This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/194,599, filed on May 28, 2021, the content of which is hereby incorporated by reference in its entirety.

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

INCORPORATION BY REFERENCE

All documents cited herein are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical science. More particularly, the invention relates to compounds and compositions useful as pharmaceuticals as potassium channel blockers.

BACKGROUND

Voltage-gated Kv1.3 potassium (K⁺) channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, and regulate a large number of physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kv1.3 channels can regulate membrane potential and thereby indirectly influence calcium signaling in human effector memory T cells. Effector memory T cells are mediators of several conditions, including multiple sclerosis, type I diabetes mellitus, psoriasis, spondylitis, parodontitis, and rheumatoid arthritis. Upon activation, effector-memory T cells increase expression of the Kv1.3 channel. Amongst human B cells, naive and early memory B cells express small numbers of Kv1.3 channels when they are quiescent. In contrast, class-switched memory B cells express high numbers of Kv1.3 channels. Furthermore, the Kv1.3 channel promotes the calcium homeostasis required for T-cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G., et al., 2004, Trends Immunol., 565-569). Blockade of Kv1.3 channels in effector memory T cells suppresses activities like calcium signaling, cytokine production (interferon-gamma, interleukin 2), and cell proliferation.

Autoimmune disease is a family of disorders resulting from tissue damage caused by attack from the body's own immune system. Such diseases may affect a single organ, as in multiple sclerosis and type I diabetes mellitus, or may involve multiple organs, as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatment is generally palliative, with anti-inflammatory and immunosuppressive drugs, which can have severe side effects. A need for more effective therapies has led to a search for drugs that can selectively inhibit the function of effector memory T cells, known to be involved in the etiology of autoimmune diseases. These inhibitors are thought to be able to ameliorate autoimmune diseases symptoms without compromising the protective immune response. Effector memory T cells (“TEMs”) express high numbers of the Kv1.3 channel and depend on these channels for their function. In vivo, Kv1.3 channel blockers paralyze TEMs at the sites of inflammation and prevent their reactivation in inflamed tissues. Kv1.3 channel blockers do not affect the motility within lymph nodes of naive and central memory T cells. Suppressing the function of these cells by selectively blocking the Kv1.3 channel offers the potential for effective therapy of autoimmune diseases with minimal side effects.

Multiple sclerosis (“MS”) is caused by autoimmune damage to the central nervous system (“CNS”). Symptoms include muscle weakness and paralysis, which severely affect quality of life for patients. MS progresses rapidly and unpredictably and eventually leads to death. The Kv1.3 channel is also highly expressed in auto-reactive 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 the Kv1.3 channel.

Compounds which are selective Kv1.3 channel blockers are thus potential therapeutic agents as immunosuppressants or immune system modulators. The Kv1.3 channel is also considered as a therapeutic target for the treatment of obesity and for enhancing peripheral insulin sensitivity in patients with type 2 diabetes mellitus. These compounds can also be utilized in the prevention of graft rejection and the treatment of immunological (e.g., autoimmune) and inflammatory disorders.

Tubulointerstitial fibrosis is a progressive connective tissue deposition on the kidney parenchyma, leading to renal function deterioration, is involved in the pathology of chronic kidney disease, chronic renal failure, nephritis, and inflammation in glomeruli, and is a common cause of end-stage renal failure. Overexpression of Kv1.3 channels in lymphocytes can promote their proliferation, leading to chronic inflammation and overstimulation of cellular immunity, which are involved in the underlying pathology of these renal diseases and are contributing factors in the progression of tubulointerstitial fibrosis. Inhibition of the lymphocyte Kv1.3 channel currents suppress proliferation of kidney lymphocytes and ameliorate the progression of renal fibrosis (Kazama I., et al., 2015, Mediators Inflamm., 1-12).

Kv1.3 channels also play a role in gastroenterological disorders including inflammatory bowel diseases (“IBDs”) such as ulcerative colitis (“UC”) and Crohn's disease. UC is a chronic IBD characterized by excessive T cell infiltration and cytokine production. UC can impair quality of life and can lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8 positive T cells in the inflamed mucosa of UC patients have been associated with production of pro-inflammatory compounds in active UC. Kv1.3 channels are thought to serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy in UC, as demonstrated in a humanized rodent model of UC (Unterweger A., et al. 2021, J. Crohns Colitis, available at https://academic.oup.com/ecco-icc/advance-article/doi/10.1093/ecco-icc/jjab078/6247959). Present 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 which may affect any part of the gastrointestinal tract. Crohn's disease is thought to be the result of intestinal inflammation due to a T cell-driven process initiated by normally safe bacteria. Thus, Kv1.3 channel inhibition can be utilized in treating the Crohn's disease.

In addition to T cells, Kv1.3 channels are also expressed in microglia, where the channel is involved in inflammatory cytokine and nitric oxide production and in microglia-mediated neuronal killing. In humans, strong Kv1.3 channel expression has been found in microglia in the frontal cortex of patients with Alzheimer's disease and on CD68⁺ cells in MS brain lesions. It has been suggested that Kv1.3 channel blockers might be able to preferentially target detrimental proinflammatory microglia functions. Kv1.3 channels are expressed on activated microglia in infarcted rodent and human brain. Higher Kv1.3 channel current densities are observed in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of a mouse model of stroke (Chen Y. J., et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

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

Kv1.3 channel blockers could be also useful for ameliorating pathology in cardiovascular disorders such as ischemic stroke, where activated microglia significantly contributes to the secondary expansion of the infarct.

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

A number of peptide toxins with multiple disulfide bonds from spiders, scorpions, and anemones are known to block Kv1.3 channels. A few selective, potent peptide inhibitors of the Kv1.3 channel have been developed. A synthetic derivative of stichodactyla toxin (“shk”) with an unnatural amino acid (shk-186) is the most advanced peptide toxin. Shk has demonstrated efficacy in preclinical models and is currently in a phase I clinical trial for treatment of psoriasis. Shk can suppress proliferation of TEMs, resulting in improved condition in animal models of multiple sclerosis. Unfortunately, Shk also binds to the closely-related Kvi channel subtype found in CNS and heart. There is a need for Kv1.3 channel-selective inhibitors to avoid potential cardio- and neuro-toxicity. Additionally, small peptides like shk-186 are rapidly cleared from the body after administration, resulting in short circulating half-lives and frequent administration events. Thus, there is a need for the development of long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases.

Thus, there remains a need for development of novel Kv1.3 channel blockers as pharmaceutical agents.

SUMMARY OF THE INVENTION

In one aspect, compounds useful as potassium channel blockers having a structure of Formula I

[Image Omitted]

are described, where the various substituents are defined herein. The compounds of Formula I disclosed herein can block Kv1.3 potassium (K⁺) channels and be used in the treatment of a variety of conditions. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for treating cancer, an immunological disorder, a CNS disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, a kidney disease, or a combination thereof.

In one aspect, a compound of Formula I or a pharmaceutically-acceptable salt thereof is described,

[Image Omitted]

wherein:

- X₁, X₂, and X₃are each independently H, halogen, CN, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, OH, SH, alkoxy, halogenated alkoxy, alkylthio, or halogenated alkylthio;
- or alternatively X₁and X₂and the carbon atoms they are connected to taken together form a 5- or 6-membered aryl;
- or alternatively X₂and X₃and the carbon atoms they are connected to taken together form a 5- or 6-membered aryl;
- Z is H, alkyl, halogenated alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogen, CN, CF₃, OCF₃, OR_a, NR_aR_b, or NR_a(C═O)R_b;
- Y₁is absent or C(R₁)₂;
- Y₂is absent, C(R₁)₂, C(R₁)₂(C═O), C(R₁)₂C(R₁)₂or C(R₁)₂C(R₁)₂(C═O);
- each occurrence of R₁is independently H, halogen, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, (CR₄R₅)_n3OR_c, or (CR₄R₅)_n3NR_cR_d;
- R₂is alkyl, heteroalkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, heteroaryl, (CR₄R₅)_n2(C═O)R₃, (CR₄R₅)_n2(C═O)N(R₄)R₃, SO₂R₃, or SO₂NR_cR_d;
- each occurrence of R₃is H, independently alkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, or heteroaryl;
- each occurrence of R₄and R₅is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
- each occurrence of R_aand R_bis independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
- or alternatively R_aand R_btogether with the nitrogen atom that they are connected to form a 3-7-membered heterocycle;
- each occurrence of R_cand R_dis independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
- or alternatively R_cand R_dtogether with the nitrogen atom that they are connected to form a 3-7-membered heterocycle;
- each heterocycle comprises 1-3 heteroatoms each independently selected from the group consisting of N, O and S;
- each of alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in X₁, X₂, X₃, Z, R₁, R₂, or R₃, where applicable, are optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(═O)R_c, COOR_c, (CR₄R₅)_n3OR_c, (CR₄R₅)_n3NR_cR_d, and (CR₄R₅)_n3NR_c(C═O)R_d, where valence permits;
- n₁is an integer from 0-4;
- n₂is an integer from 0-4; and
- n₃is an integer from 0-4.

In one aspect, a compound of Formula I or a pharmaceutically-acceptable salt thereof is described,

[Image Omitted]

wherein:

- X₁, X₂, and X₃are each independently H, halogen, CN, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, OH, SH, alkoxy, halogenated alkoxy, alkylthio, or halogenated alkylthio;
- or alternatively X₁and X₂and the carbon atoms they are connected to taken together form a 5- or 6-membered aryl;
- or alternatively X₂and X₃and the carbon atoms they are connected to taken together form a 5- or 6-membered aryl;
- Z is H, alkyl, halogenated alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogen, CN, CF₃, OCF₃, OR_a, NR_aR_b, or NR_a(C═O)R_b;
- Y₁is absent or C(R₁)₂;
- Y₂is absent, C(R₁)₂, C(R₁)₂(C═O), C(R₁)₂C(R₁)₂or C(R₁)₂C(R₁)₂(C═O);
- each occurrence of R₁is independently H, halogen, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, (CR₄R₅)_n3OR_c, or (CR₄R₅)_n3NR_cR_d;
- R₂is alkyl, heteroalkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, heteroaryl, (CR₄R₅)_n2(C═O)R₃, (CR₄R₅)_n2(C═O)N(R₄)R₃, SO₂R_c, or SO₂NR_cR_d;
- each occurrence of R₃is H, independently alkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, or heteroaryl;
- each occurrence of R₄and R₅is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
- each occurrence of R_aand R_bis independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
- or alternatively R_aand R_btogether with the nitrogen atom that they are connected to form a 3-7-membered heterocycle;
- each occurrence of R_cand R_dis independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
- or alternatively R_cand R_dtogether with the nitrogen atom that they are connected to form a 3-7-membered heterocycle;
- each heterocycle comprises 1-3 heteroatoms each independently selected from the group consisting of N, O and S;
- each of alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in X₁, X₂, X₃, Z, R₁, R₂, or R₃, where applicable, are optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(═O)R_c, COOR_c, (CR₄R₅)_n3OR_c, (CR₄R₅)_n3NR_cR_d, and (CR₄R₅)_n3NR_c(C═O)R_d, where valence permits;
- n₁is an integer from 0-4;
- n₂is an integer from 0-4; and
- n₃is an integer from 0-4.

In any one of the embodiments described herein, X₁, X₂, and X₃are each independently H, halogen, CN, alkyl, or halogenated alkyl.

In any one of the embodiments described herein, X₁, X₂, and X₃are each independently cycloalkyl or halogenated cycloalkyl.

In any one of the embodiments described herein, X₁, X₂, and X₃are each independently H, F, Cl, Br, CN, CH₃, or CF₃.

In any one of the embodiments described herein, X₁, X₂, and X₃are each independently H or Cl.

In any one of the embodiments described herein, Z is H, halogen, alkyl, or halogenated alkyl.

In any one of the embodiments described herein, Z is H, F, Cl, Br, CH₃, or CF₃.

In any one of the embodiments described herein, Z is H or Cl.

In any one of the embodiments described herein, Z is OR_aor NR_aR_b.

In any one of the embodiments described herein, each occurrence of R_aand R_bis independently H or alkyl.

In any one of the embodiments described herein, each occurrence of R_aand R_bis cycloalkyl or heterocycle.

In any one of the embodiments described herein, each occurrence of R_aand R_bis aryl or heteroaryl.

In any one of the embodiments described herein, at least two of Z, X₁, X₂, and X₃are not H.

In any one of the embodiments described herein, the structural moiety

[Image Omitted]

has the structure of

[Image Omitted]

In any one of the embodiments described herein, the structural moiety

[Image Omitted]

has the structure of

[Image Omitted]

In any one of the embodiments described herein, the structural moiety

[Image Omitted]

has the structure of

[Image Omitted]

In any one of the embodiments described herein, the structural moiety

[Image Omitted]

has the structure of

[Image Omitted]

In any one of the embodiments described herein, Y₁and Y₂are each independently absent or C(R₁)₂.

In any one of the embodiments described herein, Y₁is absent and Y₂is C(R₁)₂.

In any one of the embodiments described herein, Y₁is C(R₁)₂and Y₂is C(R₁)₂.

In any one of the embodiments described herein, the structural moiety

[Image Omitted]

has the structure of

[Image Omitted]

In any one of the embodiments described herein, the structural moiety

[Image Omitted]

has the structure of

[Image Omitted]

In any one of the embodiments described herein, at least one occurrence of R₁is H, alkyl, or cycloalkyl.

In any one of the embodiments described herein, at least one occurrence of R₁is halogen, (CR₄R₅)_n3OR_c, or (CR₄R₅)_n3NR_cR_d.

In any one of the embodiments described herein, at least one occurrence of R₁is saturated heterocycle, aryl, or heteroaryl.

In any one of the embodiments described herein, at least one occurrence of R₁is H or CH₃.

In any one of the embodiments described herein, the compound has Formula Ia:

[Image Omitted]

wherein:

- X₁, X₂, and X₃are each independently H, halogen, or alkyl;
- Z is H, halogen, alkyl, halogenated alkyl, CN, OR_a, or NR_aR_b; and
- each occurrence of R₁is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR₄R₅)_n3OR_c, or (CR₄R₅)_n3NR_cR_d.

In any one of the embodiments described herein, Z is H, halogen, alkyl, or halogenated alkyl.

In any one of the embodiments described herein, Z is H, F, Cl, Br, CH₃, or CF₃.

In any one of the embodiments described herein, Z is H.

In any one of the embodiments described herein, Z is CN, OR_a, or NR_aR_b.

In any one of the embodiments described herein, each occurrence of R_aand R_bis independently H or alkyl.

In any one of the embodiments described herein, each occurrence of R_aand R_bis cycloalkyl or heterocycle.

In any one of the embodiments described herein, each occurrence of R_aand R_bis aryl or heteroaryl.

In any one of the embodiments described herein, at least one occurrence of R₁is alkyl or cycloalkyl.

In any one of the embodiments described herein, at least one occurrence of R₁is halogen, (CR₄R₅)_n3OR_c, or (CR₄R₅)_n3NR_cR_d.

In any one of the embodiments described herein, at least one occurrence of R₁is saturated heterocycle, aryl, or heteroaryl.

In any one of the embodiments described herein, n₁is 0 or 1.

In any one of the embodiments described herein, the compound has Formula Ib:

[Image Omitted]

wherein:

- X₁, X₂, and X₃are each independently H, alkyl, or halogen;
- Z is H, halogen, alkyl, halogenated alkyl, CN, OR_a, or NR_aR_b; and
- each occurrence of R₁is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR₄R₅)_n3OR_c, or (CR₄R₅)_n3NR_cR_d.