Aryl heterobicyclic compounds as Kv1.3 potassium shaker channel blockers

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof are described, wherein the substituents are as defined herein. Pharmaceutical compositions containing the compounds and methods of using them are also described. [Formula 1] JPEG2022550641000139.jpg4051

Description

[Technical Field]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 911,642, filed October 7, 2019, the entire contents of which are incorporated herein by reference.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0020] [ka] (In the formula, each occurrence of Y is independently C(R2)2 or NR1; Z is OR a and; X1 is H, halogen, or alkyl; X2 is H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; X3 is H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; or X1 and X2 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; or X2 and X3 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; each occurrence of R is H, alkyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl; Each occurrence of R2 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, or NR a R b and; R3 is H, alkyl, or halogen; R4 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, or NR a R b and; Each occurrence of R5 is H, halogen, OR6, or alkyl, and each R5 is

[0021] [ka] may be attached to any one of the carbon ring atoms; or R1 and R4 and the nitrogen atom to which they are attached, taken together, form an optionally substituted heterocycle; or R2 and R4 and the carbon atom and nitrogen atom to which they are respectively attached, taken together, form an optionally substituted heterocycle; R a and R b each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; X1, X2, X3, R1, R2, R3, R4, R5, R, if applicable a , or R b The alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl in the formula (I) are, where valence permits, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, OR6, -(CH2) 1~2 each independently optionally substituted with 1 to 4 substituents independently selected from the group consisting of OR, N(R), (C=O)R, (C=O)N(R), NR(C=O)R, and oxo; each occurrence of R6 is independently H, alkyl, or a heterocycle optionally substituted with alkyl; or two R6 groups, taken together with the nitrogen atom to which they are attached, form a heterocycle optionally substituted with alkyl and containing the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; n1 is an integer from 0 to 1; n2 is an integer from 0 to 2; n3 is an integer between 0 and 2. is described.

[0022] In any one of the embodiments described herein, the structural moiety

[0023] [ka] but,

[0024] [ka] It has the following structure.

[0025] In any one of the embodiments described herein, the structural moiety

[0026] [ka] but,

[0027] [ka] It has the following structure.

[0028] In any one of the embodiments described herein, the structural moiety

[0029] [ka] but,

[0030] [ka] It has the following structure.

[0031] In any one of the embodiments described herein, the structural moiety

[0032] [ka] but,

[0033] [ka] It has the following structure.

[0034] In any one of the embodiments described herein, the structural moiety

[0035] [ka] but,

[0036] [ka] It has the following structure.

[0037] In any one of the embodiments described herein, the structural moiety

[0038] [ka] but,

[0039] [ka] It has the following structure.

[0040] In any one of the embodiments described herein, at least one of R1, R2, and R4 is H, alkyl, or cycloalkyl.

[0041] In any one 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.

[0042] In any one of the embodiments described herein, at least one of R2 and R4 is one or more of OR6, N(R6)2, or -(CH2) 1~2 is alkyl or cycloalkyl, each optionally substituted by OR6.

[0043] In any one of the embodiments described herein, at least one of R2 and R4 is

[0044] [ka] is.

[0045] In any one of the embodiments described herein, at least one occurrence of R2 is Me, Et,

[0046] [ka] is.

[0047] In any one of the embodiments described herein, at least one of R2 and R4 is

[0048] [ka] is.

[0049] In any one of the embodiments described herein, at least one of R1, R2, and R4 is heteroalkyl, or cycloheteroalkyl.

[0050] In any one of the embodiments described herein, at least one of R2 and R4 is NR a R bis.

[0051] In any one of the embodiments described herein, R a and R b are each independently H, alkyl, or cycloalkyl.

[0052] In any one of the embodiments described herein, at least one of R2 and R4 is NH2, NHMe, or NHMe2.

[0053] In any one of the embodiments described herein, at least one of R2 and R4 is cycloheteroalkyl optionally substituted with one or more alkyl.

[0054] In any one of the embodiments described herein, at least one of R2 and R4 is

[0055] [ka] is.

[0056] In any one of the embodiments described herein, R1 and R4 and the nitrogen atom to which they are attached together form an optionally substituted heterocycle; or R2 and R4 and the carbon atom and nitrogen atom to which they are attached, respectively, together form an optionally substituted heterocycle.

[0057] In any one of the embodiments described herein, the structural moiety

[0058] [ka] but,

[0059] [ka] It has the following structure.

[0060] In any one of the embodiments described herein, the structural moiety

[0061] [ka] but,

[0062] [ka] It has the following structure.

[0063] In any one of the embodiments described herein, at least one occurrence of R5 is H or alkyl.

[0064] In any one of the embodiments described herein, at least one occurrence of R5 is halogen or OH.

[0065] In any one of the embodiments described herein, n3 is 0 or 1.

[0066] In any one of the embodiments described herein, Z is OH, OMe, OEt, OPr, or OBu.

[0067] In any one of the embodiments described herein, Z is OH or OMe.

[0068] In any one of the embodiments described herein, Z is OH.

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

[0070] In any one of the embodiments described herein, X 1 is H or Cl.

[0071] In any one of the embodiments described herein, X2 is H, halogen, fluorinated alkyl, or alkyl.

[0072] In any one of the embodiments described herein, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0073] In any one of the embodiments described herein, X2 is H or Cl.

[0074] In any one of the embodiments described herein, X3 is H, halogen, fluorinated alkyl, or alkyl.

[0075] In any one of the embodiments described herein, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0076] In any one of the embodiments described herein, X3 is H or Cl.

[0077] In any one of the embodiments described herein, R3 is H, Me, Et, Pr, F, Cl, or Br.

[0078] In any one of the embodiments described herein, R3 is H.

[0079] In any one of the embodiments described herein, R3 is Me, Et, or Pr.

[0080] In any one of the embodiments described herein, R3 is F, Cl, or Br.

[0081] In any one of the embodiments described herein, the structural moiety

[0082] [ka] but,

[0083] [ka] It has the following structure.

[0084] In any one of the embodiments described herein, the compound has the structure of Formula II' or II:

[0085] [ka] (In the formula, R 3’ are independently H, halogen, or alkyl; n4 is an integer between 0 and 3. It has.

[0086] In any one of the embodiments described herein, n4 is 0, 1, or 2.

[0087] In any one of the embodiments described herein, n4 is 0.

[0088] In any one of the embodiments described herein, R 3’ is H or alkyl.

[0089] In any one of the embodiments described herein, R 3’ is a halogen.

[0090] In any one of the embodiments described herein, R a or R b At least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

[0091] In any one of the embodiments described herein, R a or R b at least one occurrence of independently is H, Me, Et, Pr, or

[0092] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 Optionally substituted with alkyl.

[0093] In any one of the embodiments described herein, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0094] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 1-70 shown in Table 1.

[0095] In yet another aspect, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0096] In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, comprising the step of administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0097] In any one of the embodiments described herein, the immunological disorder is transplant rejection or an autoimmune disease.

[0098] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0099] In any one of the embodiments described herein, the central nervous system disorder is Alzheimer's disease.

[0100] In any one of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

[0101] In any one of the embodiments described herein, the gastroenterological disorder is inflammatory bowel disease.

[0102] In any one of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0103] In any one of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0104] In any one of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0105] In any one of the embodiments described herein, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0106] In any one of the embodiments described herein, the mammalian species is human.

[0107] In yet another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof.

[0108] In any one of the embodiments described herein, the mammalian species is human.

[0109] Any one of the embodiments disclosed herein can be appropriately combined with any other embodiment disclosed herein.The combination of any one of the embodiments disclosed herein with any other embodiment disclosed herein is expressly contemplated.In particular, the selection of one or more embodiments for a certain substituent can be appropriately combined with the selection of one or more specific embodiments for any other substituent.Such combinations can be made with any one or more embodiments of the application described herein or any formula described herein. DETAILED DESCRIPTION OF THE INVENTION

[0110] definition The following are definitions of terms used herein. Unless otherwise specified, the initial definition provided for a group or term herein applies to that group or term throughout the specification, whether individually or as part of another group. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0111] The terms "alkyl" and "alk" refer to straight- or branched-chain alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "(C1-C4) alkyl" refers to straight- or branched-chain alkane (hydrocarbon) groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R.b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0112] The term "heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having 2 to 12 carbons, and more preferably 2 to 10 carbons, in the chain, one or more of which are replaced by a heteroatom selected from the group consisting of S, O, P, and N. Exemplary heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like. The group can be a terminal group or a bridging group.

[0113] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term "C2-C6 alkenyl" includes ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-penta- "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as (Z)-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hexa-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group having a single halogen substituent or multiple halogen substituents, such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d, C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents themselves can be optionally substituted.

[0114] The term "alkynyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NRb R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents themselves can be optionally substituted.

[0115] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF3 or CCl3, in the latter case), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2Re , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R eis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0116] The term "heterocycloalkyl" or "cycloheteroalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom, preferably 1 to 3 heteroatoms, selected from the group consisting of nitrogen, sulfur, and oxygen, in at least one ring. Each ring preferably has 3 to 10 members, more preferably 4 to 7 members. Examples of suitable heterocycloalkyl substituents include, but are not limited to, pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepane, 1,4-diazepane, 1,4-oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging group.

[0117] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl), cyano, nitro, oxo (i.e., ═O), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. bC(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0118] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, such as phenyl, biphenyl, or naphthyl, particularly a monocyclic or bicyclic group. When containing two or more aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be linked at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, in which two adjacent aromatic rings share two carbon atoms. "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably one to three substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF3 or CCl3, in the latter case), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. dS(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0119] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups linked by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group linked by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, the number of ring atoms in the heteroaryl and / or aryl ring is used to specify the aryl or heteroaryl ring size of the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be specified similarly.

[0120] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring, or a cyclic aromatic hydrocarbon group having one to five aromatic rings, such as phenyl, biphenyl, or naphthyl, particularly a monocyclic or bicyclic group. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl, as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves may be optionally substituted.

[0121] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated, cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems), including aromatic (i.e., "heteroaryl") groups, having at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heterocyclic group can independently be saturated, or partially or fully unsaturated. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms; 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 bearing a quaternary nitrogen atom, thus a positive charge.) A heterocyclic group can be attached to the remainder of the molecule at any heteroatom or carbon atom in the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, Examples of aryl include 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, Included are benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0122] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2Re , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R eis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0123] The term "oxo" refers to a ring that may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring.

[0124] [ka] When an oxo substituent is attached to a carbon ring atom on an aromatic group, such as an aryl or heteroaryl, the bonds on the aromatic ring can be rearranged to meet valence requirements. For example, a pyridine with a 2-oxo substituent is

[0125] [ka] may have the structure

[0126] [ka] Also included are the tautomeric forms thereof:

[0127] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0128] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined herein. R and R' can be the same or different dialkylamino moieties. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure can be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0129] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0130] The term "substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) is substituted with one or more substituents, preferably 1 to 6 substituents, at any available point of attachment, where valence allows. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl), in the latter case, cyano, nitro, oxo (i.e., ═O), CF, OCF, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. bC(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In the above exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be optionally substituted. The term "optionally substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) may or may not be substituted with one or more of the substituents described above.

[0131] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0132] The compounds of the present invention can form salts that are also within the scope of the present invention. Reference to a compound of the present invention is understood to include reference to its salts, unless otherwise indicated. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, when a compound of the present invention contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a phenol or a carboxylic acid, zwitterions ("internal salts") may be formed and are included in the term "salt" as used herein. Although pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts are also useful, for example, in isolation or purification steps that may be used during preparation. Salts of the compounds of the present invention can be formed, for example, by reacting a compound described herein with an equivalent amount of acid or base in a medium, such as a medium in which the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0133] Compounds of the present invention that contain a basic moiety, such as, but not limited to, an amine or a pyridine or imidazole ring, can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetate (such as those formed with acetic acid or trihaloacetic acids; e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, and the like. Salts include sulfonates (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0134] Compounds of the present invention that contain an acidic moiety, such as, but not limited to, a phenol or a carboxylic acid, can form salts with a variety of organic and inorganic bases. Exemplary base salts include ammonium salts, alkali metal salts, such as sodium, lithium, and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, t-butylamine, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl chlorides, bromides, and iodides, lauryl, myristyl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0135] Prodrugs and solvates of the compounds of the present invention are also contemplated herein.The term "prodrug" as used herein refers to a compound that, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to produce the compounds of the present invention, or their salts and / or solvates.Solvates of the compounds of the present invention include, for example, hydrates.

[0136] The compounds of the present invention, and their salts or solvates, may exist in their tautomeric form (e.g., as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of a compound includes its tautomeric form.

[0137] All stereoisomers of the present compounds, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbon atoms on various substituents), are contemplated within the scope of the present invention. Individual stereoisomers of the present compounds may be, for example, substantially free of other isomers (e.g., as pure or substantially pure optical isomers having the specified activity), e.g., as racemates, or admixed with all other or selected stereoisomers. Chiral centers of the present invention may have the S or R configuration as defined by the 1974 Recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation, or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by any suitable method, including, but not limited to, conventional methods such as, for example, salt formation with an optically active acid followed by crystallization.

[0138] After preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 90% by weight or more, e.g., 95% by weight or more, 99% by weight or more of the compound (a "substantially pure" compound), which are then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also contemplated herein as part of the present invention.

[0139] All configurational isomers of the compounds of the invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds of the invention encompasses both cis (Z) and trans (E) alkene isomers, as well as both cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0140] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0141] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0142] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0143] Isomeric mixtures containing any of a variety of isomer ratios can be utilized by the present invention. For example, when combining only two isomers, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0144] The present invention also includes isotopically labeled compounds identical to the compounds disclosed herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, that contain the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g., 3 H and 14 Those in which a radioactive isotope, such as 1C, is incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavy isotopes such as H can confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following the procedures disclosed in the following schemes and / or examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0145] For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with an asymmetric auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0146] It is understood that the compounds described herein can be substituted with any number of substituents or functional moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, and whether the substituent is included in the formula of the invention, refers to the replacement of a hydrogen radical in a given structure with the radical of the specified substituent. When more than one position in any given structure can be substituted with more than one substituent selected from the specified group, the substituents can be the same or different at all positions. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful, for example, in the treatment of proliferative disorders. As used herein, the term "stable" refers to compounds that preferably have sufficient stability to permit manufacture and maintain compound integrity for a period of time sufficient to be detected, preferably to be useful for the purposes detailed herein.

[0147] As used herein, the terms "cancer," and equivalently, "tumor," refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant. Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. Cancer can be primary or metastatic. Because diseases other than cancer can be associated with mutational changes in components of the Ras signaling pathway, the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases may include neurofibromatosis; Leopard syndrome; Noonan syndrome; Regius syndrome; Costello syndrome; cardio-facio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arteriovenous malformation.

[0148] As used herein, "effective amount" refers to any amount that is necessary or sufficient to achieve or promote a desired outcome.In some instances, an effective amount is a therapeutically effective amount.A therapeutically effective amount is any amount that is necessary or sufficient to promote or achieve a desired biological response in a subject.The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the specific drug being administered, the size of the subject, or the severity of the disease or condition.Those skilled in the art can empirically determine the effective amount of a particular drug without undue experimentation.

[0149] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including, but not limited to, non-human primates, laboratory animals, livestock, racehorses, domestic animals, and non-domestic animals.

[0150] compound Novel compounds are described as Kv1.3 potassium channel blockers. Applicants have surprisingly discovered that the compounds disclosed herein exhibit potent Kv1.3 potassium channel inhibitory properties. Furthermore, applicants have surprisingly discovered that the compounds disclosed herein selectively block Kv1.3 potassium channels and do not block hERG channels, and therefore have desirable cardiovascular safety profiles.

[0151] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof

[0152] [ka] (In the formula, each occurrence of Y is independently C(R2)2 or NR1; Z is OR a and; X1 is H, halogen, or alkyl; X2 is H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; X3 is H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; or X1 and X2 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; or X2 and X3 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; each occurrence of R is H, alkyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl; Each occurrence of R2 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, or NR a R b and; R3 is H, alkyl, or halogen; R4 is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, or NR a R b and; Each occurrence of R5 is H, halogen, OR6, or alkyl, and each R5 is

[0153] [ka] may be attached to any one of the carbon ring atoms; or R1 and R4 and the nitrogen atom to which they are attached, taken together, form an optionally substituted heterocycle; or R2 and R4 and the carbon atom and nitrogen atom to which they are respectively attached, taken together, form an optionally substituted heterocycle; R a and R b each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; X1, X2, X3, R1, R2, R3, R4, R5, R, if applicable a , or R b The alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl in the formula (I) are, where valence permits, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, OR6, -(CH2) 1~2each independently optionally substituted with 1 to 4 substituents independently selected from the group consisting of OR, N(R), (C=O)R, (C=O)N(R), NR(C=O)R, and oxo; each occurrence of R6 is independently H, alkyl, or a heterocycle optionally substituted with alkyl; or two R6 groups, taken together with the nitrogen atom to which they are attached, form a heterocycle optionally substituted with alkyl and containing the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; n1 is an integer from 0 to 1; n2 is an integer from 0 to 2; n3 is an integer between 0 and 2. is described.

[0154] In some embodiments, the structural moiety

[0155] [ka] but,

[0156] [ka] In some embodiments, the structural moiety

[0157] [ka] but,

[0158] [ka] In some embodiments, the structural moiety

[0159] [ka] but,

[0160] [ka] In some embodiments, the structural moiety

[0161] [ka] but,

[0162] [ka] In some embodiments, the structural moiety

[0163] [ka] but,

[0164] [ka] It has the following structure.

[0165] In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, n2 is an integer from 0 to 2. In some embodiments, n2 is an integer from 1 to 2. In some embodiments, n2 is 0. In some embodiments, n2 is 1 or 2. In some embodiments, n2 is 2. In some embodiments, n2 is 1.

[0166] In some embodiments, at least one occurrence of Y is C(R2)2. In other embodiments, at least one occurrence of Y is NR1. In some embodiments, Y n2 is —C(R2)2. In another embodiment, Y n2 In yet another embodiment, Y is -NR-. n2 is -C(R2)2-C(R2)2-. In yet another embodiment, the structural moiety -(C=O)-Y n2 - is -(C=O)-C(R2)2-NR1-. In yet another embodiment, the structural moiety -(C=O)-Y n2- is -(C=O)-NR1-C(R2)2-.

[0167] In some embodiments, the structural moiety

[0168] [ka] but,

[0169] [ka] In some embodiments, the structural moiety

[0170] [ka] but,

[0171] [ka] In some specific embodiments, the structural moiety

[0172] [ka] but,

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

[0174] [ka] but,

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

[0176] [ka] but,

[0177] [ka] In some specific embodiments, the structural moiety

[0178] [ka] but,

[0179] [ka] In some specific embodiments, the structural moiety

[0180] [ka] but,

[0181] [ka] It has the following structure.

[0182] In some embodiments, R1 is H, alkyl, or cycloalkyl. In other embodiments, R1 is heteroalkyl, or cycloheteroalkyl.

[0183] In some embodiments, at least one occurrence of R2 is H, alkyl, or cycloalkyl. In some specific embodiments, at least one occurrence of R2 is H, Me, Et, n-Pr, iso-Pr, n-Bu, sec-Bu, or tert-Bu. In other specific embodiments, at least one occurrence of R2 is one or more of OR6, N(R6)2, or -(CH2) 1~2 In some specific embodiments, at least one occurrence of R is alkyl or cycloalkyl, each optionally substituted with OR.

[0184] [ka] is.

[0185] In some embodiments, at least one occurrence of R2 is Me, Et,

[0186] [ka] is.

[0187] In some embodiments, at least one occurrence of R2

[0188] [ka] In some specific embodiments, at least one occurrence of R is heteroalkyl, cycloheteroalkyl, or NR a R b In some specific embodiments, at least one occurrence of R is NR, such as NH, NHMe, or NHMe. a R b In some specific embodiments, R2 is NR a R b and R a is H and R b is alkyl or cycloalkyl. In some specific embodiments, R is NR a R b and R a and R b is alkyl or cycloalkyl. In other embodiments, at least one occurrence of R2 is cycloheteroalkyl optionally substituted with one or more alkyl. In some specific embodiments, R2 is

[0189] [ka] is.

[0190] In some embodiments, R2 is heteroalkyl. In some specific embodiments, R2 is an alkyl ether, secondary or tertiary alkylamine, or 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 some embodiments, R2 is cycloheteroalkyl. Non-limiting examples of cycloheteroalkyl include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepane, 1,4-diazepane, 1,4-oxazepane, and 1,4-oxathiapane.

[0191] In some embodiments, R4 is H, alkyl, or cycloalkyl. In some specific embodiments, R4 is H, Me, Et, n-Pr, iso-Pr, n-Bu, sec-Bu, or tert-Bu. In other specific embodiments, R4 is one or more of OR6, N(R6)2, or -(CH2) 1~2 In some specific embodiments, R4 is alkyl or cycloalkyl, each optionally substituted by OR6.

[0192] [ka] is.

[0193] In some embodiments, R4 is

[0194] [ka] In some specific embodiments, R4 is heteroalkyl, cycloheteroalkyl, or NR a R b In some specific embodiments, R4 is NR, such as NH2, NHMe, or NHMe2. a Rb In some specific embodiments, R4 is NR a R b and R a is H and R b is alkyl or cycloalkyl. In some specific embodiments, R is NR a R b and R a and R b In some specific embodiments, R4 is cycloheteroalkyl optionally substituted with one or more alkyl.

[0195] [ka] is.

[0196] In some embodiments, R4 is heteroalkyl. In some specific embodiments, R4 is an alkyl ether, secondary or tertiary alkylamine, or 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 some embodiments, R4 is cycloheteroalkyl. Non-limiting examples of cycloheteroalkyl include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepane, 1,4-diazepane, 1,4-oxazepane, and 1,4-oxathiapane.

[0197] In other embodiments, R and R and the nitrogen atom to which they are attached together form an optionally substituted heterocyclic ring. In yet other embodiments, R and R and the carbon and nitrogen atoms to which they are attached, respectively, together form an optionally substituted heterocyclic ring.

[0198] In some specific embodiments, the structural moiety

[0199] [ka] but,

[0200] [ka] In some specific embodiments, the structural moiety

[0201] [ka] but,

[0202] [ka] In some specific embodiments, the structural moiety

[0203] [ka] but,

[0204] [ka] It has the following structure.

[0205] In some embodiments, at least one occurrence of R5 is H or alkyl. Non-limiting examples of alkyl include Me, Et, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl. In other embodiments, R5 is OR6 or halogen. In some specific embodiments, R5 is halogen. In some specific embodiments, R5 is OR6. In some specific embodiments, R5 is OH. In some embodiments, n3 is 2. In some embodiments, n3 is 1. In some embodiments, n3 is 0.

[0206] In some 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 containing a nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0207] In some embodiments, Z is OR a In some embodiments, Z is OH, OMe, OEt, OPr, or OBu. In some embodiments, Z is OH.

[0208] In some embodiments, X1 is H, halogen, or alkyl. In any one of the embodiments described herein, X1 can be H or halogen. In some embodiments, X1 is H or alkyl. In other embodiments, X1 is alkyl. In other embodiments, X1 is H. In some embodiments, X1 is H, F, Cl, Br, or Me. In some embodiments, X1 is H, F, or Cl. In some embodiments, X1 is F or Cl. In some embodiments, X1 is H or Cl. In some embodiments, X1 is F. In some embodiments, X1 is Cl. In some embodiments, X1 is H.

[0209] In some embodiments, X2 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In any one of the embodiments described herein, X2 can be H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X2 is H or halogen. In other embodiments, X2 is fluorinated alkyl or alkyl. In other embodiments, X2 is cycloalkyl. In some embodiments, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X2 is H, F, or Cl. In some embodiments, X2 is F or Cl. In some embodiments, X2 is H or Cl. In some embodiments, X2 is F. In some embodiments, X2 is CF3. In some embodiments, X2 is CF2Cl. In some embodiments, X2 is Cl.

[0210] In some embodiments, X3 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In any one of the embodiments described herein, X3 can be H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X3 is H or halogen. In other embodiments, X3 is fluorinated alkyl or alkyl. In other embodiments, X3 is cycloalkyl. In some embodiments, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X3 is H, F, or Cl. In some embodiments, X3 is F or Cl. In some embodiments, X3 is H or Cl. In some embodiments, X3 is F. In some embodiments, X3 is CF3. In some embodiments, X3 is CF2Cl. In some embodiments, X3 is Cl.

[0211] In some embodiments, the structural moiety

[0212] [ka] but,

[0213] [ka] It has the following structure.

[0214] In any one of the embodiments described herein, R3 is H, alkyl, or halogen. In some embodiments, R3 is H or halogen. In some embodiments, R3 is H, F, Cl, or Br. Non-limiting examples of alkyl include Me, Et, propyl, isopropyl, n-butyl, iso-butyl, and sec-butyl.

[0215] In some embodiments, the compound of formula I has the structure of formula II' or II.

[0216] [ka] (In the formula, R 3’ each occurrence of is independently H, halogen, or alkyl, n4 is an integer from 0 to 3, and other substituents are as defined herein. It has.

[0217] In some embodiments, Z is OR a In some embodiments, Z is OH, OMe, OEt, OPr, or OBu. In some embodiments, Z is OH.

[0218] In some embodiments, n4 is an integer from 0 to 3. In some embodiments, n4 is an integer from 1 to 3. In some embodiments, n4 is 0. In some embodiments, n4 is 1 or 2. In some embodiments, n4 is 1. In some embodiments, R 3’ is H or alkyl. In some embodiments, R 3’ is H. In some embodiments, R 3’ is alkyl. In some embodiments, R 3’ is a halogen.

[0219] In any one of the embodiments described herein, R a or R b is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. a or R b is independently H, Me, Et, Pr, or Bu. a or R b At least one occurrence of independently

[0220] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 Optionally substituted with alkyl.

[0221] In some embodiments, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0222] In some embodiments, the compound of formula I is selected from the group consisting of compounds 1-70 shown in Table 1 below.

[0223] [Table 1]

[0224] Preparation method The following are general synthetic schemes for preparing the compounds of the present invention. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Furthermore, various steps of the synthesis can be performed in an alternative sequence or order to obtain the desired compound. All documents cited herein are incorporated by reference in their entirety. For example, the following reactions are illustrative, but not limiting, of the preparation of some of the starting materials and compounds disclosed herein.

[0225] Schemes 1-6 below describe synthetic routes that can be used to synthesize compounds of the present invention, such as compounds having the structure of Formula I, or precursors thereof. Various modifications of these methods to achieve results similar to those of the present invention provided below may occur to those skilled in the art. In the following embodiments, synthetic routes are described using compounds having the structure of Formula I, or precursors thereof, as examples. The general synthetic routes described in Schemes 1-6 and the examples provided in the Examples section below illustrate methods used to prepare the compounds described herein.

[0226] Compounds I-1a and I-2, shown immediately below in Scheme 1, can be prepared by any method known in the art and / or are 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 groups, dialkylaminocarbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or amine groups. As shown in Scheme 1, in some embodiments, compounds disclosed herein can be synthesized from an appropriate substituted bromo- or iodobenzene I-1a, which is converted to the corresponding boronic acid I-1b by, for example, metallation with n-butyllithium and reaction with a trialkyl borate, such as trimethyl borate. The ketoester I-2 is reacted with lithium hexamethyldisilazide and a base, such as N-phenyltriflimide, to form the enol trifluoromethanesulfonate I-3. Coupling of I-3 with boronic acid I-1b in the presence of a catalyst such as 1,1'-bis(diphenylphosphino)-ferrocenedichloropalladium(II) (Pd(dppf)Cl) affords cyclic amine I-4. Hydrogenation of I-4 over a catalyst such as platinum oxide affords saturated cyclic amine ester I-5a. The protecting group of compound I-5a can then be removed to afford compounds of formula I, and such compounds bearing free phenolic OH and / or free nitrogen groups can optionally be further converted to other compounds of formula I using methods known in the art.

[0227] [ka]

[0228] Compounds I-1a and I-6, shown immediately below in Scheme 2, can be prepared by any method known in the art and / or are commercially available. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. As shown in Scheme 2, in some embodiments, compounds disclosed herein where n1=1 can be prepared by an alternative route. Iodo- or bromobenzene I-1a is coupled with pyridine boronate ester I-6 in the presence of a palladium catalyst such as Pd(dppf)Cl2 to form 4-arylpyridine I-7. Hydrogenation of I-7 over a catalyst such as platinum oxide provides 4-arylpiperidine I-5b. The protecting group of compound I-5b can then be removed to give compounds of formula I, and such compounds bearing free phenolic OH and / or free nitrogen groups can optionally be further converted into other compounds of formula I using methods known in the art.

[0229] [ka]

[0230] As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. As shown immediately below in Scheme 3, compounds disclosed herein in which R4 is H or lower alkyl can be obtained from piperidine esters I-5b, I-5c, which can be obtained from I-5a by selectively removing the protecting group on the nitrogen. The cyclic amine esters I-5b or I-5c are coupled with an appropriately protected amino acid using coupling reagents such as EDC / HOBt, HBTU, or HATU to form amides I-8. An example of a suitable amine protecting group on the nitrogen is t-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.

[0231] [ka]

[0232] As shown in Scheme 4, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. Related methods applicable to more complex R groups are shown immediately below in Scheme 4. Reaction of aminoester I-5c with chloroacetyl chloride and a base such as triethylamine provides chloroacetamide I-11. Treatment of I-11 with amine RNH and a base such as triethylamine and heating in a solvent such as ethanol provides N-substituted diketopiperazine I-9b, which is converted to I-10b by removal of the phenol protecting group.

[0233] [ka]

[0234] As shown in Scheme 5, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. Compounds disclosed herein in which Y is absent or is nitrogen can be synthesized by the method shown immediately below in Scheme 5. As shown in Scheme 5, for compounds disclosed herein in which Y is absent, reaction of aminoester I-5c with amine RNH by heating in methanol provides amide I-12. Treatment of amide I-12 with carbonyldiimidazole (CDI) in DMF causes cyclization to imidazolinedione I-13. For compounds disclosed herein in which Y is nitrogen, reaction of boc-protected aminoester I-5d with hydrazine hydrate directly provides triazolidinedione I-14. The protecting groups of compounds I-13 and I-14 can then be removed to give compounds of formula I, and such compounds bearing a free phenolic OH group can optionally be further converted into other compounds of formula I using methods known in the art.

[0235] [ka]

[0236] As shown in Scheme 6, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. The stereocontrolled synthesis of intermediate 5d, leading to chiral intermediate 5e, is shown immediately below in Scheme 6. As shown in Scheme 6, enantiomerically pure piperidone I-15 can be synthesized from protected L-aspartic acid and Meldrum's acid by the method of Org. Syn., 2008, 85, 147, and then converted to enol triflate I-16 by treatment with trifluoromethanesulfonic anhydride and base according to the procedure described in Syn. Lett., 2009, 71-74. Coupling of the enol triflate I-16 with the boronic acid I-1b using a palladium catalyst such as Pd(dppf)Cl2 affords I-17. Hydrogenation of I-17 over a catalyst such as platinum oxide affords the piperidinone I-18 predominantly as the 2S,4S enantiomer, and reduction of the amide using borane methyl sulfide complex affords enantiomerically pure I-5e, which can be used in the syntheses outlined in Schemes 3, 4, and 5.

[0237] [ka]

[0238] The reactions described above in Schemes 1-6 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, such as nitrogen or argon, or in a sealed tube. The reaction mixture can be heated in a microwave or at an elevated temperature. Suitable elevated temperatures include, but are not limited to, 40, 50, 60, 80, 90, 100, 110, 120 °C or higher, or the reflux / boiling temperature of the solvent used. Alternatively, the reaction mixture can be cooled in a cooling bath at a temperature below room temperature, such as 0, -10, -20, -30, -40, -50, -78, or -90 °C. The reaction can be worked up by removing the solvent or by partitioning the organic solvent phase with one or more aqueous phases, each optionally containing NaCl, NaHCO3, or NHCl. The solvent of the organic phase can be removed by low vacuum evaporation and the resulting residue can be purified using a silica gel column or HPLC.

[0239] Pharmaceutical Composition The present invention also provides pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0240] In yet another aspect, the present invention provides pharmaceutical compositions comprising at least one compound selected from the group consisting of compounds of formula I described herein and a pharmaceutically acceptable carrier or diluent.

[0241] 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.

[0242] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the pharmaceutical agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as butylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical preparations.The term "carrier" refers to a natural or synthetic organic or inorganic ingredient that combines with active ingredients to facilitate application. The components of the pharmaceutical compositions also are capable of being co-mingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0243] As noted above, certain embodiments of the pharmaceutical agent may be provided in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" in this context refers to the relatively non-toxic, inorganic and organic acid salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compounds of the present invention in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. (See, e.g., Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)

[0244] Pharmaceutically acceptable salts of the present compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, and the like; and salts prepared from organic acids such as acetate, butyonic acid, succinate, glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, palmitate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalate, isothionic acid, and the like.

[0245] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, e.g., Berge et al. (supra).

[0246] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0247] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0248] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0249] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as an active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0250] In the solid dosage forms of the present invention for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; agar, calcium carbonate, potato, etc. Disintegrating agents such as maize or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymers; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type can also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0251] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxybutylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0252] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxybutylmethylcellulose, other polymer matrices, liposomes, and / or microspheres that provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents into the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0253] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage form may contain solubilizers and emulsifiers, such as inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, can be used to solubilize the compound.

[0254] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0255] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0256] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0257] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0258] Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example, butane and butane.

[0259] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the drug in a suitable medium.Absorption enhancers can also be used to increase the flux of the drug of the present invention across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0260] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0261] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents; or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0262] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections to prolong the drug's effect. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the drug depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle. One strategy for depot injection involves the use of polyethylene oxide-polypropylene oxide copolymers, whose vehicles are fluid at room temperature but solidify at body temperature.

[0263] Injectable depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0264] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be given as they are or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0265] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, that is, the compounds and pharmaceutical compositions can be administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures.The specific combination of treatments (therapeutic agents or procedures) used in combination regimen will take into account the compatibility of desired therapeutic agents and / or procedures and the desired therapeutic effect achieved.It will also be understood that the treatments used can achieve the desired effect for the same disorder (for example, the compounds of the present invention can be administered simultaneously with another anticancer drug).

[0266] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds can be used to treat arthritic conditions in mammals (e.g., humans, livestock and domestic animals), racehorses, birds, lizards, and any other organisms that can tolerate the compounds.

[0267] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, optionally accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, reflecting approval by the agency of the manufacture, use, or sale for human administration.

[0268] Administration to subjects In yet another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of a compound selected from the group consisting of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and renal diseases.

[0269] In some embodiments, the cancer is selected from the group consisting of biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasia, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

[0270] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy. In some embodiments, the gastroenterological disorder is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis.

[0271] In some embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes). In some embodiments, the CNS disorder is Alzheimer's disease.

[0272] In some embodiments, the metabolic disorder is obesity or type II diabetes. In some embodiments, the cardiovascular disorder is ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0273] In some embodiments, the mammalian species is human.

[0274] In some embodiments, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0275] In yet another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the compounds described herein are selective in blocking the Kv1.3 potassium channel with minimal or no off-target inhibitory activity against other potassium channels, or against calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channel, and therefore have a desirable cardiovascular safety profile.

[0277] Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a particular outcome. Accordingly, small molecule compositions useful according to the methods of the invention can be formulated in any manner suitable for pharmaceutical use.

[0278] The formulations of the present invention are administered in pharmaceutically acceptable solutions which may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0279] For use in treatment, an effective amount of the compound can be administered to a subject by any method that allows the compound to be taken up by appropriate target cells.The "administration" of the pharmaceutical composition of the present invention can be achieved by any means known to those skilled in the art.Specific administration routes include, but are not limited to, oral, transdermal (for example, via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.).Injection can be bolus or continuous infusion.

[0280] For example, pharmaceutical compositions according to the present invention are often administered intravenously, intramuscularly, or by other parenteral means. They can also be administered intranasally, by inhalation, topically, orally, or as an implant, and even rectally or vaginally. Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, cochleated, coated on fine gold particles, contained in liposomes, nebulized, aerosolized, pellets for implantation in the skin, or dried on a sharp object for scratching into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with extended release of active compounds, in which excipients and additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers are commonly used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief overview of this method for drug delivery, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference.

[0281] The concentration of the compound contained in the composition used in the method of the present invention can range from about 1 nM to about 100 μM. An effective dose is believed to be in the range of about 100 picomoles / kg to about 100 micromoles / kg.

[0282] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders and suppositories. To treat a patient, different dosages may be required depending on the activity of the compound, the method of administration, the purpose of administration (i.e., preventive or therapeutic), the nature and severity of the disorder, and the age and weight of the patient. The administration of a given dose can be carried out by both single administration in the form of individual dosage units or several smaller dosage units. Repeated doses and multiple administrations at specific daily, weekly or monthly intervals are also contemplated by the present invention.

[0283] The composition can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. For medical use, the salt should be pharmaceutically acceptable, although non-pharmaceutically acceptable salts can be conveniently used to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. These salts can also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0284] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0285] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations that can be isotonic with the recipient's blood. Acceptable vehicles and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed, or non-mineral oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid have found use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous administration, etc. can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0286] The compounds useful in the present invention may be delivered in a mixture of three or more such compounds, which may further include one or more adjuvants in addition to the combination of compounds.

[0287] A variety of administration routes are available.The specific mode selected will naturally depend on the specific compound selected, the age and general health condition of the subject, the specific condition to be treated, and the dosage required for therapeutic effectiveness.The method of the present invention can be carried out using any medically acceptable administration mode, which generally means any mode that produces an effective level of response without causing clinically unacceptable adverse effects.Preferred administration modes are discussed above.

[0288] Composition can be conveniently provided in unit dosage form, and can be prepared by any method well known in the field of pharmacy.All methods comprise the step of associating compound with carrier that constitutes one or more accessory components.Generally, composition is prepared by associating compound with liquid carrier, finely divided solid carrier, or both, uniformly and intimately, and then, if necessary, shaping product.

[0289] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems. Such systems can avoid repeated administration of the compound, increasing convenience for patients and physicians. Many types of release delivery systems are available and known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Drug-containing microcapsules of these polymers are described, for example, in U.S. Pat. No. 5,075,109. Delivery systems also include non-polymeric systems, such as lipids containing sterols, such as cholesterol, cholesterol esters, and fatty acids, or neutral lipids, e.g., mono-, di-, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; and partially fused implants. Specific examples include, but are not limited to: (a) erosion systems in which the agents of the invention are contained within a matrix, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusion systems in which the active ingredient permeates through a polymer at a controlled rate, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. Additionally, pump-based hardware delivery systems, some of which are adapted for implantation, can be used.

[0290] Assays for determining the efficacy of Kv1.3 potassium channel blockers In some embodiments, the compound described herein is tested for its activity against Kv1.3 potassium channel.In some embodiments, the compound described herein is tested for its Kv1.3 potassium channel electrophysiology.In some embodiments, the compound described herein is tested for its hERG electrophysiology.

[0291] equivalent The following representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the present invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the complete contents of this document, including the following examples, and with reference to the scientific and patent literature cited herein. It should be further understood that the contents of these cited references are incorporated herein by reference to help illustrate the prior art. The following examples contain important additional information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof. [Example]

[0292] Examples 1-5 describe various intermediates used in the synthesis of representative compounds of Formula I disclosed herein.

[0293] [Example 1] Intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) and Intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene)

[0294] [ka]

[0295] Step A: To a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) was added Br (98.04 g, 613.49 mmol) dropwise under a nitrogen atmosphere at 0 °C. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched with saturated aqueous NaSO (500 mL) at 0 °C. The resulting mixture was extracted with EA (6 × 400 mL). The combined organic layers were washed with brine (2 × 400 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (100 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0296] Step B: To a crude mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (32 g, 125.04 mmol, 1 equiv.) and KCO (54.9 g, 396.87 mmol, 3 equiv.) in ACN (210 mL) was added MeI (16.5 mL, 116.05 mmol, 2 equiv.) dropwise at 0 °C. 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 give intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) (8.7 g, 25.7%) as a white solid: 1 H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 9.0, 1.1 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 3.92 (s, 3H); and intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene) (24.3 g, 71.77%) as a white solid: 1 H NMR (300 MHz, CDCl3) δ 7.64 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H). was obtained as.

[0297] [Example 2] Intermediate 3 ((2,3-Dichloro-6-methoxyphenyl)boronic acid)

[0298] [ka]

[0299] Step A: To a stirred solution of 3,4-dichlorophenol (120 g, 0.74 mol) in THF (400 mL) under nitrogen atmosphere at room temperature, NaOH (75 g, 1.88 mol) was added portionwise, followed by stirring for 30 minutes. To this, N,N-diethylcarbamoyl chloride (150 g, 1.11 mol) was added over 40 minutes, followed by stirring for 15 hours. 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 give 3,4-dichlorophenyl N,N-diethylcarbamate as a yellow oil (213 g, crude): LCMS (ESI) C 11 H 13 Cl2NO2[M + H] + Calculated values: 262, 264 (3 : 2), measured values: 262, 264 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.50-3.34 (m, 4H), 1.32-1.17 (m, 6H).

[0300] Step B: To a solution of DIPA (32 g, 0.32 mol) in THF (400 mL) was added n-BuLi (131 mL, 0.33 mmol) dropwise under a nitrogen atmosphere at −65° C. The resulting mixture was stirred for 1 h. To this was added a solution of 3,4-dichlorophenyl N,N-diethylcarbamate (77 g, 0.29 mol) in THF (200 mL) dropwise, followed by stirring for 1 h. To this was added a solution of I2 (82 g, 0.32 mol) in THF (200 mL) dropwise over 1 h. The resulting mixture was stirred at −65° C. for an additional 30 min. The reaction was quenched at room temperature by the addition of aqueous NH4Cl (300 mL). The resulting mixture was extracted with EA (3 × 400 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Three additional batches (3 x 77 g of 3,4-dichlorophenyl N,N-diethylcarbamate) were reacted, worked up, and then combined 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 eluting with PE / EA (50 / 1) to give an additional 75 g of pure product. 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (375 g, 83% over two steps) was obtained as an off-white solid: LCMS (ESI) C 11 H 12 Cl2INO3[M + H] + Calculated values: 388, 390 (3 : 2), measured values ​​388, 390 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.55 (q, J = 7.2 Hz, 2H), 3.42 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0301] Step C: To a stirred solution of 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (200 g, 0.52 mol) in EtOH (1.50 L) was added NaOH (165 g, 4.1 mol) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ice water (1.5 L). The mixture was then acidified to pH = 3 with aqueous HCl (6 N). The resulting mixture was extracted with EA (3 × 1 L). The combined organic layers were washed with brine (800 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 3,4-dichloro-2-iodophenol as a brown oil (202 g, crude): LCMS (ESI) C6H3Cl2IO [M - H] - Calculated values: 287, 289 (3:2), measured values: 287, 289 (3:2).

[0302] Step D: To a stirred solution of 3,4-dichloro-2-iodophenol (220 g, 0.76 mol) in DMF (700 mL) was added KCO (210 g, 1.52 mol) and MeI (119 g, 0.84 mol). The resulting mixture was stirred at room temperature for 5 hours. Another batch (100 g of 3,4-dichloro-2-iodophenol) was added and combined with the previous batch. The resulting mixture was diluted with water (5 L) at room temperature. The resulting mixture was then extracted with EA (3 × 1 L). The combined organic layers were washed with brine (4 × 400 mL) and dried over anhydrous NaSO. 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 another 64 g of the desired product. 1,2-Dichloro-3-iodo-4-methoxybenzene (192 g, 78% over two steps) was obtained as a pale yellow solid: 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 3.91 (s, 3H).

[0303] Step E: To a solution of 1,2-dichloro-3-iodo-4-methoxybenzene (100 g, 0.33 mol) in THF (1.2 L) was added i-PrMgCl (182 mL, 0.36 mol) dropwise under a nitrogen atmosphere at 0 °C. The reaction mixture was then stirred at 0 °C for 1 h. B(OMe) (86 g, 0.83 mol) was added dropwise at 0 °C. The reaction mixture was then warmed to room temperature over 1 h and stirred at room temperature for another 1 h. Aqueous HSO (5%, 500 mL) was then added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The mixture was extracted with EA (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated. The residue was stirred in DCM (200 mL) and then filtered to give intermediate 3 ((2,3-dichloro-6-methoxyphenyl)boronic acid) as an off-white solid (55 g, 76%): LCMS (ESI) C 15 H 16 Cl2N2O4[M - H] - Calculated values: 219, 221 (3 : 2), measured values: 219, 221 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 5.65 (s, 2H), 3.89 (s, 3H).

[0304] [Example 3] Intermediate 4 (1,2-di-tert-butyl (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylate)

[0305] [ka]

[0306] Step A: EDCI (4.97 g, 25.92 mmol), DMAP (3.17 g, 25.92 mmol), and Meldrum's acid (2.49 g, 17.28 mmol) were added to a solution of (3S)-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 KHSO (30 mL). The organic layer was dried over anhydrous NaSO, 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 KHSO and brine (60 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was washed with DCM / PE (1 / 2, 25 mL) to give 1,2-di-tert-butyl (2S)-4,6-dioxopiperidine-1,2-dicarboxylate as an off-white solid (3 g, 55%): LCMS (ESI) C 15 H 23 NO6[M + H-100] + Calculated value: 214, measured value 214; 1 H NMR (400 MHz, CDCl3) δ 5.09 (dd, J = 6.9, 2.2 Hz, 1H), 3.55 (d, 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).

[0307] Step B: To a solution of 1,2-di-tert-butyl (2S)-4,6-dioxopiperidine-1,2-dicarboxylate (1.0 g, 3.19 mmol) in DCM (10 mL) was added DIPEA (1.67 mL, 12.90 mmol) dropwise under a nitrogen atmosphere at 0 °C. Triflic anhydride (1.08 g, 3.83 mmol) was added dropwise to the mixture at 0 °C, followed by stirring at room temperature for 1 hour. The reaction mixture was quenched with 10 mL of aqueous NaHCO3. 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 give intermediate 4 (1,2-di-tert-butyl (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylate) as a brown solid (2.6 g, crude): LCMS (ESI) C 14 H 22 F3NO8S [M + H] + Calculated value: 446, Measured value: 446.

[0308] [Example 4] Intermediate 5 (Methyl 4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate)

[0309] [ka]

[0310] Step A: 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 was added NaCO (6.2 g, 0.06 mmol, 3 equiv.) and Pd(dppf)Cl.CHCl (3.2 g, 0.2 equiv.). After stirring at 80 °C under a nitrogen atmosphere for 3 hours, 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: LCMS (ESI) C 14 H 11 Cl2NO3[M + H] + Calculated values: 312, 314 (3:2), measured values: 312, 314 (3:2). 1 H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 5.0 Hz, 1H), 8.08 (s, 1H), 7.66-7.57 (m, 2H), 7.16 (d, J = 9.0 Hz, 1H), 4.01 (s, 3H), 3.78 (s, 3H).

[0311] Step B: 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 at room temperature, HCl (6 M, 1 mL) was added in small portions. The resulting mixture was stirred under a hydrogen atmosphere at 30 °C for 4 days. The solid was filtered and washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to give intermediate 5 (methyl 4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate) (200 mg, 52.32%) as a yellow oil: LCMS (ESI) C 14 H 17 Cl2NO3[M + H]+ Calculated values: 318, 320 (3:2), measured values: 318, 320 (3:2). 1 H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.67-3.58 (m, 1H), 3.47 (dd, J = 11.9, 3.0 Hz, 1H), 3.26-3.16 (m, 1H), 2.76 (td, J = 12.4, 2.9 Hz, 1H), 2.45-2.27 (m, 2H), 1.90 (d, J = 12.7 Hz, 1H), 1.51 (d, J = 13.1Hz, 1H).

[0312] [Example 5] Intermediate 6 (Methyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate)

[0313] [ka]

[0314] Step A: To a mixture of 1,2-di-tert-butyl (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylate (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 NaCO (1.01 g, 9.51 mmol) in dioxane (20 mL) and HO (5 mL) was added Pd(dppf)Cl.CHCl (130 mg, 0.16 mmol) in one portion at room temperature. The suspension was degassed under vacuum and purged with nitrogen three times. The reaction 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 × 15 mL). The organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 1,2-di-tert-butyl (2S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylate as a pale yellow foam (900 mg, 60%): LCMS (ESI) C 22 H 21 Cl2N7O6[M + H-100] + Calculated values: 372, 374 (3 : 2), measured values ​​372, 374 (3 : 2); 1 H NMR (400 MHz, chloroform-d) δ 7.41 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 5.92 (d, J = 2.7 Hz, 1H), 4.94 (dd, J = 7.2, 1.8 Hz, 1H), 3.78 (s, 3H), 3.13 (d, J = 18.5 Hz, 1H), 2.89 (d, J = 18.3 Hz, 1H), 1.59 (s, 9H), 1.49 (s, 9H).

[0315] Step B: To a solution of 1,2-di-tert-butyl (2S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylate (900 mg, 1.91 mmol) in EA (50 mL) and AcOH (0.50 mL) was added PtO (150 mg, 0.66 mmol) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (1.5 atm) at room temperature for 16 hours. The reaction was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 1,2-di-tert-butyl (2S,4S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidine-1,2-dicarboxylate as a colorless foam (550 mg, 61%): LCMS (ESI) C 22 H 29 Cl2NO6[M + H-100] + Calculated values: 474, 476 (3 : 2), measured values: 474, 476 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 9.0 Hz, 1H), 6.77 (d, 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).

[0316] Step C: To a solution of 1,2-di-tert-butyl (2S,4S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidine-1,2-dicarboxylate (550 mg, 1.16 mmol) in THF (10 mL) was added BH3·Me2S (0.21 mL, 2.11 mmol) at 0°C under a nitrogen atmosphere. The reaction was then stirred at room temperature for 4 hours under a nitrogen atmosphere. Then, at 0°C, 10 mL of MeOH was added dropwise, and the resulting mixture was stirred for 1 hour. To this was added 6 mL of aqueous HCl (6 M). The reaction was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to give intermediate 6 (methyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylate) (125 mg, 34%) as a colorless oil: LCMS (ESI) C 14 H 17 Cl2NO3[M + H] + Calculated values: 318, 320 (3 : 2), measured values ​​318, 320 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.38 (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).

[0317] Examples 6-8 describe synthesis and / or characterization data for representative compounds of Formula I disclosed herein.

[0318] [Example 6] Compound 1 ((8R,9aS)-2-(azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydro-1H-pyrido[1,2-a]pyrazine-1,4-dione)

[0319] [ka]

[0320] Step A: 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) under a nitrogen atmosphere at 0° C., 2-chloroacetyl chloride (170 mg, 1.51 mmol) was added. 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 as a light brown solid (500 mg, crude): LCMS (ESI) calculated for C16H18Cl3NO4 [M + H]+: 394, 396 (1:1), found 394, 396 (1:1).

[0321] Step B: 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) was added tert-butyl 3-aminoazetidine-1-carboxylate (327 mg, 1.90 mmol) at room temperature. The resulting reaction mixture was stirred at 80° C. for 16 hours and then concentrated in vacuo. The residue was dissolved in EA (20 mL). The solution was washed with brine (2×10 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 as a light brown oil (285 mg, 45%): LCMS (ESI) C 23 H 29Cl2N3O5[M + H] + Calculated value: 498, 500 (3:2), measured value: 498, 500 (3:2).

[0322] Step C: To a stirred solution of 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, 0.29 mmol, 80%) in DCM (5 mL) was added BBr (0.51 mL, 2.03 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL). The pH was adjusted to 7 by adding saturated aqueous NaHCO solution, and the resulting solution was concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column 30 × 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. Fractions containing the desired product were combined and concentrated under reduced pressure to give 2-(azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydro-1H-pyrido[1,2-a]pyrazine-1,4-dione trifluoroacetate as an off-white solid (120 mg, 86%): LCMS (ESI) C 17 H 19 Cl2N3O3[M + H] + Calculated values: 384, 386 (3:2), measured values: 384, 386 (3:2). 1H NMR (400 MHz, methanol-d4) δ 7.21 (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).

[0323] Step D: 2-(Azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydro-1H-pyrido[1,2-a]pyrazine-1,4-dione (120 mg, 0.31 mmol) was separated by chiral HPLC using 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. Fractions containing the desired product were combined and concentrated under reduced pressure to give compound 1 ((8R,9aS)-2-(azetidin-3-yl)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydro-1H-pyrido[1,2-a]pyrazine-1,4-dione) as an off-white solid (30 mg, 25%): LCMS (ESI) C 17 H 19 Cl2N3O3[M + H] + Calculated values: 384, 386 (3:2), measured values: 384, 386 (3:2). 1 H NMR (400 MHz, methanol-d4) δ 1H NMR (400 MHz, methanol-d4) δ 7.21 (d, J = 8.8 Hz, 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).

[0324] [Example 7] Compound 2 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-hexahydro-2H-pyrido[1,2-a]pyrazine-1,4-dione)

[0325] [ka]

[0326] Step A: To a stirred solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid (97 mg, 0.47 mmol) in DMF (2 mL) was added EDCI (113 mg, 0.59 mmol) and HOBT (80 mg, 0.59 mmol) at room temperature. 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 hours, then poured into HO (10 mL) and extracted with EA (3 × 5 mL). The combined organic phase was washed with brine (3 × 5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column 30 × 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. 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 as a pale yellow foam (35 mg, 18%): LCMS (ESI) C 22 H 30 Cl2N2O7[M + H] + Calculated values: 505, 507 (3:2), measured values: 505, 507 (3:2).

[0327] Step B: 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) was added TFA (0.5 mL, 6.73 mmol) at room temperature. The resulting mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was dissolved in EtOH (3 mL). TEA (21 mg, 0.21 mmol) was then added, and the reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated to give (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-hexahydro-2H-pyrido[1,2-a]pyrazine-1,4-dione as a pale yellow oil (80 mg, crude): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated values: 373, 375 (3:2), measured values: 373, 375 (3:2).

[0328] Step C: To a stirred solution of (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-hexahydro-2H-pyrido[1,2-a]pyrazine-1,4-dione (80 mg, crude) in DCM (2 mL) was added BBr (0.2 mL) at room temperature. The reaction mixture was stirred for 2 hours 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 HPLC using the following conditions: Column: XBridge Prep C18 OBD Prep Column 19 × 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. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 2 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-hexahydro-2H-pyrido[1,2-a]pyrazine-1,4-dione) as an off-white solid (12.3 mg): LCMS (ESI) C 15 H 16 Cl2N2O4[M + H] + Calculated values: 359, 361 (3 : 2), measured values ​​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).

[0329] [Example 8] The following compounds were made in a manner similar to Compound 1 (Example 6) or Compound 2 (Example 7) and / or by methods known in the art.

[0330] Table 2-1

[0331] Table 2-2

[0332] Table 2-3

[0333] Table 2-4

[0334] Table 2-5

[0335] Table 2-6

[0336] Table 2-7

[0337] Table 2-8

[0338] Table 2-9

[0339] Table 2-10

[0340] [Table 2-11]

[0341] [Table 2-12]

[0342] [Example 9] Evaluation of Kv1.3 potassium channel blocker activity This assay was used to evaluate the activity of the disclosed compounds as Kv1.3 potassium channel blockers.

[0343] cell culture CHO-K1 cells stably expressing Kv1.3 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, and G418 (500 μg / ml). Cells were grown in culture flasks at 37°C in a humidified incubator with 5% CO2.

[0344] solution Cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM MgCl, 5 mM glucose, and 10 mM HEPES; pH was adjusted to 7.4 with NaOH; pH was 295–305 mOsm. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES; pH was adjusted to 7.2 with KOH; pH was 285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted in the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. A maximum content of DMSO (0.3%) was present in the 100 μM solution.

[0345] Voltage Protocol Currents were elicited by applying 100 ms depolarizing pulses from -90 mV (holding potential) to +40 mV at a frequency of 0.1 Hz. Control (no compound) and compound pulse trains applied for each compound concentration contained 20 pulses. A 10 second break was used between pulse trains (see Table A below).

[0346] [Table 3]

[0347] Patch clamp recording and compound application Whole-cell current recording and compound application were enabled by means of the automated patch-clamp platform Patchliner (Nanion Technologies GmbH). An EPC10 patch-clamp amplifier (HEKA Elektronik Dr. Schulze GmbH) was used for data acquisition with Patchmaster software (HEKA Elektronik Dr. Schulze GmbH). Data were sampled at 10 kHz without filtering. Passive leak currents were subtracted online using the P / 4 procedure (HEKA Elektronik Dr. Schulze GmbH). Increasing compound concentrations were applied consecutively to the same cell without washout. The total compound incubation time before the next pulse train was less than 10 seconds. Inhibition of peak currents was observed during compound equilibration.

[0348] Data analysis AUC and peak values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). 50 The last single pulse in the pulse train corresponding to a given compound concentration was used to determine the IC. The resulting AUC and peak values ​​in the presence of compound were normalized to the control values ​​in the absence of compound. Origin (OridinLab) was used to determine the IC. 50 The Hill formula: compound / Icontrol =(100-A) / (1+([compound] / IC 50 )nH)+A(where, IC 50 Values ​​are derived from data fitting to (where [compound] is the concentration at which current inhibition was half-maximal, A is the fraction of unblocked current, and nH is the Hill coefficient).

[0349] [Example 10] Assessment of hERG activity This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0350] hERG electrophysiology This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0351] cell culture CHO-K1 cells stably expressing hERG were grown in Ham's F-12 medium containing 10% heat-inactivated FBS, 1% penicillin / streptomycin, hygromycin (100 μg / ml), and glutamine containing G418 (100 μg / ml). Cells were grown in culture flasks at 37°C in a humidified incubator with 5% CO2.

[0352] solution Cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM MgCl, 5 mM glucose, and 10 mM HEPES; pH was adjusted to 7.4 with NaOH; pH was 295–305 mOsm. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES; pH was adjusted to 7.2 with KOH; pH was 285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted in the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. A maximum content of DMSO (0.3%) was present in the 100 μM solution.

[0353] Voltage Protocol The voltage protocol (see Table B) was designed to simulate the voltage changes during a cardiac action potential, with a 300 ms depolarization to +20 mV (similar to the plateau phase of the cardiac action potential), a 300 ms repolarization to -50 mV (to induce tail current), and a final step to a holding potential of -80 mV. The pulse frequency was 0.3 Hz. The control (no compound) and compound pulse trains applied for each compound concentration contained 70 pulses.

[0354] [Table 4]

[0355] Patch clamp recording and compound application Whole-cell current recording and compound application were made possible by means of the automated patch clamp platform Patchliner (Nanion). An EPC10 patch clamp amplifier (HEKA) was used for data collection with Patchmaster software (HEKA Elektronik Dr. Schulze GmbH). Data were sampled at 10 kHz without filtering. Increasing compound concentrations were applied consecutively to the same cell without washout in between.

[0356] Data analysis AUC and peak values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). 50 The last single pulse in the pulse train corresponding to a given compound concentration was used to determine the IC. The resulting AUC and peak values ​​in the presence of compound were normalized to the control values ​​in the absence of compound. Origin (OridinLab) was used to determine the IC. 50 The Hill formula: compound / I control =(100-A) / (1+([compound] / IC 50 )nH)+A(where, IC50 where A is the concentration at which current inhibition was half-maximal, [compound] is the applied compound concentration, A is the fraction of unblocked current, and nH is the Hill coefficient.

[0357] Table 1 provides a summary of the inhibitory activity of certain selected compounds of the present invention against the Kv1.3 potassium channel and the hERG channel.

[0358] [Table 5-1]

[0359] [Table 5-2]

[0360] [Table 5-3]

[0361] [Table 5-4]

[0362] [Table 5-5]

[0363] [Table 5-6]

[0364] [Table 5-7]

[0365] [Table 5-8]

[0366] Table 5-9

[0367] Table 5-10 The present application also relates to the following aspects: (1) A compound of formula I or a pharmaceutically acceptable salt thereof

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Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, Each occurrence of Y independently represents C(R ２ ) ２ or NR １ and Z is OH; X １ is H, halogen, or Me; X ２ is F, Cl, Br, Me, CF ２ H, C.F. ２ Cl, CF ３ or H; X ３ is F, Cl, Br, Me, CF ２ H, C.F. ２ Cl, CF ３ or H; R １ each occurrence of is H, alkyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl; R ２ Each occurrence of is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, or NR ａ R ｂ and R ３ is H; R ４ is H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, or NR ａ R ｂ and R ５ Each occurrence of is H, halogen, OR ６ or alkyl, and each R ５ teeth 【Chemistry 2】 may be attached to any one of the carbon ring atoms of Or R １ and R ４ and the nitrogen atom to which they are attached, taken together, form an optionally substituted heterocycle; Or R ２ and R ４ and the carbon atom and nitrogen atom to which they are respectively attached, taken together, form an optionally substituted heterocycle; R ａ and R ｂ each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R ａ and R ｂ together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; If applicable, R １ , R ２ , R ４ , R ５ , R ａ , or R ｂ The alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl of the formula (I) are, when valence permits, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, OR ６ , -(CH ２ ) １～２ OR ６ , N(R ６ ) ２ , (C=O)R ６ , (C═O)N(R ６ ) ２ , N.R. ６ (C=O)R ６ and oxo; R ６ each occurrence of R is independently H, alkyl, or a heterocycle optionally substituted with alkyl; or two R ６ groups, taken together with the nitrogen atom to which they are attached, form a heterocycle optionally substituted with alkyl and containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; n １ is an integer of 1 or 0; n ２ is an integer of 1, 2, or 0; n ３ is an integer from 0 to 2, said heteroalkyl is selected from the group consisting of alkyl ethers, secondary and tertiary alkyl amines, and alkyl sulfides; The cycloheteroalkyl is a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from the group consisting of nitrogen, sulfur, and oxygen in at least one ring.

2. structural part 【Transformation 3】 but, (a) 【Chemistry 4】 or (b) 【Transformation 5】 or (c) 【Transformation 6】 or (d) 【Transformation 7】 or (e) 【Transformation 8】 or (f) 【Chemistry 9】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

3. R １ , R ２ , and R ４ at least one of is H, alkyl, or cycloalkyl; (a) R １ , R ２ , and R ４ At least one of the following is H, Me, Et, n-Pr, iso- Pr, n-Bu, sec-Bu, or tert-Bu; (b) R ２ and R ４ At least one of the following is one or more OR ６ , N(R ６ ) ２ ,Also Ha-(CH ２ ) １～２ OR ６ alkyl or cycloalkyl, each optionally substituted by Is it alkyl? (c) R ２ and R ４ At least one of 【Chemistry 10】 Or (d) R ２ At least one occurrence of Me, Et, 【Chemistry 11】 Or (e) R ２ and R ４ At least one of 【Chemistry 12】 3. The compound of claim 1 or claim 2, wherein:

4. (a) R １ , R ２ , and R ４ at least one of is heteroalkyl or cycloheteroalkyl, and R ２ and R ４ At least one of 【Chemistry 13】 Or (b) R ２ and R ４ At least one of the following is NR ａ R ｂ and (i) R ａ and R ｂ are each independently H, alkyl or cycloalkyl; or (ii) R ２ and R ４ At least one of ２ , NHMe, or NHMe ２ 3. The compound of claim 1 or claim 2, wherein:

5. R １ and R ４ and the nitrogen atom to which they are attached, taken together, form an optionally substituted heterocycle; or R ２ and R ４ and the carbon atom and nitrogen atom to which they are respectively attached, taken together to form an optionally substituted heterocycle; (a) structural part 【Chemistry 14】 but, 【Chemistry 15】 or (b) Structural part 【Chemistry 16】 but, 【Chemistry 17】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

6. (a) R ５ is H or alkyl; or (b) R ５ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein at least one occurrence of is halogen or OH.

7. n ３ 7. The compound of claim 1, wherein R is 0 or 1, or a pharmaceutically acceptable salt thereof.

8. (a) X １ is H or Cl, and / or (b) X ２ is Cl or H, and / or (c) X ３ 8. The compound of claim 1, wherein is Cl or H, or a pharmaceutically acceptable salt thereof.

9. (a) X １ is H, or Cl, and (b) X ２ is Cl or H, and (c) X ３ 8. The compound of claim 1, wherein is Cl or H, or a pharmaceutically acceptable salt thereof.

10. structural part [Chemistry 18] but, 【Chemistry 19】 8. The compound of any one of claims 1 to 7, having the structure: or a pharmaceutically acceptable salt thereof.

11. (a) R ａ or R ｂ is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; and R ａ or R ｂ at least one occurrence of is independently H, Me, Et, Pr, or 【Chemistry 20】 wherein said heterocycle, when valences permit, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C １～４ optionally substituted with alkyl; (b) R ａ and R ｂ are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, or a pharmaceutically acceptable salt thereof.

12. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds shown below. 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 。

13. 13. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

14. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

15. 13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in a method of treating a condition in a mammalian species in need thereof, comprising: the method comprises the step of administering to the mammalian species a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a central nervous system disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease; Optionally, said condition is: (a) an immunological disorder that is transplant rejection or an autoimmune disease, wherein the autoimmune disease is optionally rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes; (b) a central nervous system disorder that is Alzheimer's disease; (c) an inflammatory disorder that is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy; (d) the gastroenterological disorder is inflammatory bowel disease; (e) a metabolic disorder that is obesity or type II diabetes; (f) cardiovascular disorder, which is ischemic stroke; (g) kidney disease that is chronic kidney disease, nephritis, or chronic renal failure; or (h) is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof, and optionally, said mammalian species is human; Pharmaceutical compositions.

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