Aryl heterocycles as blockers of Kv1.3 potassium shaker channels

Abstract

JPEG2024512992000177.jpg214143 or a pharma- ceutically acceptable salt thereof, wherein the substituents are as defined herein. Pharmaceutical compositions containing same and methods of using same are also described.

Description

[Technical Field]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 168,056, filed March 30, 2021, the contents of which are incorporated herein by reference in their entirety.

[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 patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.

[0003] (Incorporated 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-dependent 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 can 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 in the resting state. 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 group of disorders resulting from tissue damage caused by attacks from the body's own immune system. These diseases may affect a single organ, such as multiple sclerosis and type 1 diabetes, or multiple organs, such as rheumatoid arthritis and systemic lupus erythematosus. Treatment is generally palliative with anti-inflammatory and immunosuppressive drugs, which can have severe side effects. The need for more effective therapies has led to the search for drugs that can selectively inhibit the function of effector memory T cells, which are known to be involved in the pathogenesis of autoimmune diseases. These inhibitors may ameliorate the symptoms of autoimmune diseases 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. Inhibiting the function of these cells by selectively blocking Kv1.3 channels offers the potential for effective therapy 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 patients' quality of life. MS progresses rapidly and unpredictably, ultimately leading to death. Kv1.3 channels are also highly expressed in autoreactive TEMs from MS patients (Wulff H., et al., 2003, J. Clin. Invest., 1703-1713; Rus H., et al., 2005, PNAS, 11094-11099). Animal models of MS have been successfully treated using blockers of Kv1.3 channels.

[0008] Therefore, compounds that are selective Kv1.3 channel blockers are potential therapeutic agents as immunosuppressants or immune system modulators. Kv1.3 channels are also considered therapeutic targets for the treatment of obesity and for increasing peripheral insulin sensitivity in type 2 diabetes patients. These compounds may also be used to prevent transplant rejection and treat immunological (e.g., autoimmune) and inflammatory disorders.

[0009] Tubulointerstitial fibrosis (TIF), the progressive deposition of connective tissue in the renal parenchyma, leads to a decline in renal function and contributes to pathologies such as chronic kidney disease, chronic renal failure, nephritis, and glomerular inflammation, making it a common cause of end-stage renal failure. Overexpression of Kv1.3 channels in lymphocytes promotes their proliferation, contributing to the underlying pathology of these kidney diseases and leading to chronic inflammation and excessive stimulation of cell-mediated immunity, which contribute to 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] The Kv1.3 channel also plays a role in gastrointestinal disorders, including inflammatory bowel disease (IBD) such as ulcerative colitis ("UC") and Crohn's disease. UC is a chronic IBD characterized by excessive T cell infiltration and cytokine production. UC can impair quality of life and lead to life-threatening complications. High levels of the Kv1.3 channel in CD4 and CD8 positive T cells of the inflamed mucosa in UC patients are associated with the production of pro-inflammatory compounds in active UC. The Kv1.3 channel is thought to function as a marker of disease activity, and pharmacological blockade may constitute a new immunosuppressive strategy in UC. Current treatment regimens for UC, including corticosteroids, salicylates, and anti-TNF-α reagents, are insufficient for many patients (Hansen L.K., et al., 2014, J. Crohns Colitis, 1378-1391). Crohn's disease is a type of IBD that can affect any part of the gastrointestinal tract. Crohn's disease is thought to be the result of intestinal inflammation by a T cell-driven process initiated by normally harmless bacteria. Therefore, inhibition of the Kv1.3 channel can be utilized for the treatment of Crohn's disease.

[0011] In addition to T cells, the Kv1.3 channel is also expressed in microglia, and this channel is involved in the production of inflammatory cytokines and nitric oxide, and microglia-mediated neuron killing. In humans, microglia in the prefrontal cortex of Alzheimer's disease patients and CD68 of brain lesions in MS +Strong Kv1.3 channel expression is observed in activated microglia in infarcted rodent and human brains. Higher Kv1.3 channel current density is observed in microglia acutely isolated 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 microglial target relevant to Alzheimer's disease pathology (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 proinflammatory microglial 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 may 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 the pathology of cardiovascular disorders such as ischemic stroke, in which activated microglia significantly contribute to the secondary expansion of the infarct.

[0014] Expression of Kv1.3 channels is associated with the regulation of proliferation, apoptosis, and cell survival in multiple cell types. These processes are important 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] Many peptide toxins with multiple disulfide bonds from spiders, scorpions, and sea anemones are known to block Kv1.3 channels. Several selective and potent peptide inhibitors of Kv1.3 channels have been developed. A synthetic derivative of Stychodactyla 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 undergoing phase I clinical trials for the treatment of psoriasis. Shk can inhibit the proliferation of TEMs, thereby improving the condition 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 administration events. Therefore, the development of long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases is necessary.

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

[0017] In one aspect,

[0018] [ka] The compounds of formula I, I', II, II', III, or IV described herein are useful as potassium channel blockers, having the structure: + ) channels and can be used to treat a variety of conditions. Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and treatment methods have many clinical applications, including as pharmaceutically active agents and methods for treating immunological disorders, CNS disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, renal diseases, or combinations thereof.

[0019] In one aspect, compounds of formula I, I', II, II', III, or IV or pharmaceutically acceptable salts thereof are described:

[0020] [ka]

[0021] [ka] During the ceremony, Each Z is independently OR a and each X1 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; each X2 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; each X3 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; or alternatively, X1 and X2 and the carbon atom to which they are attached together form an optionally substituted 5- or 6-membered aryl; or alternatively, X2 and X3 and the carbon atom to which they are attached, taken together, form an optionally substituted 5- or 6-membered aryl; Each R1 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a and Each R2 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a Or or alternatively, R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or saturated heterocycle; Each R3 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a and Each R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, (CR a R b ) n2 OR a , or (CR a R b ) n2 NR a R b Or or alternatively, two R groups together with the atoms to which they are attached form a 3- to 7-membered optionally substituted cycloalkyl or heterocycle; Each R5 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2R a and each R6 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; each R7 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; or alternatively, R6 and R7 together with the nitrogen atom to which they are attached form a heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, wherein the heterocycle, when valences permit, is selected from alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 optionally substituted by 1 to 4 substituents each independently selected from the group consisting of OR, N(R), (C=O)R, (C=O)N(R), NR(C=O)R, and oxo; Each R9 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b )n2 NR a R b , or SO2R a and R 10 each is independently H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; A1 is aryl or heteroaryl; A2 is aryl or heteroaryl; R 12 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b , (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R 13 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b , (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and Ra and R b Each of which is independently a saturated heterocyclic ring, aryl, or heteroaryl containing 1 to 3 heteroatoms each selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, N, O, and S, or alternatively, R a and R b together with the carbon or nitrogen to which they are attached form a cycloalkyl or heterocyclic ring containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, When applicable, X1, X2, X3, A1, A2, R1, R2, R3, R4, R5, R6, R7, R9, R 10 , R 12 , R 13 , R a , or R b The alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl in are each independently optionally substituted by 1 to 4 substituents each selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, Each of R8 is independently H, alkyl, or an optionally substituted heterocyclic ring, or alternatively, two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, Each of m is independently 1, 2, or 3, Each of n1 is independently an integer from 0 to 3 when the valence permits, Each of n2 is independently an integer from 0 to 3, n4 is an integer from 0 to 3, n5 is an integer from 0 to 3.

[0022] In any one of the embodiments described in this specification, each of R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, (CR a R b ) n2 NR a R b , or (CR a R b ) n2 OR a , and each of R5 is independently H, alkyl, cycloalkyl, or saturated heterocycle.

[0023] In any one of the embodiments described in this specification, each of m is independently 2 or 3.

[0024] In any one of the embodiments described in this specification, one or more occurrences of m are 1.

[0025] In any one of the embodiments described in this specification, the compound has a structure of formula Ia, Ia’, IIa, IIa’, IIIa, or IVa:

[0026]

Chemical formula

[0027]

Chemical formula

[0028] In any one of the embodiments described in this specification, the compound has a structure of formula Ib, Ib’, IIb, IIb’, IIIb, or IVb:

[0029]

Chemical formula

[0030]

Chemical formula

[0031] In any one of the embodiments described herein, one or more occurrences of R4 may be H, alkyl, cycloalkyl, or OR. a is.

[0032] In any one of the embodiments described herein, one or more occurrences of R4 is H or alkyl.

[0033] In any one of the embodiments described herein, one or more occurrences of R4 is H or CH3.

[0034] In any one of the embodiments described herein, one or more occurrences of R4 may be a saturated heterocycle, (CR a R b ) n2 OR a or (CR a R b ) n2 NR a R b is.

[0035] In any one of the embodiments described herein, one or more occurrences of n1 is 1.

[0036] In any one of the embodiments described herein, one or more occurrences of n1 is 0.

[0037] In any one of the embodiments described herein, each R5 is independently H, alkyl, cycloalkyl, or saturated heterocycle.

[0038] In any one of the embodiments described herein, each R5 is independently cycloalkyl or saturated heterocycle.

[0039] In any one of the embodiments described herein, each R5 is independently H or alkyl.

[0040] In any one of the embodiments described in this specification, each of R5 is independently H or CH3.

[0041] In any one of the embodiments described in this specification, each of R1 and R2 is independently cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3, OR a SR a halogen, NR a R b or NR b (C=O)R a is.

[0042] In any one of the embodiments described in this specification, each of R1 and R2 is independently H, alkyl optionally substituted with OR8, halogen, cycloalkyl, or fluorinated alkyl.

[0043] In any one of the embodiments described in this specification, each of R1 and R2 is independently H, CH3, CH2CH3, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, or

[0044]

Chemical formula

[0045] In any one of the embodiments described in this specification, R1 and R2 are H and H, H and Me, Me and Me, H and Et, Me and Et, or Et and Et, H and CH2OH, H and CH2CH2OH, H and CH2OCH3, H and CH2CH2OCH3, or H and

[0046]

Chemical formula

[0047] In any one of the embodiments described herein, the structural moiety -(CR1R2) m each independently represents -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH2OH)-, -CH(CH2OCH3)-, -CH2-CH2-, -CH(CH3)-CH2-, -CH2-C(CH3)2-,

[0048] [ka] is selected from the group consisting of:

[0049] In any one of the embodiments described herein, each of R and R is independently H, alkyl, cycloalkyl, or heterocycle, and alkyl, cycloalkyl, and heterocycle are selected from halogen, CN, OH, OMe, —(CH) 1-2 OMe, and -(CH2) 1-2 Optionally substituted with 1 to 2 substituents each independently selected from the group consisting of OH.

[0050] In any one of the embodiments described herein, each of R6 and R7 is independently H or alkyl, wherein the alkyl is optionally substituted with 1 to 2 substituents each independently selected from the group consisting of halogen, CN, and OH.

[0051] In any one of the embodiments described herein, each of R6 and R7 is independently H, -CH3, -CH2OH, -CH2CH2OH, or -CH2CH2CH2OH.

[0052] In any one of the embodiments described herein, R and R together with the nitrogen atom to which they are attached form a heterocycle containing a nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S, and the heterocycle may, where valences permit, be alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR, —(CH)0-2 Optionally substituted with 1 to 4 substituents each independently selected from the group consisting of OR, N(R), (C=O)N(R), (C=O)R, NR(C=O)R, and oxo.

[0053] In any one of the embodiments described herein, R and R together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle, the heterocycle being selected from the group consisting of alkyl, alkyl halide, halogen, CN, OH, and —(CH) 1-2 Optionally substituted with 1 to 2 substituents each independently selected from the group consisting of OH.

[0054] In any one of the embodiments described herein, the 4-, 5-, or 6-membered heterocycle is azetidine, pyrrolidine, piperidine, or piperazine.

[0055] In any one of the embodiments described herein, the 4-, 5-, or 6-membered heterocycle is selected from the group consisting of OH and —(CH) 1-2 OH.

[0056] In any one of the embodiments described herein, R6 and R7 together with the nitrogen atom to which they are attached form an azetidine.

[0057] In any one of the embodiments described herein, R6 and R7 together with the nitrogen atom to which they are attached form a pyrrolidine.

[0058] In any one of the embodiments described herein, each of R6 and R7 is independently alkylaryl or alkylheteroaryl.

[0059] In any one of the embodiments described herein, the structural moiety

[0060] [ka] Each of them is independently

[0061]

Chemical formula

[0062] In any one of the embodiments described herein, each of R9 is independently cycloalkyl, saturated heterocyclic ring, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.

[0063] In any one of the embodiments described herein, each of R9 is independently (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , (C=O)NR a R b , or SO2R a .

[0064] In any one of the embodiments described herein, each of R9 is independently H or alkyl.

[0065] In any one of the embodiments described herein, each of R9 is independently H or CH3.

[0066] In any one of the embodiments described herein, each of R 10 is independently H, alkyl, cycloalkyl, or heterocyclic ring, and the alkyl, cycloalkyl, heterocyclic ring is optionally substituted by 1 to 2 substituents each independently selected from the group consisting of halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 OH.

[0067] In any one of the embodiments described herein, R 10 One or more occurrences of is alkyl, which is optionally substituted with 1 to 2 substituents each independently selected from the group consisting of halogen, CN, and OH.

[0068] In any one of the embodiments described herein, R 10 is independently H, —CH 3 , —CH 2 OH, or —CH 2 CH 2 OH.

[0069] In any one of the embodiments described herein, A1 is a 5- or 6-membered aryl or heteroaryl.

[0070] In any one of the embodiments described herein, A1 is

[0071] [ka] is selected from the group consisting of:

[0072] In any one of the embodiments described herein, A1 is

[0073] [ka]

[0074] [ka] is selected from the group consisting of:

[0075] In any one of the embodiments described herein, A1 is

[0076] [ka] is.

[0077] In any one of the embodiments described herein, R 12 Each of is independently H, halogen, fluorinated alkyl, or alkyl.

[0078] In any one of the embodiments described herein, R 12 One or more occurrences of is H.

[0079] In any one of the embodiments described herein, A2 is a 5- or 6-membered aryl or heteroaryl.

[0080] In any one of the embodiments described herein, A2 is

[0081] [ka] is selected from the group consisting of:

[0082] In any one of the embodiments described herein, A2 is

[0083] [ka] is selected from the group consisting of:

[0084] In any one of the embodiments described herein, A2 is

[0085] [ka] is.

[0086] In any one of the embodiments described herein, R 13 Each of is independently H, halogen, fluorinated alkyl, or alkyl.

[0087] In any one of the embodiments described in this specification, one or more occurrences of R 13 are H.

[0088] In any one of the embodiments described in this specification, each of Z is independently OH or O(C1-C4 alkyl).

[0089] In any one of the embodiments described in this specification, each of Z is independently OMe, OEt, or OH.

[0090] In any one of the embodiments described in this specification, one or more occurrences of Z are OH.

[0091] In any one of the embodiments described in this specification, each of X1 is independently H, halogen, fluorinated alkyl, or alkyl.

[0092] In any one of the embodiments described in this specification, each of X1 is independently H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0093] In any one of the embodiments described in this specification, one or more occurrences of X1 are H.

[0094] In any one of the embodiments described in this specification, each of X2 is independently H, halogen, fluorinated alkyl, or alkyl.

[0095] In any one of the embodiments described in this specification, each of X2 is independently H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0096] In any one of the embodiments described in this specification, one or more occurrences of X2 are Cl.

[0097] In any one of the embodiments described herein, each of X3 is independently H, a halogen, a fluorinated alkyl, or an alkyl.

[0098] In any one of the embodiments described herein, each of X3 is independently H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0099] In any one of the embodiments described herein, one or more occurrences of X3 are Cl.

[0100] In any one of the embodiments described herein, each of R3 is independently H, an alkyl, CF3, OR a , SR a , a halogen, NR a R b , or NR b (C=O)R a is.

[0101] In any one of the embodiments described herein, each of R3 is independently H, a halogen, a fluorinated alkyl, or an alkyl.

[0102] In any one of the embodiments described herein, one or more occurrences of R3 are H.

[0103] In any one of the embodiments described herein, the structural moiety

[0104]

Chem.

[0105]

Chem.

[0106] In any one of the embodiments described herein, the structural moiety

[0107] [ka] At least one occurrence of

[0108] [ka] It has the following structure.

[0109] In any one of the embodiments described herein, the compound has formula Ic, Ic', Id, Id', IIc, IIc', IId, IId', IIIc, IIId, IVc, or IVd:

[0110] [ka]

[0111] [ka] having the structure In the formula, R 11 are independently H, halogen, or alkyl, and each n3 is independently an integer of 0 to 3.

[0112] In any one of the embodiments described herein, each n3 is independently 0, 1, or 2.

[0113] In any one of the embodiments described herein, R 11 Each of is independently H or alkyl.

[0114] In any one of the embodiments described herein, R 11 At least one occurrence of is a halogen.

[0115] In any one of the embodiments described herein, at least one occurrence of Z is selected from the group consisting of OR a is.

[0116] In any one of the embodiments described herein, at least one occurrence of Z is OH, OMe, or OEt.

[0117] In any one of the embodiments described herein, at least one occurrence of Z is OH.

[0118] 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.

[0119] 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

[0120] [ka]

[0121] [ka] and the heterocycle, when valence allows, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1-4 Optionally substituted with alkyl.

[0122] In any one of the embodiments described herein, R a or R b At least one occurrence of is H, Me, or

[0123] [ka] is.

[0124] 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 a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0125] In any one of the embodiments described herein, each R8 is independently H, alkyl, or a heterocycle optionally substituted with alkyl, halogen, or OH.

[0126] In any one of the embodiments described herein, each R8 is independently H or alkyl.

[0127] In any one of the embodiments described herein, each R8 is independently H or Me.

[0128] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 31-79 shown in Table 7.

[0129] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 1 to 15 shown in Table 1, compounds 16 to 20 shown in Table 2, compounds 1a to 15a shown in Table 3, compounds 16a to 30a shown in Table 4, compounds 1b to 15b shown in Table 5, and compounds 16b to 30b shown in Table 6.

[0130] In another aspect, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0131] In yet another aspect, a method of treating a condition 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, or a pharmaceutical composition 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.

[0132] In any one of the embodiments described herein, the immunological disorder is transplant rejection or an autoimmune disease.

[0133] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0134] In any one of the embodiments described herein, the central nervous system (CNS) disorder is Alzheimer's disease.

[0135] In any one of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or inflammatory neuropathy.

[0136] In any one of the embodiments described herein, the gastroenterological disorder is inflammatory bowel disease.

[0137] In any one of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0138] In any one of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0139] In any one of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0140] 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, periodontal disease, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0141] In any one of the embodiments described herein, the mammalian species is human.

[0142] In yet another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, the method 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, or a pharmaceutical composition thereof.

[0143] In any one of the embodiments described herein, the mammalian species is human.

[0144] Any one of the embodiments disclosed herein may be suitably 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. Specifically, the selection of one or more embodiments for one substituent may be suitably combined with the selection of one or more specific embodiments for any other substituent. Such combinations may be made in any one or more embodiments of the applications described herein or any formulas described herein. DETAILED DESCRIPTION OF THE INVENTION

[0145] definition The following are definitions of terms used herein. The initial definition provided for a group or term in this specification applies to that group or term throughout the specification, individually or as part of another group, unless otherwise specified. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0146] The terms "alkyl" and "alk" refer to a straight- or branched-chain alkane (hydrocarbon) radical containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutylpentyl, 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 a straight- or branched-chain alkane (hydrocarbon) radical containing 1 to 4 carbon atoms, e.g., 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, in the latter case forming, for example, an alkyl group with a group 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 , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e (R a Each of which is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, and R b , R c , and R d Each of which is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or the above R b and R c Together with the N to which they are attached, optionally form a heterocycle, and R e Each of which is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may be optionally substituted themselves.

[0147] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon radical having 2 to 12 carbon atoms and at least one carbon-carbon double bond. Examples of such groups include ethenyl or allyl. The term "C2-C6 alkenyl" refers to a straight-chain or branched-chain hydrocarbon radical containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as, for example, ethenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl-(E)-but-2-enyl, 2-methyl-(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, 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., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b , S(=O)2R e , NR b , P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)ORd , 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 (R a are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or any of the R 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. The exemplary substituents may themselves be optionally substituted.

[0148] The term "alkynyl" refers to a straight- or branched-chain hydrocarbon radical 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 radical 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, in the latter case forming, for example, an alkyl group with a group such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re, S(=0)2Re, P(=0)2Re, S(=0)2ORe, P(=0)2ORe, NRbRc, N RbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or any of the R b and R c optionally form a heterocycle together with the N to which they are attached, and R eEach of which is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted.

[0149] 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 at any available attachment point with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or an alkyl group having CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re (each of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, and R b , R c , and R d each of which is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or the above R b and R c together with the N to which they are attached optionally form a heterocycle, and 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, where the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0150] 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 attachment point. 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, in the latter case forming, for example, a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re, S(=0)2Re, P(=0)2Re, S(=0)2ORe, P(=0)2ORe, NRbRc, N RbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R dare independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or any of the R 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. 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, where the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0151] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two or more aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be bonded 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, in the latter case forming, for example, an alkyl group with a group such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re, S(=0)2Re, P(=0)2Re, S(=0)2ORe, P(=0)2ORe, NRbRc, N RbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or any of the R b and R c optionally form a heterocycle together with the N to which they are attached, and R eis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused ring groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0152] 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 rings is used to specify the size of the aryl or heteroaryl ring in a substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is bonded to a 6-membered aryl group. Other combinations and ring sizes can be similarly specified.

[0153] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, in particular a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocycle group substituted at any available bond with one or more substituents, preferably 1 to 4 substituents. Examples of substituents include, but are not limited to, the substituents described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include a spiro bond or a fused cyclic substituent at any available bond, in particular a spiro-bonded cycloalkyl, spiro-bonded cycloalkenyl, spiro-bonded heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0154] The terms "heterocycle" and "heterocyclic" refer to fully saturated, partially, or fully unsaturated, including aromatic (i.e., "heteroaryl") cyclic groups (e.g., 3- to 7-membered, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic systems) that have at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heterocyclic group may independently be saturated, or partially or fully unsaturated. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms; the nitrogen and sulfur heteroatoms may optionally be oxidized; and the nitrogen heteroatom may optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group having a quaternary nitrogen atom and therefore a positive charge. The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuran ... tetrahydrofuryl, thienyl, oxazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 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, benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (e.g., furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl, etc.), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0155] "Replacement complex ring" and "replacement complex ring formula" (such as "replacement heteroaryl") refer to a complex ring or a complex ring group substituted with one or more substituents, preferably 1 to 4 substituents, at any available bonding point. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case, forming a group such as CF3 or an alkyl group having CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re (each of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, and R b , R c , and R d are each independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or the above R b and R c together with the N to which they are attached optionally form a heterocycle, and 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, and the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0156] The term "oxo"

[0157] [ka] The term "oxo" refers to a substituent, which may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring. When the oxo substituent is attached to a carbon ring atom of an aromatic group, such as an aryl or heteroaryl, the bonds on the aromatic ring may be rearranged to meet valence requirements. For example, a pyridine with a 2-oxo substituent is

[0158] [ka] which may also have the structure

[0159] [ka] This also includes tautomeric forms of:

[0160] 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.

[0161] 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 in a dialkylamino moiety. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure 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.

[0162] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0163] 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 bond point, provided the valence allows. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or an alkyl group having CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re (each of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, and R b , R c , and R d are each independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or R b and R c together with the N to which they are attached optionally form a heterocycle, and R eEach of them is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In the foregoing exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl 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 above substituents.

[0164] Unless otherwise specified, a heteroatom with an unsatisfied valence is considered to not have enough hydrogen atoms to satisfy the valence.

[0165] The compounds of the present invention can form salts that are also within the scope of the present invention. References to the compounds of the present invention are understood to include references to their salts unless otherwise indicated. As used herein, the term "salt" means acidic and / or basic salts formed with inorganic and / or organic acids and bases. Further, when the compounds of the present invention contain both a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety such as, but not limited to, phenol or carboxylic acid, zwitterions ("inner salts") can be formed and are included within the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, but other salts may also be useful, for example, in isolation or purification steps that may be used during preparation. The salts of the compounds of the present invention can be formed, for example, by reacting the compounds described herein with an amount of an acid or base, such as an equivalent, in a medium in which the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0166] The compounds of the present invention containing a basic moiety such as, but not limited to, an amine, pyridine or imidazole ring can form salts with various organic and inorganic acids. Exemplary acid addition salts include acetate (such as those formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (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 those formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, etc.

[0167] The compounds of the present invention containing an acidic moiety such as, but not limited to, phenol or carboxylic acid can form salts with various organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts 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. The basic nitrogen-containing group is quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides), aralkyl halides (e.g., benzyl and phenethyl bromides) and others.

[0168] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. As used herein, the term "prodrug" means a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to produce a compound of the present invention, or a salt and / or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0169] The compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric forms (e.g., as amides or iminoethers). All such tautomeric forms are contemplated herein as part of the present invention. When used herein, any depicted structure of a compound includes its tautomeric forms.

[0170] All stereoisomers of the compounds of the invention, including enantiomeric and diastereomeric forms (e.g., those that may exist due to chiral carbons on various substituents), are contemplated to be within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be, for example, in racemic form, or mixed with all or other selected stereoisomers. The chiral centers of the invention may have an 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 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 salt formation with an optically active acid followed by crystallization.

[0171] Following their preparation, the compounds of the invention are preferably isolated and purified to give a composition containing 90% by weight or more, such as 95% by weight or more, 99% by weight or more of the compound. (A "substantially pure" compound), and then used or formulated as described herein. Such "substantially pure" compounds of the invention are also contemplated herein as part of the invention.

[0172] All configurational isomers of the compounds of the invention are considered to be either in mixture or in pure or substantially pure form. The definition of the compounds of the invention includes both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbons or heterocycles.

[0173] Throughout this specification, groups and their substituents can be selected to provide stable moieties and compounds.

[0174] The definitions of certain functional groups and chemical terms are described in more detail herein. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., back cover, and certain functional groups are generally defined herein below. Further, general principles of organic chemistry, and specific functional group moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito (1999), the entire content of which is incorporated herein by reference.

[0175] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds including cis and trans isomers, R and S enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof, which are 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 within the present invention.

[0176] Isomer mixtures containing any of a variety of isomer ratios can be utilized in accordance with the present invention. For example, if only two isomers are combined, 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. One of ordinary skill in the art will readily understand that similar ratios are contemplated for more complex isomer mixtures.

[0177] The present invention also includes isotopically labeled compounds that are identical to the compounds disclosed herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include, respectively,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 and other isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine are included. Compounds of the present invention, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, 3 H and 14 C and other compounds incorporated with radioactive isotopes are useful in drug and / or substrate tissue distribution assays. Tritium labeling, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H can provide certain therapeutic benefits due to increased metabolic stability, e.g., increased in vivo half-life or decreased required dosage, and may therefore be preferred in some situations. Isotopically labeled compounds can generally be prepared by replacing readily available non-isotopically labeled reagents with isotopically labeled reagents and performing the procedures disclosed in the following schemes and / or examples.

[0178] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary group 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 formed diastereomers by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0179] It will be 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 the substituents contained in the formulae of the present invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be either 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 sense, 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 organic compound substituents described herein that satisfy the valence of the heteroatom. Furthermore, this invention is not intended to be limited in any manner by the permissible organic compound substituents. 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. The term "stable" as used herein preferably refers to a compound that is stable enough to allow for manufacture and maintains the integrity of the compound for a period of time sufficient to be detected, preferably for a period of time sufficient to be useful for the purposes detailed herein.

[0180] 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. Diseases other than cancer may be associated with mutational alterations in components of the Ras signaling pathway, and the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases may include neurofibromatosis, Leopard syndrome, Noonan syndrome, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, hereditary gingival fibromatosis type 1, autoimmune lymphoproliferative syndrome, and capillary malformation-arteriovenous malformation.

[0181] As used herein, "effective amount" refers to any amount necessary or sufficient to achieve or promote a desired result. In some cases, an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.

[0182] 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.

[0183] 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 a desirable cardiovascular safety profile.

[0184] In one aspect, compounds of formula I, I', II, II', III, or IV, or pharmaceutically acceptable salts thereof, are described:

[0185] [ka]

[0186] [ka] During the ceremony, Each Z is independently OR a and each X1 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; each X2 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; each X3 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; Alternatively, X1 and X2 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl, or alternatively, X2 and X3 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl, each of R1 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3, OR a SR a halogen, NR a R b or NR b (C=O)R a and each of R2 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3, OR a SR a halogen, NR a R b or NR b (C=O)R a or alternatively, R1 and R2 together with the carbon atom to which they are attached form cycloalkyl or a saturated heterocycle, each of R3 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, CN, CF3, OCF3, OR a SR a halogen, NR a R b or NR b (C=O)R a and each of R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, halogen, CN, CF3, OR a (CR a R b ) n2 OR a oxo, (C=O)R a, O(C=O)R a , (C=O)OR a , or (CR a R b ) n2 NR a R b is, alternatively, two R4 groups, together with the atoms to which they are attached, form a 3- to 7-membered optionally substituted cycloalkyl or heterocyclic ring, each of R5 is independently H, alkyl, cycloalkyl, saturated heterocyclic ring, aryl, heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2R a is, each of R6 is independently H, alkyl, cycloalkyl, heterocyclic ring, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of R7 is independently H, alkyl, cycloalkyl, heterocyclic ring, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, or alternatively, R6 and R7, together with the nitrogen atom to which they are attached, form a heterocyclic ring containing the nitrogen atom and 0 to 3 additional heteroatoms each independently selected from the group consisting of N, O, and S, and the heterocyclic ring is optionally substituted by 1 to 4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, Each R9 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2R a and R 10 each is independently H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; A1 is aryl or heteroaryl; A2 is aryl or heteroaryl; R 12 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogens, (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R 13 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogens, (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NRa R b , or (CR a R b ) n2 NR b (C=O)R a and R a and R b each independently is H, alkyl, alkenyl, cycloalkyl, saturated heterocycle containing 1 to 3 heteroatoms each selected from the group consisting of N, O, and S, aryl, or heteroaryl, or alternatively, R a and R b together with the carbon or nitrogen to which they are attached form a cycloalkyl or heterocyclic ring containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; X1, X2, X3, A1, A2, R1, R2, R3, R4, R5, R6, R7, R9, R, if applicable 10 , R 12 , R 13 , R a , or R b The alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in the formula (I) are, when valences permit, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR, -(CH) 0-2 optionally substituted by 1 to 4 substituents each independently selected from the group consisting of OR, N(R), (C=O)R, (C=O)N(R), NR(C=O)R, and oxo; each R is independently H, alkyl, or an optionally substituted heterocycle, or alternatively, two R 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; each m is independently 0, 1, 2, or 3; each n1 independently, where valence allows, is an integer from 0 to 3; Each n2 is independently an integer of 0 to 3; n4 is an integer from 0 to 3, n5 is an integer from 0 to 3.

[0187] In another aspect, a compound of formula I, I', II, II', III, or IV, or a pharmaceutically acceptable salt thereof is described,

[0188] [Chemical formula]

[0189] [Chemical formula] wherein, each of Z is independently OR a and each of X1 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl, each of X2 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl, each of X3 is independently H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl, or alternatively, X1 and X2 and the carbon atom to which they are attached together form an optionally substituted 5- or 6-membered aryl, alternatively, X2 and X3 and the carbon atom to which they are attached together form an optionally substituted 5- or 6-membered aryl, each of R1 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3, OR a , SR a , halogen, NR a R b , or NR b (C=O)R a and Each of R2 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3, OR a , SR a , halogen, NR a R b , or NR b (C=O)R a or, alternatively, R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or a saturated heterocycle, Each of R3 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, CN, CF3, OCF3, OR a , SR a , halogen, NR a R b , or NR b (C=O)R a and, Each of R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, (CR a R b ) n2 OR a , or (CR a R b ) n2 NR a R b or, alternatively, two R4 groups together with the atom to which they are attached form a 3- to 7-membered optionally substituted cycloalkyl or heterocycle, Each of R5 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2R a and, Each of R6 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of R7 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, or alternatively, R6 and R7 together with the nitrogen atom to which they are attached form a heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, and the heterocycle is optionally substituted by 1 to 4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, each of R9 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C=O)(CR a R b ), n2 OR a , (C=O)(CR a R b ), n2 NR a R b , or SO2R a , each of R 10 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, A1 is aryl or heteroaryl, A2 is aryl or heteroaryl, each of R 12 is independently H, alkyl, CN, CF3, OCF3, OR a , SR a , halogen, (CR a R b ), n2OR a 、(C=O)NR a R b 、(CR a R b ) n2 NR a R b 、 or (CR a R b ) n2 NR b (C=O)R a and R 13 each is independently H, alkyl, CN, CF3, OCF3, OR a 、 SR a 、 halogen, (CR a R b ) n2 OR a 、(C=O)NR a R b 、(CR a R b ) n2 NR a R b 、 or (CR a R b 0]]) n2 NR b (C=O)R a and R a and R b each is independently H, alkyl, alkenyl, cycloalkyl, a saturated heterocyclic ring containing 1 to 3 heteroatoms each selected from the group consisting of N, O, and S, aryl, or heteroaryl, or alternatively, R a and R b together with the carbon or nitrogen to which they are attached form a cycloalkyl or heterocyclic ring containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, where applicable, X1, X2, X3, A1, A2, R1, R2, R3, R4, R5, R6, R7, R9, R 10 、 R 12 、 R 13 、 R a 、 or R bThe alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl therein are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, and each of R8 is independently H, alkyl, or an optionally substituted heterocycle, or alternatively, two R8 groups 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, each of m is independently 0, 1, 2, or 3, each of n1 is independently an integer from 0 to 3 when the valence permits, each of n2 is independently an integer from 0 to 3, n4 is an integer from 0 to 3, n5 is an integer from 0 to 3.

[0190] In some embodiments, each of R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, (CR a R b ) n2 NR a R b , or (CR a R b ) n2 OR a and each of R5 is independently H, alkyl, cycloalkyl, or a saturated heterocycle.

[0191] In some embodiments, at least one occurrence of m is 0. In some embodiments, each of m is independently an integer from 1 to 3. In some embodiments, each of m is independently 2 or 3. In some embodiments, each of m is independently 1 or 2. In some embodiments, at least one occurrence of m is 1. In some embodiments, at least one occurrence of m is 2. In some embodiments, at least one occurrence of m is 3.

[0192] In some embodiments, the compound has a structure of formula Ia, Ia’, IIa, IIa’, IIIa, or IVa:

[0193]

Chemical formula

[0194]

Chemical formula

[0195] In some embodiments, the compound has a structure of formula Ia:

[0196]

Chemical formula

[0197] In some embodiments, the compound has a structure of formula Ib, Ib’, IIb, IIb’, IIIb, or IVb:

[0198]

Chemical formula

[0199]

Chemical formula

[0200] In some embodiments, the compound has the structure of formula Ib:

[0201]

Chemical formula

[0202] In some embodiments, at least one occurrence of R4 is H, CN, alkyl, cycloalkyl, aryl, heteroaryl, CF3, or OR a is. In some embodiments, at least one occurrence of R4 is halogen, saturated heterocycle, alkylaryl, alkylheteroaryl, (CR a R b ) n2 OR a , oxo, (C=O)R a , O(C=O)R a , (C=O)OR a , or (CR a R b ) n2 NR a R b . In some embodiments, at least one occurrence of R4 is oxo, (C=O)R a O(C=O)R a , or (C=O)OR a . In some embodiments, at least one occurrence of R4 is (CR a R b ) n2 OR aIt is. In some embodiments, at least one occurrence of R4 is H or alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, at least one occurrence of R4 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, at least one occurrence of R4 is halogen. Non-limiting examples of halogen include F, Cl, Br, and I.

[0203] In some embodiments, one or more occurrences of R4 are (CR a R b ) n2 OR a or (CR a R b ) n2 NR a R b It is. In some embodiments, at least one occurrence of R4 is (CR a R b ) n2 NR a R b It is. In some embodiments, one or more occurrences of R4 are OR a , NR a R b , -CH2OR a , -CH2NR a R b , -CH2CH2OR a , or -CH2CH2NR a R b It is.

[0204] In some specific embodiments, at least one occurrence of R4 is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, at least one occurrence of R4 is OH, CH2OH, or CH2NH2.

[0205] In yet other embodiments, at least one occurrence of R4 is a optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S. In further embodiments, at least one occurrence of R4 is a heterocycle selected from the group consisting of

[0206]

Chemical formula

[0207]

Chemical formula

[0208]

Chemical formula

[0209]

Chemical formula

[0210] In some embodiments, each of R4 is independently H, Me, Et, Pr, Bu, or

[0211]

Chemical formula

[0212]

Chemical formula

[0213] [Chemistry] a saturated heterocyclic ring or heteroaryl selected from the group consisting of, and the saturated heterocyclic ring or heteroaryl, when valency permits, is cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1-4 optionally substituted by alkyl.

[0214] In some specific embodiments, at least one occurrence of R4 is H, halogen, alkyl, OR a , NR a R b , or oxo. In other specific embodiments, at least one occurrence of R4 is H, F, Cl, Br, Me, Et, Pr, iso-Pr, Bu, iso-Bu, sec-Bu, or tert-Bu. In other specific embodiments, at least one occurrence of R4 is OH, NH2, NHMe, NMe2, NHEt, NMeEt, NEt2, or oxo. In still other specific embodiments, at least one occurrence of R4 is H, halogen, alkyl, OH, NH2, CN, CF3, or OCF3. In still other specific embodiments, at least one occurrence of R4 is H, Me or Et.

[0215] In a further embodiment, two R4 groups, together with the atoms to which they are attached, form a 3- to 7-membered optionally substituted cycloalkyl or heterocyclic ring.

[0216] In some embodiments, at least one occurrence of n1 is an integer from 0 to 2. In some embodiments, at least one occurrence of n1 is 0 or 1. In some embodiments, at least one occurrence of n1 is 0. In some embodiments, at least one occurrence of n1 is 1.

[0217] In some specific embodiments, at least one occurrence of n1 is 0, and at least one occurrence of R5 is H or alkyl. In some specific embodiments, at least one occurrence of n1 is 1, and at least one occurrence of R5 is H or alkyl.

[0218] In some embodiments, each R5 is independently H, alkyl, cycloalkyl, aryl, heteroaryl, (C=O)R a , (C=O)(CR a R b ), n2 OR a , (C=O)(CR a R b ), n2 NR a R b , or SO2R a . In some embodiments, at least one occurrence of R5 is H, alkyl, or cycloalkyl. In some embodiments, at least one occurrence of R5 is aryl or heteroaryl. In some specific embodiments, at least one occurrence of R5 is (C=O)R a , (C=O)(CR a R b ), n2 OR a , (C=O)(CR a R b ), n2 NR a R b , or SO2R a . In some specific embodiments, at least one occurrence of R5 is (C=O)R a or (C=O)-(CR a R b ), 1-2 -OR a . In some specific embodiments, at least one occurrence of R5 is (C=O)-(CR a R b ), 1-2 -NR a R b or (C=O)NR a R bIt is. In some specific embodiments, at least one occurrence of R5 is (C=O)NR a R b , (C=O)CH2NR a R b , or (C=O)CH2CH2NR a R b It is. In some specific embodiments, at least one occurrence of R5 is H. In other specific embodiments, at least one occurrence of R5 is methyl. In other specific embodiments, at least one occurrence of R5 is ethyl.

[0219] In some embodiments, each of R1 and R2 is independently H, alkyl optionally substituted with OR8, halogen, cycloalkyl, or fluorinated alkyl. In some specific embodiments, each of R1 and R2 is independently H, CH3, CH2CH3, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, or

[0220]

Chemical formula

[0221]

Chemical formula

[0222] [Chemical] is selected from the group consisting of.

[0223] In some embodiments, at least one occurrence of R1 or R2 is independently cycloalkyl, saturated heterocycle, aryl, heteroaryl. In some embodiments, at least one occurrence of R1 or R2 is independently CN, CF3, OCF3, OR a , SR a , NR a R b , or NR b (C=O)R a is.

[0224] In some embodiments, each of R6 and R7 is independently cycloalkyl or heterocycle, and the cycloalkyl or heterocycle is optionally substituted by 1 to 2 substituents independently selected from the group consisting of halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 OH. In some embodiments, each of R6 and R7 is independently H or alkyl, and the alkyl is optionally substituted by 1 to 2 substituents independently selected from the group consisting of halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 OH. In some specific embodiments, each of R6 and R7 is independently H, -CH3, -CH2OH, -CH2CH2OH, or -CH2CH2CH2OH. In some embodiments, each of R6 and R7 is independently alkylaryl or alkylheteroaryl, and the alkylaryl or alkylteteroaryl is optionally substituted by 1 to 2 substituents independently selected from the group consisting of halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 OH.

[0225] In some embodiments, R6 and R7, together with the nitrogen atom to which they are attached, form a heterocyclic ring containing the nitrogen atom and 0 to 3 additional heteroatoms each independently selected from the group consisting of N, O, and S. The heterocyclic ring, when valence permits, is alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, and is optionally substituted by 1 to 4 substituents each independently selected from the group consisting of.

[0226] In some embodiments, R6 and R7, together with the nitrogen atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclic ring. The heterocyclic ring is alkyl, halogenated alkyl, halogen, CN, OH, and -(CH2) 1-2 OH, and is optionally substituted by 1 to 2 substituents each independently selected from the group consisting of. Non-limiting examples of 4-, 5-, or 6-membered heterocyclic rings include azetidine, pyrrolidine, piperidine, and piperazine. In some specific embodiments, the 4-, 5-, or 6-membered heterocyclic ring is OH and -(CH2) 1-2 OH, and is substituted by 1 to 2 substituents each independently selected from the group consisting of. In some specific embodiments, the 4-, 5-, or 6-membered heterocyclic ring is

[0227]

Chemical formula

[0228] In some specific embodiments, R6 and R7, together with the nitrogen atom to which they are attached, form an azetidine optionally substituted by alkyl or OH. In other specific embodiments, R6 and R7, together with the nitrogen atom to which they are attached, form a pyrrolidine optionally substituted by alkyl or OH. In other specific embodiments, R6 and R7, together with the nitrogen atom to which they are attached, form a piperidine optionally substituted by alkyl or OH.

[0229] In certain embodiments, the structural moiety

[0230]

Chemical formula

[0231]

Chemical formula

[0232]

Chemical formula

[0233] In some embodiments, each of R9 is independently cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, at least one occurrence of R9 is (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , (C=O)NR a R b , or SO2R aIt is. In some specific embodiments, at least one occurrence of R9 is H or alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In other specific embodiments, at least one occurrence of R9 is H or CH3.

[0234] In embodiments, at least one occurrence of R 10 is cycloalkyl or heterocycle, and the cycloalkyl or heterocycle is optionally substituted by one or two substituents each independently selected from the group consisting of halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 OH. In some embodiments, at least one occurrence of R 10 is H or alkyl, and the alkyl is optionally substituted by one or two substituents each independently selected from the group consisting of halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 OH. In further embodiments, at least one occurrence of R 10 is alkyl optionally substituted by one or two substituents each independently selected from the group consisting of halogen, CN, and OH. In some specific embodiments, at least one occurrence of R 10 is H, -CH3, -CH2OH, or -CH2CH2OH.

[0235] In some embodiments, A1 is a 5- or 6-membered heteroaryl containing one to three heteroatoms each selected from the group consisting of N, O, and S. In further embodiments, A1 is

[0236]

Chemical formula

[0237]

Chemical formula

[0238] In some embodiments, A1 is an N-containing heteroaryl, and the heteroaryl is alkyl, OH, oxo, or (C=O)C when the valence permits 1-4 Optionally substituted by alkyl. Non-limiting examples of N-containing heteroaryl include

[0239]

Chemical formula

[0240]

Chemical formula

[0241] In some embodiments, A1 is a 5- or 6-membered heteroaryl, or phenyl. In some embodiments, A1 is a 5-membered heteroaryl. A1 is

[0242]

Chemical formula

[0243]

Chemical formula

[0244] In some embodiments, A1 is a bicyclic of 7 to 11 members, or a tricyclic aryl or heteroaryl of 8 to 16 members. Non-limiting examples of the bicyclic or tricyclic ring include biphenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl], or furo[2,3-b]pyridinyl, etc.), carbazolyl, phenanthrolinyl, acridinyl, and phenanthridinyl.

[0245] In some embodiments, A1 is

[0246]

Chemical formula

[0247]

Chemical formula

[0248] In some embodiments, A2 is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms each selected from the group consisting of N, O, and S. In a further embodiment, A2 is

[0249]

Chemical formula

[0250]

Chemical formula

[0251] In some embodiments, A2 is an N-containing heteroaryl, and the heteroaryl is, when valency permits, alkyl, OH, oxo, or (C=O)C 1-4 Optionally substituted by alkyl. Non-limiting examples of N-containing heteroaryl include

[0252]

Chemical formula

[0253]

Chemical formula

[0254]

Chemical formula

[0255] In some embodiments, A2 is a 5- or 6-membered heterocyclic ring, or phenyl. In some embodiments, A2 is a 5-membered heteroaryl. In some embodiments, A2 is

[0256]

Chemical formula

[0257]

Chemical formula

[0258]

Chemical formula

[0259] In some embodiments, A2 is a 7- to 11-membered bicyclic, or an 8- to 16-membered tricyclic aryl or heteroaryl. Non-limiting examples of the bicyclic or tricyclic ring include biphenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl], or furo[2,3-b]pyridinyl, etc.), carbazolyl, phenanthrolinyl, acridinyl, and phenanthridinyl.

[0260] In some embodiments, A2 is

[0261]

Chemical formula

[0262]

Chemical formula

[0263] In some embodiments, each of R 12 is independently H, alkyl, CF3, or halogen. In embodiments, at least one occurrence of R 12 is CN, CF3, OCF3, OR a , or SR a . In some embodiments, at least one occurrence of R 12 is halogen, NR a R b , or NR b (C=O)R a . In some embodiments, at least one occurrence of R 12 is OR a , SR a , or NR a R bis. In some embodiments, R 12 at least one occurrence of is NR b (C=O)R a is. In some embodiments, R 12 at least one occurrence of is (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a is. In some embodiments, R 12 at least one occurrence of is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, R 12 at least one occurrence of is H, fluorinated alkyl, or alkyl. In some embodiments, R 12 at least one occurrence of is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3. In some specific embodiments, R 12 at least one occurrence of is H.

[0264] In some embodiments, each of R 13 is independently H, alkyl, CF3, or halogen. In some embodiments, R 13 at least one occurrence of is CN, CF3, OCF3, OR a , or SR a is. In some embodiments, R 13 at least one occurrence of is halogen, NR a R b , or NR b (C=O)R a is. In some embodiments, R 13 at least one occurrence of is OR a , SRa or NR a R b is. In some embodiments, R 13 at least one occurrence of is NR b (C=O)R a is. In some embodiments, R 12 at least one occurrence of is (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a is. In some embodiments, R 13 at least one occurrence of is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, R 13 at least one occurrence of is H, fluorinated alkyl, or alkyl. In some embodiments, R 13 at least one occurrence of is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3. In some specific embodiments, R 13 at least one occurrence of is H.

[0265] 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.

[0266] In some embodiments, n5 is an integer from 0 to 3. In some embodiments, n5 is an integer from 1 to 3. In some embodiments, n5 is 0. In some embodiments, n5 is 1 or 2. In some embodiments, n5 is 1.

[0267] In some embodiments, at least one occurrence of Z is OR a In some embodiments, at least one occurrence of Z is OH or O-(C1-C4 alkyl). In some embodiments, at least one occurrence of Z is OH, OMe, OEt, OPr, Oi-Pr, OBu, Oi-Bu, Osec-Bu, or Ot-Bu. In some embodiments, at least one occurrence of Z is OH.

[0268] In some embodiments, each of X1 is independently H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, at least one occurrence of X1 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, at least one occurrence of X1 is H or halogen. In other embodiments, at least one occurrence of X1 is fluorinated alkyl or alkyl. In other embodiments, at least one occurrence of X1 is cycloalkyl. In some embodiments, at least one occurrence of X1 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, at least one occurrence of X1 is H, F, or Cl. In some embodiments, at least one occurrence of X1 is F or Cl. In some embodiments, at least one occurrence of X1 is H or Cl. In some embodiments, at least one occurrence of X1 is F. In some embodiments, at least one occurrence of X1 is Cl. In some embodiments, at least one occurrence of X1 is CF3 or CF2H. In some embodiments, at least one occurrence of X1 is CF2Cl. In some embodiments, at least one occurrence of X1 is H.

[0269] In some embodiments, each of X2 is independently H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, at least one occurrence of X2 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, at least one occurrence of X2 is H or halogen. In other embodiments, at least one occurrence of X2 is fluorinated alkyl or alkyl. In other embodiments, at least one occurrence of X2 is cycloalkyl. In some embodiments, at least one occurrence of X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, at least one occurrence of X2 is H, F, or Cl. In some embodiments, at least one occurrence of X2 is F or Cl. In some embodiments, at least one occurrence of X2 is H or Cl. In some embodiments, at least one occurrence of X2 is F. In some embodiments, at least one occurrence of X1 is Cl. In some embodiments, at least one occurrence of X2 is CF3 or CF2H. In some embodiments, at least one occurrence of X2 is CF2Cl. In some embodiments, at least one occurrence of X2 is H.

[0270] In some embodiments, each of X3 is independently H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, at least one occurrence of X3 is H, halogen, alkyl, or halogenated alkyl. In some embodiments, at least one occurrence of X3 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, at least one occurrence of X3 is H or halogen. In other embodiments, at least one occurrence of X3 is fluorinated alkyl or alkyl. In some embodiments, at least one occurrence of X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, at least one occurrence of X3 is H, F, or Cl. In some embodiments, at least one occurrence of X3 is F or Cl. In some embodiments, at least one occurrence of X3 is H or Cl. In some embodiments, at least one occurrence of X3 is F. In some embodiments, at least one occurrence of X1 is Cl. In some embodiments, at least one occurrence of X3 is CF3 or CF2H. In some embodiments, at least one occurrence of X3 is CF2Cl. In some embodiments, at least one occurrence of X3 is H.

[0271] In embodiments, at least one occurrence of R3 is H, alkyl, CF3, or halogen. In embodiments, at least one occurrence of R3 is cycloalkyl or saturated heterocycle. In embodiments, at least one occurrence of R3 is aryl or heteroaryl. In embodiments, at least one occurrence of R3 is CN, CF3, OCF3, OR a , or SR a . In embodiments, at least one occurrence of R3 is halogen, NR a R b , or NR b (C=O)R ais. In some embodiments, at least one occurrence of R3 is OR a , SR a , or NR a R b . In some embodiments, at least one occurrence of R3 is NR b (C=O)R a . In some embodiments, at least one occurrence of R3 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, at least one occurrence of R3 is H, fluorinated alkyl, or alkyl. In some embodiments, at least one occurrence of R3 is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3. In some particular embodiments, at least one occurrence of R3 is H.

[0272] In some embodiments, the structural moiety

[0273]

Chemical formula

[0274]

Chemical formula

[0275]

Chemical formula

[0276] In some embodiments, the structural moiety

[0277]

Chemical formula

[0278]

Chemical formula

[0279] In some embodiments, the compounds of Formula I, I', II, II', III, or IV are of Formula Ic, Ic', Id, Id', IIc, IIc', IId, IId', IIIc, IIId, IVc, or IVd:

[0280]

Chem.

[0281]

Chem.

[0282]

Chem.

[0283] In some embodiments, each of n3 is independently an integer from 0 to 3. In some embodiments, at least one occurrence of n3 is an integer from 1 to 3. In some embodiments, at least one occurrence of n3 is 0. In some embodiments, at least one occurrence of n3 is 1 or 2. In some embodiments, at least one occurrence of n3 is 1.

[0284] In some embodiments, each of R 11 is independently H, halogen, fluorinated alkyl, or alkyl. In some embodiments, at least one occurrence of R 11 is H or halogen. In some embodiments, at least one occurrence of R 11At least one occurrence of is alkyl or fluorinated alkyl. In some embodiments, R 11 At least one occurrence of is H, Cl, Br, CF3, CHF2, or Me. In some embodiments, R 11 At least one occurrence of is H.

[0285] In some embodiments, R a or R b At least one occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. In some embodiments, R a or R b At least one occurrence of is independently H, alkyl, or alkenyl. In some embodiments, R a or R b At least one occurrence of is independently H, Me, Et, Pr, or Bu. In some embodiments, R a or R b At least one occurrence of is independently

[0286]

Chemical formula

[0287]

Chemical formula

[0288]

Chemical formula

[0289] In some embodiments, R a and R b together with the carbon atom to which they are attached, when the valence allows, are alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, and are each independently selected from the group consisting of 1 to 4 substituents which may be substituted by cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R a and R b together with the nitrogen atom to which they are attached, are a nitrogen atom, and when the valence allows, are alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, and are each independently selected from the group consisting of 1 to 4 substituents which may be substituted by a substituted heterocyclic ring containing 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S. Non-limiting examples of the heterocyclic ring include

[0290]

Chemical formula

[0291]

Chemical formula

[0292] In some embodiments, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in X1, X2, and X3 are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, when the valence permits. In some embodiments, aryl and heteroaryl in A1 and A2 are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, when the valence permits. In some embodiments, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R1 and R2 are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, when the valence permits. In some embodiments, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R3 are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, when the valence permits. In some embodiments, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R4 are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2Optionally substituted by 1 to 4 substituents each independently selected from the group consisting of OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo. In some embodiments, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R5, when valency permits, are alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 Optionally substituted by 1 to 4 substituents each independently selected from the group consisting of OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo. In some embodiments, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R6 and R7, when valency permits, are alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 Optionally substituted by 1 to 4 substituents each independently selected from the group consisting of OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo. In some embodiments, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R9, when valency permits, are alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 Optionally substituted by 1 to 4 substituents each independently selected from the group consisting of OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo. In some embodiments, R 10 The alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in, when valency permits, are alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 Optionally substituted by 1 to 4 substituents each independently selected from the group consisting of OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo. In some embodiments, R12 and R 13 The alkyl in is optionally substituted by 1 to 4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo. In some embodiments, R a and R b The alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in are optionally substituted by 1 to 4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo.

[0293] In some embodiments, each of the R8s is independently H, alkyl, or a heterocycle optionally substituted by alkyl, OH, or alkoxy. In some embodiments, each of the R8s is independently H or alkyl. In some embodiments, each of the R8s is a substituted heterocycle. In some embodiments, two R8 groups together with the nitrogen atom to which they are attached form a substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S. In some particular embodiments, each of the R8s is independently H or Me.

[0294] In some embodiments, the compound of formula I is selected from the group consisting of Compounds 1 to 15 shown in Table 1 below. In some embodiments, the compound of formula I' is selected from the group consisting of Compounds 16 to 30 shown in Table 2 below. In some embodiments, the compound of formula II is selected from the group consisting of Compounds 1a to 15a shown in Table 3 below. In some embodiments, the compound of formula II' is selected from the group consisting of Compounds 16a to 30a shown in Table 4 below. In some embodiments, the compound of formula III is selected from the group consisting of Compounds 1b to 15b shown in Table 5 below. In some embodiments, the compound of formula IV is selected from the group consisting of Compounds 16b to 30b shown in Table 6 below. The compounds listed in Tables 1 to 6 are representative and non-limiting compounds of the embodiments disclosed herein.

[0295]

Table 1-1

[0296]

Table 1-2

[0297]

Table 2-1

[0298]

Table 2-2

[0299]

Table 3-1

[0300]

Table 3-2

[0301]

Table 4-1

[0302]

Table 4-2

[0303]

Table 5-1

[0304]

Table 5-2

[0305]

Table 6-1

[0306]

Table 6-2

[0307] Abbreviations

[0308]

Table 7

[0309] Modulation method The following is the general synthetic scheme for producing the compounds of the present invention. These schemes are illustrative and are not meant to limit the possible techniques available to those skilled in the art for producing the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Further, the various steps in the synthesis can be carried out in an alternating order or sequence to obtain the desired compounds. All documents cited herein are hereby incorporated by reference in their entirety. For example, the following reactions are illustrative and do not limit the preparation of some of the starting materials and compounds disclosed herein.

[0310] The following Schemes 1-3 describe synthetic routes that can be used for the synthesis of the compounds of the present invention, for example, compounds having the structures of Formula I, I', II, II', III, or IV, or precursors thereof. Various modifications to these methods can be envisioned by those skilled in the art to achieve results similar to those of the present invention as shown below. In the following embodiments, the synthetic routes are described using, by way of example, compounds having the structures of Formula I, I', II, II', III, or IV, or precursors thereof. The general synthetic routes described in Schemes 1-3 and the examples described in the following Examples section illustrate the methods used for the preparation of the compounds described herein.

[0311] The compound I-1 shown in Scheme 1 can be prepared by any method known in the art and / or is commercially available. As shown in Scheme 1, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and other protecting groups known in the art suitable for use as protecting groups for OH or amine groups. Other substituents are defined herein. Benzaldehyde I-1 can be reacted with (S)-t-butylsulfinamide in the presence of a Lewis acid such as titanium tetraisopropoxide to obtain sulfinylimine I-2S. The Reformatsky reaction of I-2S with methyl 2-bromomethylacrylate and zinc gives I-3 having the R configuration at the benzylamine position. The sulfinamide is then removed by treatment with dilute acid to obtain amine I-4, which is reprotected as toluenesulfonamide I-5 under standard conditions. Reacting I-5 with a base such as sodium hydride in a polar aprotic solvent such as DMF and heating, for example, at 100 °C gives pyrrolidine ester I-6 as a mixture of epimers at the ester position. The tosyl group is removed by treatment with magnesium metal in methanol to obtain I-7. Amine I-7 is reprotected, for example, with a Boc group and the ester is hydrolyzed to form I-8. I-8 is converted to an amide by reaction with a suitable amine R6R7NH and a coupling reagent such as HATU, and all protecting groups are removed under standard conditions to obtain pyrrolidine amide I-9.

[0312] [Chemical formula] The compound I-10 shown in Scheme 2 can be prepared by any method known in the art and / or is commercially available. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and other protecting groups known in the art suitable for use as protecting groups for OH. The other substituents shown in Scheme 2 are defined herein. As shown in Scheme 2, compound I-10 is deprotonated using a base such as n-butyllithium and reacted with 1-t-butyl 2-ethyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate to form ketone I-11. Alternatively, a phenol having a halogen such as iodine or bromine adjacent to the phenol can be used and metallated by metal-halogen exchange using an agent such as an organolithium reagent such as isopropylmagnesium chloride / lithium chloride (Turbo Grignard) or n-butyllithium. Removal of the Boc group using TFA results in cyclization to imine I-12. Reduction of the imine to pyrrolidine can be carried out by various methods including catalytic hydrogenation on a catalyst such as platinum oxide in a solvent such as ethyl acetate or using sodium borohydride to obtain pyrrolidine I-13 as the cis isomer. The pyrrolidine nitrogen is then protected with a protecting group such as Boc to obtain I-14.

[0313] [Chemical Structure]

[0314] Compound I-2R shown in Scheme 3 can be prepared by any method known in the art and / or is commercially available. As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and other protecting groups known in the art suitable for use as protecting groups for OH or amine groups. Other substituents shown in Scheme 3 are defined herein. For the compounds of formula I disclosed herein where R2 is H and m is 1, a pyrrolidine ring having an extended chain at C4 (see compound I-15 labeled at the 4-position) can be obtained by the synthesis described in Scheme 3. As shown in Scheme 3, benzenesulfinylimine I-2R undergoes an addition cyclization with trimethylenemethane precursor 2-((trimethylsilyl)methyl)-prop-2-enyl acetate in a solvent such as THF in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium to give 2R-phenylpyrrolidine I-15. One way to introduce a side chain at C4 is by cross-metathesis with methyl acrylate and Grubbs second-generation catalyst to form unsaturated ester I-16. I-16 is hydrogenated on a catalyst such as platinum oxide in a solvent such as methanol to give I-17 as a mixture of epimers. Ester I-17 is hydrolyzed with an agent such as lithium hydroxide, and the resulting carboxylic acid is reacted with a coupling reagent such as amine R6R7NH and HATU to be converted to amide I-18. Standard methods are used to remove the sulfinamide and phenol protecting groups to give amide I-19 as a mixture of isomers, which can be separated by chromatography. In an alternative route to I-19, 2R-phenylpyrrolidine I-15 is first converted to Boc-protected pyrrolidine I-20 by hydrolyzing the sulfinamide with an acid and re-protecting with Boc anhydride. I-20 is reacted with an oxidizing agent such as ruthenium chloride to form a diol, which is cleaved in situ with sodium periodate to give ketone I-22.The Wittig reaction of I-22 with appropriately substituted triphenylphosphanylidene acetate or a similar reagent gives unsaturated ester I-22 similar to I-16, where R1 can be H, alkyl, etc. Hydrogenation of I-22 over a catalyst such as platinum oxide gives ester I-23 as a mixture of isomers. Hydrolysis of I-23 gives acid I-24, which is converted to amide I-19 by amide coupling and deprotection in the same order as I-16.

[0315]

Chemical formula

[0316] For compounds of formula I disclosed herein where either or both of R1 or R2 are not H and m is 1, substitution on the extended chain can be obtained by the synthesis described in Scheme 4. Compound I-23a shown in Scheme 4 can be obtained from ketone I-21 by the Wittig reaction with unsubstituted triphenylphosphanylidene acetate or from I-17 by exchanging the sulfinamide with Boc. As shown in Scheme 4, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and other protecting groups known in the art suitable for use as protecting groups for OH or amine groups. The other substituents shown in Scheme 4 are defined herein. Alkylation of I-23a is carried out by forming an enolate with a strong base such as LDA and reacting with halide R1X to give I-23. Alkylation can be repeated with a second R2X which may be the same or different to give geminal disubstituted ester I-23b. Hydrolysis, amide coupling, and deprotection then give substituted amide I-19a.

[0317]

Chemical formula

[0318] Compound I-24 shown in Scheme 5 can be prepared by any method known in the art and / or is commercially available. As shown in Scheme 5, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and other protecting groups known in the art suitable for use as protecting groups for OH or amine groups. The other substituents shown in Scheme 5 are defined herein. For the compounds of formula III disclosed herein where R2 is H and m is 1, the aryl or heteroaryl ring can be obtained by a decarboxylative photoredox reaction as shown in Scheme 5. Under irradiation with blue light, in DMSO, in the presence of an iridium catalyst [4,4'-bis(t-butyl)-2,2'-bipyridine-κN 1 ,κN 1 bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN 1 phenyl κC-iridium hexafluorophosphate, nickel(II) chloride DME complex, di(t-butyl)-4,4'-bipyridine, phthalimide, and t-butyl-tetramethylguanidine, the reaction of an optionally protected aryl halide A1X (where X is bromine or iodine) with carboxylic acid I-24 replaces the carboxylic acid with aryl ring A1 to give I-25 after deprotection.

[0319]

Chemical Structure

[0320] The compound I-8 shown in Scheme 6 can be prepared by any method known in the art and / or is commercially available. As shown in Scheme 6, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and other protecting groups known in the art suitable for use as protecting groups for OH or amine groups. The other substituents shown in Scheme 6 are defined herein. For the compounds of formula I' disclosed herein where R2 and R9 are H and m is 1, an amide side chain having an alternative orientation can be obtained by the synthesis described in Scheme 6. As shown in Scheme 6, carboxylic acid I-8 is converted to primary amide I-26 by reacting it in a solvent such as DMF with ammonium chloride, a coupling agent such as HATU, and a base such as triethylamine. Reduction of the primary amine of I-26 to I-27 is achieved by heating I-26 with a borane reducing agent (e.g., borane-methyl sulfide complex) in an ether solvent such as THF to obtain I-27. Then, using a coupling agent such as HATU and a base such as triethylamine in a solvent such as DMF, amine I-27 is acylated with carboxylic acid R 10 CO2H to obtain amide I-28. Deprotection under standard conditions gives amide I-29 where R1 = H and R2 = H. To obtain a compound where R1 is a substituent such as an alkyl group, acid I-8 is first converted to Weinreb amide I-30 using N,O-dimethylhydroxylamine under amide coupling conditions. Then, I-30 is treated with a Grignard reagent R1MgBr to obtain ketone I-31. Formation of the oxime of I-31 and reduction, for example, by hydrogenation over Raney nickel gives amine I-32. I-32 is acylated and deprotected in the same manner as I-27 to obtain I-29.

[0321]

Chemical Structure

[0322] The compound I-14 shown in Scheme 7 can be prepared by any method known in the art and / or is commercially available. As shown in Scheme 7, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and other protecting groups known in the art suitable for use as protecting groups for OH or amine groups. The other substituents shown in Scheme 7 are defined herein. For the compounds of formula II disclosed herein where R1 and R2 are H and m is 1, a pyrrolidine ring having an extended chain at C5 (see compound I-14 labeled at the 5-position) can be obtained by the synthesis described in Scheme 7. As shown in Scheme 7. The ester I-14 is reduced to the alcohol I-34 using, for example, sodium borohydride. Then, I-34 is treated with an agent such as tosyl chloride and a base such as triethylamine, and the resulting tosylate is replaced by heating with tetrabutylammonium cyanide in a solvent such as DMF to form the nitrile I-35. Hydrolysis of I-35 using sodium hydroxide and hydrogen peroxide gives the primary amide I-36, which is then deprotected to give I-37. Further hydrolysis of I-36 to the carboxylic acid I-38, followed by reaction with a coupling reagent such as an amine R6R7NH and HATU, can give a substituted amide. The protecting group is removed under standard conditions to give the pyrrolidine amide I-37a.

[0323]

Chemical formula

[0324] Pharmaceutical composition The present invention also provides a pharmaceutical composition comprising at least one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0325] In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of the compounds of formula I, I', II, II', III, or IV described herein, and a pharmaceutically acceptable carrier or diluent.

[0326] 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.

[0327] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material involved in carrying or transporting the subject pharmaceutical 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 substances that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as butylene glycol; polyols such as glycerin, sorbitol, mannitol, polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations. The term "carrier" means a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate its application. The components of the pharmaceutical composition can also be mixed with the compounds of the present invention and with each other such that there is no interaction that substantially impairs the desired pharmaceutical efficiency.

[0328] As described above, certain embodiments of the present pharmaceutical may be provided in the form of a pharmaceutically acceptable salt. In this regard, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compounds of the present invention in free base form with a suitable organic or inorganic acid and isolating the thus formed salt. 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 lauryl sulfonate, among others. See, for example, Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19 (incorporated herein by reference in its entirety).

[0329] Pharmaceutically acceptable salts of the subject compounds include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and salts prepared from organic acids such as acetic acid, butyric (butionic) acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

[0330] In other cases, the compounds disclosed herein may contain one or more acidic functional groups and, accordingly, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic base addition salts of the compounds disclosed herein. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, 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, among others. Representative organic amines useful in the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, for example, Berge et al. (supra).

[0331] Wetting agents, emulsifying agents, lubricants such as sodium lauryl sulfate, magnesium stearate, polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants can also be present in the composition.

[0332] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will depend upon the host to be treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount that produces a therapeutically effective composition. Generally, out of 100%, this amount will range from about 1% to about 99%, preferably from about 5% to about 70%, and most preferably from about 10% to about 30% of the active ingredient.

[0333] The methods for preparing these formulations or compositions include the step of associating a compound of the present invention with a carrier and optionally one or more accessory components. Generally, the formulations are prepared by uniformly and intimately associating the compound of the present invention with a liquid carrier or a micronized solid carrier or both, and then, if necessary, shaping the product.

[0334] Formulations of the present invention suitable for oral administration include capsules, cachets, pills, tablets, lozenges (usually using a flavor base of sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or water-in-oil or oil-in-water type liquid emulsions, or as elixirs or syrups, or as troches (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compound of the present invention can also be administered as a bolus, a pastille, or a paste.

[0335] 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 sodium citrate or dicalcium phosphate, and / or one or more pharmaceutically acceptable carriers such as any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retardants such as paraffin; absorption promoters such as quaternary ammonium compounds; wetting agents such as, for example, cetyl alcohol, glyceryl monostearate, and polyethylene oxide-polybutylene oxide copolymer; 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 a buffering agent. Solid compositions of the same 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 glycol.

[0336] Tablets can be prepared by compression or molding, using one or more accessory ingredients as required. Compressed tablets can be prepared using a binder (such as gelatin or hydroxybutyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (such as sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersing agent. Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0337] Tablets of the pharmaceutical compositions disclosed herein, as well as other solid dosage forms such as dragees, capsules, pills, and granules, can optionally be provided or prepared using coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using different ratios of hydroxypropylmethylcellulose, other polymeric matrices, liposomes, and / or microspheres to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be those of the active ingredient alone or preferentially thereof, releasing in a particular portion 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 may also, where appropriate, be in the form of microcapsules having one or more of the excipients described above.

[0338] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. Furthermore, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, can be used to solubilize the compounds.

[0339] In addition to the inert diluent, the oral composition can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, fragrances, and preservatives.

[0340] In addition to the active compound, the suspension can contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0341] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0342] Ointments, pastes, creams, and gels can contain, in addition to the active compound of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0343] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In addition, sprays can contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0344] The transdermal patch has the added advantage of providing controlled delivery of the compounds disclosed herein to the body. Such dosage forms can be prepared by dissolving or dispersing the pharmaceutical in a suitable medium. Penetration enhancers can also be used to increase the flux of the pharmaceutical across the skin. The rate of such flux can be controlled either by providing a flow control membrane or by dispersing the compound in a polymeric matrix or gel.

[0345] Ophthalmic formulations, eye ointments, eye drops, powders, solutions, etc. are also contemplated as being within the scope of the present invention.

[0346] The 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; or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use (which may contain antioxidants, buffers, bacteriostats, or solutes that render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents).

[0347] In some cases, it is desirable to delay the absorption of a drug from a subcutaneous or intramuscular injection in order to prolong its effect. This can be achieved by using a liquid suspension of a crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends on its dissolution rate and, similarly, on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered dosage form is achieved by dissolving or suspending the drug in an oily vehicle. One strategy for depot injections involves the use of polyethylene oxide - polypropylene oxide copolymers in which the vehicle is liquid at room temperature and solidifies at body temperature.

[0348] Injectable depot forms are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as polylactic acid - polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0349] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they can be provided by themselves or, for example, in combination with a pharmaceutically acceptable carrier as a pharmaceutical composition containing 0.1% - 99.5% (more preferably, 0.5% - 90%) of the active ingredient.

[0350] 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 particular combination of therapies (therapeutic agents or procedures) used in the combination regimen will take into account the compatibility of the desired therapeutic agent and / or procedure and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve the desired effect for the same disorder (for example, the compounds of the present invention can be administered simultaneously with another anti - cancer agent).

[0351] The compounds of the present invention can be administered by intravenous, intramuscular, intraperitoneal, subcutaneous, topical, oral, or other acceptable means. The compounds can be used to treat arthritic conditions in mammals (such as humans, livestock, and companion animals), racehorses, birds, lizards, and other organisms that are resistant to the compounds.

[0352] The present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the pharmaceutical composition of the present invention. Optionally, such containers can be associated with a notice in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals or biological products, and the notice reflects the agency's approval for manufacture, use, or sale for human administration.

[0353] Administration to a subject In yet another aspect, the present invention is a method of treating a condition in a mammalian species in need of treatment of the condition, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from the group consisting of compounds of Formula I, I', II, II', III, or IV, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, CNS disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0354] 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.

[0355] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy. In some embodiments, the gastrointestinal disorder is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis.

[0356] In some embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, MS, systemic lupus erythematosus, or type I diabetes). In some embodiments, the CNS disorder is Alzheimer's disease.

[0357] 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 insufficiency.

[0358] In some embodiments, the mammalian species is human.

[0359] 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 mellitus, Alzheimer's disease, inflammatory skin conditions, inflammatory nerve disorders, psoriasis, spondylitis, periodontal disease, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal insufficiency, and combinations thereof.

[0360] In yet another aspect, a method of blocking a Kv1.3 potassium channel in a mammalian species in need thereof is described, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound of Formula I, I', II, II', III, or IV, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0361] In some embodiments, the compounds described herein are selective in blocking the Kv1.3 potassium channel and have minimal or no off-target inhibitory activity against other potassium channels, or against calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channel and thus have a desirable cardiovascular safety profile.

[0362] Some aspects of the invention include administering to a subject a composition in an effective amount to achieve a particular result. Accordingly, the small molecule compositions useful in accordance with the methods of the invention can be formulated by any method suitable for pharmaceutical use.

[0363] The formulations of the present invention are administered in a pharmaceutically acceptable solution which may routinely contain salts, buffers, preservatives, suitable carriers, adjuvants, and optionally other therapeutic ingredients at pharmaceutically acceptable concentrations.

[0364] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that enables the compound to be taken up by the appropriate target cells. "Administration" of the pharmaceutical compositions of the present invention can be achieved by any means known to those skilled in the art. Specific routes of administration include, but are not limited to, oral, transdermal (e.g., by patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, rectal, vaginal, etc.). Injections can be bolus or continuous infusion.

[0365] For example, the pharmaceutical compositions according to the present invention are often administered by intravenous, intramuscular, or other parenteral means. They can also be administered by intranasal application, inhalation, topical, oral, or implant, and are also suitable for rectal or vaginal use. Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous solutions or saline for injection or inhalation, microencapsulation, encochleation, coating onto fine gold particles, inclusion in liposomes, atomization, aerosols, pellets for skin implantation, or drying on sharp objects to wound the skin, etc. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations for the delayed release of the active compound, which preparations contain excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweetening agents, or solubilizing agents, and are used conventionally as described above. The pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief overview of current drug delivery methods, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference in its entirety.

[0366] The concentration of the compound contained in the composition used in the method of the present invention can be in the range of about 1 nM to about 100 μM. The effective dose is considered to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0367] The pharmaceutical composition is 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. Different doses may be required for the treatment of a patient depending on the activity of the compound, the method of administration, the purpose of administration (i.e., prevention or treatment), the nature and severity of the disorder, age, and the weight of the patient. Administration of a given dose can be effected by a single administration in the form of an individual dosage unit or by both in the form of several smaller dosage units. Repeated and multiple administrations of the dose at specific intervals separated by days, weeks, or months are also contemplated by the present invention.

[0368] The composition can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt must be pharmaceutically acceptable, but pharmaceutically unacceptable salts can be conveniently used to prepare their pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Also, such salts can be prepared as alkali metal salts or alkaline earth salts such as sodium, potassium, or calcium salts of carboxylic acid groups.

[0369] Suitable buffers include the following: 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 the following: 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).

[0370] Compositions suitable for parenteral administration advantageously include a sterile aqueous preparation 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 have been conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed mineral or non-mineral oil containing synthetic monoglycerides or diglycerides can be used. Further, fatty acids such as oleic acid have found use in the preparation of injectables. Carrier formulations suitable for administration by subcutaneous, intramuscular, intraperitoneal, intravenous, etc. can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA (incorporated herein by reference in its entirety).

[0371] The compounds useful in the present invention can be delivered as a mixture of three or more such compounds. The mixture can further include one or more adjuvants in addition to the combination of compounds.

[0372] A variety of administration routes are available. The particular mode selected will, of course, depend on the particular compound selected, the age and general health of the subject, the particular condition being treated, and the dosage required for a therapeutic effect. Generally speaking, the methods of the present invention can be practiced using any medically acceptable mode of administration, i.e., any mode that produces a response at an effective level without causing clinically unacceptable side effects. Preferred modes of administration are discussed above.

[0373] The composition may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. All methods include the step of bringing the compound into association with a carrier which constitutes one or more accessory ingredients. Generally, the compositions are prepared by uniformly and intimately bringing the compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0374] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems. Such systems can avoid repeated dosing of the composition, thereby improving convenience for the subject and the physician. Many types of release delivery systems are available and are known to those skilled in the art. They include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactone, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the aforementioned polymers containing drugs are described, for example, in U.S. Patent No. 5,075,109. Delivery systems also include the following non-polymeric systems: lipids containing sterols such as cholesterol, cholesterol esters, and fatty acids, or neutral fats such as mono-, di-, and tri-glycerides; hydrogel release systems; elastomeric systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants, etc. Specific examples include, but are not limited to: (a) erosion systems in which the agent of the present invention is contained in matrix form as 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 from the polymer at a controlled rate as described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. Furthermore, pump-based hardware delivery systems can be used, some of which are suitable for implantation.

[0375] Assay for the effectiveness of Kv1.3 potassium channel blockers In some embodiments, the compounds described herein are tested for their activity against the Kv1.3 potassium channel. In some embodiments, the compounds described herein are tested for their Kv1.3 potassium channel electrophysiology. In some embodiments, the compounds described herein are tested for their hERG electrophysiology.

[0376] Equivalents The following representative examples are intended to help illustrate the present invention and are not intended to limit the scope of the present invention and should not be construed as limiting. In fact, in addition to what is shown and described herein, various modifications of the present invention and many further embodiments thereof will become apparent to those skilled in the art from the complete content of this document, including the examples and references to scientific and patent literature cited hereinbelow. It should be further understood that the content of these cited references is incorporated herein by reference to assist in the description of the state of the art. The following examples include important additional information, illustrations, and guidance that can be adapted for the practice of the present invention in various embodiments of the present invention and their equivalents.

Examples

[0377] Examples 1-11 describe various intermediates used in the synthesis of representative compounds of formula I, I', II, II', III, or IV disclosed herein. Example 1. Intermediate 1a ((R)-N-[[2,3-dichloro-6-(methoxymethoxy)phenyl]methylidene]-2-methylpropan-2-sulfinamide) and Intermediate 1b ((S)-N-[[2,3-dichloro-6-(methoxymethoxy)phenyl]methylidene]-2-methylpropan-2-sulfinamide)

[0378]

Chemical formula

[0379] Step a: To a stirred solution of 2,3-dichloro-6-(methoxymethoxy)benzaldehyde (2.00 g, 8.51 mmol) and (R)-2-methylpropan-2-sulfinamide (1.55 g, 12.8 mmol) in THF (20 mL) was added Ti(OEt)4 (5.82 g, 25.52 mmol) at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 16 h, quenched with saturated aqueous NaHCO3 (50 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give ((R)-N-[[2,3-dichloro-6-(methoxymethoxy)phenyl]methylene]-2-methylpropan-2-sulfinamide) as a pale yellow oil (2.60 g, 81%): C 13 H 17 Cl2NO3S [M+H] + LCMS (ESI) calcd for: 338,340 (3:2) found 338,340 (3:2); 1 H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 5.23 (s, 2H), 3.48 (s, 3H), 1.31 (s, 9H). The (S) enantiomer intermediate 1b was prepared in the same manner using (R)-2-methylpropan-2-sulfinamide.

[0380] Example 2. Intermediate 2 (tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-oxopyrrolidine-1-carboxylate)

[0381]

Chemical formula

[0382] Step b: To a stirred solution of (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-methylene-1-[(R)-2-methylpropan-2-sulfinyl]pyrrolidine (7.30 g, 18.6 mmol) in MeOH (60 mL) was added aqueous HCl (4 N, 15 mL) dropwise at room temperature. The resulting reaction solution was stirred at room temperature for 1 h, basified to pH 8 with saturated aqueous NaHCO3, and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To the crude product were added Boc2O (6.25 g, 28.6 mmol) and TEA (5.31 mL, 38.2 mmol) in DCM (60 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-methylenepyrrolidine-1-carboxylate as a pale yellow oil (7.30 g, 89%): C 18 H 23 Cl2NO4[M+H] + LCMS (ESI) calcd for 388,390 (3:2): 388,390; found 388,390 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 5.73 - 5.55 (m, 1H), 5.21 (d, J = 7.1 Hz, 1H), 5.11 (d, J = 7.0 Hz, 1H), 5.05 - 4.93 (m, 2H), 4.23 - 4.13 (m, 2H), 3.45 (s, 3H), 3.11 - 3.00 (m, 1H), 2.82 - 2.73 (m, 1H), 1.17 (s, 9H).

[0383] Step c: A stirred mixture of tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-methylidenepyrrolidine-1-carboxylate (7.30 g, 18.8 mmol) in DCM (40 mL) and ACN (40 mL) was added with NaIO4 (12.1 g, 56.4 mmol), H2O (60 mL), 2,6-lutidine (4.03 g, 37.6 mmol), and RuCl3·H2O (0.420 g, 1.88 mmol) at room temperature. The resulting reaction mixture was stirred for 1 h, quenched with saturated aqueous NH4HCO3 (200 mL), and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to afford tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-oxopyrrolidine-1-carboxylate as a pale yellow oil (5.60 g, 69%): C 17 H 21 Cl2NO5[M+H-56] + LCMS (ESI) calcd for 334,336 (3:2); found 334,336 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.55 - 7.31 (m, 1H), 7.02 (dd, J = 20.2, 8.4 Hz, 1H), 6.12 - 5.89 (m, 1H), 5.20 - 5.08 (m, 2H), 4.00 - 3.88 (m, 2H), 3.45 - 3.37 (m, 3H), 3.15 (dd, J = 18.8, 11.1 Hz, 1H), 2.61 - 2.48 (m, 1H), 1.28 (s, 9H).

[0384] Example 3. Intermediate 3 (tert-butyl (2R,4Z)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate)

[0385]

Chemical Structure

[0386] Example 4. Intermediate 4a (tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate)

[0387]

Chem.

[0388] Example 5. Intermediate 4a {tert-butyl (2R,4S)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate} and Intermediate 4b {tert-butyl (2R,4R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate}

[0389]

Chem.

[0390] Example 6. Intermediate 5 ([(5R)-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidin-3-yl]acetic acid)

[0391]

Chemical Structure

[0392] Example 7. Intermediate 5a ([(3S,5R)-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidin-3-yl]acetic acid)

[0393]

Chem.

[0394] Example 8. Intermediate 6a ((Ethyl (3S,5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]-1-(4-methylbenzenesulfonyl)pyrrolidine-3-carboxylate) and Intermediate 6b ((Ethyl (3R,5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]-1-(4-methylbenzenesulfonyl)pyrrolidine-3-carboxylate)

[0395]

Chemical Structure

[0396] Step b: To a stirred solution of ethyl (4R)-4-[2,3-dichloro-6-(methoxymethoxy)phenyl]-2-methylidene-4-[[(S)-2-methylpropan-2-sulfinyl]amino]butanoate (1.56 g, 3.45 mmol) in MeOH (10.50 mL) was added aqueous HCl (2 M, 3.50 mL) at room temperature. The reaction mixture was stirred for 1 h, basified to pH 8 with saturated aqueous NaHCO3, and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To a solution of the residue in DCM (10 mL) were added TsCl (0.660 g, 3.45 mmol), DMAP (0.110 g, 0.86 mmol), and TEA (1.00 mL, 7.18 mmol) at room temperature. The resulting solution was stirred for 2 h, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give ethyl (4R)-4-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(4-methylbenzenesulfonamido)-2-methylidenebutanoate as a pale yellow solid (1.10 g, 76%): C 22 H 25 Cl2NO6S[M+Na] +LCMS (ESI) calculated value: 524, 526 (3:2); measured value 524, 526 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.57 - 7.51 (m, 2H), 7.14 (d, J = 9.0 Hz, 1H), 7.07 - 7.02 (m, 2H), 6.82 (d, J = 9.1 Hz, 1H), 6.22 (d, J = 1.2 Hz, 1H), 5.94 (d, J = 10.9 Hz, 1H), 5.60 (q, J = 1.1 Hz, 1H), 5.30 - 5.25 (m, 1H), 5.25 - 5.18 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.57 (s, 3H), 3.00 - 2.90 (m, 1H), 2.73 - 2.64 (m, 1H), 2.31 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0397] Step c: To a stirred solution of ethyl (4R)-4-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(4-methylbenzenesulfonamido)-2-methylidenebutanoate (0.600 g, 1.19 mmol) in DMF (6 mL) was added NaH (53.0 mg, 0.12 mmol, 60% in oil) at room temperature. The reaction mixture was stirred at 110 °C for 16 h. The resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 3 / 1) to give ethyl (5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]-1-(4-methylbenzenesulfonyl)pyrrolidine-3-carboxylate isomer 1 as a pale yellow solid (0.150 g, 24%): C 22 H 25 Cl2NO6S [M + H] + LCMS (ESI) calculated value: 502, 504 (3:2); measured value 502, 504 (3:2); 11H NMR (300 MHz, CDCl3) δ 7.73 - 7.61 (m, 2H), 7.37 - 7.28 (m, 3H), 7.04 - 6.91 (m, 1H), 5.52 - 5.38 (m, 1H), 5.22 - 5.02 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.14 - 4.01 (m, 1H), 3.78 (t, J = 11.2 Hz, 1H), 3.59 - 3.46 (m, 4H), 2.79 - 2.60 (m, 1H), 2.50 - 2.38 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), and (ethyl (5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]-1-(4-methylbenzenesulfonyl)pyrrolidine-3-carboxylate isomer 2) was obtained as a pale yellow solid (0.29 g, 46%): C 22 H 25 Cl2NO6S [M+H] + The LCMS (ESI) calculated value for: 502, 504 (3:2); found 502, 504 (3:2); 1 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 8.9 Hz, 1H), 7.25 (d, J = 7.8H, 2H), 7.02 (d, J = 9.0 Hz, 1H), 5.60 - 5.47 (m, 1H), 5.27 - 5.05 (m, 2H), 4.00 - 3.85 (m, 4H), 3.55 (s, 3H), 3.26 - 3.15 (m, 1H), 2.63 - 2.47 (m, 1H), 2.43 (s, 3H), 2.39 - 2.24 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H).

[0398] Example 9. Intermediate 7 (methyl (5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]-1-(4-methylbenzenesulfonyl)pyrrolidine-3-carboxylate)

[0399]

Chemical Structure

[0400] Example 10. Intermediate 8a (1-(tert-butyl) 3-methyl (3S,5R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1,3-dicarboxylate) and Intermediate 8b (1-(tert-butyl) 3-methyl (3R,5R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1,3-dicarboxylate)

[0401]

Chemical formula

[0402] Step b: To a stirred solution of methyl (5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-3-carboxylate (4.00 g, 11.9 mmol) and TEA (2.42 g, 23.9 mmol) in DCM (50.0 mL) was added Boc2O (5.22 g, 23.9 mmol) dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h, diluted with water (100 mL), and extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (4 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% EA in PE to give the first eluted component, methyl 1-(tert-butyl) 3-methyl (3R,5R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1,3-dicarboxylate (Intermediate 8b) as a pale yellow oil (1.20 g, 23%): C 19 H 25 Cl2NO6[M+H] + The LCMS (ESI) calculated value for: 434,436 (3:2) found 434,436 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 5.49 (t, J = 9.1 Hz, 1H), 5.30 - 5.14 (m, 2H), 4.02 (dd, J = 10.4, 8.0 Hz, 1H), 3.75 (s, 3H), 3.72 - 3.64 (m, 1H), 3.48 (s, 3H), 3.23 - 3.11 (m, 1H), 2.60 - 2.37 (m, 2H), 1.15 (s, 9H). The second eluted component, methyl 1-(tert-butyl) 3-methyl (3S,5R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1,3-dicarboxylate (Intermediate 8a) was obtained as a pale yellow solid (1.8 g, 35%): C 19 H 25 Cl2NO6[M+H] +LCMS (ESI) calculated value: 434, 436 (3:2); measured value 434, 436 (3:2). The trans isomer, 1-(tert-butyl) 3-methyl (3S,5R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1,3-dicarboxylate (1.80 g, 4.11 mmol) was re-purified by preparative SFC using the following conditions: column: CHIRALPAK IF, 3 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 50 mL / min; gradient: isocratic 15% B; column temperature: 35 °C; back pressure: 100 bar; wavelength: 220 nm; retention time: 9.98 min; sample solvent: MeOH-preparative; injection volume: 0.5 mL. The fraction containing the desired product was collected and concentrated under reduced pressure to give 1-(tert-butyl) 3-methyl (3S,5R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1,3-dicarboxylate as a pale yellow oil (1.20 g, 66%): C 19 H 25 Cl2NO6 [M+H] + LCMS (ESI) calculated value: 434, 436 (3:2); measured value 434, 436 (3:2). 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 9.2 Hz, 1H), 5.59 (t, J = 8.1 Hz, 1H), 5.28 - 5.08 (m, 2H), 4.00 (d, J = 11.0 Hz, 1H), 3.79 - 3.75 (s, 4H), 3.49 (s, 3H), 3.26 - 3.18 (m, 1H), 2.64 (t, J = 9.7 Hz, 1H), 2.33 - 2.20 (m, 1H), 1.15 (s, 9H).

[0403] Example 11. Intermediate 9a (tert-butyl (2R,4S)-4-carbamoyl-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate) and Intermediate 9b (tert-butyl (2R,4R)-4-carbamoyl-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate)

[0404] [Chemical formula] Step a: To a stirred mixture of 1-tert-butyl 3-methyl (3S,5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1,3-dicarboxylate (0.200 g, 0.460 mmol) in MeOH (2 mL) and H2O (0.5 mL), LiOH·H2O (39.0 mg, 0.920 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. To a stirred mixture of the crude product, NH4Cl (49.0 mg, 0.920 mmol) and HATU (0.350 g, 0.920 mmol) in DMF (2 mL), TEA (93.0 mg, 0.920 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, dissolved in MeOH (0.5 mL), and purified by reverse-phase chromatography eluting with 45% ACN in water (+0.05% TFA) to give tert-butyl (2R,4S)-4-carbamoyl-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate (Intermediate 9a) as a pale yellow oil (0.150 g, 77%): C 18 H 24 Cl2N2O5[M+H] + Calculated LCMS (ESI): 419, 421 (3:2); Found 419, 421 (3:2); 1 H NMR (400 MHz, CDCL3) δ 7.33 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 5.83 - 5.53 (m, 3H), 5.27 - 5.11 (m, 2H), 4.01 - 3.72 (m, 2H), 3.49 (s, 3H), 3.17 - 3.08 (m, 1H), 2.71 - 2.60 (m, 1H), 2.36 - 2.25 (m, 1H), 1.16 (s, 9H). Using 1-tert-butyl 3-methyl (3R,5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1,3-dicarboxylate (0.200 g, 0.460 mmol), the (R,R) diastereomer Intermediate 9b was prepared in the same manner. C 18 H 24 Cl2N2O5[M+H] +LCMS(ESI) calculated value: 419, 421 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 7.07 - 7.02 (m, 1H), 5.61 - 5.39 (m, 3H), 5.31 - 5.18 (m, 2H), 4.01 (t, J = 9.2 Hz, 1H), 3.77 - 3.65 (m, 1H), 3.49 (s, 3H), 3.07 - 2.94 (m, 1H), 2.58 - 2.41 (m, 2H), 1.16 (s, 9H).

[0405] Examples 12 - 20 describe the synthesis of representative compounds of Formula I, I', II, II', III, or IV disclosed herein.

[0406] Example 12. Compounds 31 (2 - [(3S,5R) - 5 - (2,3 - dichloro - 6 - hydroxyphenyl)pyrrolidin - 3 - yl]acetamide) and Compound 32 (2 - [(3S,5R) - 5 - (2,3 - dichloro - 6 - hydroxyphenyl)pyrrolidin - 3 - yl]acetamide)

[0407]

Chemical Structure

[0408] Step b: To a stirred solution of tert-butyl (2R)-4-(carbamoylmethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate (0.240 g, 0.55 mmol) in DCM (2 mL) was added dropwise BBr3 (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, quenched with MeOH (3 mL) at 0 °C and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 30% ACN in water (+10 mM NH4HCO3) to give 2-[(5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]acetamide as an off-white solid (96.0 mg, 59%):C 12 H 14 Cl2N2O2[M+H] + LCMS (ESI) calcd for 289,291 (3:2); found 289,291 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.18 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.9, 1.1 Hz, 1H), 5.01 - 4.89 (m, 1H), 3.50 - 3.37 (m, 1H), 2.92 - 2.83 (m, 1H), 2.76 - 2.59 (m, 2H), 2.46 - 2.32 (m, 2H), 1.55 - 1.43 (m, 1H).

[0409] Step c: 2-[(5R)-5-(2,3-Dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]acetamide (96.0 mg, 0.330 mmol) was separated by preparative chiral HPLC using the following conditions: Column: CHIRALPAK IH, 2 × 25 cm, 5 μm; Mobile phase A: Hex(+0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 25 min; Wavelength: 220 / 254 nm; Retention time 1: 16.45 min; Retention time 2: 22.00 min; Sample solvent: EtOH-HPLC; Injection volume: 1.2 mL; Number of runs: 8. The enantiomer eluting faster at 16.45 min, 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]acetamide, was obtained. The product was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD Column, 19 × 150 mm, 5 μm 10 nm; Mobile phase A: water(+0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 10% B to 30% B, 30% B in 6.8 min; Wavelength: 210 nm; Retention time: 4.30 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]acetamide as an off-white solid (Compound 31) (57.2 mg, 42%): C 12 H 14 Cl2N2O2[M+H] + The LCMS(ESI) calculated value for: 289,291(3:2) found 289,291(3:2); 1H NMR (400 MHz, CD3OD) δ 7.47 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 5.30 (dd, J = 11.6, 7.0 Hz, 1H), 3.67 (dd, J = 11.3, 7.7 Hz, 1H), 3.38 (d, J = 10.9 Hz, 1H), 2.90-2.78 (m, 1H), 2.58 (dd, J = 15.2, 6.2 Hz, 1H), 2.52-2.42 (m, 2H), 2.21-2.10 (m, 1H). The slower eluting enantiomer, 2-[(3R,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]acetamide, was obtained at 22.00 min. The product was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD Column, 19 × 150 mm, 5 μm 10 nm; Mobile Phase A: Water (+0.05% TFA), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 10% B to 30% B, 30% B in 6.8 min; Wavelength: 210 nm; Retention Time: 4.35 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 2-[(3R,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]acetamide (Compound 32) as a purple solid (10.8 mg, 8%): C 12 H 14 Cl2N2O2[M+H] + LCMS (ESI) calculated: 289,291 (3:2) found: 289,291 (3:2); 1 H NMR(400MHz,CD3OD)δ 7.47(d,J=8.9Hz,1H),6.93(d,J=8.9Hz,1H),5.36(t,J=9.1Hz,1H),3.84(dd,J=11.4,7.0Hz ,1H),3.23(dd,J=11.4,8.3Hz,1H),3.18-3.02(m,1H),2.61-2.41(m,3H),2.24-2.13(m,1H).

[0410] tert-Butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate or tert-butyl (2R)-2-[3,4-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate, and starting from the corresponding amines that were available from commercial sources, the compounds in Table 7A below were prepared in a manner similar to that described for Compound 31.

[0411]

Table 8-1

[0412]

Table 8-2

[0413] tert-Butyl (2R,4S)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate, and starting from the corresponding amines that were available from commercial sources, the compounds in Table 7B below were prepared in a manner similar to that described for Compound 31.

[0414]

Table 9-1

[0415]

Table 9-2

[0416]

Table 9-3

[0417]

Table 9-4

[0418]

Table 9-5

[0419] Example 13. Compound 44 (2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]propanamide isomer 1) and Compound 45 (2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]propanamide isomer 2)

[0420]

Chem.

[0421] Step b: To a stirred mixture of tert-butyl (2R,4Z)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-1-oxopropan-2-ylidene)pyrrolidine-1-carboxylate (0.220 g, 0.460 mmol) in MeOH (3 mL) and aqueous HCl (6 M, 0.3 mL) was added PtO2 (41.0 mg, 0.180 mmol) at room temperature. The reaction mixture was degassed under reduced pressure, purged twice with hydrogen, and stirred under a hydrogen atmosphere (1.5 atm) for 6 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 2 / 1) to give tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate as a pale yellow oil (0.170 g, 69%): C 22 H 31 Cl2NO6 [M + H - 56] + The LCMS (ESI) calculated values for: 420, 422 (3:2); found 420, 422 (3:2); 1 1H NMR (300 MHz, CDCl3) δ 7.33 - 7.29 (m, 1H), 7.06 - 6.98 (m, 1H), 5.54 - 5.38 (m, 1H), 5.31 - 5.08 (m, 2H), 4.23 - 4.07 (m, 2H), 3.98 - 3.80 (m, 1H), 3.53 - 3.44 (m, 3H), 3.31 - 3.05 (m, 1H), 2.50 - 2.34 (m, 3H), 2.00 - 1.84 (m, 1H), 1.31 - 1.22 (m, 6H), 1.14 (d, J = 1.8 Hz, 9H).

[0422] Step c: To a stirred mixture of tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (0.170 g, 0.360 mmol) in MeOH (2 mL) and H2O (1 mL), LiOH·H2O (30.0 mg, 0.710 mmol) was added at room temperature. The reaction mixture was stirred for 1 h and concentrated under reduced pressure. To the crude product in DMF (2 mL), HATU (0.200 g, 0.530 mmol), TEA (72.0 mL, 0.710 mmol), and NH4Cl (38.0 mg, 0.710 mmol) were added at room temperature. The reaction mixture was stirred for 2 h and purified by reverse-phase chromatography eluting with 40% ACN in water (+0.05% TFA) to afford tert-butyl (2R)-4-(1-carbamoylethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate as a pale yellow solid (0.130 g, 73%): C 20 H 28 Cl2N2O5[M+H] + Calculated LCMS (ESI) for: 447, 449 (3:2); found 447, 449 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.35 - 7.29 (m, 1H), 7.06 - 6.98 (m, 1H), 5.49 - 5.40 (m, 1H), 5.27 - 5.01 (m, 2H), 3.98 - 3.87 (m, 1H), 3.49 (s, 3H), 3.33 - 3.09 (m, 1H), 2.49 - 2.36 (m, 2H), 2.31 - 2.19 (m, 2H), 1.32 - 1.25 (m, 3H), 1.13 (d, J = 11.3 Hz, 9H).

[0423] Step d: To a stirred mixture of tert-butyl (2R)-4-(1-carbamoylethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate (0.130 g, 0.290 mmol) in DCM (2 mL) was added BBr3 (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, quenched with MeOH (3 mL), basified to pH 8 with saturated aqueous NaHCO3, and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD Column, 19 × 150 mm, 5 μm 10 nm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10% B to 30% B in 6.8 min; wavelength: 210 nm; retention time 1: 5.67 min, retention time 2: 6.80 min. The fraction containing the desired product at 5.67 min was collected and concentrated under reduced pressure to give 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]propanamide isomer 1 as an off-white solid (22.8 mg, 18%): C 13 H 16 Cl2N2O2[M+H] + Calculated LCMS (ESI) for: 303,305 (3:2) Found 303,305 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.47 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 5.30 (dd, J = 11.6, 7.0 Hz, 1H), 3.62 (dd, J = 11.3, 7.7 Hz, 1H), 3.40 (t, J = 11.2 Hz, 1H), 2.74 - 2.61 (m, 1H), 2.58 - 2.48 (m, 1H), 2.39 - 2.30 (m, 1H), 2.22 (q, J = 11.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H). The fraction containing the desired product at 6.80 min was collected and concentrated under reduced pressure to give 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]propanamide isomer 2 as an off-white solid (5.60 mg, 4.6%): C 13 H16 Cl2N2O2[M+H] + LCMS(ESI) calculated value: 303.305 (3:2), measured value 303.305 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.47 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.31 (dd, J = 11.7, 6.9 Hz, 1H), 3.54 (dd, J = 11.3, 7.8 Hz, 1H), 3.41 (t, J = 10.9 Hz, 1H), 2.74 - 2.61 (m, 1H), 2.54 - 2.42 (m, 2H), 2.16 (q, J = 11.9 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H).

[0424] Starting from tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-oxopyrrolidine-1-carboxylate, the compounds in Table 7C below were prepared in a similar manner to that described for Compound 45.

[0425]

Table 10

[0426] Example 14. Compound 48 (N-{[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]methyl}-2-hydroxyacetamide)

[0427]

Chemical Structure

[0428] Step b: To a stirred solution of tert-butyl (2R,4S)-4-(aminomethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate (60.0 mg, 0.150 mmol) and glycolic acid (23.0 mg, 0.300 mmol) in DMF (2 mL) were added HATU (0.120 g, 0.300 mmol) and TEA (30.0 mg, 0.300 mmol) at room temperature. The reaction mixture was stirred for 2 h and dissolved in MeOH (1 mL). The resulting solution was purified by reverse-phase chromatography eluting with 48% ACN in water (+0.05% TFA) to give tert-butyl (2R,4S)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-[(2-hydroxyacetamido)methyl]pyrrolidine-1-carboxylate as a colorless oil (50.0 mg, 72.9%). C 20 H 28 Cl2N2O6[M+H] + LCMS (ESI) calculated for: 463, 465 (3:2); found 463, 465 (3:2).

[0429] Step c: To a stirred solution of tert-butyl (2R,4R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-[(2-hydroxyacetamido)methyl]pyrrolidine-1-carboxylate (50.0 mg, 0.110 mmol) in MeOH (0.4 mL) was added concentrated HCl (0.8 mL) at room temperature. The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep C18 OBD Column, 19×150 mm, 5 μm; mobile phase A: water (+10 mM NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 40% B in 4.5 min, hold at 40% B; wavelength: 210 nm; retention time: 4.35 min. The fractions containing the desired product were collected and concentrated under reduced pressure to afford N-{[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]methyl}-2-hydroxyacetamide as an off-white solid (16.9 mg, 49%): C 13 H 16 Cl2N2O3[M+H] + Calculated for LCMS (ESI): 319, 321 (3:2); found 319, 321 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.18 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.99 (t, J = 8.4 Hz, 1H), 4.01 (s, 2H), 3.41 - 3.34 (m, 3H), 2.90 (dd, J = 10.7, 6.8 Hz, 1H), 2.72 - 2.51 (m, 1H), 2.34 - 2.24 (m, 1H), 1.92 - 1.80 (m, 1H).

[0430] Starting from tert-butyl (2R,4R)-4-carbamoyl-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate, the compounds in Table 7D below were prepared in a manner similar to that described for Compound 48.

[0431]

Table 11

[0432] Example 15. Compound 50 (2-[5R-(2,3-dichloro-6-hydroxyphenyl)-3-methylpyrrolidin-3-yl]acetamide)

[0433]

Chemical formula

[0434] Step b: To a stirred solution of tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)-4-methylpyrrolidine-1-carboxylate (0.180 g, 0.380 mmol) in MeOH (3 mL) and H2O (1 mL) was added LiOH (18.0 mg, 0.760 mmol) at room temperature. The reaction was stirred for 1 h and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL), and HATU (0.220 g, 0.570 mmol), NH4Cl (0.100 g, 1.89 mmol), and TEA (76.0 mg, 0.760 mmol) were added. The reaction mixture was stirred for a further 1 h at room temperature, diluted with EA (20 mL) and water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give tert-butyl (2R)-4-(carbamoylmethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-methylpyrrolidine-1-carboxylate as a yellow oil (0.110 g, 65%): C 20 H 28 Cl2N2O5 [M + H] + The LCMS (ESI) calculated values for: 447, 449 (3:2); found 447, 449 (3:2); 11H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 9.0, 3.0 Hz, 1H), 7.07 - 6.99 (m, 1H), 5.80 - 5.46 (m, 1H), 5.29 - 5.07 (m, 2H), 3.63 (d, J = 10.3 Hz, 1H), 3.54 - 3.43 (m, 4H), 2.53 - 1.87 (m, 4H), 1.43 - 1.31 (m, 3H), 1.15 (s, 9H).

[0435] Step c: To a stirred solution of tert-butyl (2R)-4-(carbamoylmethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-methylpyrrolidine-1-carboxylate (0.100 g, 0.220 mmol) in MeOH (2.00 mL) was added concentrated HCl (2.00 mL) at room temperature. The reaction was stirred for 1 h, concentrated under reduced pressure, and purified by preparative HPLC using the following conditions: column: XBridge Prep C18 OBD Column, 19 × 150 mm, 5 μm; mobile phase A: water (+10 mM NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 50% B in 5.5 min, 50% B; wavelength: 210 nm; retention time: 5.2 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give 2-[5R-(2,3-dichloro-6-hydroxyphenyl)-3-methylpyrrolidin-3-yl]acetamide as an off-white solid (35.0 mg, 52%): C 13 H 16 Cl2N2O2 [M + H] + Calculated for LCMS (ESI): 303, 305 (3:2); found 303, 305 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 7.17 (dd, J = 8.9, 1.1 Hz, 1H), 6.59 (dd, J = 8.9, 1.2 Hz, 1H), 5.08 - 4.99 (m, 1H), 3.21 (d, J = 11.3 Hz, 1H), 3.09 - 2.95 (m, 1H), 2.66 - 2.29 (m, 3H), 1.78 - 1.54 (m, 1H), 1.28 (d, J = 5.8 Hz, 3H).

[0436] Example 16. Compound 51 (2-[(3R,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-2-methylpropanamide) and Compound 52 (2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-2-methylpropanamide)

[0437]

Chemical formula

[0438] Step b: To a stirred solution of i-Pr2NH (0.210 g, 2.08 mmol) in THF (1 mL) was added n-BuLi (1 mL, 2.43 mmol, 2.5 M in hexane) dropwise at -60 °C under a nitrogen atmosphere. After 30 minutes, tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (0.330 g, 0.690 mmol) in THF (2 mL) was added at -78 °C. The reaction solution was stirred at -78 °C for 30 minutes under a nitrogen atmosphere, and CH3I (0.980 g, 6.93 mmol) was added. The reaction mixture was stirred at -78 °C for an additional 2 hours under a nitrogen atmosphere. The resulting mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) at room temperature and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 50% ACN in water (+20 mM NH4HCO3) to give tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate as a yellow oil (0.150 g, 47% over 2 steps): C 23 H 33 Cl2NO6[M+H] + Calculated LCMS (ESI) for: 490,492 (3:2) Found 490,492 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.35 - 7.30 (m, 1H), 7.09 - 6.98 (m, 1H), 5.56 - 5.34 (m, 1H), 5.29 - 5.05 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.80 - 3.63 (m, 1H), 3.55 - 3.27 (m, 4H), 2.85 - 2.47 (m, 1H), 2.40 - 1.92 (m, 1H), 1.73 - 1.53 (m, 1H), 1.32 - 1.20 (m, 9H), 1.19 - 1.08 (m, 9H).

[0439] Step c: A stirred solution of tert-butyl (2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (0.300 g, 0.610 mmol) in MeOH (3 mL) and H2O (0.6 mL) was added NaOH (98.0 mg, 2.45 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 16 h. The resulting mixture was acidified to pH 2 with saturated aqueous citric acid, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-[(5R)-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidin-3-yl]-2-methylpropanoic acid as a yellow solid (0.300 g, crude), which was used directly in the next step without purification: C 21 H 29 Cl2NO6[M+H-56] + The LCMS (ESI) calculated value for : 406, 408 (3:2); found 406, 408 (3:2).

[0440] Step d: To a stirred solution of 2-[(5R)-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidin-3-yl]-2-methylpropanoic acid (0.300 g, 0.650 mmol) and HATU (0.370 g, 0.970 mmol) in DMF (3 mL) were added TEA (0.200 g, 1.95 mmol) and NH4Cl (69.0 mg, 1.30 mmol) at room temperature. The reaction mixture was stirred for 3 h, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2R)-4-(1-carbamoyl-1-methylethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate as a yellow oil (0.300 g, crude), which was used directly in the next step without purification: C 21H 30 Cl2N2O5[M+H] + LCMS(ESI) calculated value of: 461, 463 (3:2), measured value 461, 463 (3:2).

[0441] Step e: To a stirred solution of tert-butyl (2R)-4-(1-carbamoyl-1-methylethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate (0.300 g, crude) in MeOH (3 mL) was added concentrated HCl (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD Column, 19×150 mm, 5 μm 10 nm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 20% B to 20% B, 20% B in 6.8 minutes; detector UV: 210 nm; retention time 1: 6.27 minutes, retention time 2: 7.58 minutes. The enantiomer eluting faster at 6.27 minutes, 2-[(3R,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-2-methylpropanamide (Compound 51) was obtained as a purple solid (6.00 mg, 2.3% over 3 steps): C 14 H 18 Cl2N2O2[M+H] + LCMS(ESI) calculated value of: 317, 319 (3:2), measured value 317, 319 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.46 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 5.26 (t, J = 9.4 Hz, 1H), 3.70 (dd, J = 11.4, 7.8 Hz, 1H), 3.49 - 3.41 (m, 1H), 3.02 - 2.87 (m, 1H), 2.42 - 2.24 (m, 2H), 1.30 (d, J = 3.1 Hz, 6H). The enantiomer eluting slower at 7.58 minutes, 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-2-methylpropanamide was obtained as an off-white solid (Compound 52) (10.6 mg, 4.0% over 3 steps): C14 H 18 Cl2N2O2[M+H] + LCMS(ESI) calculated value: 317, 319 (3:2); measured value 317, 319 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 5.27 (dd, J = 10.3, 8.2 Hz, 1H), 3.69 - 3.56 (m, 1H), 3.49 (dd, J = 11.4, 8.4 Hz, 1H), 2.88 - 2.74 (m, 1H), 2.39 - 2.25 (m, 2H), 1.30 (d, J = 4.8 Hz, 6H).

[0442] Example 17. Compound 53 (2 - ((2S,5R)-5-(2,3 - dichloro - 6 - hydroxyphenyl)pyrrolidin - 2 - yl)acetamide)

[0443]

Chemical Structure

[0444] Step b: To a stirred solution of ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,3-dichloro-6-methoxyphenyl)-5-oxopentanoate (1.20 g, 2.76 mmol) in DCM (12 mL) was added TFA (3 mL) at room temperature. The reaction mixture was stirred at 40 °C for 3 h, neutralized to pH 7 at 0 °C with saturated aqueous NaHCO3 (20 mL), and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl (2S)-5-(2,3-dichloro-6-methoxyphenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate as a yellow oil (1.20 g, crude), which was used directly in the next step without purification: C 14 H 15 Cl2NO3[M+H] + LCMS(ESI) calculated value of: 316, 318 (3:2); measured value 316, 318 (3:2): 1 H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 5.02 - 4.88 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.06 - 2.76 (m, 2H), 2.46 - 2.25 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0445] Step c: To a stirred solution of ethyl (2S)-5-(2,3-dichloro-6-methoxyphenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (1.20 g, 3.76 mmol) in EA (12 mL) was added PtO2 (0.172 g, 0.759 mmol) at room temperature. The reaction mixture was stirred for 2 h under a hydrogen atmosphere (1.5 atm). The resulting mixture was filtered and the filter cake was washed with EA (3 × 20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography eluting with 37% ACN in water (+0.05% TFA) to give ethyl (2S,5R)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-carboxylate trifluoroacetate as a yellow oil (0.800 g, 67% overall for 2 steps): C 14 H 17 Cl2NO3[M+H] + LCMS (ESI) calcd for: 318,320 (3:2) found 318,320 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 9.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 5.47 - 5.34 (m, 1H), 4.79 (d, J = 10.7 Hz, 1H), 4.46 - 4.30 (m, 2H), 4.03 (s, 3H), 2.84 - 2.59 (m, 1H), 2.47 - 2.27 (m, 2H), 2.27 - 2.13 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H).

[0446] Step d: A stirred solution of ethyl (2S,5R)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-carboxylate (0.800 g, 2.51 mmol) and NaHCO3 (0.422 g, 5.03 mmol) in THF (8 mL) and H2O (2 mL) was treated with Boc2O (0.690 g, 3.02 mmol) at room temperature. The reaction mixture was stirred for 2 h, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 67% ACN in water (+10 mmol / L NH4HCO3) to afford 1-tert-butyl 2-ethyl (2S,5R)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylate as a yellow oil (0.400 g, 38%): C 19 H 25 Cl2NO5[M+H] + LCMS (ESI) calcd for 418,420 (3:2); found 418,420 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.38 - 7.30 (m, 1H), 6.76 (d, J = 8.9 Hz, 1H), 5.49 - 5.34 (m, 1H), 4.60 - 4.44 (m, 1H), 4.34 - 4.16 (m, 2H), 3.79 (s, 3H), 2.49 - 2.10 (m, 4H), 1.49 - 1.09 (m, 12H).

[0447] Step e: To a stirred solution of 1-tert-butyl 2-ethyl (2S,5R)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (0.400 g, 0.960 mmol) in MeOH (8 mL) was added NaBH4 (0.720 g, 19.1 mmol) portionwise at room temperature. The reaction solution was stirred for 4 h, quenched with water (10 mL), and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 62% ACN in water (+10 mmol / L NH4HCO3) to afford tert-butyl (2R,5S)-2-(2,3-dichloro-6-methoxyphenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate as a colorless oil (0.200 g, 56%): C 17 H 23 Cl2NO4[M+H] + Calculated LCMS (ESI) for C14H19Cl2NO4[M+H]: 376, 378 (3:2); found 376, 378 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 5.38 (t, J = 8.4 Hz, 1H), 4.32 - 4.16 (m, 1H), 3.99 - 3.89 (m, 1H), 3.86 (s, 3H), 3.81 - 3.67 (m, 1H), 2.27 - 2.04 (m, 3H), 1.89 - 1.74 (m, 1H), 1.14 (s, 9H).

[0448] Step f: To a stirred solution of tert-butyl (2R,5S)-2-(2,3-dichloro-6-methoxyphenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate (0.200 g, 0.530 mmol) and TEA (0.110 g, 1.06 mmol) in DCM (3 mL) was added TsCl (0.200 g, 1.06 mmol) at room temperature. The reaction mixture was stirred for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to afford tert-butyl (2R,5S)-2-(2,3-dichloro-6-methoxyphenyl)-5-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate as a colorless oil (0.160 g, 57%): C 24 H 29 Cl2NO6S [M+H] + LCMS (ESI) calcd for: 530,532 (3:2); found 530,532 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.89 - 7.81 (m, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 9.1 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 5.30 (t, J = 8.8 Hz, 1H), 4.35 - 4.06 (m, 3H), 3.74 (s, 3H), 2.47 (s, 3H), 2.20 - 2.07 (m, 2H), 2.07 - 1.93 (m, 2H), 1.20 (d, J = 74.1 Hz, 9H).

[0449] Step g: To a stirred solution of tert-butyl (2R,5S)-2-(2,3-dichloro-6-methoxyphenyl)-5-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.140 g, 0.26 mmol) in DMF (2 mL) was added Bu4NCN (0.280 g, 1.06 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h, diluted with water (30 mL), and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 70% ACN in water (+10 mmol / L NH4HCO3) to give tert-butyl (2S,5R)-2-(cyanomethyl)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate as a pale yellow oil (50.0 mg, 49%): C 18 H 22 Cl2N2O3 [M-56] + LCMS (ESI) calcd for: 329, 331 (3:2); found 329, 331 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 5.41 - 5.30 (m, 1H), 4.38 - 4.27 (m, 1H), 3.80 (s, 3H), 3.17 - 3.03 (m, 1H), 2.73 (dd, J = 16.5, 10.0 Hz, 1H), 2.34 - 2.02 (m, 4H), 1.11 (s, 9H).

[0450] Step h: To a stirred solution of tert-butyl (2S,5R)-2-(cyanomethyl)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate (50.0 mg, 0.130 mmol) and NaOH (16.0 mg, 0.390 mmol) in MeOH (1 mL) and H2O (0.2 mL), H2O2 (13.0 mg, 0.390 mmol) was added at room temperature. The reaction mixture was stirred for 4 h, quenched with saturated aqueous Na2SO3 (2 mL) at 0 °C, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN in water (+10 mmol / L NH4HCO3) to give tert-butyl (2S,5R)-2-(carbamoylmethyl)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate as a yellow oil (30.0 mg, 57%): C 18 H 24 Cl2N2O4[M+H] + LCMS (ESI) calcd for 403,405 (3:2); found 403,405 (3:2).

[0451] Step i: To a stirred solution of tert-butyl (2S,5R)-2-(carbamoylmethyl)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate (50.0 mg, 0.120 mmol) in DCM (1 mL) was added BBr3 (0.190 g, 0.740 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 4 h, quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 Column, 19×250 mm, 5 μm; mobile phase A: water (+10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 20% B to 50% B in 5.2 min, 50% B; detector: UV 254 / 220 nm; retention time: 5.08 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give 2-[(2S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-2-yl]acetamide as a pale yellow solid (4.00 mg, 18%): C 12 H 14 Cl2N2O2 [M+H] + LCMS (ESI) calculated for: 289,291 (3:2) found 289,291 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.20 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.93 - 4.91 (m, 1H), 3.78 - 3.70 (m, 1H), 2.59 - 2.55 (m, 2H), 2.48 - 2.37 (m, 1H), 2.22 - 2.11 (m, 1H), 1.86 - 1.66 (m, 2H).

[0452] Example 18. Compound 54 (3,4-dichloro-2-[(2R,4R)-4-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-yl]phenol)

[0453]

Chem.

[0454] Step b: A solution of tert-butyl 4-{[(3R,5R)-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidin-3-yl]methyl}pyrazole-1-carboxylate (40.0 mg, 0.07 mmol) in concentrated HCl (0.5 mL) and MeOH (0.5 mL) was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN in water (+10 mmol / L NH4HCO3) to give 3,4-dichloro-2-[(2R,4R)-4-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-yl]phenol as an off-white solid (12.3 mg, 55%): C 14 H 15 Cl2N3O[M+H] + The LCMS (ESI) calculated for 312,314 (3:2), found 312,314 (3:2): 1 H NMR (400 MHz, CD3OD) δ 7.45 (s, 1H), 7.37 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 8.9 Hz, 1H), 4.95 - 4.92 (m, 1H), 3.38 - 3.34 (m, 1H), 2.93 (dd, J = 11.1, 8.2 Hz, 1H), 2.74 - 2.68 (m, 2H)), 2.65 - 2.51 (m, 2H), 1.64 - 1.48 (m, 1H).

[0455] Starting from Intermediate 5a and the corresponding halogenated heteroaryl, the compounds in Table 7E below were prepared in a manner similar to that described for Compound 54.

[0456]

Table 12

[0457] Example 19. Compound 74 (2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-3-methoxypropanamide isomer 1) and Compound 75 (2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-3-methoxypropanamide isomer 2)

[0458]

Chem.

[0459] Step b: To a stirred solution of tert-butyl (2R,4S)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-3-methoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (0.550 g, 1.09 mmol) in MeOH (6 mL) was added LiOH·H2O (91.2 mg, 2.17 mmol) and H2O (2 mL) at room temperature. The reaction was stirred for 3 h and concentrated under reduced pressure. The residue was dissolved in DMF (6 mL), and HATU (0.619 g, 1.63 mmol), NH4Cl (87.1 mg, 1.63 mmol), and TEA (0.329 g, 3.26 mmol) were added. The resulting reaction mixture was stirred for 1 h, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with water (+0.05% TFA) 45% ACN to afford tert-butyl (2R,4S)-4-(1-carbamoyl-2-methoxyethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate as a yellow oil (0.420 g, 81%)C 21 H 30 Cl2N2O6[M + H] + The LCMS (ESI) calculated values for: 477, 479 (3:2); found 477, 479 (3:2); 11H NMR (300 MHz, CDCl3) δ 7.34 - 7.27 (m, 1H), 7.00 (dd, J = 9.09, 4.29 Hz, 1H), 6.52 - 5.83 (m, 2H), 5.65 - 5.34 (m, 1H), 5.34 - 5.01 (m, 2H), 3.99 - 3.84 (m, 1H), 3.79 - 3.51 (m, 1H), 3.46 - 3.26 (m, 4H), 3.27 - 3.08 (m, 4H), 2.67 - 2.26 (m, 3H), 2.07 - 1.79 (m, 1H), 1.48 - 0.94 (m, 9H).

[0460] Step c: To a stirred solution of tert-butyl (2R,4S)-4-(1-carbamoyl-2-methoxyethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate (0.150 g, 0.314 mmol) in MeOH (1 mL) was added aqueous HCl (1 mL, 4 M) at room temperature. The reaction mixture was stirred for 1 h and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: Sun Fire Prep C18 OBD Column, 19×150 mm, 5 μm 10 nm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 18% B to 23% B in 5 min, detector: UV 254 / 220 nm; retention time 1: 3.85 min, retention time 2: 5.65 min. The isomer eluting faster at 3.85 min, 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-3-methoxypropanamide isomer 1 was obtained as an off-white solid (8.50 mg, 6%): C 14 H 18 Cl2N2O3 [M+H] + The LCMS (ESI) calculated value for: 333, 335 (3:2) found 333, 335 (3:2); 11H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 8.90 Hz, 1H), 6.91 (d, J = 8.91 Hz, 1H), 5.24 (dd, J = 11.49, 7.08 Hz, 1H), 3.66 - 3.59 (m, 2H), 3.54 (dd, J = 9.53, 5.76 Hz, 1H), 3.41 (t, J = 11.04 Hz, 1H), 3.36 (s, 3H), 2.74 - 2.64 (m, 2H), 2.39 - 2.19 (m, 2H). An isomer eluting later at 5.65 minutes, 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-3-methoxypropanamide isomer 2 was obtained as an off-white solid (12.1 mg, 9%): C 14 H 18 Cl2N2O3 [M+H] + Calculated LCMS (ESI) values for: 333, 335 (3:2); found 333, 335 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 7.45 (dd, J = 8.92, 0.85 Hz, 1H), 6.91 (d, J = 8.92 Hz, 1H), 5.27 (dd, J = 11.64, 6.85 Hz, 1H), 3.67 - 3.54 (m, 2H), 3.54 - 3.45 (m, 2H), 3.34 (s, 3H), 2.79 - 2.62 (m, 2H), 2.50 - 2.36 (m, 1H), 2.21 (q, J = 11.86 Hz, 1H).

[0461] Example 20. Compound 76 (2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-3-hydroxypropanamide isomer 1) and Compound 77 (2-[(3S,5R)-5-2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-3-hydroxypropanamide isomer 2)

[0462]

Chemical Structure

[0463] Starting from tert-butyl (2R,4S)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate, the compounds in Table 7F below were prepared in a manner similar to that described for Compounds 74 and 75.

[0464]

Table 13

[0465] Example 21. Evaluation of Kv1.3 potassium channel blocker activity This assay is used to evaluate the activity of compounds disclosed as Kv1.3 potassium channel blockers.

[0466] 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). The cells were grown in culture flasks in a 37 °C, 5% CO2 humidified incubator.

[0467] Solution The cells were immersed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, and 10 mM HEPES. The pH was adjusted to 7.4 with NaOH. 295 - 305 mOsm. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES. The pH was adjusted to 7.2 with KOH. 285 mOsm. All compounds were dissolved in 30 mM DMSO. The compound stock solution was freshly diluted with the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. The highest DMSO content (0.3%) was present at 100 μM.

[0468] Voltage protocol Currents were induced by applying 100 - ms depolarizing pulses from -90 mV (holding potential) to +40 mV at a frequency of 0.1 Hz. Each compound concentration applied (control without compound and compound pulse trains) contained 20 pulses.

[0469] A 10 - second pause was used between pulse trains (see Table A below).

[0470] [Table 14]

[0471] Patch - clamp recording and compound application Using the automated patch clamp platform Patchliner (Nanion Technologies GmbH), recording of whole-cell currents and application of compounds became possible. Patchmaster software (HEKA Elektronik Dr.Schulze GmbH) was used for data acquisition together with an EPC10 patch clamp amplifier (HEKA Elektronik Dr.Schulze GmbH). The data was sampled at 10 kHz without filtering. The passive leak current was subtracted online using the P / 4 procedure (HEKA Elektronik Dr.Schulze GmbH). Compounds were applied continuously to the same cells while increasing the compound concentration and without washout in between. The total compound incubation time until the next pulse train was within 10 seconds. Peak current inhibition was observed during compound equilibration.

[0472] Data analysis AUC and peak values were obtained with Patchmaster (HEKA Elektronik Dr.Schulze GmbH). IC 50 To determine, the last single pulse of the pulse train corresponding to a given compound concentration was used. The AUC and peak values obtained in the presence of the compound were normalized against the control values in the absence of the compound. Using Origin (OridinLab), IC 50 was derived from the data fitted to the Hill equation: I 化合物 / I 対照 =(100 - A) / (1 + ([compound] / IC 50 ))nH + A. IC 50 is the concentration at which the current inhibition is half of the maximum, [compound] is the applied compound concentration, A is the fraction of the current not blocked, and nH is the Hill coefficient.

[0473] Example 22. Evaluation of hERG activity This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0474] hERG electrophysiology This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0475] Cell culture CHO-K1 cells stably expressing hERG were grown in Ham's F-12 medium containing glutamine supplemented with 10% heat-inactivated FBS, 1% penicillin / streptomycin, hygromycin (100 μg / ml), and G418 (100 μg / ml). Cells were grown in culture flasks in a 37 °C, 5% CO2 humidified incubator.

[0476] Solutions Cells were immersed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, and 10 mM HEPES. pH was adjusted to 7.4 with NaOH. 295 - 305 mOsm. The internal solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES. pH was adjusted to 7.2 with KOH. 285 mOsm. All compounds were dissolved in 30 mM DMSO. The compound stock solution was freshly diluted with the external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. The maximum DMSO content (0.3%) was present at 100 μM.

[0477] 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 a tail current), and a final step to a holding potential of -80 mV. The pulse frequency was 0.3 Hz. Each compound concentration applied had a control (no compound) and a compound pulse train containing 70 pulses.

[0478] [Table 15]

[0479] Patch-clamp recording and compound application Automated patch-clamp platform Patchliner (Nanion) enabled the recording of whole-cell currents and the application of compounds. Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) was used for data acquisition together with an EPC10 patch-clamp amplifier (HEKA). The data were sampled at 10 kHz without filtering. Compounds were applied continuously to the same cells while increasing the compound concentration and without washout in between.

[0480] Data analysis AUC and PEAK values were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). To determine the IC 50 , the last single pulse of the pulse train corresponding to a given compound concentration was used. The AUC and PEAK values obtained in the presence of the compound were normalized against the control values in the absence of the compound. Using Origin (OridinLab), the IC 50 was derived from the data fitted to Hill's equation: I 化合物 / I 対照 =(100 - A) / (1 + ([compound] / IC 50 ))nH)+A. IC 50 is the concentration at which the current inhibition is half of the maximum, [compound] is the applied compound concentration, A is the fraction of the non-blocked current, and nH is the Hill coefficient.

[0481] Table 7 provides a summary of the inhibitory activities of certain selected compounds of the present invention against the Kv1.3 potassium channel and the hERG channel.

[0482]

Table 16 - 1

[0483]

Table 16 - 2

[0484]

Table 16-3

[0485]

Table 16-4

[0486]

Table 16-5

[0487]

Table 16-6

[0488]

Table 16-7

Claims

1. A compound selected from the group consisting of the following: 【Chemical 8】 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical Formula 11】 or a pharmaceutically acceptable salt thereof 。

2. The compound according to claim 1, wherein the compound is 【Chemical Formula 12】 . or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is 【Chemical 13】 . or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound is 【Chemical 14】 . or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is 【Chemical Formula 15】 . or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound is 【Chemical 16】 . or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound is 【Chemical 17】 . or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein the compound is 【Chemical Formula 18】 . or a pharmaceutically acceptable salt thereof.

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

10. A pharmaceutical composition for treating the condition in a human in need of treatment for the condition, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, autoimmune diseases, central nervous system disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

11. The pharmaceutical composition according to claim 10, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

12. The pharmaceutical composition according to claim 10, wherein the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontal disease, or an inflammatory nerve disorder.

13. The pharmaceutical composition according to claim 10, wherein 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 nerve disorders, psoriasis, spondylitis, periodontal disease, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

14. The pharmaceutical composition according to claim 10.

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