were washed with brine (800 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 3,4-dichloro-2-iodophenol (202 g, crude) as a brown oil: C6H3Cl2IO [M - H] - LCMS (ESI) calcd for: 287, 289 (3: 2), found 287, 289 (3: 2).

[0315] Step d:

[0316] To a stirred solution of 3,4-dichloro-2-iodophenol (220 g, 0.76 mol) in DMF (700 mL) was added K2CO3 (210 g, 1.52 mol) and MeI (119 g, 0.84 mol). The resulting mixture was stirred at room temperature for 5 h. Another batch (100 g of 3,4-dichloro-2-iodophenol) was reacted and combined with the previous batch. The resulting mixture was diluted with water (5 L) at room temperature. Then the resulting mixture was extracted with EA (3 x 1 L). The combined organic layers were washed with brine (4 x 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was slurried in PE (300 mL) and then filtered to give 128 g of the desired product. The filtrate was purified by silica gel column chromatography, eluting with PE / EA (40 / 1) to give an additional 64 g of the desired product. 1,2-Dichloro-3-iodo-4-methoxybenzene (192 g, 78% over 2 steps) was obtained as a pale yellow solid: 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J J = 8.9 Hz, 1H), 6.70 (d, J J = 8.9 Hz, 1H), 3.91 (s, 3H).

[0317] Step e:

[0318] To a solution of 1,2-dichloro-3-iodo-4-methoxybenzene (100 g, 0.33 mol) in THF (1.2 L) at 0 °C under a nitrogen atmosphere was added dropwise i i-PrMgCl (182 mL, 0.36 mol). The reaction mixture was then stirred at 0 °C for 1 h. B(OMe)3 (86 g, 0.83 mol) was added dropwise at 0 °C. Then, the reaction mixture was warmed to room temperature over 1 h and stirred at room temperature for an additional 1 h. Then, aqueous H2SO4 (5%, 500 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The mixture was extracted with EA (2 x 500 mL). The organic layers were combined, washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was stirred in DCM (200 mL) and then filtered to give the intermediate 3 ((2,3-dichloro-6-methoxyphenyl)boronic acid) (55 g, 76%) as an off-white solid: C 15 H 16 Cl2N2O4 [M - H] -LCMS (ESI) calculated values: 219, 221 (3:2); found 219, 221 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J J = 8.8 Hz, 1H), 6.82 (d, J J = 8.9 Hz, 1H), 5.65 (s, 2H), 3.89 (s, 3H).

[0319] Example 3. Intermediate 4 ((2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester)

[0320]

[0321] Step a:

[0322] EDCI (4.97 g, 25.92 mmol), DMAP (3.17 g, 25.92 mmol) and maleic acid (2.49 g, 17.28 mmol) were added to a solution of (3 S )-4-(tert-butoxy)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoic acid (5.0 g, 17.28 mmol) in DCM (70 mL) at 0 °C. The mixture was stirred at room temperature for 3 h and then washed with aqueous KHSO4 solution (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in EA (170 mL) and refluxed overnight. The resulting mixture was cooled, washed with aqueous KHSO4 solution (60 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was washed with DCM / PE (1 / 2, 25 mL) to give (2S)-4,6-dioxopiperidine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (3 g, 55%) as an off-white solid: C 15 H 23 NO6 [M + H-100] + LCMS (ESI) calculated value: 214, found 214; 1 H NMR (400 MHz, CDCl3) δ 5.09 (dd, J J = 6.9, 2.2 Hz, 1H), 3.55 (d, J J = 19.5 Hz, 1H), 3.39 (d, J= 19.4 Hz, 1H), 3.04 (dd, J = 17.6, 2.2 Hz, 1H), 2.85 (dd, J = 17.6, 6.9 Hz, 1H), 1.57 (s, 9H), 1.48 (s, 9H).

[0323] Step b:

[0324] At 0 °C under a nitrogen atmosphere, DIPEA (1.67 mL, 12.90 mmol) was added dropwise to a solution of (2S)-4,6-dioxopiperidine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (1.0 g, 3.19 mmol) in DCM (10 mL). Trifluoromethanesulfonic anhydride (1.08 g, 3.83 mmol) was added dropwise thereto at 0 °C, and then the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 10 mL of aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (10 mL). The organic phases were combined, washed with brine (10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the intermediate 4 ((2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester) (2.6 g, crude): C 14 H 22 F3NO8S [M + H] + Calculated value of LCMS (ESI): 446, found 446.

[0325] Example 4. Intermediate 5 (methyl 4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate)

[0326]

[0327] Step a:

[0328] To a solution of 2-bromo-3,4-dichloro-1-methoxybenzene (Intermediate 1, Example 1) (5 g, 0.02 mmol, 1 equiv) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (6.2 g, 0.02 mmol, 1.2 equiv) in dioxane and water were added Na2CO3 (6.2 g, 0.06 mmol, 3 equiv) and Pd(dppf)Cl2·CH2Cl2 (3.2 g, 0.2 equiv). After stirring at 80 °C for 3 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give methyl 4-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carboxylate (1 g, 16.4%) as a pale yellow solid: C 14 H 11 Cl2NO3 [M + H] + Calculated for LCMS (ESI): 312, 314 (3:2), found 312, 314 (3:2). 1 H NMR (400 MHz, CD3OD) δ 8.78 (d, J J = 5.0 Hz, 1H), 8.08 (s, 1H), 7.66 - 7.57 (m, 2H), 7.16 (d, J J = 9.0 Hz, 1H), 4.01 (s, 3H), 3.78 (s, 3H).

[0329] Step b:

[0330] To a solution of PtO2 (65.5 mg, 0.29 mmol, 0.3 equiv) and methyl 4-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carboxylate (300 mg, 0.96 mmol, 1 equiv) in MeOH was added HCl (6 M, 1 mL) portionwise at room temperature. The resulting mixture was stirred at 30 °C for 4 days under a hydrogen atmosphere. The solid was filtered off and washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to give Intermediate 5 (methyl 4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate) as a yellow oil (200 mg, 52.32%): C 14 H 17 Cl2NO3 [M + H] + Calculated for LCMS (ESI): 318, 320 (3:2), found 318, 320 (3:2). 11H NMR (400 MHz, CD3OD) δ 7.38 (d, J J = 8.9 Hz, 1H), 6.96 (d, J J = 9.0 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.67 - 3.58 (m, 1H), 3.47 (dd, J J = 11.9, 3.0 Hz, 1H), 3.26 - 3.16 (m, 1H), 2.76 (td, J J = 12.4, 2.9 Hz, 1H), 2.45 - 2.27 (m, 2H), 1.90 (d, J J = 12.7 Hz, 1H), 1.51 (d, J J = 13.1 Hz, 1H).

[0331] Example 5. Intermediate 6 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylic acid methyl ester)

[0332]

[0333] Step a:

[0334] At room temperature, Pd(dppf)Cl2·CH2Cl2 (130 mg, 0.16 mmol) was added in one portion to a mixture of (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (Intermediate 4, Example 3) (2.52 g, crude), (2,3-dichloro-6-methoxyphenyl)boronic acid (Intermediate 3, Example 2) (700 mg, 3.17 mmol) and Na2CO3 (1.01 g, 9.51 mmol) in dioxane (20 mL) and H2O (5 mL). The suspension was degassed under vacuum and purged with nitrogen 3 times. The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h and then concentrated under reduced pressure. The residue was dissolved in EA (30 mL) and washed with brine (2 x 15 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5 / 1) to give (2S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester as a pale yellow foam (900 mg, 60%): C 22 H 21 Cl2N7O6 [M + H - 100]+ LCMS (ESI) calculated values: 372, 374 (3:2); found 372, 374 (3:2); 1 1H NMR (400 MHz, chloroform-d) δ 7.41 (d, J J = 8.9 Hz, 1H), 6.79 (d, J J = 9.0 Hz, 1H), 5.92 (d, J J = 2.7 Hz, 1H), 4.94 (dd, J J = 7.2, 1.8 Hz, 1H), 3.78 (s, 3H), 3.13 (d, J J = 18.5 Hz, 1H), 2.89 (d, J J = 18.3 Hz, 1H), 1.59 (s, 9H), 1.49 (s, 9H).

[0335] Step b:

[0336] Under a nitrogen atmosphere, PtO2 (150 mg, 0.66 mmol) was added to a solution of (2S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (900 mg, 1.91 mmol) in EA (50 mL) and AcOH (0.50 mL). The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at room temperature under hydrogen (1.5 atm) for 16 h. Then, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5 / 1) to afford (2S,4S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (550 mg, 61%) as a colorless foam: C 22 H 29 Cl2NO6 [M + H - 100] + LCMS (ESI) calculated values: 474, 476 (3:2); found 474, 476 (3:2); 1 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J J = 9.0 Hz, 1H), 6.77 (d, J J = 9.0 Hz, 1H), 4.61 (dd, J= 8.7, 7.2 Hz, 1H), 4.01 - 3.87 (m, 1H), 3.82 (s, 3H), 3.40 - 3.23 (m, 1H), 2.66 - 2.48 (m, 2H), 2.36 - 2.27 (m, 1H), 1.56 (s, 9H), 1.49 (s, 9H).

[0337] Step c:

[0338] Under a nitrogen atmosphere at 0 °C, BH3•Me2S (0.21 mL, 2.11 mmol) was added to a solution of (2S,4S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (550 mg, 1.16 mmol) in THF (10 mL). Then, the reaction mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. Then, 10 mL of MeOH was added dropwise at 0 °C, and the resulting mixture was stirred for 1 h. 6 mL of aqueous HCl solution (6 M) was added thereto. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain the intermediate 6 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylic acid methyl ester) as a colorless oil (125 mg, 34%): C 14 H 17 Cl2NO3 [M + H] + The LCMS (ESI) calculated values for : 318, 320 (3:2), found 318, 320 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.69 - 3.53 (m, 1H), 3.47 (dd, J = 11.9, 3.0 Hz, 1H), 3.25 - 3.16 (m, 1H), 2.76 (td, J = 12.4, 2.9 Hz, 1H), 2.45 - 2.25 (m, 2H), 1.90 (d, J = 12.7 Hz, 1H), 1.51 (d, J = 13.0 Hz, 1H).

[0339] Examples 6 - 8 describe the synthesis and / or characterization data of representative compounds of Formula I disclosed herein.

[0340] Example 6. Compound 1 ((8 R ,9a S )-2-(azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydro-1 H -pyrido[1,2-a]pyrazine-1,4-dione)

[0341]

[0342] Step a:

[0343] To a stirred solution of methyl 4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate (Intermediate 5, Example 4) (400 mg, 1.01 mmol, 80%) and TEA (509 mg, 5.03 mmol) in DCM (8 mL) at 0 °C under a nitrogen atmosphere was added 2-chloroacetyl chloride (170 mg, 1.51 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated to give methyl 1-(2-chloroacetyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate (500 mg, crude) as a light brown solid: LCMS (ESI) calculated for C16H18Cl3NO4 [M + H]+: 394, 396 (1:1), found 394, 396 (1:1).

[0344] Step b:

[0345] To a stirred solution of methyl 1-(2-chloroacetyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate (500 mg, 1.27 mmol) and TEA (385 mg, 3.80 mmol) in EtOH (10 mL) at room temperature was added tert-butyl 3-aminoazetidine-1-carboxylate (327 mg, 1.90 mmol). The resulting reaction mixture was stirred at 80 °C for 16 h and then concentrated in vacuo. The residue was dissolved in EA (20 mL). The solution was washed with brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by reverse phase HPLC to give tert-butyl 3-[8-(2,3-dichloro-6-methoxyphenyl)-1,4-dioxo-octahydro-1H-pyrido[1,2-a]pyrazin-2-yl]azetidine-1-carboxylate (285 mg, 45%) as a light brown oil: C 23 H 29Cl2N3O5 [M + H] + Calculated LCMS (ESI) for

[0346] Step c:

[0347] To a stirred solution of tert-butyl 3-[8-(2,3-dichloro-6-methoxyphenyl)-1,4-dioxooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl]azetidine-1-carboxylate (285 mg, 0.29 mmol, 80%) in DCM (5 mL) at room temperature was added BBr3 (0.51 mL, 2.03 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL). The pH was adjusted to 7 by adding saturated aqueous NaHCO3 and the resulting solution was concentrated in vacuo. The residue was purified by preparative high performance liquid chromatography (Prep-HPLC) under the following conditions: column: Xselect CSH OBD column 30 x 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 25% B in 9 min; detector: UV 220 nm; retention time: 8.20 min. The fractions containing the desired product were combined and concentrated under reduced pressure to afford 2-(azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)octahydro-1 H -pyrido[1,2-a]pyrazine-1,4-dione trifluoroacetate (120 mg, 86%) as an off-white solid: C 17 H 19 Cl2N3O3 [M + H] + Calculated LCMS(ESI) for 1 H NMR (400 MHz, methanol- d 4) δ7.21 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 5.04 - 4.95 (m, 1H), 4.75 - 4.60 (m, 1H), 4.30 - 4.04 (m, 3H), 3.98 - 3.83 (m, 2H), 3.82 - 3.58 (m,3H), 2.87 - 2.71 (m, 1H), 2.61 - 2.40 (m, 2H), 2.14 (d,J = 12.9 Hz, 1H), 1.64 (d, J = 13.2 Hz, 1H).

[0348] Step d:

[0349] 2-(Azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydro-1 H -pyrido[1,2-a]pyrazine-1,4-dione (120 mg, 0.31 mmol) was separated by chiral-HPLC under the following conditions: column: CHIRALPAK IG, 2 x 25 cm, 5 μm; mobile phase A: Hex (0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 30% B to 30% B in 21 min; detector: UV 220 / 254 nm; retention time: 17.719 min. The fractions containing the desired product were combined and concentrated under reduced pressure to give compound 1 ((8 R ,9a S )-2-(Azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydro-1 H -pyrido[1,2-a]pyrazine-1,4-dione) (30 mg, 25%): C 17 H 19 Cl2N3O3 [M + H] + The LCMS (ESI) calculated value for 384, 386 (3:2), found 384, 386 (3:2). 1 1H NMR (400 MHz, methanol- d 4) δ 1 1H NMR (400 MHz, methanol- d 4) δ 7.21 (d, J = 8.8Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.02 - 4.93 (m, 1H), 4.75 - 4.63 (m, 1H), 4.29 - 4.04 (m, 3H), 4.04 - 3.90 (m, 2H), 3.87 - 3.67 (m, 3H), 2.86 - 2.73 (m, 1H), 2.60 - 2.40 (m, 2H), 2.15 (d, J = 12.9 Hz, 1H), 1.63 (d, J= 13.2 Hz, 1H).

[0350] Example 7. Compound 2 ((3 R ,8 R ,9a S )-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-hexahydro-2 H -pyrido[1,2-a]pyrazine-1,4-dione)

[0351]

[0352] Step a:

[0353] At room temperature, EDCI (113 mg, 0.59 mmol) and HOBT (80 mg, 0.59 mmol) were added to a stirred solution of (2 R )-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid (97 mg, 0.47 mmol) in DMF (2 mL). Then TEA (119 mg, 1.18 mmol) and methyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate (Intermediate 6, Example 5) (125 mg, 0.40 mmol) were added, and the resulting mixture was stirred for 12 h, then poured into H2O (10 mL) and extracted with EA (3 x 5 mL). The combined organic phases were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography under the following conditions: column: Xselect CSH OBD column 30 x 150 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 60% B in 8 min; detector: UV 220 nm; retention time: 7.12. The fractions containing the desired product were collected and concentrated under reduced pressure to give methyl (2S,4R)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate (35 mg, 18%) as a pale yellow foam: C 22 H 30 Cl2N2O7 [M + H] + LCMS (ESI) calculated for: 505, 507 (3:2), found 505, 507 (3:2).

[0354] Step b:

[0355] At room temperature, TFA (0.5 mL, 6.73 mmol) was added to a stirred solution of methyl (2S,4R)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate (35 mg, 0.07 mmol) in DCM (1 mL). The resulting mixture was stirred for 30 min and concentrated under reduced pressure. The residue was dissolved in EtOH (3 mL). Then TEA (21 mg, 0.21 mmol) was added and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to give (3 R ,8 R ,9a S )-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-hexahydro-2 H -pyrido[1,2-a]pyrazine-1,4-dione (80 mg, crude): C 16 H 18 Cl2N2O4 [M + H] + Calculated for LCMS (ESI): 373, 375 (3:2), found 373, 375 (3:2).

[0356] Step c:

[0357] At room temperature, BBr3 (0.2 mL) was added to a stirred solution of (3 R ,8 R ,9a S )-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-hexahydro-2 H -pyrido[1,2-a]pyrazine-1,4-dione (80 mg, crude) in DCM (2 mL). The reaction mixture was stirred for 2 h and then added dropwise to 3 mL of MeOH at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography under the following conditions: column: XBridge Prep C18 OBD Prep column, 19 x 150 mm, 5 µm; mobile phase A: water (+ 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 40% B in 7 min; detector: UV 220 nm; retention time: 6.58 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 2 as an off-white solid ((3 R ,8 R ,9a S)-8-(2,3-Dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-hexahydro-2 H -pyrido[1,2-a]pyrazine-1,4-dione) (12.3 mg): C 15 H 16 Cl2N2O4 [M + H] + LCMS (ESI) calculated for: 359, 361 (3:2), found 359, 361 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.22 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.79 - 4.68 (m, 1H), 4.14 - 3.96 (m, 3H), 3.75 (dd, J = 11.0, 2.6 Hz, 2H), 2.78 (td, J = 13.2, 3.0 Hz, 1H), 2.59 - 2.41 (m, 2H), 2.26 - 2.15 (m, 1H), 1.66 (d, J = 13.3 Hz, 1H).

[0358] Example 8. The following compounds were prepared in a manner similar to the preparation of Compound 1 (Example 6) and / or Compound 2 (Example 7) and / or by methods known in the art.

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] Example 9. Evaluation of Kv1.3 potassium channel blocker activity

[0372] This assay was used to evaluate the activity of the disclosed compounds as Kv1.3 potassium channel blockers.

[0373] Cell culture

[0374] CHO-K1 cells stably expressing Kv1.3 were cultured in DMEM containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, and G418 (500 μg / ml). Cells were cultured in flasks at 37 °C in a 5% CO2 humidified incubator.

[0375] Solution

[0376] Cells were immersed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, 10 mM HEPES; the pH was adjusted to 7.4 with NaOH; 295 - 305 mOsm. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, 10 mM HEPES; the pH was adjusted to 7.2 with KOH; 285 mOsm. All compounds were dissolved at 30 mM in DMSO. 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 content of DMSO (0.3%) was present in 100 μM.

[0377] Voltage protocol

[0378] Currents were evoked by applying 100 ms depolarizing pulses from -90 mV (holding potential) to +40 mV at a frequency of 0.1 Hz. Controls (no compound) and compound trains for each compound concentration applied contained 20 pulses.

[0379] A 10 s interval was used between trains (see Table A below).

[0380]

[0381] Patch-clamp recording and compound application

[0382] Whole-cell current recordings and compound applications were achieved with the automated patch-clamp platform Patchliner (Nanion Technologies GmbH). The EPC 10 patch-clamp amplifier (HEKA Elektronik Dr. Schulze GmbH) and Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) were used for data acquisition. Data were sampled at 10 kHz without filtering. The P / 4 protocol (HEKA Elektronik Dr. Schulze GmbH) was used to subtract passive leak current online. Increasing compound concentrations were applied continuously to the same cell without rinsing. The total compound incubation time before the next train of pulses was not more than 10 s. Peak current inhibition was observed during compound equilibration.

[0383] Data analysis

[0384] AUC and peak were obtained with Patchmaster (HEKA Elektronik Dr. Schulze GmbH). To determine the IC 50 , the last single pulse in the train corresponding to the given compound concentration was used. The AUC and peak obtained in the presence of the compound were normalized to the control values in the absence of the compound. Using Origin (OridinLab), the IC 50 was obtained from data fitted to the Hill equation: I 化合物 / I 对照 = (100 - A) / (1 + ([compound] / IC 50 ))nH + A, where the IC 50 value is the concentration at which current inhibition is half-maximal, [compound] is the concentration of the compound applied, A is the fraction of current not blocked, and nH is the Hill coefficient.

[0385] Example 10. Evaluation of hERG Activity

[0386] This assay was used to evaluate the inhibitory activity of the disclosed compounds on the hERG channel.

[0387] hERG electrophysiology

[0388] This assay was used to evaluate the inhibitory activity of the disclosed compounds on the hERG channel.

[0389] Cell culture

[0390] CHO-K1 cells stably expressing hERG were cultured in Ham's F-12 medium (containing glutamine) supplemented with 10% heat-inactivated FBS, 1% penicillin / streptomycin, hygromycin (100 μg / ml), and G418 (100 μg / ml). Cells were cultured in culture flasks at 37°C in a 5% CO2 humidified incubator.

[0391] Solution

[0392] 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. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES; the pH was adjusted to 7.2 with KOH; 285 mOsm. All compounds were dissolved at 30 mM in DMSO. 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 content of DMSO (0.3%) was present in 100 μM.

[0393] Voltage protocol

[0394] The voltage protocol (see Table B) was designed to mimic the 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 (to induce a tail current), and a final step to a holding potential of -80 mV. The pulse frequency was 0.3 Hz. Controls (no compound) and compound pulse trains for each compound concentration applied contained 70 pulses.

[0395]

[0396] Patch-clamp recording and compound application

[0397] Whole-cell current recordings and compound applications were achieved using an automated patch-clamp platform, Patchliner (Nanion). An EPC 10 patch-clamp amplifier (HEKA) and Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) were used for data acquisition. Data were sampled at 10 kHz without filtering. Increasing compound concentrations were applied continuously to the same cells without rinsing.

[0398] Data analysis

[0399] The AUC and PEAK values were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). To determine the IC 50 , the last single pulse in the train corresponding to the given compound concentration was used. The AUC and PEAK values obtained in the presence of the compound were normalized to the control values in the absence of the compound. Using Origin (OridinLab), the IC 50 : I 化合物 / I 对照 = (100 - A) / (1 + ([compound] / IC 50 ))nH + A, where IC 50 is the concentration at which current inhibition is half-maximal, [compound] is the concentration of the applied compound, A is the fraction of current not blocked, and nH is the Hill coefficient.

[0400] Table 1 provides a summary of the inhibitory activities of certain selected compounds of the present invention against the Kv1.3 potassium channel and the hERG channel.

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein Y is C(R2)2; Z is OH; X1 is H, a halogen or C 1-6 an alkyl group; X2 is a halogen or a C 1-6 alkyl group; X3 is a halogen or a C 1-6 alkyl group; Each occurrence of R2 is H, C 1-6 alkyl, C 2-10 heteroalkyl; R3 is H; R4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, a 3- to 10-membered monocyclic heterocycloalkyl containing one nitrogen atom, or NH2; R5 is H; alternatively, R2 and R4 together with the carbon and nitrogen atoms to which they are attached form a 3- to 7-membered monocyclic saturated heterocycle; When applicable, the alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl in R2 and R4 are each independently and optionally substituted with 1-4 substituents, and each of the substituents is independently selected from halogen, OR6, -(CH2) 1-2 OR6 and N(R6)2, and each occurrence of R6 is independently H or C 1-6 alkyl, when the valence allows; n1 is 1; n2 is 1; and n3 is 0.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural moiety has the structure 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural moiety has the structure 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural moiety has the structure 5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein at least one of R2 and R4 is H, C 1-6 alkyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein at least one of R2 and R4 is H, Me, Et, n-Pr, iso-Pr, n-Bu, sec-Bu or tert-Bu.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein at least one of R2 and R4 is C 1-6 alkyl, each of which is optionally substituted by one or more OH or NH2.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein at least one of R2 and R4 is 9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 appears at least once as Me, Et, 10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is selected from 11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is selected from 12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 and R4 together with the carbon and nitrogen atoms to which they are attached form a 3- to 7-membered saturated monocyclic heterocycle.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the structural moiety has the structure 14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the structural moiety has the structure 15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is H, halogen or Me.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is H or Cl.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X2 is H, F, Cl, Br, Me.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X2 is H or Cl.

19. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X3 is F, Cl, Br, Me.

20. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X3 is H or Cl.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural moiety has the structure 22. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Compounds 1-70 shown in the following table:

23. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22 and a pharmaceutically acceptable carrier or diluent.

24. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22 or a pharmaceutical composition according to claim 23 in the manufacture of a medicament for treating a condition by blocking the Kv1.3 potassium channel in a mammalian species in need thereof.

25. The use according to claim 24, wherein the condition is selected from cancer, transplant rejection, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, arthritis, inflammatory neuropathy, inflammatory bowel disease, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis and combinations thereof.

26. The use according to claim 24, wherein the condition is selected from rheumatoid arthritis, chronic renal failure and combinations thereof.

27. The use according to any one of claims 24-26, wherein the mammalian species is human.

28. Use of a compound according to any one of claims 1 - 22 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 23 for the manufacture of a medicament for blocking Kv1.3 potassium channels in a mammalian species in need thereof.

29. Use according to claim 28, wherein the mammalian species is a human.

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