Spiroindolinone compounds as blockers of Kv1.3 potassium shaker channels

Abstract

Compounds of formula (I), or pharma- ceutically acceptable salts thereof, are described, wherein the substituents are as defined herein. Pharmaceutical compositions containing same and methods of using same are also described. [Formula 1] JPEG2024522280000168.jpg35128

Description

[Technical Field]

[0001] (Priority Claim) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 194,599, filed May 28, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] (Copyright) 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] FIELD OF THE INVENTION 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] 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 are associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are thought to serve as a marker of disease activity, and pharmacological blockade may constitute a novel immunosuppressive strategy in UC, as demonstrated in a humanized rodent model of UC (Unterweger A., ​​et al. 2021, J. Crohns Colitis, available at https: / / academic.oup.com / ecco-jcc / advance-article / doi / 10.1093 / ecco-jcc / jjab078 / 6247959). Current treatment regimens for UC, including corticosteroids, salicylates, and anti-TNF-α agents, are insufficient for many patients (Hansen LK, et al., 2014, J. Crohns Colitis, pp. 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 result from intestinal inflammation driven by a T cell-driven process initiated by normally harmless bacteria. Therefore, inhibition of Kv1.3 channels can be used to treat Crohn's disease.

[0011] In addition to T cells, Kv1.3 channels are also expressed in microglia, where they are involved in the production of inflammatory cytokines and nitric oxide, and in microglia-mediated neuronal killing. In humans, CD68 channels are expressed in microglia in the frontal cortex of patients with Alzheimer's disease and in brain lesions of 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. Summary of the Invention [Problem to be solved by the invention]

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

[0017] In one embodiment, a compound of formula I

[0018] [ka] Compounds useful as potassium channel blockers are described 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 or pharmaceutically acceptable salts thereof are described:

[0020] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, CN, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, OH, SH, alkoxy, alkoxy halide, alkylthio, or alkylthio halide; or alternatively, X1 and X2 and the carbon atom to which they are attached together form a 5- or 6-membered aryl; or alternatively, X2 and X3 and the carbon atom to which they are attached 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 , N.R. a R b , or NRa (C=O)R b and Y1 is absent or is C(R1)2; Y2 is absent, C(R1)2, C(R1)2(C=O), C(R1)2C(R1)2, or C(R1)2C(R1)2(C=O); Each occurrence of R is independently H, halogen, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d and R2 is 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 c R d and each occurrence of R3 is H, independently alkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, or heteroaryl; each occurrence of R4 and R5 is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; R a and R b each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or alternatively, R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring, R c and R d each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or alternatively, R c and R d together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring, each heterocycle contains 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S; Each of the alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in X1, X2, X3, Z, R1, R2, or R3, if applicable and valence permits, is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: n1 is an integer from 0 to 4, n2 is an integer from 0 to 4, and n3 is an integer from 0 to 4.

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

[0022] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, CN, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, OH, SH, alkoxy, alkoxy halide, alkylthio, or alkyl halide DTP or thio; or alternatively, X1 and X2 and the carbon atom to which they are attached together form a 5- or 6-membered aryl; or alternatively, X2 and X3 and the carbon atom to which they are attached 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 , N.R. a R b , or NR a (C=O)R b and Y1 is absent or is C(R1)2; Y2 is absent, C(R1)2, C(R1)2(C=O), C(R1)2C(R1)2, or C(R1)2C(R1)2(C=O); Each occurrence of R is independently H, halogen, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d and R2 is 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 c R d and each occurrence of R3 is H, independently alkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, or heteroaryl; each occurrence of R4 and R5 is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; R a and R b each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or alternatively, R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring, R c and R d each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or alternatively, R c and R d together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring, each heterocycle contains 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S; Each of the alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in X1, X2, X3, Z, R1, R2, or R3, if applicable and valence permits, is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: n1 is an integer from 0 to 4, n2 is an integer from 0 to 4, and n3 is an integer from 0 to 4.

[0023] In any one of the embodiments described herein, X1, X2, and X3 are each independently H, halogen, CN, alkyl, or alkyl halide.

[0024] In any one of the embodiments described herein, X1, X2, and X3 are each independently cycloalkyl or halogenated cycloalkyl.

[0025] In any one of the embodiments described herein, X1, X2, and X 3は , each independently H, F, Cl, Br, CN, CH3, or CF3.

[0026] In any one of the embodiments described herein, X1, X2, and X3 are each independently H or Cl.

[0027] In any one of the embodiments described herein, Z is H, halogen, alkyl, or halogenated alkyl.

[0028] In any one of the embodiments described herein, Z is H, F, Cl, Br, CH3, or CF3.

[0029] In any one of the embodiments described herein, Z is H or Cl.

[0030] In any one of the embodiments described herein, Z is OR a or NR a R b is.

[0031] In any one of the embodiments described herein, R a and R b Each occurrence of is independently H or alkyl.

[0032] In any one of the embodiments described herein, R a and R b Each occurrence of is a cycloalkyl or heterocycle.

[0033] In any one of the embodiments described herein, R a and R b Each occurrence of is aryl or heteroaryl.

[0034] In any one of the embodiments described herein, at least two of Z, X1, X2, and X3 are not H.

[0035] In any one of the embodiments described herein, the structural moiety

[0036] [ka] teeth,

[0037] [ka] It has the following structure.

[0038] In any one of the embodiments described herein, the structural moiety

[0039] [ka] teeth,

[0040] [ka] It has the following structure.

[0041] In any one of the embodiments described herein, the structural moiety

[0042] [ka] teeth,

[0043] [ka] It has the following structure.

[0044] In any one of the embodiments described herein, the structural moiety

[0045] [ka] teeth,

[0046] [ka] It has the following structure.

[0047] In any one of the embodiments described herein, Y1 and Y2 are each independently absent or C(R1)2.

[0048] In any one of the embodiments described herein, Y1 is absent and Y2 is C(R1)2.

[0049] In any one of the embodiments described herein, Y1 is C(R1)2 and Y2 is C(R1)2.

[0050] In any one of the embodiments described herein, the structural moiety

[0051] [ka] teeth,

[0052] [ka] It has the following structure.

[0053] In any one of the embodiments described herein, the structural moiety

[0054] [ka] teeth,

[0055] [ka] It has the following structure.

[0056] In any one of the embodiments described herein, at least one occurrence of R1 is H, alkyl, or cycloalkyl.

[0057] In any one of the embodiments described herein, at least one occurrence of R is halogen, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d is.

[0058] In any one of the embodiments described herein, at least one occurrence of R1 is a saturated heterocycle, aryl, or heteroaryl.

[0059] In any one of the embodiments described herein, at least one occurrence of R1 is H or CH3.

[0060] In any one of the embodiments described herein, the compound has formula Ia:

[0061] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, or alkyl; Z is H, halogen, alkyl, alkyl halide, CN, ORa , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d (It is).

[0062] In any one of the embodiments described herein, Z is H, halogen, alkyl, or halogenated alkyl.

[0063] In any one of the embodiments described herein, Z is H, F, Cl, Br, CH3, or CF3.

[0064] In any one of the embodiments described herein, Z is H.

[0065] In any one of the embodiments described herein, Z is CN, OR a or NR a R b is.

[0066] In any one of the embodiments described herein, R a and R b Each occurrence of is independently H or alkyl.

[0067] In any one of the embodiments described herein, R a and R b Each occurrence of is a cycloalkyl or heterocycle.

[0068] In any one of the embodiments described herein, R a and R b Each occurrence of is aryl or heteroaryl.

[0069] In any one of the embodiments described herein, at least one occurrence of R1 is alkyl or cycloalkyl.

[0070] In any one of the embodiments described herein, at least one occurrence of R is halogen, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d is.

[0071] In any one of the embodiments described herein, at least one occurrence of R1 is a saturated heterocycle, aryl, or heteroaryl.

[0072] In any one of the embodiments described herein, n1 is 0 or 1.

[0073] In any one of the embodiments described herein, the compound has formula Ib:

[0074] [ka] (In the formula, X1, X2, and X3 are each independently H, alkyl, or halogen; Z is H, halogen, alkyl, alkyl halide, CN, OR a , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d (It is).

[0075] In any one of the embodiments described herein, Z is H, halogen, alkyl, or halogenated alkyl.

[0076] In any one of the embodiments described herein, Z is H, F, Cl, Br, CH3, or CF3.

[0077] In any one of the embodiments described herein, Z is H.

[0078] In any one of the embodiments described herein, Z is CN, OR a or NR a R b is.

[0079] In any one of the embodiments described herein, R a and R b Each occurrence of is independently H or alkyl.

[0080] In any one of the embodiments described herein, R a and R b Each occurrence of is a cycloalkyl or heterocycle.

[0081] In any one of the embodiments described herein, R a and R b Each occurrence of is aryl or heteroaryl.

[0082] In any one of the embodiments described herein, at least one occurrence of R1 is alkyl or cycloalkyl.

[0083] In any one of the embodiments described herein, at least one occurrence of R is halogen, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d is.

[0084] In any one of the embodiments described herein, at least one occurrence of R1 is a saturated heterocycle, aryl, or heteroaryl.

[0085] In any one of the embodiments described herein, n1 is 0 or 1.

[0086] In any one of the embodiments described herein, R2 is alkyl, cycloalkyl, or heteroalkyl.

[0087] In any one of the embodiments described herein, R2 is heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.

[0088] In any one of the embodiments described herein, R2 is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[0089] In any one of the embodiments described herein, R2 is SO2R c or SO2NR c R d is.

[0090] In any one of the embodiments described herein, R2 is (CR4R5) n2 OR c , (CR4R5) n2 (CR4)((CR4R5) n3 OR c )2, (C=O)(CR4R5) n2 OR c , (C=O)(CR4R5) n2 (CR4)((CR4R5) n3 OR c )2, (CR4R5) n2 COOR c , (C=O)(CR4R5) n2 NR c R d , or (CR4R5) n2 NR c (C=O)R d is.

[0091] In any one of the embodiments described herein, R2 is (CR4R5)n2 (C=O)R3 or (CR4R5) n2 (C=O)NR3R4.

[0092] In any one of the embodiments described herein, each occurrence of R3 is alkyl or cycloalkyl.

[0093] In any one of the embodiments described herein, each occurrence of R3 is heterocycle, aryl, or heteroaryl.

[0094] In any one of the embodiments described herein, each occurrence of R3 is alkylaryl or alkylheteroaryl.

[0095] In any one of the embodiments described herein, each occurrence of R3 is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[0096] In any one of the embodiments described herein, each occurrence of R4 and R5 is independently H, alkyl, cycloalkyl, or heterocycle.

[0097] In any one of the embodiments described herein, each occurrence of R4 and R5 is independently aryl or heteroaryl.

[0098] In any one of the embodiments described herein, R c and R d Each occurrence of is independently H, alkyl, or cycloalkyl.

[0099] In any one of the embodiments described herein, R c and R d Each occurrence of is independently a heterocycle, an aryl, or a heteroaryl.

[0100] In any one of the embodiments described herein, each occurrence of n2 and n3 is independently 0, 1, or 2.

[0101] In any one of the embodiments described herein, each occurrence of n2 and n3 is independently 3 or 4.

[0102] In any one of the embodiments described herein, the compound has formula Ic:

[0103] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, or alkyl; Z is H, halogen, alkyl, alkyl halide, CN, OR a , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d and R3 is alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl, where valences permit, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c and (CR4R5) n3 NR c R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0104] In any one of the embodiments described herein, Z is H, halogen, alkyl, or halogenated alkyl.

[0105] In any one of the embodiments described herein, Z is H, F, Cl, Br, CH3, or CF3.

[0106] In any one of the embodiments described herein, Z is H or Cl.

[0107] In any one of the embodiments described herein, at least one occurrence of R1 is H, alkyl, or cycloalkyl.

[0108] In any one of the embodiments described herein, n1 is 0 or 1.

[0109] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d and is alkyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0110] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R dand is cycloalkyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0111] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d and R is a heterocyclic ring optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0112] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d and is an aryl or heteroaryl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0113] In any one of the embodiments described herein, R3 is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[0114] In any one of the embodiments described herein, the compound has formula Id:

[0115] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, or alkyl; Z is H, halogen, alkyl, alkyl halide, CN, OR a , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d and R3 is alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl, where valences permit, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c and (CR4R5) n3 NR c R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0116] In any one of the embodiments described herein, Z is H, halogen, alkyl, or halogenated alkyl.

[0117] In any one of the embodiments described herein, Z is H, F, Cl, Br, CH3, or CF3.

[0118] In any one of the embodiments described herein, Z is H or Cl.

[0119] In any one of the embodiments described herein, at least one occurrence of R1 is H, alkyl, or cycloalkyl.

[0120] In any one of the embodiments described herein, n1 is 0 or 1.

[0121] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d and is alkyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0122] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d and is cycloalkyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0123] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3NR c R d and R is a heterocyclic ring optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0124] In any one of the embodiments described herein, R3 may be, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d and is an aryl or heteroaryl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0125] In any one of the embodiments described herein, R3 is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[0126] In any one of the embodiments described herein, R2 is

[0127] [ka]

[0128] [ka]

[0129] [ka] is.

[0130] In any one of the embodiments described herein, R2 is

[0131] [ka] is.

[0132] In any one of the embodiments described herein, R2 is

[0133] [ka] is.

[0134] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 1-159 shown in Table 1.

[0135] 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.

[0136] 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.

[0137] In any one of the embodiments described herein, the immunological disorder is transplant rejection or an autoimmune disease.

[0138] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0139] In any one of the embodiments described herein, the central nervous system (CNS) disorder is Alzheimer's disease.

[0140] In any one of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or inflammatory neuropathy.

[0141] In any one of the embodiments described herein, the gastroenterological disorder is inflammatory bowel disease.

[0142] In any one of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0143] In any one of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0144] In any one of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0145] 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.

[0146] In any one of the embodiments described herein, the mammalian species is human.

[0147] 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.

[0148] In any one of the embodiments described herein, the mammalian species is human.

[0149] 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

[0150] 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.

[0151] 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 , 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 each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0152] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing 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 or branched chain hydrocarbon radical containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl ... "Hex-enyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group having a single halogen substituent or multiple halogen substituents such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or 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)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 each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). The exemplary substituents may themselves be optionally substituted.

[0153] 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, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NRb R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). The exemplary substituents may themselves be optionally substituted.

[0154] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, 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, OR a , S.R. a , S(=O)R e , S(=O)2R e, P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R 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.

[0155] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming, for example, a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , 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)Ra , 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 each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. 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.

[0156] 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, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c, N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused 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.

[0157] 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.

[0158] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring, or a cyclic aromatic hydrocarbon group having one to five aromatic rings, particularly 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 carbocyclic group substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Examples of substituents include, but are not limited to, those listed above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0159] 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, benzo Included are furazanyl, 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), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0160] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, 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, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2Re , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R 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.

[0161] The term "bicycloalkyl" or "spiroalkyl" refers to a compound containing at least one cycloalkyl ring that shares one or more ring atoms with at least one other cycloalkyl ring. The term "heterobicycloalkyl" or "heterospiroalkyl" refers to a bicycloalkyl group in which at least one, preferably 1 to 3, carbon atoms in at least one ring are replaced with a heteroatom selected from the group consisting of N, S, O, or P. The heteroatom may occupy a terminal position or a bridging position (i.e., the point of attachment between two rings). Exemplary bicycloalkyl groups include adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, etc. Exemplary spiro bicycloalkyl groups include spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, spiro[4.5]decyl, etc. "Substituted bicycloalkyl," "substituted spiroalkyl," "substituted heterobicycloalkyl," and "substituted heterospiroalkyl" refer to a bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl 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 an alkyl group with, for example, a group such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -Ra S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R 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.

[0162] The term "oxo"

[0163] [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

[0164] [ka] which may also have the structure

[0165] [ka] This also includes tautomeric forms of:

[0166] The term "alkylamino" refers to a group having the structure -NHR', where R' is alkyl, 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.

[0167] 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.

[0168] The term "alkoxy" refers to a group having the structure -OR', where R' is alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl, as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, cyclopropoxy, n-butoxy, tert-butoxy, neopentyloxy, n-pentyloxy, hexyloxy, cyclohexyloxy, and the like.

[0169] The term "alkylthio" refers to a group having the structure -SR', where R' is alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl, as defined herein. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, n-propylthio, iso-propylthio, cyclopropylthio, n-butylthio, tert-butylthio, neopentylthio, n-pentylthio, hexylthio, cyclohexylthio, and the like.

[0170] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0171] The term "substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group, or any other group disclosed herein) is substituted with one or more substituents, preferably 1 to 6 substituents, at any available point of attachment, where valence allows. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, 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, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2Re , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R eis 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 can 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 substituents as described above.

[0172] Unless otherwise specified, heteroatoms with unsatisfied valences are assumed to not have enough hydrogen atoms to satisfy the valences.

[0173] The compounds of the present invention can form salts that are also within the scope of the present invention. Reference to a compound of the present invention is understood to include reference to its salts, unless otherwise indicated. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, when a compound of the present invention contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a phenol or a carboxylic acid, zwitterions ("internal salts") may be formed and are included in the term "salt" as used herein. While pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts are also useful, for example, in isolation or purification steps that may be used during preparation. Salts of the compounds of the present invention can be formed, for example, by reacting a compound described herein with an amount, such as an equivalent amount, of an acid or base in a medium that precipitates the salt, or in an aqueous medium, followed by lyophilization.

[0174] The compounds of the present invention that contain a basic moiety, such as, but not limited to, an amine, pyridine, or imidazole ring, can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetate (such as those formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanoate, and the like. Examples of suitable carboxylic acids include toluenesulfonates such as benzenesulfonates (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as that formed with sulfuric acid), sulfonate, tartrate, thiocyanate, tosylate, and other toluenesulfonates, undecanoate, and the like.

[0175] The compounds of the present invention that contain an acidic moiety, such as, but not limited to, a phenol or a carboxylic acid, can form salts with a variety of organic and inorganic bases. Exemplary base salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, t-butylamine, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups are quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and chlorides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl chlorides, bromides, and chlorides, lauryl, myristyl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0176] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. As used herein, the term "prodrug" refers to a compound that, upon administration to a subject, 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.

[0177] The compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of a compound includes its tautomeric forms.

[0178] All stereoisomers of the present compounds (e.g., those that may exist due to asymmetric carbon atoms on various substituents), including enantiomeric and diastereomeric forms, are contemplated within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having the specified activity), or may be present, for example, as racemates or mixed with all or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the 1974 Recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

[0179] Following their preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 90% by weight or more, e.g., 95% by weight or more, 99% by weight or more of the compound ("substantially pure" compounds), which are then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also contemplated herein as part of the present invention.

[0180] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds of the present invention encompasses both cis (Z) and trans (E) alkene isomers, and cis and trans isomers of cyclic hydrocarbons or heterocycles.

[0181] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0182] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The specific functional groups are generally defined herein below, and are identified according to the back cover of the Ed. Further, general principles of organic chemistry, and specific functional moieties and reactivities, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0183] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates and is within the scope of all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0184] Isomeric mixtures containing any of a variety of isomer ratios can be utilized in accordance with the present invention. For example, when 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. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0185] The present invention also includes isotopically labeled compounds that are identical to the compounds disclosed herein, except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into 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 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as Cl. Compounds of the invention, or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the invention. Certain isotopically labeled compounds of the invention, e.g., 3 H and 14 Compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic benefits due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the following schemes and / or examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0186] 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.

[0187] 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.

[0188] 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, Regius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, hereditary gingival fibromatosis type 1, autoimmune lymphoproliferative syndrome, and capillary malformation-arteriovenous malformation.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] In one aspect, compounds of formula I or pharmaceutically acceptable salts thereof are described:

[0193] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, CN, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, OH, SH, alkoxy, alkoxy halide, alkylthio, or alkylthio halide; or alternatively, X1 and X2 and the carbon atom to which they are attached together form a 5- or 6-membered aryl; or alternatively, X2 and X3 and the carbon atom to which they are attached 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 , N.R. a R b , or NRa (C=O)R b and Y1 is absent or is C(R1)2; Y2 is absent, C(R1)2, C(R1)2(C=O), C(R1)2C(R1)2, or C(R1)2C(R1)2(C=O); Each occurrence of R is independently H, halogen, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d and R2 is 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 c R d and each occurrence of R3 is independently H, alkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, or heteroaryl; each occurrence of R4 and R5 is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; R a and R b each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or alternatively, R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring, R c and R deach occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or alternatively, R c and R d together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring, each heterocycle contains 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S; Each of the alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in X1, X2, X3, Z, R1, R2, or R3, if applicable and valence permits, is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: n1 is an integer from 0 to 4, n2 is an integer from 0 to 4, and n3 is an integer from 0 to 4.

[0194] In some embodiments, X1 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, X1 is OH, SH, alkoxy, halogenated alkoxy, alkylthio, or halogenated alkylthio. In some embodiments, X1 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X1 is H or halogen. In other embodiments, X1 is fluorinated alkyl or alkyl. In some embodiments, X1 is cycloalkyl. In some embodiments, X1 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X1 is H, F, or Cl. In some embodiments, X1 is F or Cl. In some embodiments, X1 is H or Cl. In some embodiments, X1 is F. In some embodiments, X1 is Cl. In some embodiments, X1 is CH3. In some embodiments, X1 is CF3 or CF2H. In some embodiments, X1 is CF2Cl. In some embodiments, X 1 is H.

[0195] In some embodiments, X2 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, X2 is OH, SH, alkoxy, halogenated alkoxy, alkylthio, or halogenated alkylthio. In some embodiments, X2 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X2 is H or halogen. In other embodiments, X2 is fluorinated alkyl or alkyl. In some embodiments, X2 is cycloalkyl. In some embodiments, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X2 is H, F, or Cl. In some embodiments, X2 is F or Cl. In some embodiments, X2 is H or Cl. In some embodiments, X2 is F. In some embodiments, X2 is Cl. In some embodiments, X2 is CH3. In some embodiments, X2 is CF3 or CF2H. In some embodiments, X2 is CF2Cl. In some embodiments, X2 is H.

[0196] In some embodiments, X3 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, X3 is OH, SH, alkoxy, halogenated alkoxy, alkylthio, or halogenated alkylthio. In some embodiments, X3 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X3 is H or halogen. In other embodiments, X3 is fluorinated alkyl or alkyl. In some embodiments, X3 is cycloalkyl. In some embodiments, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X3 is H, F, or Cl. In some embodiments, X3 is F or Cl. In some embodiments, X3 is H or Cl. In some embodiments, X3 is F. In some embodiments, X3 is Cl. In some embodiments, X3 is CH3. In some embodiments, X3 is CF3 or CF2H. In some embodiments, X3 is CF2Cl. In some embodiments, X3 is H.

[0197] In some embodiments, Z is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, Z is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, Z is H or halogen. In other embodiments, Z is fluorinated alkyl or alkyl. In some embodiments, Z is cycloalkyl. In some embodiments, Z is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, Z is H, F, or Cl. In some embodiments, Z is F or Cl. In some embodiments, Z is H or Cl. In some embodiments, Z is F. In some embodiments, Z is Cl. In some embodiments, Z is CH3. In some embodiments, Z is CF3 or CF2H. In some embodiments, Z is CF2Cl. In some embodiments, Z is H.

[0198] In some embodiments, Z is OR a In some embodiments, Z is OH or O—(C1-C4 alkyl). In some embodiments, Z is OH, OMe, OCF3, OEt, OPr, Oi-Pr, OBu, Oi-Bu, Osec-Bu, or Ot-Bu. In some embodiments, Z is OH. In some embodiments, Z is NR a R b or NR a (C=O)R b In some embodiments, Z is NH, NHMe, NHEt, or NMe. In some embodiments, Z is NHCOMe, NMeCOEt, or NHCOEt.

[0199] In some embodiments, at least two of Z, X1, X2, and X3 are not H. In some embodiments, X1 and Z are not H. In some embodiments, X2 and Z are not H. In some embodiments, X3 and Z are not H. In some embodiments, X1 and X2 are not H. In some embodiments, X1 and X3 are not H. In some embodiments, X2 and X3 are not H. In some embodiments, Z, X1, and X2 are not H. In some embodiments, Z, X1, and X3 are not H. In some embodiments, Z, X2, and X3 are not H. In some embodiments, X1, X2, and X3 are not H.

[0200] In some embodiments, at least two of Z, X1, X2, and X3 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, X1 and Z are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, X2 and Z are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, X3 and Z are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, X1 and X2 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, X1 and X3 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, X2 and X3 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, Z, X1, and X2 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, Z, X1, and X3 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, Z, X2, and X3 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl. In some embodiments, X1, X2, and X3 are not H and are each selected from the group consisting of alkyl, halogen, halogenated alkyl, and cycloalkyl.

[0201] In some embodiments, at least two of Z, X1, X2, and X3 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, X1 and Z are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, X2 and Z are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, X3 and Z are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, X1 and X2 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, X1 and X3 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, X2 and X3 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, Z, X1, and X2 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, Z, X1, and X3 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, Z, X1, and X3 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, Z, X2, and X3 are not H and are each selected from the group consisting of halogen and alkyl. In some embodiments, X 1 , X 2 , and X 3 are not H and are each selected from the group consisting of halogen and alkyl.

[0202] In some embodiments, at least two of Z, X1, X2, and X3 are each independently Cl, Br, or methyl. In some embodiments, X1 and Z are each independently Cl, Br, or methyl. In some embodiments, X2 and Z are each independently Cl, Br, or methyl. In some embodiments, X3 and Z are each independently Cl, Br, or methyl. In some embodiments, X1 and X2 are each independently Cl, Br, or methyl. In some embodiments, X1 and X3 are each independently Cl, Br, or methyl. In some embodiments, X2 and X3 are each independently Cl, Br, or methyl. In some embodiments, Z, X1, and X2 are each independently Cl, Br, or methyl. In some embodiments, Z, X1, and X3 are each independently Cl, Br, or methyl. In some embodiments, Z, X2, and X3 are each independently Cl, Br, or methyl. In some embodiments, X1, X2, and X3 are each independently Cl, Br, or methyl.

[0203] In some embodiments, at least two of Z, X1, X2, and X3 are each Cl. In some embodiments, X1 and Z are each Cl. In some embodiments, X2 and Z are each Cl. In some embodiments, X3 and Z are each Cl. In some embodiments, X1 and X2 are each Cl. In some embodiments, X1 and X3 are each Cl. In some embodiments, X2 and X3 are each Cl. In some embodiments, Z, X1, and X2 are each Cl. In some embodiments, Z, X1, and X3 are each Cl. In some embodiments, Z, X2, and X3 are each Cl. In some embodiments, X1, X2, and X3 are each Cl.

[0204] In some embodiments, the structural moiety

[0205] [ka] teeth,

[0206] [ka] In some embodiments, the structural moiety

[0207] [ka] teeth,

[0208] [ka] In some embodiments, the structural moiety

[0209] [ka] teeth,

[0210] [ka] It has the following structure.

[0211] In some embodiments, the structural moiety

[0212] [ka] teeth,

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

[0214] In some embodiments, Y is absent. In some embodiments, Y is C(R).

[0215] In some embodiments, Y2 is absent. In some embodiments, Y2 is C(R1)2. In some embodiments, Y2 is C(R1)2C(R1)2. In some embodiments, Y2 is C(R1)2(C=O) or C(R1)2C(R1)2(C=O).

[0216] In some embodiments, Y and Y are each independently absent or C(R). In some embodiments, Y is absent and Y is C(R). In some embodiments, Y is C(R) and Y is C(R).

[0217] In some embodiments, the structural moiety

[0218] [ka] teeth,

[0219] [ka] In some embodiments, the structural moiety

[0220] [ka] teeth,

[0221] [ka] In some embodiments, the structural moiety

[0222] [ka] teeth,

[0223] [ka] It has the following structure.

[0224] In some embodiments, n1 is 0. In some embodiments, n1 is an integer from 1 to 3. In some embodiments, n1 is 2 or 3. In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 0 or 1. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3.

[0225] In some embodiments, at least one occurrence of R is H, alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, at least one occurrence of R is halogen, saturated heterocycle, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d In some embodiments, at least one occurrence of R is H, alkyl, or cycloalkyl. In some embodiments, at least one occurrence of R 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 R is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, at least one occurrence of R is halogen. Non-limiting examples of halogen include F, Cl, Br, and I.

[0226] In some embodiments, one or more occurrences of R1 is (CR4R5) n3 OR c or CR4R5) n3 NR c R d In some embodiments, one or more occurrences of R is OR c , N.R. c R d , -CH2OR c , -CH2NR c R d , -CH2CH2OR c , or -CH2CH2NR c R d In some particular embodiments, at least one occurrence of R is NH, CHNH, or CHCHNH. In other particular embodiments, at least one occurrence of R is OH, CHOH, or CHNH.

[0227] In still other embodiments, at least one occurrence of R1 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1-3 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, at least one occurrence of R1 is heteroaryl. In some embodiments, at least one occurrence of R1 is aryl. In some embodiments, at least one occurrence of R1 is

[0228] [ka] is selected from the group consisting of:

[0229] In some embodiments, the compound of Formula I has the structure of Formula Ia:

[0230] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, or alkyl; Z is H, halogen, alkyl, alkyl halide, CN, OR a , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d (It is).

[0231] In some embodiments, Z is H, halogen, alkyl, or alkyl halide. In some embodiments, Z is H, F, Cl, Br, CH3, or CF3. In some embodiments, Z is H. In some embodiments, Z is CN, OR a , or NR a R b In some embodiments, R a and R b Each occurrence of is independently H or alkyl. In some embodiments, R a and R b Each occurrence of is a cycloalkyl or heterocycle. a and R b Each occurrence of is aryl or heteroaryl.

[0232] In some specific embodiments, at least one occurrence of R is alkyl or cycloalkyl. In some embodiments, at least one occurrence of R is halogen, (CR4R5) n3 OR c or CR4R5) n3 NR c R d In some embodiments, at least one occurrence of R is a saturated heterocycle, aryl, or heteroaryl. In some embodiments, n is 0 or 1.

[0233] In some embodiments, the compound of Formula I has the structure of Formula Ib:

[0234] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, or alkyl; Z is H, halogen, alkyl, alkyl halide, CN, OR a , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d (It is).

[0235] In some embodiments, Z is H, halogen, alkyl, or alkyl halide. In some embodiments, Z is H, F, Cl, Br, CH3, or CF3. In some embodiments, Z is H. In some embodiments, Z is CN, OR a , or NR a R b In some embodiments, R a and R b Each occurrence of is independently H or alkyl. In some embodiments, R a and R b Each occurrence of is a cycloalkyl or heterocycle. a and R b Each occurrence of is aryl or heteroaryl.

[0236] In some specific embodiments, at least one occurrence of R is alkyl or cycloalkyl. In some embodiments, at least one occurrence of R is halogen, (CR4R5) n3 OR c or CR4R5) n3 NR c R d In some embodiments, at least one occurrence of R is a saturated heterocycle, aryl, or heteroaryl. In some embodiments, n is 0 or 1.

[0237] In some embodiments, R2 is alkyl, cycloalkyl, or heteroalkyl. In some embodiments, R2 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R2 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0238] In some embodiments, R2 is heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R2 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1-3 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R2 is heteroaryl. In some embodiments, R2 is aryl. In some embodiments, R2 is

[0239] [ka] wherein R2 heterocycle or heteroaryl, when valence permits, is alkyl, OH, oxo, or (C=O)C 1~4 and optionally substituted with alkyl.

[0240] In some embodiments, R2 is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl. Exemplary bicycloalkyl groups include, but are not limited to, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, and the like. Exemplary spirobicycloalkyl groups include, but are not limited to, spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, spiro[4.5]decyl, and the like. As used herein, the term "heterobicycloalkyl" refers to a bicycloalkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced with nitrogen, oxygen, or sulfur. As used herein, the term "heterospiroalkyl" refers to a spiroalkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced with nitrogen, oxygen, or sulfur. In some embodiments, R2 is

[0241] [ka] is selected from the group consisting of:

[0242] In yet other embodiments, R2 is (CR4R5) n2 (C=O)R3 or (CR4R5) n2 In some embodiments, R is CH(C=O)R, CHCH(C=O)R, (C=O)R, CH(C=O)NRR, or (C=O)NRR.

[0243] In some embodiments, R3 is H, alkyl, or cycloalkyl. In some embodiments, R3 is 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, R3 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0244] In some embodiments, R3 is heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R3 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1-3 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R3 is heteroaryl. In some embodiments, R3 is aryl. In some embodiments, R3 is

[0245] [ka] wherein R3 heterocycle or heteroaryl, when valence permits, is alkyl, OH, oxo, or (C=O)C 1~4 and optionally substituted with alkyl.

[0246] In some embodiments, R3 is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl. Exemplary bicycloalkyl groups include, but are not limited to, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, and the like. Exemplary spirobicycloalkyl groups include, but are not limited to, spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, spiro[4.5]decyl, and the like. As used herein, the term "heterobicycloalkyl" refers to a bicycloalkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced with nitrogen, oxygen, or sulfur. As used herein, the term "heterospiroalkyl" refers to a spiroalkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced with nitrogen, oxygen, or sulfur. In some embodiments, R3 is

[0247] [ka] is selected from the group consisting of:

[0248] In some embodiments, each of the alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in X, X, X, Z, R, R, or R, where applicable and valences permit, is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , C(=O)R c , COOR c , (CR4R5) n3 ORc , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0249] In some embodiments, R2 is SO2R c or SO2NR c R d In some embodiments, R2 is (CR4R5) n2 OR c , (CR4R5) n2 (CR4)((CR4R5) n3 OR c )2, (C=O)(CR4R5) n2 OR c , (C=O)(CR4R5) n2 (CR4)((CR4R5) n3 OR c )2, (CR4R5) n2 COOR c , (C=O)(CR4R5) n2 NR c R d , or (CR4R5) n2 NR c (C=O)R d In some particular embodiments, R2 is selected from the group consisting of SO2Me, SO2NHMe, SO2NMe2, SO2NHEt, CH2OH, CH2CH2OH, CHOMe, CH2CH(CH2OH)2, CH2CH(CH2CH2OH)2, CH2CH2CH(CH2OH)2, (C=O)CH2OH, (C=O)CH2CH2OH, (C=O)CH2CH(CH2OH)2, (C=O)CH2CH2CH(CH2CH2OH)2, (C=O)CH2CH2CH(CH2OH)2, CH2COOH, CH2CH2COOH, CH2COOMe, (C=O)CH2NH2, (C=O)NH2, (C=O)CH2NHMe, (C=O)NMe2, CH2NH(C=O)Me, and NH(C=O)Et.

[0250] In some embodiments, each occurrence of R4 and R5 is independently H, alkyl, cycloalkyl, or heterocycle. In some embodiments, each occurrence of R4 and R5 is independently H, CH3, or CH2CH3. In other particular embodiments, each occurrence of R4 and R5 is independently H and H, H and Me, Me and Me, H and Et, Me and Et, or Et and Et. In some embodiments, at least one occurrence of R4 or R5 is independently aryl or heteroaryl.

[0251] In some embodiments, R a and R b Each occurrence of is independently H or alkyl. In some embodiments, R a and R b Each occurrence of is independently H, CH, or CHCH. In some embodiments, R a and R b Each occurrence of is independently a cycloalkyl or a saturated heterocycle. a and R b Each occurrence of is independently aryl or heteroaryl.

[0252] Some embodiments include R a and R b are taken together with the nitrogen atom to which they are attached to form a heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R a and R b together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle. Non-limiting examples of 4-, 5-, or 6-membered heterocycles include azetidine, pyrrolidine, piperidine, and piperazine. In some particular embodiments, the 4-, 5-, or 6-membered heterocycle is

[0253] [ka] is.

[0254] In some embodiments, R c and R d Each occurrence of is independently H or alkyl. In some particular embodiments, R c and R d Each occurrence of is independently H, CH, or CHCH. In some embodiments, R c and R d Each occurrence of is independently a cycloalkyl or a heterocycle. c and R d Each occurrence of is independently aryl or heteroaryl.

[0255] Some embodiments include R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R c and R d together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle. Non-limiting examples of 4-, 5-, or 6-membered heterocycles include azetidine, pyrrolidine, piperidine, and piperazine. In some particular embodiments, the 4-, 5-, or 6-membered heterocycle is

[0256] [ka] is.

[0257] In some embodiments, n2 is an integer from 0 to 3. In some embodiments, n2 is an integer from 1 to 3. In some embodiments, n2 is 0. In some embodiments, n2 is 1 or 2. In some embodiments, n2 is 1. In some embodiments, n2 is 3 or 4.

[0258] In some embodiments, n3 is an integer from 0 to 3. In some embodiments, n3 is an integer from 1 to 3. In some embodiments, n3 is 0. In some embodiments, n3 is 1 or 2. In some embodiments, n3 is 1. In some embodiments, n3 is 3 or 4.

[0259] In some embodiments, the compound of Formula I has the structure of Formula Ic:

[0260] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, or alkyl; Z is H, halogen, alkyl, alkyl halide, CN, OR a , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d and R3 is alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl, where valences permit, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c and (CR4R5) n3 NR c R dand optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0261] In some embodiments, Z is H, halogen, alkyl, or alkyl halide. In some embodiments, Z is H, F, Cl, Br, CH3, or CF3. In some embodiments, Z is H. In some embodiments, Z is CN, OR a , or NR a R b In some embodiments, R a and R b Each occurrence of is independently H or alkyl. In some embodiments, R a and R b Each occurrence of is a cycloalkyl or heterocycle. a and R b Each occurrence of is aryl or heteroaryl.

[0262] In some specific embodiments, at least one occurrence of R is alkyl or cycloalkyl. In some embodiments, at least one occurrence of R is halogen, (CR4R5) n3 OR c or CR4R5) n3 NR c R d In some embodiments, at least one occurrence of R is a saturated heterocycle, aryl, or heteroaryl. In some embodiments, n is 0 or 1.

[0263] In some particular embodiments, R3 is, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R dIn some particular embodiments, R3 is, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d In some particular embodiments, R3 is, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d In some particular embodiments, R3 is, if valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d In some embodiments, R3 is a bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[0264] In some embodiments, the compound of Formula I has the structure of Formula Id:

[0265] [ka] (In the formula, X1, X2, and X3 are each independently H, halogen, or alkyl; Z is H, halogen, alkyl, alkyl halide, CN, OR a , or NR a R b and Each occurrence of R is independently H, alkyl, cycloalkyl, halogen, saturated heterocycle, aryl, heteroaryl, (CR4R5) n3 OR c , or (CR4R5) n3 NR c R d and R3 is alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl, where valences permit, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c and (CR4R5) n3 NR c R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0266] In some embodiments, Z is H, halogen, alkyl, or alkyl halide. In some embodiments, Z is H, F, Cl, Br, CH3, or CF3. In some embodiments, Z is H. In some embodiments, Z is CN, OR a , or NR a R bIn some embodiments, R a and R b Each occurrence of is independently H or alkyl. In some embodiments, R a and R b Each occurrence of is a cycloalkyl or heterocycle. a and R b Each occurrence of is aryl or heteroaryl.

[0267] In some specific embodiments, at least one occurrence of R is alkyl or cycloalkyl. In some embodiments, at least one occurrence of R is halogen, (CR4R5) n3 OR c or CR4R5) n3 NR c R d In some embodiments, at least one occurrence of R is a saturated heterocycle, aryl, or heteroaryl. In some embodiments, n is 0 or 1.

[0268] In some particular embodiments, R3 is, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d In some particular embodiments, R3 is, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR cR d In some particular embodiments, R3 is, where valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d In some particular embodiments, R3 is, if valence permits, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , and (CR4R5) n3 NR c R d In some embodiments, R3 is a bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[0269] In some embodiments, R2 is

[0270] [ka]

[0271] [ka]

[0272] [ka] is selected from the group consisting of:

[0273] In some embodiments, R2 is

[0274] [ka] is selected from the group consisting of:

[0275] In some embodiments, R2 is

[0276] [ka] is selected from the group consisting of:

[0277] In some embodiments, the alkyl, cycloalkyl, and heteroalkyl in X, X, and X are, where valences permit, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR4R5) n3 OR c , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d In some embodiments, the alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in Z are optionally substituted, if valence permits, with 1 to 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) n3 OR c , (CR4R5)n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d In some embodiments, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R are optionally substituted, if valence permits, with 1 to 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) n3 OR c , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d In some embodiments, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R2 are optionally substituted, if valence permits, with 1 to 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) n3 OR c , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d In some embodiments, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R3 are optionally substituted, if valence permits, with 1 to 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 , COORc , (CR4R5) n3 OR c , (CR4R5) n3 NR c R d , and (CR4R5) n3 NR c (C=O)R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0278] In some embodiments, the compound of formula I is selected from the group consisting of compounds 1-159 shown in Table 1 below.

[0279] [Table 1]

[0280] Preparation method Below are general synthetic schemes for preparing compounds of the present invention. These schemes are illustrative and are not meant to limit the possible techniques that one skilled in the art can use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Furthermore, the various steps in the synthesis can be performed in an alternating order or sequence to obtain the desired compounds. All documents cited herein are incorporated by reference in their entirety. For example, the following reactions are illustrative and not limiting of the preparation of some of the starting materials and compounds disclosed herein.

[0281] Schemes 1-6 below describe synthetic routes that can be used to synthesize compounds of the present invention, e.g., compounds having the structure of Formula I or precursors thereof. Various modifications to these methods can be envisioned by one skilled in the art to achieve results similar to the inventions described below. In the following embodiments, synthetic routes are described using compounds having the structure of Formula I or precursors thereof as examples. The general synthetic routes described in Schemes 1-6 and the examples provided in the Examples section below illustrate methods that may be used to prepare compounds described herein.

[0282] Compound I-1, shown in Scheme 1, can be prepared by any method known in the art and / or is commercially available. The substituents shown in Scheme 1 are defined herein.

[0283] Isatin I-1 can be reacted with trimethylsilylmethyl Grignard to give I-2. I-2 can undergo elimination in the presence of a Lewis acid such as boron trifluoride etherate to form methylene indolinone I-3. 1,3-Dipolar cycloaddition of I-3 with the dipolar precursor I-4 gives the spirocyclic system I-5. When R1 is not H, a mixture of regioisomers is obtained. Removal of the N-benzyl group can be achieved using 1-chloroethyl chloroformate or by catalytic hydrogenolysis to give I-6, a precursor to many compounds of the present invention. In some cases, the indolinone nitrogen must be protected to perform reactions on the basic nitrogen. This can be achieved by reacting I-5 with a protecting reagent such as paramethoxybenzyl chloride and a base such as potassium carbonate, optionally in the presence of potassium iodide, to give I-5a. The pyrrolidine nitrogen of I-5a can then be deprotected in a manner similar to that of I-5 to give I-6a.

[0284] [ka]

[0285] Alternatively, I-6 can be prepared by the route shown in Scheme 2. Compound I-7, shown in Scheme 2, can be prepared by any method known in the art and / or is commercially available. The substituents shown in Scheme 2 are defined herein. Phenylacetic acid ester 7 can be reacted with a nitrating reagent, such as a mixture of sulfuric and nitric acids, to give I-8. I-8 is converted to unsaturated ester I-9 by heating with aqueous formaldehyde and a base, such as potassium carbonate. Cycloaddition of I-9 with the 1,3-dipole precursor I-4 and an acid, such as TFA, in an aprotic solvent, such as THF, gives pyrrolidine I-10. When R1 is not H, a mixture of regioisomers is obtained. The nitro group of I-10 can be reduced by reaction with a reducing agent, such as zinc and hydrochloric acid, resulting in cyclization to spiroindolinone I-5. Removal of the N-benzyl group using 1-chloroethyl chloroformate as described in Scheme 1 gives I-6.

[0286] [ka]

[0287] A third route to spirocyclic systems, shown in Scheme 3, can also provide access to compounds substituted at each of the carbons in the pyrrolidine ring, starting from a suitably substituted indole I-11. Compound I-11, shown in Scheme 3, can be prepared by any method known in the art and / or is commercially available. The substituents shown in Scheme 3 are defined herein. Formylation of I-11 using DMF and phosphorus oxychloride under Villsmeier conditions affords I-12. I-12 can be condensed with a nitralkane, which also serves as a solvent, in the presence of a catalyst such as ammonium acetate to form nitroalkene I-13a (where R is a substituent such as alkyl). Similarly, reaction with nitromethane affords unsubstituted nitroalkene I-13b. Reduction of I-13a and I-13b is carried out in two steps, first by reducing the double bond with sodium borohydride, followed by reduction of the nitro group with a metal such as zinc in an acidic solvent such as acetic acid to form tryptamine I-15a or I-15b. Substitution at the carbon attached to the indole ring is achieved by reacting I-13b with the Grignard reagent R1MgBr in an ethereal solvent such as THF to form I-14. Reduction of I-14 with zinc and acetic acid affords tryptamine I-15c. Pictet-Spengler cyclization of I-15a or I-15c with formaldehyde, followed by protection of the amine with a Boc group, affords β-carbolines I-16a and I-16c, respectively. Cyclization of I-15b with an aldehyde R1CHO, optionally with an acid catalyst such as sulfuric acid, followed by Boc protection, affords I-16b. Treatment of β-carbolines I-16a, I-16b, and I-16c with N-bromosuccinimide in water and acetic acid results in rearrangement to the spiro ring system. After removal of the protecting groups, the substituted spiro pyrrolidines I-6b, I-6c, and I-6d are obtained as single positional isomers in each case. Pyrrolidines substituted at two or three different carbon atoms can be obtained by combining these routes, as shown in Scheme 3.

[0288] [ka]

[0289] Enantioselective synthesis of the spiroindolinone core can be carried out using the method described in Mukaiyama et al., Chem. Eur. J. 2014, 20, 13583-13588, as shown in Scheme 4. Compound I-1, shown in Scheme 4, can be prepared by any method known in the art and / or is commercially available. The substituents shown in Scheme 4 are defined herein.

[0290] A suitably substituted isatin I-1 is first protected on the nitrogen with a group such as benzyl or PMB to give I-17. Reaction of I-17 with acetaldehyde and a base such as DBU in a solvent such as THF while cooling to a low temperature, such as -25 °C, yields the aldol product I-18. Dehydration of I-18 under acidic conditions, such as sulfuric acid, in a solvent mixture containing acetic acid, water, and THF affords the enal I-19. Asymmetric Michael addition of nitromethane to I-19 using the R chiral auxiliary I-21 in isopropanol-containing water affords I-20, enriched in the S enantiomer. Treatment of I-20 with zinc in acetic acid and ethanol results in reduction of the nitro group, cyclization to the imine, and further reduction to give the spirocyclic pyrrolidine I-5aS as the S enantiomer. Removal of the PMB protecting group may be carried out either before or after further elaboration of the amine under acidic conditions, such as using a mixture of trifluoromethanesulfonic acid and trifluoroacetic acid, to give I-5S.

[0291] [ka]

[0292] As shown in Scheme 5, spiropiperidines such as compound I-22, which are commercially available or can be prepared by literature methods, are synthesized from imdolinones. The substituents shown in Scheme 5 are defined herein. A suitably substituted indolinone I-22 is reacted with N-boc bis(2-chloroethyl)amine in an inert solvent such as THF in the presence of a base such as sodium hydride to form spiropiperidine I-23. Removal of the Boc group under standard conditions affords I-24.

[0293] [ka]

[0294] Compounds bearing a spiropyrrolidine ring rather than a spiropyrrolidine can be prepared by the reaction sequence shown in Scheme 6. The substituents shown in Scheme 6 are defined herein. A suitably substituted isatin I-1 is first protected on the nitrogen with a group such as benzyl or p-methoxybenzyl. Condensation of the protected isatin I-17 with a cyanoacetic acid, such as methyl cyanoacetate, and an amine base, such as piperidine, affords I-25. Michael addition of nitromethane as a solvent in the presence of a base, such as piperidine, affords I-26. Heating I-26 with an alkali, such as potassium hydroxide, in water and alcohol results in hydrolysis and decarboxylation to afford the nitrile I-27. Hydrolysis of I-27 to the primary amide I-28 is achieved using acetamide and palladium chloride in aqueous THF. Reduction of the nitro group in I-28 with zinc in acetic acid leads to cyclization to afford the spiropyrrolidone I-29. I-29 can be N-alkylated with R3X under standard conditions and deprotected to give I-30.

[0295] [ka]

[0296] Pharmaceutical Composition The present invention also provides pharmaceutical compositions comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0297] In yet another aspect, the present invention provides pharmaceutical compositions comprising at least one compound selected from the group consisting of compounds of formula I described herein and a pharmaceutically acceptable carrier or diluent.

[0298] In certain embodiments, the composition is in the form of a hydrate, solvate, or a 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.

[0299] 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, that is involved in carrying or transporting a pharmaceutical agent of interest 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 harmful to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as butylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic compatible substances used in pharmaceutical preparations. The term "carrier" refers to a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate application. The components of the pharmaceutical compositions also are capable of being co-mingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0300] As mentioned above, certain embodiments of the pharmaceutical agent may be provided in the form of a pharmaceutically acceptable salt. In this regard, the term "pharmaceutically acceptable salt" refers to the 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 salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. See, for example, Berge et al., (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19, which is incorporated herein by reference in its entirety.

[0301] Pharmaceutically acceptable salts of the subject compounds include the conventional non-toxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and salts prepared from organic acids such as acetic acid, butionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

[0302] In other cases, the compounds disclosed herein may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds disclosed herein. These salts can also be prepared in situ during the final isolation and purification of the compounds, or separately from the purified compounds in their free acid form by reacting them 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. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, e.g., Berge et al. (supra).

[0303] Wetting agents, emulsifiers, lubricants, such as sodium lauryl sulfate, magnesium stearate, polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweeteners, flavors, perfumes, preservatives, and antioxidants can also be present in the composition.

[0304] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will depend upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0305] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0306] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (usually using a flavored base of sucrose and acacia or tragacanth), powder, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0307] In the solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; agar, calcium carbonate, potato, etc. Disintegrating agents such as potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymers; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0308] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxybutylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0309] Tablets and other solid dosage forms of the pharmaceutical compositions disclosed herein, such as dragees, capsules, pills, and granules, can optionally be provided or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. They can also be formulated to sustain or control the release of the active ingredient therein, for example, using different ratios of hydroxypropylmethylcellulose, other polymer 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 before use. These compositions can also optionally contain opacifying agents and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in the form of a microcapsule, if appropriate, with one or more of the above-mentioned excipients.

[0310] 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, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (e.g., 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.In addition, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, can be used to solubilize the compounds.

[0311] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, perfuming and preservative agents.

[0312] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0313] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0314] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0315] Powders and sprays may 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 may contain certain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0316] Transdermal patches have the added advantage of providing controlled delivery of the compounds disclosed herein to the body. Such dosage forms can be made by dissolving or dispersing the pharmaceutical agent in a suitable medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agent across the skin. The rate of such flux can be controlled by either providing a flux-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0317] Ophthalmic formulations, eye ointments, drops, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0318] 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 before use (which may contain antioxidants, buffers, bacteriostats, or solutes that render the formulation isotonic with the blood of the intended recipient or with suspending or thickening agents).

[0319] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn depends on the size and crystalline form of the crystals. Alternatively, delayed absorption of parenterally administered dosage forms can be achieved by dissolving or suspending the drug in an oil vehicle. One strategy for depot injection involves the use of polyethylene oxide-polypropylene oxide copolymers, whose vehicle is liquid at room temperature and solidifies at body temperature.

[0320] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. 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.

[0321] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they can be provided as they are, or they can be given as pharmaceutical compositions containing 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0322] 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 treatments. The specific combination of therapies (therapeutic agents or treatments) used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or treatments 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).

[0323] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds can be used to treat arthritic conditions in mammals (e.g., humans, livestock, and farm animals), racehorses, birds, lizards, and other organisms that can tolerate the compounds.

[0324] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, which containers may, if desired, be associated with a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting approval by the agency for manufacture, use, or sale for human administration.

[0325] Administration to subjects In yet another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from the group consisting of the compounds of Formula I, 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 CNS disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a renal disease.

[0326] 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.

[0327] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitis, or inflammatory neuropathies. In some embodiments, the gastroenterological disorder is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis.

[0328] 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.

[0329] 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 renal disease is chronic kidney disease, nephritis, or chronic renal failure.

[0330] In some embodiments, the mammalian species is human.

[0331] In some embodiments, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes mellitus, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontal disease, inflammatory bowel disease, obesity, type 2 diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0332] In yet another aspect, a method for blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0333] 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 therefore have a desirable cardiovascular safety profile.

[0334] Some aspects of the invention involve administering to a subject an effective amount of a composition to achieve a particular result. Accordingly, small molecule compositions useful according to the methods of the invention can be formulated in any manner suitable for pharmaceutical use.

[0335] The formulations of the present invention are administered in pharmaceutically acceptable solutions which may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0336] For use in therapy, an effective amount of the compound can be administered to a subject by any method that allows the compound to be taken up by appropriate target cells. "Administration" of the pharmaceutical composition of the present invention can be achieved by any means known to those skilled in the art. Specific administration routes include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, rectal, intravaginal, etc.). Injection can be bolus or continuous infusion.

[0337] For example, pharmaceutical compositions according to the present invention are often administered intravenously, intramuscularly, or by other parenteral means. They can also be administered intranasally, by inhalation, topically, orally, or by implant, and can also be used rectally or vaginally. Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous solutions or saline solutions for injection or inhalation, microencapsulated, encochleated, coated on fine gold particles, contained in liposomes, nebulized, aerosolized, pellets for skin implantation, or dried on a sharp object to scratch the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations that release the active compound slowly, which contain excipients and additives and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners, or solubilizers, as conventionally used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of current drug delivery methods, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference in its entirety.

[0338] The concentration of the compound contained in the composition used in the method of the present invention can range from about 1 nM to about 100 μM. Effective doses are believed to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0339] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders, and suppositories. Treatment of a patient may require different doses 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, the age, and the weight of the patient. The administration of a given dose can be carried out both by single administration in the form of individual dosage units, or in the form of several smaller dosage units. Repeated and multiple administration of the dose at specific intervals separated by days, weeks, or months is also contemplated by the present invention.

[0340] The composition can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. For pharmaceutical use, the salt must be pharmaceutically acceptable, although non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Additionally, such salts can be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0341] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0342] Compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations that can be isotonic with the recipient's blood. Acceptable vehicles and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed mineral or non-mineral oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid have found use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, and other administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA (incorporated herein by reference in its entirety).

[0343] The compounds useful in the present invention can be delivered in a mixture of three or more such compounds, which can further include one or more adjuvants in addition to the combination of compounds.

[0344] 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 therapeutic efficacy. Generally speaking, the methods of the present invention can be practiced using any medically acceptable mode of administration, i.e., any mode that provides an effective level of response without causing clinically unacceptable side effects. Preferred modes of administration are discussed above.

[0345] Composition can be conveniently presented in unit dosage form, and can be prepared by any method known in pharmaceutical technology.All methods include the step of associating compound with carrier that constitutes one or more auxiliary ingredients.Generally, composition is prepared by associating compound with liquid carrier, finely divided solid carrier, or both, uniformly and intimately, and then, if necessary, shaping product.

[0346] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems. Such systems can avoid repeated administration of the composition, thereby improving convenience for the patient and the physician. Many types of release delivery systems are available and known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Drug-containing microcapsules of the aforementioned polymers are described, for example, in U.S. Pat. No. 5,075,109. Delivery systems also include non-polymeric systems, such as lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids, or neutral lipids such as mono-, di-, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants, and the like. Specific examples include, but are not limited to: (a) erosion systems in which the agent of the invention is contained within a matrix, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusion systems in which the active ingredient permeates through a polymer at a controlled rate, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. Additionally, pump-based hardware delivery systems can be used, some of which are suitable for implantation.

[0347] Assay for efficacy of Kv1.3 potassium channel blockers In some embodiments, the compounds described herein are tested for their activity against 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.

[0348] equivalent The following representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the complete contents of this document, including the examples and references to the scientific and patent literature cited herein below. It is further understood that the contents of these cited references are incorporated herein by reference to help describe the state of the art. The following examples contain important additional information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof. [Example]

[0349] Examples 1-6 describe various intermediates used in the synthesis of representative compounds of Formula I disclosed herein.

[0350] Example 1. Intermediate 1S ((3S)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one) and Intermediate 1R ((3R)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0351] [ka]

[0352] Step A: To a stirred solution of 5,6-dichloro-1H-indole-2,3-dione (50.0 g, 231 mmol) in THF (3.50 L) was added (trimethylsilyl)methylmagnesium chloride (600 mL, 4.08 mol, 1.3 M in THF) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred for 2 h, quenched with saturated aqueous NH4Cl (1 L) at 0° C., and extracted with EA (3 × 1 L). The combined organic layers were washed with brine (2 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was suspended in PE and stirred for 15 min. The solid was collected by filtration and washed with PE (3×1 L) to give 5,6-dichloro-3-hydroxy-3-[(trimethylsilyl)methyl]-1H-indol-2-one as a yellow solid (52.0 g, crude), which was used in the next step without purification: C 12 H 15 Cl2NO2Si[MH] - LCMS (ESI) calculated for: 302, 304 (3:2); found: 302, 304 (3:2); 1 H NMR (300MHz, DMSO-d6) δ10.53(s,1H),7.49(s,1H),7.01(s,1H),5.96(s,1H),1.53-1.08(m,2H),-0.27(s,9H).

[0353] Step B: To a stirred mixture of 5,6-dichloro-3-hydroxy-3-[(trimethylsilyl)methyl]-1H-indol-2-one (52.0 g, 171 mmol) in DCM (520 mL) was added BF3Et2O (140 mL, 1.10 mol) under a nitrogen atmosphere at −78 °C. The reaction mixture was stirred at room temperature for 2 h. The precipitated solid was collected by filtration and washed with DCM (3 × 1 L) to give 5,6-dichloro-3-methylidene-1H-indol-2-one as a yellow solid (50.0 g, crude), which was used in the next step without purification. CH5Cl2NO:[MH] - LCMS (ESI) calculated for: 212, 214 (3:2); found: 212, 214 (3:2); 1H NMR (300MHz, DMSO-d6) δ10.73(s,1H),7.91(s,1H),7.01(s,1H),6.47(s,1H),6.28(s,1H).

[0354] Step C: To a stirred solution of 5,6-dichloro-3-methylidene-1H-indol-2-one (50.0 g, 233 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (83.2 g, 350 mmol) in THF (700 mL) was added TFA (26.0 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 70% ACN in water (+10 mM NH4HCO3) to give 1'-benzyl-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a yellow solid (20.0 g, 25% over three steps): C 18 H 16 Cl2N2O[M+H] + LCMS (ESI) calculated for: 347, 349 (3:2); found: 347, 349 (3:2); 1 H NMR(300MHz,DMSO-d6)δ10.61(s,1H),7.54(s,1H),7.42-7.12(m,5H),7.00(s,1H),3.71 (s,2H),3.31(s,1H),3.08(td,J=8.3,4.3Hz,1H),2.84-2.59(m,2H),2.27-1.85(m,2H).

[0355] Step D: A solution of 1'-benzyl-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one (20.0 g, 57.6 mmol) and chloroethyl chloroformate (32.9 g, 230 mmol) in DCE (200 mL) was stirred at 60 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (200 mL) and stirred at 60 °C for 30 min. The crude product was purified by reverse-phase flash chromatography eluting with 30% ACN in water (+10 mM NH4HCO3) to give 5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one as an off-white solid (9.60 g, 54%): C 11 H 10 Cl2N2O[M+H] + LCMS (ESI) calculated for: 257, 259 (3:2); found: 257, 259 (3:2); 1 H NMR (300MHz, DMSO-d6) δ10.46(s,1H),7.65(s,1H),7.01(s,1H),3.26-3.19(m,1H),3.06-2.94(m,3H),2.19-1.82(m,2H).

[0356] Step E: 5,6-Dichloro-1H-spiro[indole-3,3-pyrrolidin]-2-one (10.0 g, 38.9 mmol) was separated by preparative chiral SFC using the following conditions: Column: CHIRALPAK IG, 3 × 25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: MeOH (0.1% 2M NH-MEOH); Flow rate: 70 mL / min; Gradient: 60% B; Column temperature: 34 °C; Back pressure: 100 bar; Detector: UV 220 nm; Retention time 1: 4.99 min; Retention time 2: 9.00 min; Injection volume: 2 ml; Number of runs: 100. The faster eluting enantiomer, (3S)-5,6-dichloro-1H-spiro[indole-3,3-pyrrolidin]-2-one, at 4.99 min was obtained as an off-white solid (2.50 g, 24%): C 11 H 10 Cl2N2O[M+H] + LCMS (ESI) calculated for: 257, 259 (3:2); found: 257, 259 (3:2); 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.63 (s, 1H), 6.99 (s, 1H), 3.25-3.10 (m, 1H), 2.98 (dd, J = 11.8, 1.6 Hz, 3H), 2.10 (ddd, J = 13.3, 8.0, 5.5 Hz, 1H), 1.88 (ddd, J = 12.7, 7.9, 6.5 Hz, 1H). The slower eluting enantiomer, (3R)-5,6-dichloro-1H-spiro[indole-3,3-pyrrolidin]-2-one, was obtained as an off-white solid at 9.00 min (2.90 g, 26%): C 11 H 10 Cl2N2O[M+H] + LCMS (ESI) calculated for: 257, 259 (3:2); found: 257, 259 (3:2); 1 H NMR (300MHz, DMSO-d6) δ11.02(s,1H),7.96(d,J=1.2Hz,1H),7.09(s,1H),3.62-3.35(m,4H),2.36-2.08(m,2H).

[0357] Example 2. Intermediate 2 (5,6,7-trichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0358] [ka]

[0359] Step A: A mixture of 3,4,5-trichlorophenylboronic acid (2.00 g, 8.88 mmol), glycine ethyl ester hydrochloride (1.90 g, 13.6 mmol), NaNO (1.10 g, 16.0 mmol), and NHCl (1.90 g, 35.5 mmol) in toluene (20 mL) and HO (1 mL) was stirred at 100 °C for 16 h, diluted with EA (50 mL), and washed with brine (10 mL). The organic phase was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give ethyl 2-(3,4,5-trichlorophenyl)acetate as a pale yellow oil (1.65 g, 70%): 1 H NMR (400MHz, CDCl3) δ7.35(s,2H),4.20(q,J=7.1Hz,2H),3.57(s,2H),1.29(t,J=7.1Hz,3H).

[0360] Step B: To a solution of ethyl 2-(3,4,5-trichlorophenyl)acetate (2.00 g, 7.48 mmol) in concentrated H2SO4 (20 mL) was added concentrated HNO3 (0.600 g, 9.50 mmol) dropwise over 15 minutes at -10 °C to 0 °C. The reaction mixture was allowed to warm to room temperature over 1 hour and stirred for an additional 1 hour. The resulting mixture was poured into ice water (50 mL). The precipitate was filtered, and the filter cake was washed with water (100 mL) and dried under reduced pressure to give ethyl 2-(3,4,5-trichloro-2-nitrophenyl)acetate as an off-white solid (1.70 g, 73%): 1 H NMR (400MHz, CDCl3) δ7.53 (s, 1H), 4.21 (q, J = 7.1Hz, 2H), 3.64 (s, 2H), 1.29 (t, J = 7.1Hz, 3H).

[0361] Step C: To a solution of ethyl 2-(3,4,5-trichloro-2-nitrophenyl)acetate (1.80 g, 5.76 mmol) in HCHO (10 mL, 30% in HO) was added a solution of KCO (1.19 g, 8.64 mmol) in HO (4 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours and filtered. The filter cake was washed with water (10 mL) and dried under reduced pressure to give ethyl 2-(3,4,5-trichloro-2-nitrophenyl)prop-2-enoate as an off-white solid (1.70 g, 91%): 1 H NMR (400MHz, CDCl3) δ7.46(s,1H),6.66(s,1H),5.96(s,1H),4.27(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).

[0362] Step D: To a stirred solution of ethyl 2-(3,4,5-trichloro-2-nitrophenyl)prop-2-enoate (1.60 g, 4.93 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (1.29 g, 5.42 mmol) in THF (20 mL) was added TFA (0.620 g, 5.42 mmol) at room temperature. The reaction mixture was stirred for 2 hours, basified to pH 8 with saturated aqueous NaHCO3, and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (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 (5 / 1) to give ethyl 1-benzyl-3-(3,4,5-trichloro-2-nitrophenyl)pyrrolidine-3-carboxylate as a pale yellow foam (1.70 g, 75%): C 20 H 19 Cl3N2O4[M+H] + LCMS (ESI) calculated: 457, 459, 461 (3:3:1); found: 457, 459, 461 (3:3:1); 1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.41-7.34(m,4H),7.34-7.32(m,1H),4.27-4.17(m,1H),4.16-4.04(m,1H),3.79(d,J=12.9Hz,1H),3.56(d,J =13.0Hz,1H),3.18(d,J=9.9Hz,1H),3.00-2.88(m,2H),2.82(d,J=10.0Hz,1H),2.70(q,J=8.0Hz,1H),2.13-2.00(m,1H),1.23(t,J=7.1Hz,3H).

[0363] Step E: To a solution of ethyl 1-benzyl-3-(3,4,5-trichloro-2-nitrophenyl)pyrrolidine-3-carboxylate (0.400 g, 0.870 mmol) in EtOH (12 mL) and aqueous HCl (8 mL, 3 M) was added Zn (1.20 g, 18.4 mmol) portionwise at room temperature. The reaction mixture was stirred at 80 °C for 16 h, filtered through Celite, and washed with water (2 × 20 mL). The filtrate was basified to pH 9 with saturated aqueous NaHCO and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 1'-benzyl-5,6,7-trichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a pale yellow solid (0.250 g, 75%): C 18 H 15 Cl3N2O[M+H] + LCMS (ESI) calculated for: 381, 383, 385 (3:3:1); found: 381, 383, 385 (3:3:1); 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),7.57(s,1H),7.40-7.30(m,4H),7.28-7.21(m,1H),3.71(s,2H) ),3.14-3.01(m,1H),2.84(d,J=9.2Hz,1H),2.72-2.53(m,2H),2.28-2.16(m,1H),2.06-1.94(m,1H).

[0364] Step F: To a solution of 1'-benzyl-5,6,7-trichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.220 g, 0.580 mmol) in DCE (5 mL) was added chloroethyl chloroformate (0.390 g, 2.69 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL), stirred at 60 °C for 2 hours, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 55% ACN in water (+10 mM NH4HCO3) to give 5,6,7-trichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one as an off-white solid (0.120 g, 71%): C 11 H9Cl3N2O[M+H] + LCMS (ESI) calculated: 291, 293, 295 (3:3:1); found: 291, 293, 295 (3:3:1); 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),7.29(s,1H),3.53-3.37(m,2H),3.32-3.17(m,1H),3.05(d,J=11.9Hz,1H),2.55-1.96(m,3H).

[0365] Example 3. Intermediate 3 (5,6-dichloro-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0366] [ka]

[0367] Step A: To DMF (20 mL) was added dropwise POCl (2.47 g, 16.1 mmol) under a nitrogen atmosphere at −20° C. The solution was stirred for 0.5 h, and then a solution of 5,6-dichloro-1H-indole (2.00 g, 10.8 mmol) in DMF (5 mL) was added and stirred for an additional 1 h. The mixture was poured into ice water (50 mL), stirred for 15 min, and extracted with EA (3 × 50 mL). The aqueous solution was basified to pH 8 with KOH (20%) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 5,6-dichloro-1H-indole-3-carbaldehyde (1.80 g, 78%) as an orange solid: CHClNO [M+H]. + LCMS (ESI) calculated: 214, 216 (3:2); found: 214, 216 (3:2); 1 H NMR (300MHz, DMSO-d6) δ 12.36 (s, 1H), 9.94 (s, 1H), 8.42 (s, 1H), 8.23 ​​(s, 1H), 7.80 (s, 1H).

[0368] Step B: A mixture of 5,6-dichloro-1H-indole-3-carbaldehyde (1.80 g, 8.41 mmol) and ammonium acetate (0.780 g, 10.1 mmol) in aqueous CHNO (15 mL) was stirred at 90 °C for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give 5,6-dichloro-3-[(1E)-2-nitroprop-1-en-1-yl]-1H-indole as an orange solid (1.50 g, 66%): C 11 H8Cl2N2O2[MH] - LCMS (ESI) calculated: 269, 271 (3:2); found: 269, 271 (3:2); 1 H NMR (400MHz, CDCl3) δ8.74(s,1H),8.36(s,1H),7.91(s,1H),7.60(s,1H),7.59(d,J=2.8Hz,1H),2.55(s,3H).

[0369] Step C: To a solution of 5,6-dichloro-3-[(1E)-2-nitroprop-1-en-1-yl]-1H-indole (0.900 g, 3.32 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBH (0.500 g, 13.3 mmol) at room temperature. The reaction mixture was stirred for 2 h, quenched with water (50 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the residue was concentrated under reduced pressure and dissolved in AcOH (8 mL). Zn (1.30 g, 19.9 mmol) was added, and the reaction mixture was stirred for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography eluting with 45% ACN in water (+10 mM NH4HCO3) to give 1-(5,6-dichloro-1H-indol-3-yl)propan-2-amine as a pale yellow foam (0.400 g, 49%): C 11 H 12 Cl2N2[M+H] + LCMS (ESI) calculated: 243, 245 (3:2); found: 243, 245 (3:2); 1 H NMR(400MHz,CDCl3)δ8.34(s,1H),7.68(s,1H),7.47(s,1H),7.09(s,1H),3.37-3.22(m ,1H),2.84(dd,J=14.3,5.1Hz,1H),2.66(dd,J=14.3,8.2Hz,1H),1.20(d,J=6.3Hz,3H).

[0370] Step D: To a stirred solution of 1-(5,6-dichloro-1H-indol-3-yl)propan-2-amine (0.300 g, 1.23 mmol) in HFIP (5 mL) was added HCHO (0.120 g, 1.48 mmol, 37% aqueous solution) at room temperature. The reaction mixture was stirred for 1.5 h and concentrated under reduced pressure. The residue was dissolved in DCM (8 mL), and TEA (0.370 g, 3.70 mmol) and BocO (0.320 g, 1.48 mmol) were added. The reaction mixture was stirred for 1 h, diluted with water (50 mL), and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 6,7-dichloro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate as a yellow solid (0.450 g, crude), which was used directly in the next step without purification: C 17 H 20 Cl2N2O2[MH] - LCMS (ESI) calculated: 353, 355 (3:2); found: 353, 355 (3:2).

[0371] Step E: To a solution of tert-butyl 6,7-dichloro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (0.450 g, 1.27 mmol) in THF (8 mL), HO (4 mL), and AcOH (0.8 mL) was added NBS (0.250 g, 1.39 mmol) at room temperature. The reaction mixture was stirred for 1 h and concentrated under reduced pressure to give tert-butyl 5,6-dichloro-5'-methyl-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carboxylate as a brown oil (0.450 g, crude), which was used directly in the next step without purification: C 17 H 20 Cl2N2O3[MH] - LCMS (ESI) calculated: 369, 371 (3:2); found: 369, 371 (3:2).

[0372] Step F: To a stirred mixture of tert-butyl 5,6-dichloro-5'-methyl-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carboxylate (0.450 g, 1.21 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 20% ACN in water (+0.05% TFA) to give 5,6-dichloro-5'-methyl-1H-spiro[indole-3,3'-pyrrolidine]-2-one as a yellow solid (0.300 g, 64%): C 12 H 12 Cl2N2O[M+H] + LCMS (ESI) calculated for: 271, 273 (3:2); found: 271, 273 (3:2); 1 H NMR(300MHz,CD3OD)δ7.72(d,J=2.1Hz,1H),7.12(d,J=5.6Hz,1H),4.37-4.11(m,1H), 3.83-3.43(m,2H),2.62-2.39(m,1H),2.27-2.09(m,1H),1.57(dd,J=6.5,3.7Hz,3H).

[0373] Example 4. Intermediate 3b (5,6-dichloro-2'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0374] [ka]

[0375] Step A: To a stirred solution of 5,6-dichloro-1H-indole-3-carbaldehyde (2.00 g, 9.34 mmol) in CHNO (60.0 mL) was added CHCOONH (0.860 g, 11.2 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 5,6-dichloro-3-[(E)-2-nitroethenyl]-1H-indole as an orange solid (1.10 g, 46%): C 10H6Cl2N2O2[MH] - LCMS (ESI) calculated for: 255, 257 (3:2); found: 255, 257 (3:2); 1 H NMR (300MHz, DMSO-d6) δ12.38 (s, 1H), 8.43-8.35 (m, 2H), 8.33 (s, 1H), 8.16 (d, J = 13.5Hz, 1H), 7.78 (s, 1H).

[0376] Step B: To a stirred solution of 5,6-dichloro-3-[(E-2-nitroethenyl)-1H-indole (1.10 g, 4.28 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBH (0.320 g, 8.56 mmol) portionwise at room temperature. The reaction mixture was stirred for 30 min, quenched with water (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give 5,6-dichloro-3-(2-nitroethyl)-1H-indole as a yellow solid (0.730 g, 66%): C 10 H8Cl2N2O2[MH] - LCMS (ESI) calculated for: 257, 259 (3:2); found: 257, 259 (3:2); 1 H NMR (300MHz, CDCl3) δ8.11(s,1H),7.66(s,1H),7.50(s,1H),7.11(dd,J=2.3,1.0Hz,1H),4.73-4.62(m,2H),3.50-3.40(m,2H).

[0377] Step C: To a stirred solution of 5,6-dichloro-3-(2-nitroethyl)-1H-indole (0.730 g, 2.82 mmol) in HOAc (10.0 mL) was added Zn (1.84 g, 28.2 mmol) at room temperature. The reaction mixture was stirred for 16 hours and filtered. The filter cake was washed with EA (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN in water (+10 mM NH4HCO3) to give 2-(5,6-dichloro-1H-indol-3-yl)ethanamine as a colorless oil (0.550 g, 85%): C 10 H 10 Cl2N2[MH] - LCMS (ESI) calculated for: 227, 229 (3:2); found: 227, 229 (3:2); 1 H NMR (300MHz, CDCl3)8.05(s,1H),7.70(s,1H),7.49(s,1H),7.10(s,1H),3.04(t,J=6.7Hz,2H),2.87(t,J=6.7Hz,2H).

[0378] Step D: To a stirred solution of 2-(5,6-dichloro-1H-indol-3-yl)ethanamine (0.450 g, 1.96 mmol) in MeOH (10 mL) and HO (2 mL) was added acetaldehyde (0.129 g, 2.95 mmol) and concentrated HSO (19.26 mg, 0.196 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 6 hours and concentrated under reduced pressure. The crude product was dissolved in DCM (10 mL), and TEA (0.596 g, 5.89 mmol) and BocO (0.643 g, 2.95 mmol) were added at room temperature. The reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 78% ACN in water (+10 mM NH4HCO3) to give tert-butyl 6,7-dichloro-1-methyl-1H,3H,4H,9H-pyrido[3,4-b]indole-2-carboxylate as a yellow solid (0.250 g, 36%): C 17 H 20 Cl2N2O2[MH] -LCMS (ESI) calculated for: 353, 355 (3:2); found: 353, 355 (3:2); 1 H NMR(300MHz,CDCl3)δ7.55(s,1H),7.42(s,1H),5.47-5.15(m,1H),4.57-4.21(m ,1H),3.25-2.99(m,1H),2.87-2.59(m,2H),1.54(s,9H),1.49(d,J=6.77Hz,3H).

[0379] Step E: To a stirred solution of tert-butyl 6,7-dichloro-1-methyl-1H,3H,4H,9H-pyrido[3,4-b]indole-2-carboxylate (0.250 g, 0.704 mmol) in HO (1.00 mL), THF (2.00 mL), and AcOH (0.200 mL) was added NBS (0.250 g, 1.41 mmol) at room temperature. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The crude product was dissolved in DCM (2 mL), and TFA (0.500 mL) was added to the solution. The reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 45% ACN in water (+10 mM NH4HCO3) to give 5,6-dichloro-2'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a yellow oil (0.150 g, 79%): C 12 H 12 Cl2N2O[M+H] + LCMS (ESI) calculated: 271, 273 (3:2); found: 271, 273 (3:2): 1 H NMR(400MHz,CDCl3)δ8.21(s,1H),7.28(d,J=5.47Hz,1H),7.05(d,J=7.60Hz,1H),3.6 4-3.12(m,3H),2.61-2.31(m,1H),2.31-2.02(m,1H),0.98(dd,J=69.74,6.49Hz,3H).

[0380] Example 5. Intermediate 3c (5,6-dichloro-4'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0381] [ka]

[0382] Step A: To a stirred solution of 5,6-dichloro-3-[E-2-nitroethenyl]-1H-indole (1.10 g, 4.28 mmol) in THF (30 mL) was added dropwise CHMgBr (10.7 mL, 10.7 mmol, 1 M in THF) at −60° C. under a nitrogen atmosphere. The reaction mixture was stirred for 3 h, quenched with saturated aqueous NHCl (20 mL), and extracted with EA (3×50 mL). The combined organic layers were washed with brine (3×30 mL) and dried over anhydrous NaSO. 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 5,6-dichloro-3-(1-nitropropan-2-yl)-1H-indole as a yellow oil (0.950 g, 81%): C 11 H 10 Cl2N2O2[MH] - LCMS (ESI) calculated for: 271, 273 (3:2); found: 271, 273 (3:2); 1 H NMR(400MHz,DMSO-d6)δ11.27(s,1H),7.91(s,1H),7.61(s,1H),7.40(d,J= 2.4Hz, 1H), 4.89-4.78 (m, 2H), 3.82 (q, J=7.2Hz, 1H), 1.35 (d, J=7.0Hz, 3H).

[0383] Step B: To a stirred solution of 5,6-dichloro-3-(1-nitropropan-2-yl)-1H-indole (1.00 g, 3.66 mmol) in AcOH (15.0 mL) was added Zn (2.39 g, 36.6 mmol) at room temperature. The reaction mixture was stirred for 16 hours and filtered. The filter cake was washed with EA (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 60% ACN in water (+10 mM NH4HCO3) to give 2-(5,6-dichloro-1H-indol-3-yl)propan-1-amine as a yellow oil (0.80 g, 90%): C11 H 12 Cl2N2[MH] - LCMS (ESI) calculated for: 241,243 (3:2); found: 241,243 (3:2); 1 H NMR(300MHz,CDCl3)δ8.20(s,1H),7.73(s,1H),7.48(s,1H),7.05(d,J=2.3Hz,1H), 3.06(dd,J=12.9,6.4Hz,1H),3.05-2.88(m,2H),1.37(d,J=6.7Hz,2H),1.32(s,3H).

[0384] Step C: To a stirred solution of 2-(5,6-dichloro-1H-indol-3-yl)propan-1-amine (0.400 g, 1.65 mmol) in HFIP (8.00 mL) was added HCHO (0.260 g, 3.29 mmol) at room temperature. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The crude product was dissolved in DCM (5 mL), and TEA (0.332 g, 3.29 mmol) and BocO (0.538 g, 2.47 mmol) were added. The resulting reaction mixture was stirred for 4 hours and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 60% ACN in water (+10 mM NH4HCO3) to give tert-butyl 6,7-dichloro-4-methyl-1H,3H,4H,9H-pyrido[3,4-b]indole-2-carboxylate as a yellow oil (0.160 g, 27%): C 17 H 20 Cl2N2O2[MH] - LCMS (ESI) calculated for: 353, 355 (3:2); found: 353, 355 (3:2).

[0385] Step D: To a stirred solution of tert-butyl 6,7-dichloro-4-methyl-1H,3H,4H,9H-pyrido[3,4-b]indole-2-carboxylate (0.160 g, 0.450 mmol) in HO (1.00 mL), THF (2.00 mL), and AcOH (0.200 mL) was added NBS (0.160 g, 0.900 mmol) at room temperature. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The crude product was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The resulting reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 35% ACN in water (+0.05% TFA) to afford 5,6-dichloro-4'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a yellow oil (60.0 mg, 49%): C 12 H 12 Cl2N2O[MH] - LCMS (ESI) calculated for: 269, 271 (3:2); found: 269, 271 (3:2).

[0386] Example 6. Intermediate 4: (5,6-dichloro-1-[(4-methoxyphenyl)methyl]spiro[indole-3,3'-pyrrolidin]-2-one)

[0387] [ka]

[0388] Step A: To a stirred solution of 1'-benzyl-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one (8.50 g, 24.5 mmol) in DMF (100 mL) was added NaH (1.96 g, 49.0 mmol, 60% in oil) and PMBCl (4.60 g, 29.4 mmol) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 2 h, diluted with water (50 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 1'-benzyl-5,6-dichloro-1-[(4-methoxyphenyl)methyl]spiro[indole-3,3'-pyrrolidin]-2-one as a pale yellow oil (11.0 g, 96%): C 26 H 24 Cl2N2O2[M+H] + LCMS (ESI) calculated for: 467, 469 (3:2); found: 467, 469 (3:2); 1 H NMR(400MHz,DMSO-d6)δ7.61(s,1H),7.40-7.29(m,4H),7.28-7.19(m,4H),6.92-6.84(m,2H),4.83(s,2H),3.75-3.68(m,5H),3 .15-3.07(m,1H),2.82(d,J=9.07Hz,1H),2.70(d,J=9.08Hz,1H),2.61(q,J=8.29Hz,1H),2.30-2.21(m,1H),2.07-1.98(m,1H).

[0389] Step B: To a solution of 1'-benzyl-5,6-dichloro-1-[(4-methoxyphenyl)methyl]spiro[indole-3,3'-pyrrolidin]-2-one (9.00 g, 19.3 mmol) in DCE (90 mL) was added chloroethyl chloroformate (11.3 g, 78.8 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours and concentrated under reduced pressure. The residue was dissolved in MeOH (90 mL), stirred at 60 °C for 1 hour, and concentrated under reduced pressure. The residue was suspended in MTBE (30 mL) and filtered. The filter cake was dried under vacuum to give 5,6-dichloro-1-[(4-methoxyphenyl)methyl]spiro[indole-3,3'-pyrrolidin]-2-one as a pale yellow solid (5.00 g, 69%): C 19 H 18 Cl2N2O2[M+H] + LCMS (ESI) calculated for: 377, 379 (3:2); found: 377, 379 (3:2); 1 H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.28-7.18(m,3H),6.94-6.84(m,2H),4.84(s,2H), 3.71(s,3H),3.27-3.15(m,2H),3.10-2.99(m,2H),2.22-2.11(m,1H),2.03-1.88(m,1H).

[0390] Examples 7-23 describe the synthesis of representative compounds of Formula I disclosed herein.

[0391] Example 7. Compound 1 ((3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1), Compound 2 ((3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2) ), compound 3 ((3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 3), and compound 4 ((3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 4).

[0392] [ka]

[0393] Step A: To a stirred solution of (3S)-5,6-dichloro-1H-spiro[indole-3,3-pyrrolidin]-2-one (0.100 g, 0.390 mmol) and 1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-3-carboxylic acid (99.0 mg, 0.430 mmol) in DMF (2 mL) was added HOBT (68.0 mg, 0.510 mmol), EDCI (97.0 mg, 0.510 mmol), and TEA (0.120 g, 1.17 mmol) at room temperature. The reaction mixture was stirred for 1 h, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (5 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 3-[[(3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3-pyrrolidin]-1-yl]carbonyl]-4-hydroxypyrrolidine-1-carboxylate as a yellow oil (0.200 g, crude), which was used directly in the next step without purification: C 21 H 25 Cl2N3O5[M+H] +LCMS (ESI) calculated for: 470, 472 (3:2); found: 470, 472 (3:2).

[0394] Step B: To a stirred solution of tert-butyl 3-[[(3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3-pyrrolidin]-1-yl]carbonyl]-4-hydroxypyrrolidine-1-carboxylate (0.200 g, crude) in DCM (4 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The residue 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 50% B, 50% B in 5.3 min; Wavelength: UV 254 / 210 nm; Retention Time: 5.20 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give (3S)-5,6-dichloro-1-(4-hydroxypyrrolidine-3-carbonyl)-1H-spiro[indole-3,3-pyrrolidin]-2-one as an off-white solid (84.2 mg, 58% overall for 2 steps): C 16 H 17 Cl2N3O3[M+H] + LCMS (ESI) calculated for: 370, 372 (3:2); found: 370, 372 (3:2); 1 H NMR(300MHz,CD3OD)δ7.66-7.37(m,1H),7.12-7.08(m,1H),4.76-4.46(m,1H) ,4.25-3.65(m,4H),3.63-3.36(m,1H),3.28-2.74(m,4H),2.55-2.16(m,2H).

[0395] Step C: (3S)-5,6-Dichloro-1'-(4-hydroxypyrrolidine-3-carbonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (80.0 mg, 0.220 mmol) was separated by preparative chiral HPLC using the following conditions: Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; Mobile phase A: Hex (+0.3% IPA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 16 mL / min; Gradient: 50% B to 50% B in 25 min; Wavelength: UV 220 / 254 nm; Retention time 1: 11.61 min; Retention time 2: 21.49 min; Sample solvent: EtOH-HPLC; Injection volume: 1 mL. Two peaks, each containing two isomers, were isolated, with peak 1 eluting faster at 11.61 minutes and peak 2 eluting slower at 21.49 minutes. Peak 1 was further separated by preparative chiral HPLC using the following conditions: Column: CHIRALPAK AD-H, 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 28 min; Wavelength: UV 220 / 254 nm; Retention time 1: 10.95 min; Retention time 2: 21.24 min; Sample solvent: EtOH-HPLC; Injection volume: 2 mL; Run number: 3. The faster eluting isomer at 10.95 min, (3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1, was obtained as an off-white solid (8.30 mg, 10%): C 16 H 17 Cl2N3O3[M+H] + LCMS (ESI) calculated for: 370, 372 (3:2); found: 370, 372 (3:2); 1H NMR(400MHz,CD3OD)δ7.47(d,J=19.8Hz,1H),7.11(d,J=4.7Hz,1H),4.59-4.44(m,1H),4.27-3.61(m,4 H),3.43-3.36(m,0.5H),3.30-3.25(m,0.5H),3.23-2.97(m,3H),2.90-2.76(m,1H),2.49-2.18(m,2H). The slower eluting isomer, (3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2, was obtained as an off-white solid at 21.24 min (8.50 mg, 10%): C 16 H 17 Cl2N3O3[M+H] + LCMS (ESI) calculated for: 370, 372 (3:2); found: 370, 372 (3:2); 1 H NMR(400MHz,CD3OD)δ7.48(d,J=35.7Hz,1H),7.11(d,J=3.7Hz,1H),4.58-4.40(m,1H),4.15-3.66(m,4 H),3.41-3.35(m,0.5H),3.30-3.23(m,0.5H),3.22-3.01(m,3H),2.90-2.78(m,1H),2.50-2.20(m,2H). Peak 2 from the first separation was further separated by preparative chiral HPLC using the following conditions: Column: CHIRALPAK ID, 2 × 25 cm, 5 μm; Mobile phase A: MtBE (+0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 24 min; Wavelength: UV 220 / 254 nm; Retention time 1: 12.97 min; Retention time 2: 22.25 min; Sample solvent: EtOH-HPLC; Injection volume: 1 mL; Run number: 3. The faster eluting isomer at 12.97 min, (3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 3, was obtained as an off-white solid (2.40 mg, 3%): C 16 H 17 Cl2N3O3[M+H] +LCMS (ESI) calculated for: 370, 372 (3:2); found: 370, 372 (3:2); 1 H NMR (300 MHz, CD3OD) δ 7.52 (d, J = 80.3 Hz, 1H), 7.10 (d, J = 3.7 Hz, 1H), 4.74-4.45 (m, 1H), 4.23-3.65 (m, 4H), 3.56-3.44 (m, 1H), 3.23-2.86 (m, 4H), 2.56-2.14 (m, 2H). The slower eluting isomer, (3S)-5,6-dichloro-1'-[4-hydroxypyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 4, was obtained as an off-white solid at 22.25 min (3.90 mg, 4%): C 16 H 17 Cl2N3O3[M+H] + LCMS (ESI) calculated for: 370, 372 (3:2); found: 370, 372 (3:2); 1 H NMR(300MHz,CD3OD)δ7.52(d,J=80.3Hz,1H),7.11(d,J=3.7Hz,1H),4.77-4.49(m ,1H),4.17-3.66(m,4H),3.58-3.40(m,1H),3.23-2.85(m,4H),2.56-2.14(m,2H).

[0396] The compounds in Table 1A below were prepared in a manner similar to that described for compound 1, starting from intermediate 1S and the corresponding carboxylic acid (available from commercial sources).

[0397] [Table 2-1]

[0398] [Table 2-2]

[0399] [Table 2-3]

[0400] Table 2-4

[0401] Table 2-5

[0402] Table 2-6

[0403] Table 2-7

[0404] Table 2-8

[0405] Table 2-9

[0406] Table 2-10

[0407] Table 2-11

[0408] Table 2-12

[0409] Table 2-13

[0410] [Table 2-14]

[0411] [Table 2-15]

[0412] [Table 2-16]

[0413] [Table 2-17]

[0414] [Table 2-18]

[0415] [Table 2-19]

[0416] Example 8. Compound 93 ((3S)-5,6-dichloro-1'-[(1r,3r)-3-hydroxy-3-(hydroxymethyl)cyclobutanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one) and Compound 94 ((3S)-5,6-dichloro-1'-[(1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one))

[0417] [ka]

[0418] Step A: To a stirred solution of 3-methylidenecyclobutane-1-carboxylic acid (38.0 mg, 0.340 mmol) in DMF (1 mL) was added EDCI (89.0 mg, 0.470 mmol) and HOBT (63.0 mg, 0.470 mmol) at room temperature. To the above mixture was added TEA (94.0 mg, 0.930 mmol) and (3S)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one (80.0 mg, 0.310 mmol). The reaction mixture was stirred for 1.5 hours, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (3S)-5,6-dichloro-1'-(3-methylidenecyclobutanecarbonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one as an off-white solid (0.120 g, 62%), which was used directly in the next step without purification: C 17 H 16 Cl2N2O2[M+H] + LCMS (ESI) calculated for: 351, 353 (3:2); found: 351, 353 (3:2).

[0419] Step B: To a stirred mixture of (3S)-5,6-dichloro-1'-(3-methylidenecyclobutanecarbonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (80.0 mg, 0.230 mmol) in THF (0.5 mL), acetone (0.5 mL), and HO (0.5 mL) was added NMO (0.160 g, 1.37 mmol) and KOsO 2HO (8.39 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred for 3 h, quenched with saturated aqueous NaSO (0.5 mL), and concentrated under reduced pressure. The residue 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 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 50% B, 50% B in 4.5 min; Wavelength: UV 254 / 210 nm; Retention time: 4.35 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give (3S)-5,6-dichloro-1'-[3-hydroxy-3-(hydroxymethyl)cyclobutanecarbonyl]-1H-spiro[indole-3,3'[-pyrrolidin]-2-one as an off-white solid (61.0 mg, 69%): C 17 H 18 Cl2N2O4[M+H] + LCMS (ESI) calculated for: 385, 387 (3:2); found: 385, 387 (3:2); 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.51(dd,J=36.2,10.1Hz,1H),7.05(dd,J=4.1,1.1Hz,1H),4.97-4. 76(m,1H),4.63-4.44(m,1H),3.78-3.35(m,4H),3.31-3.08(m,3H),2.34-2.18(m,2H),2.18-1.87(m,3H).

[0420] Step C: (3S)-5,6-Dichloro-1'-[3-hydroxy-3-(hydroxymethyl)cyclobutanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one (57.0 mg, 0.150 mmol) was separated by preparative chiral HPLC using the following conditions: Column: Lux 5 μm Cellulose-4, 2.12 × 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: 20% B to 20% B in 35 min; wavelength: 220 / 254 nm; retention time 1: 6.76 min; retention time 2: 12.28 min; sample solvent: MeOH:EtOH = 1:1-HPLC; injection volume: 0.6 mL; run number: 4. The faster eluting isomer at 6.76 min, (3S)-5,6-dichloro-1'-[(1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one, was obtained as an off-white solid (12.9 mg, 22%): C 17 H 18 Cl2N2O4[M+H] + LCMS (ESI) calculated for: 385, 387 (3:2); found: 385, 387 (3:2); 1 H NMR(400MHz,DMSO-d6)δ10.79-10.72(brs,1H),7.50(d,J=35.98Hz,1H),7.05(d,J=3.91Hz,1H),4.93(d,J=15.89Hz,1H),4.56(d,J=4 7.76Hz,1H),3.64-3.80(m,2H),3.53-3.64(m,2H),3.37(s,1H),3.29(s,1H),2.60-2.88(m,1H),2.19-2.35(m,2H),1.95-2.19(m,4H). The slower eluting isomer, (3S)-5,6-dichloro-1'-[(1r,3r)-3-hydroxy-3-(hydroxymethyl)cyclobutanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one, was obtained at 12.28 min as an off-white solid (13.6 mg, 23%): C 17 H 18 Cl2N2O4[M+H] +LCMS (ESI) calculated for: 385, 387 (3:2); found: 385, 387 (3:2); 1 H NMR(400MHz,DMSO-d6)δ10.78-10.72(brs,1H),7.52(d,J=36.80Hz,1H),7.05(d,J=4.16Hz,1H),4.82(d,J=27.34Hz,1H),4.39- 4.57(m,1H),3.61-3.77(m,2H),3.52-3.60(m,2H),3.07-3.30(m,3H),2.20-2.38(m,3H),2.08-2.20(m,1H),1.88-2.07(m,2H).

[0421] Starting from intermediate 1S and commercially available 3-methylidenecyclopentane-1-carboxylic acid (available from commercial sources), the following compounds in Table 1B were prepared in a manner similar to that described for compound 93.

[0422] [Table 3]

[0423] Example 9. Compound 99 ((3S)-5,6-dichloro-1'-[(1R,3R)-rel-3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1) and Compound 100 ((3S)-5,6-dichloro-1'-[(1R,3R)-rel-3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2)

[0424] [ka]

[0425] Step A: To a stirred solution of 3-methylidenecyclopentane-1-carboxylic acid (0.120 g, 0.930 mmol), EDCI (0.220 g, 1.17 mmol) and HOBT (0.160 g, 1.17 mmol) in DMF (3 mL) was added TEA (0.240 g, 2.33 mmol) and (3S)-5,6-dichloro-1H-spiro[indole-3,3′-pyrrolidin]-2-one (0.200 g, 0.780 mmol) at room temperature. The reaction mixture was stirred for 2 h, quenched with MeOH (0.5 mL), and purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3S)-5,6-dichloro-1′-(3-methylidenecyclopentanecarbonyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a pale yellow solid (0.200 g, 70%): C 18 H 18 Cl2N2O2[M+H] + LCMS (ESI) calculated for: 365, 367 (3:2); found: 365, 367 (3:2); 1 H NMR(300MHz,CDCl3)δ8.14-8.37(m,1H),7.23(s,1H),7.09(d,J=8.62Hz,1H),4.85-4.99(m,2H),3.82-4. 14(m,3H),3.65-3.82(m,1H),2.78-3.11(m,1H),2.46-2.78(m,4H),2.19-2.46(m,2H),1.88-2.19(m,2H).

[0426] Step B: To a stirred solution of (3S)-5,6-dichloro-1'-(3-methylidenecyclopentanecarbonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.150 g, 0.410 mmol) in THF (5 mL) was added BH3-Me2S (94 μL, 1.23 mmol, 10 M) dropwise at 0 °C. The resulting reaction solution was stirred at 0 °C for 2 h under a nitrogen atmosphere. NaOH (41.0 mg, 1.03 mmol) and HO2 (35.0 mg, 1.03 mmol, 30%) were then added to the reaction mixture, which was then stirred for 30 min, 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 preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD Column, 19 × 150 mm, 5 μm; Mobile phase A: water (+10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 50% B, 50% B in 4.5 min; Wavelength: 210 nm; Retention time: 4.35 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give (3S)-5,6-dichloro-1'-[3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidine]-2-1 as an off-white solid (50.0 mg, 31%): C 18 H 20 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 383, 385 (3:2); found: 383, 385 (3:2); 1 H NMR(400MHz,CD3OD)δ7.36-7.47(m,1H),7.10(d,J=4.35Hz,1H),3.94-4.12(m,1H),3.62- 3.93(m,3H),3.40-3.58(m,2H),2.88-3.18(m,1H),2.10-2.47(m,3H),1.28-2.09(m,6H).

[0427] Step C: (3S)-5,6-Dichloro-1'-[3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one (50.0 mg, 0.130 mmol) was separated by preparative chiral HPLC using the following conditions: Column: CHIRALPAK IF, 2 x 25 cm, 5 μm; Mobile phase A: MtBE (+0.5% IPA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 10% B to 10% B in 30 min; Wavelength: UV 220 / 254 nm; Retention time 1: 16.34 min; Retention time 2: 24.17 min; Sample solvent: EtOH-HPLC; Injection volume: 0.75 mL; Number of runs: 4. Two peaks, each containing two isomers, were isolated: Peak 1, which eluted faster at 16.34 min, was obtained as an off-white solid (18.0 mg, 36%), and Peak 2, which eluted slower at 24.17 min, was obtained as an off-white solid (18.0 mg, 36%).

[0428] Step D: Peak 1 (18.0 mg, 0.047 mmol) was separated by preparative chiral-HPLC using the following conditions: Column: CHIRALPAK IG, 2 x 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: 50% B to 50% B in 21 min; wavelength: UV220 / 254 nm; retention time 1: 9.31 min; retention time 2: 16.17 min; sample solvent: EtOH-HPLC; injection volume: 1 mL; number of runs: 2. The faster eluting isomer at 9.31 min, (3S)-5,6-dichloro-1'-[(1R,3R)-rel-3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1, was obtained as an off-white solid (4.40 mg, 24%): C 18 H 20 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 383, 385 (3:2); found: 383, 385 (3:2); 1H NMR(400MHz,CD3OD)δ7.42(d,J=28.8Hz,1H),7.10(d,J=4.0Hz,1H),4.11-3.95(m,1H),3.93-3.65(m ,3H),3.54-3.40(m,2H),3.15-2.96(m,1H),2.46-2.18(m,3H),2.08-1.63(m,4H),1.46-1.30(m,2H). The slower eluting isomer, (3S)-5,6-dichloro-1'-[(1R,3S)-rel-3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1, was obtained at 16.17 min as an off-white solid (5.00 mg, 27%): C 18 H 20 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 383, 385 (3:2); found: 383, 385 (3:2); 1 H NMR(400MHz,CD3OD)δ7.42(d,J=30.4Hz,1H),7.10(d,J=4.6Hz,1H),4.11-3.96(m,1H),3.93-3.66(m,3H),3.60-3.46(m ,2H),3.16-2.96(m,1H),2.47-2.28(m,2H),2.26-2.10(m,2H),2.09-1.94(m,1H),1.92-1.77(m,2H),1.61-1.45(m,2H).

[0429] Step E: Peak 2 (18.0 mg, 0.05 mmol) was separated by preparative chiral HPLC using the following conditions: Column: CHIRALPAK IG, 2 x 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: 50% B to 50% B in 36 min; wavelength: UV220 / 254 nm; retention time 1: 12.42 min; retention time 2: 24.05 min; sample solvent: EtOH-HPLC; injection volume: 0.5 mL; number of runs: 2. The faster eluting isomer at 12.42 min was isolated to give (3S)-5,6-dichloro-1'-[(1R,3R)-rel-3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2 as a pale blue solid (4.60 mg, 25%): C 18 H 20 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 383, 385 (3:2); found: 383, 385 (3:2); 1 H NMR(400MHz,CD3OD)δ7.42(d,J=25.8Hz,1H),7.10(d,J=4.6Hz,1H),4.12-3.94(m,1H),3.93-3.65(m ,3H),3.52-3.38(m,2H),3.15-2.94(m,1H),2.49-2.17(m,3H),2.13-1.58(m,5H),1.49-1.25(m,1H). The slower eluting isomer at 24.05 min gave (3S)-5,6-dichloro-1'-[(1R,3S)-rel-3-(hydroxymethyl)cyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2 as a pale blue solid (4.80 mg, 26):C 18 H 20 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 383, 385 (3:2); found: 383, 385 (3:2); 1H NMR(400MHz,CD3OD)δ7.42(d,J=24.4Hz,1H),7.10(d,J=3.9Hz,1H),4.11-3.95(m,1H),3.91-3.66(m,3H),3.59-3.48(m ,2H),3.15-2.96(m,1H),2.45-2.31(m,3H),2.26-2.10(m,2H),2.06-1.93(m,1H),1.92-1.76(m,2H),1.49-1.25(m,1H).

[0430] Example 10. Compound 101 ((3S)-5,6-dichloro-1'-[(1S,3R,4S)-3,4-dihydroxycyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one) and Compound 102 ((3S))-5,6-dichloro-1'-[(1R,3R,4S)-3,4-dihydroxycyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0431] [ka]

[0432] Step A: To a stirred solution of cyclopent-3-ene-1-carboxylic acid (52.0 mg, 0.470 mmol), EDCI (0.110 g, 0.580 mmol), and HOBT (79.0 mg, 0.580 mmol) in DMF (2 mL) was added TEA (79.0 mg, 0.780 mmol) and (3S)-5,6-dichloro-1H-spiro[indole-3,3′-pyrrolidin]-2-one (0.100 g, 0.390 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, quenched with MeOH (0.5 mL), and purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3S)-5,6-dichloro-1′-(cyclopent-3-ene-1-carbonyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a pale yellow solid (0.110 g, 80%): C 17 H 16 Cl2N2O2[M+H] +LCMS (ESI) calculated for: 351, 353 (3:2); found: 351, 353 (3:2); 1 H NMR(400MHz,DMSO-d6)δ10.77(d,J=10.54Hz,1H),7.56(d,J=34.26Hz,1H),7.06(d,J=7.42Hz,1H),5.54-5.77(m,2H),3.83 -3.96(m,1H),3.78(s,1H),3.67-3.74(m,1H),3.58-3.67(m,2H),3.14-3.41(m,1H),2.53-2.69(m,3H),2.12-2.32(m,2H).

[0433] Step B: To a stirred solution of (3S)-5,6-dichloro-1'-(cyclopent-3-ene-1-carbonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.110 g, 0.310 mmol) and NMO (0.110 g, 0.940 mmol) in THF (0.5 mL), acetone (0.5 mL), and HO (0.5 mL) was added KOsO 2HO (12.0 mg, 0.03 mmol) at room temperature. The reaction mixture was stirred for 1 h, diluted with saturated aqueous NaSO (10 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue 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 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 20 mL / min; Gradient: 40% B to 60% B to 60% B in 4.5 min; Wavelength: 254 / 210 nm; Retention Time 1: 4.35 min, Retention Time 2: 5.01 min. The faster eluting isomer at 4.35 min, (3S)-5,6-dichloro-1'-[(1S,3R,4S)-3,4-dihydroxycyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one, was obtained as an off-white solid (47.1 mg, 39%): C 17 H 18 Cl2N2O4[M+H] +LCMS (ESI) calculated for: 385, 387 (3:2); found: 385, 387 (3:2); 1 H NMR(400MHz,DMSO-d6)δ10.69-10.60(brs,1H),7.55(d,J=33.7Hz,1H),7.05(d,J=5.7Hz,1H),4.48-4.31(m,2H),3. 97-3.79(m,3H),3.76-3.50(m,3H),3.26-3.03(m,1H),2.26(t,J=7.1Hz,1H),2.19-2.11(m,1H),1.95-1.63(m,4H). The slower eluting isomer, (3S)-5,6-dichloro-1'-[(1R,3R,4S)-3,4-dihydroxycyclopentanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one, was obtained as an off-white solid at 5.01 min (2.50 mg, 2%): C 17 H 18 Cl2N2O4[M+H] + LCMS (ESI) calculated for: 385, 387 (3:2); found: 385, 387 (3:2); 1 H NMR(400MHz,DMSO-d6)δ7.53(d,J=32.7Hz,1H),7.05(d,J=5.9Hz,1H),4.48-4.31(m,2H),3.97-3.79(m,2H),3.76 -3.53(m,4H),2.91-2.72(m,1H),2.26(t,J=7.1Hz,1H),2.19-2.07(m,1H),2.03-1.87(m,2H),1.78-1.65(m,2H).

[0434] Example 11 Compound 103 ((3S)-5,6-dichloro-1'-[(1R,(3R,4R)-rel)-3,4-dihydroxycyclohexanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1) and Compound 104 ((3S)-5,6-dichloro-1'-[(1R,(3R,4R)-rel)-3,4-dihydroxycyclohexanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2)

[0435] [ka]

[0436] Step A: To a stirred solution of (1R)-cyclohex-3-ene-1-carboxylic acid (59.0 mg, 0.470 mmol), EDCI (0.110 g, 0.580 mmol), and HOBT (79.0 mg, 0.580 mmol) in DMF (2 mL) was added TEA (79.0 mg, 0.780 mmol) and (3S)-5,6-dichloro-1H-spiro[indole-3,3′-pyrrolidin]-2-one (0.100 g, 0.390 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, quenched with MeOH (1 mL), and purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3S)-5,6-dichloro-1′-[(1R)-cyclohex-3-ene-1-carbonyl]-1H-spiro[indole-3,3′-pyrrolidin]-2-one as an off-white solid (0.120 g, 84%): C 18 H 18 Cl2N2O2[M+H] + LCMS (ESI) calculated for: 365, 367 (3:2); found: 365, 367 (3:2); 1 H NMR(400MHz,DMSO-d6)δ10.77(d,J=8.2Hz,1H),7.55(d,J=45.7Hz,1H),7.05(d,J=6.7Hz,1H),5.78-5.58(m,2H),3.95- 3.78(m,2H),3.71-3.54(m,2H),2.76-2.56(m,1H),2.36-1.94(m,6H),1.80(dd,J=40.4,13.0Hz,1H),1.56-1.39(m,1H).

[0437] Step B: To a stirred solution of (3S)-5,6-dichloro-1'-[(1R-cyclohex-3-ene-1-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.150 g, 0.410 mmol) and HO (0.5 mL, 6.44 mmol, 30%) in ACN (1 mL) and HO (1 mL) was added HCOOH (0.5 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. Aqueous NaOH (2 mL, 10 M) was added dropwise to the mixture, which was then stirred at 40 °C for 4 h and concentrated under reduced pressure. The residue was dissolved in water (+10 mmol / L Purification by reverse phase chromatography eluting with 30% ACN in NH4HCO3 gave (3S)-5,6-dichloro-1'-[(1R)-(trans)-3,4-dihydroxycyclohexanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one as an off-white solid (80.0 mg, 48%), which was used in the next step without purification: C 18 H 20 Cl2N2O4[M+H] + LCMS (ESI) calculated for: 399, 401 (3:2); found: 399, 401 (3:2).

[0438] Step C: (3S)-5,6-Dichloro-1'-[(1R)-(trans)-3,4-dihydroxycyclohexanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one (80.0 mg, 0.200 mmol) was separated by preparative chiral HPLC using the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 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 24 min; wavelength: UV 254 / 220 nm; retention time 1: 9.18 min; retention time 2: 20.67 min; sample solvent: EtOH-HPLC; injection volume: 1.2 mL; number of runs: 3. The faster eluting isomer at 9.18 min, (3S)-5,6-dichloro-1'-[(1R,(3R,4R)]-rel)-3,4-dihydroxycyclohexanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1, was obtained as an off-white solid (26.2 mg, 32%): C 18 H 20 Cl2N2O4[M+H] + LCMS (ESI) calculated for: 399, 401 (3:2); found: 399, 401 (3:2); 1 H NMR(400MHz,CD3OD)δ7.42(d,J=20.1Hz,1H),7.10(d,J=3.9Hz,1H),4.12-3.97(m,1H),3.98-3.84(m,2H),3.84-3.75(m ,1H),3.74-3.56(m,2H),3.05-2.84(m,1H),2.48-2.31(m,2H),2.28-2.01(m,2H),1.98-1.80(m,2H),1.76-1.61(m,2H). The slower eluting isomer, (3S)-5,6-dichloro-1'-[(1R,(3R,4R)-rel)-3,4-dihydroxycyclohexanecarbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2, was obtained at 20.67 min as an off-white solid (31.5 mg, 39%): C 18 H 20 Cl2N2O4[M+H] +LCMS (ESI) calculated for: 399, 401 (3:2); found: 399, 401 (3:2); 1 H NMR(400MHz,CD3OD)δ7.43(d,J=32.8Hz,1H),7.10(d,J=5.2Hz,1H),4.09-3.98(m,1H),3.98-3.75(m,3H),3.65( d,J=12.3Hz,1H),3.53-3.37(m,1H),2.79-2.59(m,1H),2.44-2.28(m,2H),2.09-1.90(m,2H),1.82-1.27(m,4H).

[0439] The compounds in Table 1C below were prepared in a manner similar to that described for compound 103, starting from intermediate 1S and the corresponding (1S)-cyclopent-3-ene-1-carboxylic acid or (1S)-cyclohex-3-ene-1-carboxylic acid (available from commercial sources).

[0440] [Table 4]

[0441] Example 12. Compound 109 ((3S)-5,6-dichloro-1'-[(3S,5S)-5-(methoxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one) and Compound 110 ((3S)-5,6-dichloro-1'-[(3R,5S)-5-(methoxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0442] [ka]

[0443] Step A: To a stirred solution of tert-butyl (2S,4S)-4-cyano-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.500 g, 2.21 mmol) in THF (5 mL) was added NaH (0.180 g, 4.38 mmol, 60% in oil) portionwise at 0 °C under a nitrogen atmosphere. After stirring for 15 min, CHI (0.630 g, 4.42 mmol) was added, and the reaction mixture was then stirred at room temperature for 1 h, quenched with water (20 mL) at 0 °C, and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 4) to give tert-butyl (2S,4S)-4-cyano-2-(methoxymethyl)pyrrolidine-1-carboxylate as a pale yellow solid (0.260 g, 48%): C 12 H 20 N2O3[M+H-56] + LCMS (ESI) calculated for: 185; found: 185; 1 H NMR(400MHz,DMSO-d6)δ3.83-3.93(m,1H),3.71-3.83(m,1H),3.33-3.54(m,3H), 3.26-3.33(m,4H),2.28-2.46(m,1H),1.97-2.10(m,1H),1.41(d,J=2.41Hz,9H).

[0444] Step B: To a stirred solution of tert-butyl (2S,4S)-4-cyano-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.250 g, 1.04 mmol) in MeOH (1 mL) was added a solution of NaOH (83.0 mg, 2.08 mmol) in HO (1 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 h, cooled to room temperature, and diluted with water (20 mL). The mixture was acidified to pH 6 with saturated aqueous citric acid and extracted with EA (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxymethyl)pyrrolidine-3-carboxylic acid as a yellow oil (0.230 g, 83%), which was used directly in the next step without purification: C 12 H 21 NO5[M+H] + LCMS (ESI) calculated for: 260; found: 260.

[0445] Step C: To a stirred solution of (3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxymethyl)pyrrolidine-3-carboxylic acid (97.0 mg, 0.370 mmol) in DMF (1.50 mL) was added HOBT (50.0 mg, 0.370 mmol), EDCI (71.0 mg, 0.370 mmol), TEA (94.0 mg, 0.930 mmol), and (3S)-5,6-dichloro-1H-spiro[indole-3,3-pyrrolidin]-2-one (80.0 mg, 0.310 mmol) at room temperature. The reaction mixture was stirred overnight, quenched with MeOH (0.5 mL), and purified by reverse-phase chromatography eluting with 56% ACN in water (+0.05% TFA) to give tert-butyl (2S,4S)-4-[[(3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3-pyrrolidin]-1-yl]carbonyl]-2-(methoxymethyl)pyrrolidine-1-carboxylate as a yellow solid (0.100 g, 64%): C 23 H 29 Cl2N3O5[M+H] +LCMS (ESI) calculated for: 498, 500 (3:2); found: 498, 500 (3:2); 1 H NMR(300MHz,CDCl3)δ7.96-8.21(m,1H),7.16-7.27(m,1H),7.08(d,J=11.39Hz,1H),4.05-4.19(m,2H),3.80-4.05(m, 3H), 3.56-3.80 (m, 3H), 3.29-3.51 (m, 5H), 2.41-2.57 (m, 1H), 2.17-2.41 (m, 2H), 1.98-2.17 (m, 1H), 1.46-1.54 (m, 9H).

[0446] Step D: To a stirred solution of tert-butyl (2S,4S)-4-[[(3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3-pyrrolidin]-1-yl]carbonyl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.100 g, 0.200 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 60% ACN in water (+0.05% TFA) to give an off-white solid (60.0 mg). The product was separated by preparative chiral HPLC using the following conditions: Column: (R,R-WHELK-O1-Kromasil, 2.11 × 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 35 min; wavelength: UV 220 / 254 nm; retention time 1: 21.14 min; retention time 2: 25.96 min; sample solvent: EtOH-HPLC; injection volume: 1 mL; number of runs: 3. The faster eluting isomer at 21.14 min, (3S)-5,6-dichloro-1'-[(3S,5S)-5-(methoxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one, was obtained as an off-white solid (23.8 mg, 29%): C 18 H 21 Cl2N3O3[M+H] +LCMS (ESI) calculated for: 398, 400 (3:2); found: 389, 400 (3:2); 1 H NMR(300MHz,CD3OD)δ7.45(d,J=18.13Hz,1H),7.10(d,J=3.60Hz,1H),3.91-4.13(m,1H),3.61-3.91( m,3H),3.40-3.52(m,2H),3.34-3.40(m,4H),3.00-3.30(m,3H),2.02-2.5(m,3H),1.73-1.98(m,1H). The slower eluting enantiomer, (3S)-5,6-dichloro-1'-[(3R,5S)-5-(methoxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one, was obtained as an off-white solid at 25.96 min (2.40 mg, 3%): C 18 H 21 Cl2N3O3[M+H] + LCMS (ESI) calculated: 398, 400 (3:2); found: 389, 400 (3:2); 1 H NMR(300MHz,CD3OD)δ7.38-7.53(m,1H),7.10(d,J=2.90Hz,1H),3.96-4.12(m,1H),3.60-3.96(m,3H) ,3.44-3.54(m,2H),3.39(d,J=3.23Hz,3H),2.99-3.27(m,4H),2.08-2.47(m,3H),1.62-1.88(m,1H).

[0447] The compounds in Table 1D below were prepared in a manner similar to that described for compound 109, starting from intermediate 1S and (3R,5R)-1-(tert-butoxycarbonyl)-5-(methoxymethyl)pyrrolidine-3-carboxylic acid, which was then prepared in a manner similar to (3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxymethyl)pyrrolidine-3-carboxylic acid, starting from tert-butyl (2R,4R)-4-cyano-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

[0448] [Table 5]

[0449] Example 13. Compound 113 (3S)-5,6-dichloro-1-[(3S,5S)-5-(hydroxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one) and Compound 114 ((3S)-5,6-dichloro-1'-[(3R,5S)-5-(hydroxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0450] [ka]

[0451] Step A: To a stirred solution of tert-butyl (2S-4-[[(3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3-pyrrolidin]-1-yl]carbonyl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.100 g, 0.200 mmol) in DCM (2 mL) at 0 °C under a nitrogen atmosphere was added BBr (0.100 g, 0.40 mmol). The reaction mixture was stirred at room temperature for 1 h, quenched with MeOH (2 mL), and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 56% ACN in water (+0.05% TFA) to give an off-white solid (50.0 mg). The product (50.0 mg) was separated by preparative chiral HPLC using the following conditions: Column: Lux 5 μm Cellulose-2, 2.12 × 25 cm, 5 μm; Mobile phase A: Hex (+0.5% IPA)-HPLC, Mobile phase B: IPA-HPLC; Flow rate: 18 mL / min; Gradient: 50% B to 50% B in 35 min; Wavelength: UV 220 / 254 nm; Retention time 1: 15.26 min; Retention time 2: 27.23 min; Injection volume: 1 mL; Number of runs: 4. The slower eluting isomer, (3S)-5,6-dichloro-1-[(3S,5S)-5-(hydroxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3-pyrrolidin]-2-one, was obtained as an off-white solid at 15.26 min (17.0 mg, 22%): C17 H 19 Cl2N3O3[M+H] + LCMS (ESI) calculated for: 384, 386 (3:2); found: 384, 386 (3:2); 1 H NMR (300 MHz, CD3OD) δ 7.49 (d, J = 18.79 Hz, 1H), 7.11 (d, J = 3.62 Hz, 1H), 3.90-4.12 (m, 2H), 3.74-3.90 (m, 3H), 3.56-3.74 (m, 3H), 3.39-3.56 (m, 2H), 1.99-2.50 (m, 4H). The slower eluting isomer, (3S)-5,6-dichloro-1-[(3R,5S)-5-(hydroxymethyl)pyrrolidine-3-carbonyl]-1H-spiro[indole-3,3-pyrrolidin]-2-one, was obtained as an off-white solid (4.40 mg, 5%) at 27.23 min: C 17 H 19 Cl2N3O3[M+H] + LCMS (ESI) calculated for: 384, 386 (3:2); found: 384, 386 (3:2); 1 H NMR(300MHz,CD3OD)δ7.45(d,J=14.37Hz,1H),7.10(d,J=3.44Hz,1H),3.77-4.12( m,4H),3.60-3.70(m,3H),2.98-3.31(m,3H),2.17-2.48(m,3H),1.68-1.93(m,1H).

[0452] The following compounds in Table 1E were prepared in a manner similar to that described for Compound 113, starting from tert-butyl (2R)-4-[[(3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3-pyrrolidin]-1-yl]carbonyl]-2-(methoxymethyl)pyrrolidine-1-carboxylate.

[0453] [Table 6]

[0454] The compounds in Table 1F were prepared in a manner similar to that described for compound 1, starting from glycolic acid and an appropriately substituted 1H-spiro[indole-3,3'-pyrrolidin]-2-one intermediate, which was then prepared in a manner similar to intermediates 1S and 1R.

[0455] [Table 7]

[0456] Example 14. Compound 121 ((3S-5,6,7-trichloro-1'-(2-hydroxyacetyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one) and Compound 122 ((3R-5,6,7-trichloro-1'-(2-hydroxyacetyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0457] [ka]

[0458] Step A: To a stirred solution of glycolic acid (45.0 mg, 0.590 mmol), HOBT (91.0 mg, 0.670 mmol), and EDCI (0.130 g, 0.680 mmol) in DMF (2 mL) was added TEA (0.180 g, 1.80 mmol) and 4,5,6-trichloro-1H-spiro[indole-3,3′-pyrrolidin]-2-one (Intermediate 2, 80.0 mg, 0.270 mmol) at room temperature. The reaction mixture was stirred for 2 h, quenched with MeOH (0.5 mL), and purified by reverse phase chromatography eluting with 55% ACN in water (+10 mM NH4HCO3) to give 5,6,7-trichloro-1'-(2-hydroxyacetyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one as an off-white solid (47.4 mg, 30%): C 13 H 11 Cl3N2O3[M+H] +LCMS (ESI) calculated for: 349, 351, 353 (3:3:1); found: 349, 351, 353 (3:3:1); 1 H NMR(400MHz,DMSO-d6)δ11.29(s,1H),7.60(d,J=41.32Hz,1H),4.72-4.67(brs,1H),4 .03-4.25(m,1H),3.99(s,1H),3.67-3.8(m,3H),3.61-3.67(m,1H),2.16-2.35(m,2H).

[0459] Step B: 5,6,7-Trichloro-1'-(2-hydroxyacetyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (40.0 mg, 0.110 mmol) was separated by preparative chiral HPLC under the following conditions: Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; Mobile phase A: Hex (+0.5% IPA), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 30.5 min; Detector: UV 220 / 254 nm; Retention time 1: 16.04 min; Retention time 2: 25.32 min. The faster eluting enantiomer, (3S-5,6,7-trichloro-1'-(2-hydroxyacetyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one) was obtained at 16.04 min as an off-white solid (13.9 mg, 34%): C 13 H 11 Cl3N2O3[M+H] + LCMS (ESI) calculated for: 349, 351, 353 (3:3:1); found: 349, 351, 353 (3:3:1); 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 7.60 (d, J = 41.3 Hz, 1H), 4.72-4.67 (brs, 1H), 4.03-4.22 (m, 1H), 3.99 (s, 1H), 3.66-3.8 (m, 3H), 3.64 (d, J = 2.8 Hz, 1H), 2.24-2.36 (m, 1H), 2.16-2.24 (m, 1H). The slower eluting enantiomer, (3R-5,6,7-trichloro-1'-(2-hydroxyacetyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one, was obtained as an off-white solid (12.9 mg, 32%) at 25.32 min: 13 H 11 Cl3N2O3[M+H] + LCMS (ESI) calculated for: 349, 351, 353 (3:3:1); found: 349, 351, 353 (3:3:1); 1 H NMR(400MHz,DMSO-d6)δ11.21(s,1H),7.60(d,J=41.3Hz,1H),4.72-4.67(brs,1H),4.03-4.22(m ,1H),3.99(s,1H),3.66-3.8(m,3H),3.64(d,J=2.8Hz,1H),2.24-2.36(m,1H),2.16-2.24(m,1H).

[0460] Example 15. Compound 129 ((3S)-5,6-dichloro-1'-(2-hydroxyacetyl)-7-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0461] [ka]

[0462] Step A: To a stirred solution of 3,4-dichloro-2-methylaniline (1.70 g, 9.66 mmol) and NaSO (8.23 g, 57.9 mmol) in HO (40.0 mL) was added hydroxylamine hydrochloride (2.01 g, 29.0 mmol) and chloral hydrate (1.92 g, 11.6 mmol) in small portions at room temperature. HCl (0.48 mL, 12 N) was then added dropwise over 3 minutes. The reaction mixture was stirred at 70 °C for 5 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with water (3 × 10 mL) to give N-(3,4-dichloro-2-methylphenyl)-2-(N-hydroxyimino)acetamide as a yellow solid (1.70 g, 71%): CHClNO[MH] - LCMS (ESI) calculated for: 245, 247 (3:2); found: 245, 247 (3:2); 1 H NMR (300MHz, CDCl3) δ8.24(s,2H),7.80(d,J=8.8Hz,1H),7.63(s,1H),7.36(d,J=8.8Hz,1H),2.40(s,3H).

[0463] Step B: N-(3,4-Dichloro-2-methylphenyl)-2-(N-hydroxyimino)acetamide (1.70 g, 6.88 mmol) was added portionwise to concentrated H2SO4 (15 mL) at 80 °C. The reaction mixture was stirred for 2 h. After cooling to room temperature, the reaction was poured into ice water (60 mL). The precipitate was filtered off and washed with water (3 × 10 mL) to give 5,6-dichloro-7-methyl-1H-indole-2,3-dione as a light brown solid (1.30 g, 82%): CH5Cl2NO2[MH] - LCMS (ESI) calculated for: 228, 230 (3:2); found: 228, 230 (3:2); 1 H NMR (300MHz, DMSO-d6) δ11.27(s,1H),7.64(s,1H),2.28(s,3H).

[0464] Step C: To a solution of 5,6-dichloro-7-methyl-1H-indole-2,3-dione (1.30 g, 5.65 mmol) in THF (30 mL) was added (trimethylsilyl)methylmagnesium chloride (18 mL, 159 mmol) in THF at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred for 2 h, quenched with saturated aqueous NH4Cl (25 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 (3 / 1) to give 5,6-dichloro-3-hydroxy-7-methyl-3-[(trimethylsilyl)methyl]-1H-indol-2-one as a yellow solid (0.800 g, 44%): C 13 H 17 Cl2NO2Si[MH] - LCMS (ESI) calculated for: 316, 318 (3:2); found: 316, 318 (3:2); 1 H NMR (400MHz, CDCl3) δ9.17(s,1H),7.33(s,1H),3.15(s,1H),2.37(s,3H),1.52(s,2H),-0.16(s,9H).

[0465] Step D: A solution of 5,6-dichloro-3-hydroxy-7-methyl-3-[(trimethylsilyl)methyl]-1H-indol-2-one (0.800 g, 2.51 mmol) in DCM (2 mL) was added to BF3 . EtO (3.50 g, 24.7 mmol) was added at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours and filtered. The filter cake was washed with DCM (5 mL) to give 5,6-dichloro-7-methyl-3-methylidene-1H-indol-2-one as a yellow solid (0.470 g, 82%): C 10 H7Cl2NO[M+H] + LCMS (ESI) calculated for: 228, 230 (3:2); found: 228, 230 (3:2); 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H), 7.83(s,1H), 6.48(s,1H), 6.28(s,1H), 2.29(s,3H).

[0466] Step E: To a solution of 5,6-dichloro-7-methyl-3-methylidene-1H-indol-2-one (0.470 g, 2.06 mmol) in THF (8 mL) was added TFA (0.258 g, 2.27 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (0.538 g, 2.27 mmol) under a nitrogen atmosphere at −78° C. The reaction mixture was stirred at room temperature for 2 hours, basified to pH 8 with saturated aqueous NaHCO and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 1'-benzyl-5,6-dichloro-7-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a pale yellow solid (0.500 g, 67%): C 19 H 18 Cl2N2O[M+H] + LCMS (ESI) calculated for: 361, 363 (3:2); found: 361, 363 (3:2); 1 H NMR(300MHz,CDCl3)δ8.68(s,1H),7.51(s,1H),7.44-7.29(m,5H),3.78(s,2H),3.25 -3.11(m,1H),3.00-2.62(m,3H),2.49-2.39(m,1H),2.36(s,3H),2.16-2.00(m,1H).

[0467] Step F: To a solution of 1'-benzyl-5,6-dichloro-7-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.500 g, 1.38 mmol) in DCE (5 mL) was added chloroethyl chloroformate (1.00 g, 6.99 mmol) in one portion at room temperature. The reaction mixture was stirred at 60 °C for 2 hours and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL), stirred at 60 °C for 1 hour, and evaporated. The residue was purified by reverse-phase chromatography eluting with 45% ACN in water (+20 mM NH4HCO3) to give 5,6-dichloro-7-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a pale yellow solid (0.220 g, 59%): C 12 H 12 Cl2N2O[M+H] + LCMS (ESI) calculated for: 271, 273 (3:2); found: 271, 273 (3:2); 1 H NMR (300MHz, CD3OD) δ7.50 (s, 1H), 3.80-3.59 (m, 3H), 3.56-3.49 (m, 1H), 2.53-2.30 (m, 5H).

[0468] Step G: To a solution of glycolic acid (67.0 mg, 0.890 mmol), EDCI (0.212 g, 1.11 mmol), and HOBT (0.149 g, 1.11 mmol) in DMF (1 mL) was added 5,6-dichloro-7-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.200 g, 0.738 mmol) and TEA (0.224 g, 2.21 mmol) at room temperature. The reaction mixture was stirred for 2 hours, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 5,6-dichloro-1'-(2-hydroxyacetyl)-7-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one as an off-white solid (70.0 mg, 29%): C 14 H 14 Cl2N2O3[M+H]+ LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR (300MHz, CD3OD) δ7.32 (d, J = 18.3Hz, 1H), 4.33-4.17 (m, 2H), 3.92-3.68 (m, 4H), 2.46-2.25 (m, 5H).

[0469] Step H: 5,6-Dichloro-1'-(2-hydroxyacetyl)-7-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one (30.0 mg, 0.0911 mmol) was separated by preparative chiral HPLC using the following conditions: Column: (R,R)-WHELK-O1-Kromasil, 2.12 x 25 cm, 5 μm; Mobile phase A: Hex (+0.5% IPA), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 35% B to 35% B in 22 min; Detector: UV 220 / 254 nm; Retention time 1: 15.22 min; Retention time 2: 19.77 min; Sample solvent: EtOH. The slower eluting enantiomer, (3S)-5,6-dichloro-1'-(2-hydroxyacetyl)-7-methyl-1H-spiro[indole-3,3'-pyrrolidine]-2-1, was obtained as an off-white solid at 15.22 min (10.0 mg, 33%): C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.43 (d, J = 29.4 Hz, 1H), 4.73-4.61 (m, 1H), 4.24-3.95 (m, 2H), 3.73 (q, J = 7.7 Hz, 2H), 3.63 (d, J = 14.1 Hz, 2H), 2.31 (s, 3H), 2.27-2.19 (m, 1H), 2.18-2.07 (m, 1H). The slower eluting enantiomer, (3R)-5,6-dichloro-1'-(2-hydroxyacetyl)-7-methyl-1H-spiro[indole-3,3'-pyrrolidine]-2-1, was obtained as an off-white solid at 19.77 min (12.2 mg, 41%): C14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR(300MHz,DMSO-d6)δ10.91(s,1H),7.43(d,J=29.4Hz,1H),4.73-4.61(m,1H),4.24-3.95(m,2H) ,3.73(q,J=7.7Hz,2H),3.63(d,J=14.1Hz,2H),2.31(s,3H),2.27-2.19(m,1H),2.18-2.07(m,1H).

[0470] The compounds in Table 1G below were prepared in a manner similar to that described for compound 129, starting from either the corresponding aniline or the corresponding 1H-indole-2,3-dione (available from commercial sources).

[0471] [Table 8]

[0472] Example 16 Compound 123 (5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1), Compound 124 (5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2), Compound 125 (5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 3), and Compound 126 (5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 4)

[0473] [ka]

[0474] Step A: To a stirred mixture of glycolic acid (44.0 mg, 0.580 mmol) and HOBT (79.0 mg, 0.580 mmol) in DMF (2 mL), 5,6-dichloro-5′-methyl-1H-spiro[indole-3,3′-pyrrolidin]-2-one (Intermediate 3, 0.150 g, 0.390 mmol) and TEA (0.120 g, 1.17 mmol) were added at room temperature. The reaction was stirred at 40 °C for 1 h, quenched with MeOH (0.5 mL), and 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: 20 mL / min; Gradient: 30% B to 40% B, 40% B in 5.5 min; Wavelength: UV 254 / 210 nm; Retention Time 1: 3.75 min; Retention Time 2: 5.00 min. The fraction at 3.75 min gave 5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereomer A as a colorless oil (45.0 mg, 27%): C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.12 (s, 2H), 4.61-4.23 (m, 1H), 4.23-4.03 (m, 2H), 3.81-3.53 (m, 2H), 2.53-2.02 (m, 2H), 1.48 (dd, J = 6.3, 2.5 Hz, 3H). The 5.00 min fraction gave 5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereomer B (45.0 mg, 27%) as a colorless oil: C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1H NMR(400MHz,CD3OD)δ7.60(d,J=7.4Hz,1H),7.07(s,1H),4.60-4.35(m,1H),4.32-4.04 (m,2H),3.88-3.53(m,2H),2.68-2.44(m,1H),2.19-1.95(m,1H),1.47(d,J=6.2Hz,3H).

[0475] Step B: 5,6-Dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereoisomer A (45.0 mg, 0.140 mmol) was separated by preparative chiral HPLC using the following conditions: Column: CHIRAL ART Amylose-SA, 2 x 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: 50% B to 50% B in 16 min; wavelength: UV220 / 254 nm; retention time 1: 6.95 min; retention time 2: 12.33 min; sample solvent: EtOH-HPLC; injection volume: 1.5 mL; number of runs: 4. The faster eluting isomer at 6.95 min, 5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 1, was obtained as an off-white solid (12.6 mg, 28%): C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR (300 MHz, CD3OD) δ 7.59 (s, 1H), 7.06 (s, 1H), 4.64-4.35 (m, 1H), 4.36-4.00 (m, 2H), 3.85-3.55 (m, 2H), 2.68-2.36 (m, 1H), 2.21-1.97 (m, 1H), 1.47 (d, J = 6.3 Hz, 3H). The slower eluting isomer, 5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 2, was obtained as an off-white solid at 12.33 min (17.3 mg, 38%): C14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR(300MHz,CD3OD)δ7.59(s,1H),7.06(s,1H),4.60-4.33(m,1H),4.31-4.01(m,2 H),3.89-3.48(m,2H),2.66-2.35(m,1H),2.24-1.97(m,1H),1.47(d,J=6.3Hz,3H).

[0476] Step C: 5,6-Dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereoisomer B (45.0 mg, 0.140 mmol) was separated by preparative chiral HPLC using the following conditions: Column: CHIRAL ART Amylose-SA, 2 x 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: 50% B to 50% B in 10 min; wavelength: UV220 / 254 nm; retention time 1: 5.29 min; retention time 2: 8.44 min; sample solvent: EtOH-HPLC; injection volume: 1.5 mL; number of runs: 3. The faster eluting isomer at 5.29 min, 5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 3, was obtained as an off-white solid (13.5 mg, 30%): C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1H NMR (300 MHz, CD3OD) δ 7.12 (s, 2H), 4.60-4.41 (m, 1H), 4.34-4.01 (m, 2H), 3.80-3.55 (m, 2H), 2.54-1.98 (m, 2H), 1.48 (d, J = 6.1 Hz, 3H). The slower eluting isomer, 5,6-dichloro-1'-(2-hydroxyacetyl)-5'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one isomer 4, was obtained as an off-white solid at 8.44 min (15.7 mg, 35%): C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR(300MHz,CD3OD)δ7.12(s,2H),4.61-4.39(m,1H),4.34-4.01(m,2H),3.7 9-3.60(m,2H),2.55-2.27(m,1H),2.27-2.03(m,1H),1.48(d,J=6.2Hz,3H).

[0477] Example 17. Compound 133 (5,6-dichloro-1'-(2-hydroxyacetyl)-2'-methylspiro[indoline-3,3'-pyrrolidin]-2-one diastereoisomer 1) and Compound 134 (5,6-dichloro-1'-(2-hydroxyacetyl)-2'-methylspiro[indoline-3,3'-pyrrolidin]-2-one diastereoisomer 2)

[0478] [ka]

[0479] Step A: To a stirred solution of glycolic acid (54.7 mg, 0.719 mmol), HOBT (97.2 mg, 0.719 mmol), and EDCI (0.137 g, 0.715 mmol) in DMF (0.5 mL) was added TEA (0.145 g, 1.44 mmol) and 5,6-dichloro-2'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.130 g, 0.479 mmol) at room temperature. The mixture was stirred for 2 hours, 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 preparative HPLC using the following conditions: Column: X Bridge 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, 40% B in 5.5 min; Detector: UV 254 / 220 nm; Retention time 1: 4.80 min, Retention time 2: 5.30 min.

[0480] The faster eluting isomer, 5,6-dichloro-1'-(2-hydroxyacetyl)-2'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereomer 1, was obtained at 4.80 min as an off-white solid (44.6 mg, 28%): C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.48-7.36 (m, 1H), 7.13-7.05 (m, 1H), 4.37-4.16 (m, 3H), 4.07-3.88 (m, 1H), 3.88-3.76 (m, 1H), 2.58-2.37 (m, 1H), 2.35-2.22 (m, 1H), 1.37-1.25 (m, 3H). The slower eluting isomer, 5,6-dichloro-1'-(2-hydroxyacetyl)-2'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereomer 2, was obtained as an off-white solid at 5.30 min (3.5 mg, 2%): C14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR (400MHz, CD3OD) δ7.54(s,1H),7.10(s,1H),4.33-4.13(m,3H),4.01-3.69(m,2H),2.61-2.39(m,1H),2.39-2.15(m,1H),1.42-1.22(m,3H).

[0481] Example 18. Compound 130 (5,6-dichloro-1'-(2-hydroxyacetyl)-4'-methylspiro[indoline-3,3'-pyrrolidin]-2-one diastereoisomer 1) and Compound 131 (5,6-dichloro-1'-(2-hydroxyacetyl)-4'-methylspiro[indoline-3,3'-pyrrolidin]-2-one diastereoisomer 2)

[0482] [ka]

[0483] Step A: To a stirred solution of glycolic acid (25.2 mg, 0.331 mmol), HOBT (44.9 mg, 0.332 mmol), and EDCI (63.6 mg, 0.332 mmol) in DMF (1 mL) was added TEA (67.2 mg, 0.663 mmol) and 5,6-dichloro-4'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one (60.0 mg, 0.221 mmol) at room temperature. The reaction mixture was stirred for 2 h, diluted with water (30 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: X Bridge Prep C18 OBD Column, 19 × 100 mm, 5 μm; Mobile phase A: water (+10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B, 50% B in 4.5 min; Detector: UV 254 / 220 nm; Retention time 1: 4.35 min, Retention time 2: 4.60 min. The faster eluting isomer at 4.35 min, 5,6-dichloro-1'-(2-hydroxyacetyl)-4'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereomer 1, was obtained as an off-white solid (2.60 mg, 4%): C 14 H 14 Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2); 1 H NMR (300 MHz, CD3OD) δ 7.27 (d, J = 38.03 Hz, 1H), 7.14 (s, 1H), 4.42-4.21 (m, 1H), 4.21-3.90 (m, 2H), 3.87-3.69 (m, 2H), 3.53-3.36 (m, 1H), 2.97-2.71 (m, 1H), 0.75 (d, J = 6.78 Hz, 3H). The slower eluting diastereomer, 5,6-dichloro-1'-(2-hydroxyacetyl)-4'-methyl-1H-spiro[indole-3,3'-pyrrolidin]-2-one diastereomer 2, was obtained at 4.60 min as an off-white solid (4.40 mg, 6%). 14 H 14Cl2N2O3[M+H] + LCMS (ESI) calculated for: 329, 331 (3:2); found: 329, 331 (3:2): 1 H NMR(300MHz,CD3OD)δ7.55(d,J=3.10Hz,1H),7.08(d,J=1.56Hz,1H),4.32-4.14(m,2H),4.03-3.91(m,1H),3. 88-3.76(m,1H),3.72(d,J=12.42Hz,1H),3.61-3.50(m,1H),2.93-2.66(m,1H),0.88(dd,J=6.78,2.30Hz,3H).

[0484] Example 19. Compound 144 ((3S)-1'-(5-aminopyrazin-2-yl)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0485] [ka]

[0486] Step A: To a stirred solution of (3S)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one (60.0 mg, 0.233 mmol) and 2-chloro-5-nitropyrazine (45.0 mg, 0.282 mmol) in DMA (1.00 mL) was added CsCO (0.152 g, 0.467 mmol) at room temperature. The reaction mixture was stirred for 1 h and directly purified by reverse-phase chromatography eluting with 50% ACN in water (+10 mM NH4HCO3) to give (3S)-5,6-dichloro-1'-(5-nitropyrazin-2-yl)-1H-spiro[indole-3,3'-pyrrolidine]-2-one as a yellow solid (60.0 mg, 68%). 15 H 11 Cl2N5O3[MH] - LCMS (ESI) calculated: 378, 380 (3:2); found: 378, 380 (3:2); 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.08(s,1H),8.02(d,J=48.2Hz,1H),7.70(s,1H),7.09(s,1H),4.03-3.93(m,4H),2.41(s,2H).

[0487] Step B: To a stirred solution of (3S)-5,6-dichloro-1'-(5-nitropyrazin-2-yl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (60.0 mg, 0.159 mmol) and CaCl2 (79.0 mg, 0.712 mmol) in EtOH (4 mL) and HO (1 mL) was added Fe (0.264 g, 4.73 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h and filtered. The filter cake was washed with EtOH (3 × 10 mL), and 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; Mobile phase A: water (+10 mM NH4OAc), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 50% B, 50% B in 4.5 min; Detector: UV 254 / 210 nm; Retention time: 4.35 min; Fractions containing the desired product were collected and concentrated under reduced pressure to give (3S)-1'-(5-aminopyrazin-2-yl)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidine]-2-1 as a yellow solid (2.10 mg, 4%): C 15 H 13 Cl2NO[M+H] + LCMS (ESI) calculated for: 350, 352 (3:2); found: 350, 352 (3:2): 1 H NMR(400MHz,CD3OD)δ7.69(d,J=1.7Hz,1H),7.51(d,J=1.7Hz,1H),7.37(s, 1H), 7.11(s, 1H), 3.89-3.63(m, 4H), 2.55-2.45(m, 1H), 2.35-2.24(m, 1H).

[0488] The following compounds in Table 1H were prepared in a manner similar to that described for Compound 144, starting from (3S)-5,6-dichloro-1H-spiro[indole-3,3′-pyrrolidin]-2-one and the corresponding heteroaryl chloride (available from commercial sources).

[0489] [Table 9]

[0490] Example 20. Compound 153 ((3S)-5,6-dichloro-1'-(1H-pyrazol-3-yl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0491] [ka]

[0492] Step A: To a stirred mixture of 5,6-dichloro-1-[(4-methoxyphenyl)methyl]spiro[indole-3,3-pyrrolidin]-2-one (0.150 g, 0.398 mmol) and 3-bromo-1-(tetrahydropyran-2-yl)pyrazole (0.184 g, 0.796 mmol) in dioxane (2 mL), EPhos Pd G4 (36.5 mg, 0.0400 mmol), EPhos (21.3 mg, 0.0400 mmol), and CsCO (0.259 g, 0.795 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 2 h, quenched 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 55% ACN in water (+0.05% TFA) to give 5,6-dichloro-1-[(4-methoxyphenyl)methyl]-1'-[1-(tetrahydropyran-2-yl)pyrazol-3-yl]spiro[indole-3,3'-pyrrolidin]-2-one as a brown solid (0.110 g, 42%): C 27 H28 Cl2N4O3[M+H] + LCMS (ESI) calculated for: 527, 529 (3:2); found: 527, 529 (3:2); 1 H NMR(300MHz,CDCl3)δ7.46(d,J=2.51Hz,1H),7.35(d,J=1.07Hz,1H),7.24-7.18(m, 2H),6.93-6.87(m,2H),6.84(s,1H),5.67(d,J=2.54Hz,1H),5.32(s,1H),5.30-5.2 2(m,1H),4.96-4.77(m,2H),4.14-4.04(m,1H),4.04-3.97(m,1H),3.85-3.69(m,5H ),3.59(d,J=9.55Hz,1H),2.66-2.49(m,2H),2.22-1.97(m,4H),1.80-1.52(m,2H).

[0493] Step B: To a stirred solution of 5,6-dichloro-1-[(4-methoxyphenyl)methyl]-1-[1-(tetrahydropyran-2-yl)pyrazol-3-yl]spiro[indole-3,3-pyrrolidin]-2-one (0.110 g, 0.208 mmol) in DCM (1 mL) and TFA (1 mL) was added trifluoromethanesulfonic acid (0.313 g, 2.09 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The residue 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 50% B in 4.5 min; Detector: UV 254 / 210 nm; Retention time: 4.30 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 5,6-dichloro-1-(1H-pyrazol-3-yl)-1H-spiro[indole-3,3-pyrrolidin]-2-one as an off-white solid (60.0 mg, 89%): C 14 H 12 Cl2N4O [M+H] +LCMS (ESI) calculated for: 323, 325 (3:2); found: 323, 325 (3:2); 1 H NMR(400MHz,CD3OD)δ7.47(s,1H),7.35(s,1H),7.10(s,1H),5.70(s,1H),3.81-3.70 (m,1H),3.70-3.61(m,1H),3.61-3.52(m,2H),2.57-2.44(m,1H),2.27-2.15(m,1H).

[0494] Step C: 5,6-Dichloro-1'-(1H-pyrazol-3-yl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (28.0 mg, 0.0866 mmol) was purified by preparative chiral-HPLC using the following conditions: Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Mobile phase A: Hex (+0.3% IPA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 15% B to 15% B in 15 min; Wavelength: UV 220 / 254 nm; Retention time 1: 10.80 min; Retention time 2: 13.84 min; Sample solvent: EtOH-DCM = 1:1; Injection volume: 1 mL; Run number: 2. The faster eluting enantiomer, (3S)-5,6-dichloro-1'-(1H-pyrazol-3-yl)-1H-spiro[indole-[3,3'-pyrrolidin]-2-one, was obtained as an off-white solid (11.0 mg, 39%) at 10.80 min: C 14 H 12 Cl2N4O [M+H] + LCMS (ESI) calculated for: 323, 325 (3:2); found: 323, 325 (3:2); 1H NMR (300 MHz, CD3OD) δ 7.47 (d, J = 2.41 Hz, 1H), 7.35 (s, 1H), 7.09 (s, 1H), 5.70 (d, J = 2.40 Hz, 1H), 3.81-3.70 (m, 1H), 3.69-3.59 (m, 1H), 3.56 (d, J = 3.06 Hz, 2H), 2.56-2.42 (m, 1H), 2.28-2.14 (m, 1H). The slower eluting enantiomer, (3R)-5,6-dichloro-1'-(1H-pyrazol-3-yl)-1H-spiro[indole-[3,3'-pyrrolidin]-2-one, was obtained as an off-white solid at 13.84 min (10.0 mg, 36%): C 14 H 12 Cl2N4O[M+H] + LCMS (ESI) calculated for: 323, 325 (3:2); found: 323, 325 (3:2); 1 H NMR(300MHz,CD3OD)δ7.47(d,J=2.40Hz,1H),7.35(s,1H),7.09(s,1H),5.69(d,J=2.41Hz,1H),3. 81-3.70(m,1H),3.70-3.58(m,1H),3.56(d,J=3.10Hz,2H),2.56-2.42(m,1H),2.27-2.17(m,1H).

[0495] The following compounds in Table 1I were prepared in a manner similar to that described for Compound 153, starting from 5,6-dichloro-1-[(4-methoxyphenyl)methyl]spiro[indole-3,3-pyrrolidin]-2-one and the corresponding heteroaryl bromide (available from commercial sources).

[0496] [Table 10]

[0497] Example 21. Compound 132 ((S)-1'-(5-amino-1,3,4-oxadiazol-2-yl)-5,6-dichlorospiro[indoline-3,3'-pyrrolidin]-2-one)

[0498] [ka]

[0499] Step A: To a stirred solution of (3S)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one (0.100 g, 0.389 mmol) in THF (2 mL) was added CDI (0.189 g, 1.34 mmol) portionwise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 6 h, quenched 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (3S)-5,6-dichloro-1'-(imidazole-1-carbonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a light brown oil (0.120 g, 88%), which was used directly in the next step without purification: C 15 H 12 Cl2N4O2[M+H] + LCMS (ESI) calculated for: 351, 353 (3:2); found: 351, 353 (3:2).

[0500] Step B: To a stirred solution of (3S)-5,6-dichloro-1'-(imidazole-1-carbonyl)-1H-spiro[indole-3,3'-pyrrolidine]-2-one (0.120 g, 0.342 mmol) in THF (2 mL) was added hydrazine hydrate (28.5 mg, 0.558 mmol, 98%) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 4 hours and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carbohydrazide as a pale yellow oil (0.100 g, 83%): C 12 H 12 Cl2N4O2[M+H] + LCMS (ESI) calculated for: 315, 317 (3:2); found: 315, 317 (3:2); 1H NMR (400MHz, DMSO-d6) δ10.82(s,1H),9.17(s,1H),7.55(s,1H),7.07(s,1H),3.77-3.55(m,4H),2.26(t,J=7.1Hz,2H).

[0501] Step C: To a stirred solution of (3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carbohydrazide (0.100 g, 0.317 mmol) in EtOH (2 mL) was added BrCN (67.2 mg, 0.634 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 16 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD Column, 19 x 150 mm, 5 μm; Mobile Phase A: water (+0.05% TFA), Mobile Phase B: ACN; Flow Rate: 20 mL / min; Gradient: 25% B to 50% B, 50% B in 4.5 min; Wavelength: UV 254 / 210 nm; Retention Time: 4.35 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give (S)-1'-(5-amino-1,3,4-oxadiazol-2-yl)-5,6-dichlorospiro[indoline-3,3'-pyrrolidin]-2-one as an off-white solid (21.7 mg, 20%): C 13 H 11 Cl2N5O2[M+H] + LCMS (ESI) calculated for: 340, 342 (3:2); found: 340, 342 (3:2); 1 H NMR(400MHz,CD3OD)δ7.47(s,1H),7.11(s,1H),3.93-3.75(m,2H),3.77(d,J =10.4Hz,1H),3.68(d,J=10.3Hz,1H),2.49-2.47(m,1H),2.46-2.44(m,1H).

[0502] Example 22. Compound 138 ((3S)-5,6-dichloro-1'-(2-hydroxyethanesulfonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one)

[0503] [ka]

[0504] Step A: To a stirred mixture of (3S)-5,6-dichloro-1H-spiro[indole-3,3'-pyrrolidin]-2-one (40.0 mg, 0.155 mmol) in DCM (1.00 mL) was added TEA (31.0 mg, 0.208 mmol) and 2-methoxyethanesulfonyl chloride (25.0 mg, 0.158 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h, diluted with water (20 mL), and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (3S)-5,6-dichloro-1'-(2-methoxyethanesulfonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a yellow solid (51.4 mg, 87%), which was used directly in the next step without purification: C 14 H 16 Cl2N2O4S[M+H] + LCMS (ESI) calculated for: 379, 381 (3:2); found: 379, 381 (3:2).

[0505] Step B: To a stirred solution of (3S)-5,6-dichloro-1'-(2-methoxyethanesulfonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one (51.0 mg, 0.134 mmol) in DCM (1.00 mL) was added BBr3 (68.0 mg, 0.271 mmol) at room temperature. The reaction mixture was stirred for 2 h, quenched with MeOH (5 mL), and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; Mobile phase A: water (+10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 22% B to 50% B in 5.2 min; Detector UV: 210 nm; Retention time: 5.14 min; Fractions containing the desired product were collected and concentrated under reduced pressure to give (3S)-5,6-dichloro-1'-(2-hydroxyethanesulfonyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one as an off-white solid (22.7 mg, 46%): C 13 H 14 Cl2N2O4S[M+H] + LCMS (ESI) calculated for: 365, 367 (3:2); found: 365, 367 (3:2); 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.63(s,1H),7.05(s,1H),5.09(t,J=5.4Hz,1H),3.82(q,J =6.1Hz,2H),3.73-3.60(m,2H),3.55(q,J=10.1Hz,2H),3.37(d,J=6.3Hz,2H),2.30-2.15(m,2H).

[0506] The following compounds in Table 1J were prepared in a similar manner as described for Compound 138, starting from (3S)-5,6-dichloro-1H-spiro[indole-3,3′-pyrrolidin]-2-one and the corresponding sulfonyl chloride (available from commercial sources).

[0507] [Table 11]

[0508] Example 23 Compound 154 ((3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carboxamide) and Compound 155 ((3R)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carboxamide)

[0509] [ka]

[0510] Step A: To a stirred solution of 5,6-dichloro-1H-spiro[indole-3,3-pyrrolidin]-2-one (0.100 g, 0.389 mmol) and TEA (0.118 g, 0.791 mmol) in DCM (2.00 mL) was added isocyanatotrimethylsilane (89.6 mg, 0.778 mmol) dropwise at 0 °C. The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 × 150 mm, 5 μm, 13 nm; Mobile phase A: water (+10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 50% B in 4.3 min; Detector: UV 254 / 210 nm; Retention time: 4.20 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 5,6-dichloro-2-oxo-1H-spiro[indole-3,3-pyrrolidine]-1-carboxamide as an off-white solid (65.0 mg, 56%): C 12 H 11 Cl2N3O2[M+H] + LCMS (ESI) calculated for: 300, 302 (3:2); found: 300, 302 (3:2); 1 H NMR (300MHz, DMSO-d6) δ10.76(s,1H),7.47(s,1H),7.06(s,1H),5.89(s,2H),3.68-3.53(m,2H),3.49(s,2H),2.29-2.06(m,2H).

[0511] Step B: 5,6-Dichloro-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carboxamide (58.0 mg, 0.193 mmol) was purified by preparative chiral HPLC using the following conditions: Column: CHIRAL ART Amylose-SA, 2 × 25 cm, 5 μm; Mobile phase A: Hex (+0.3% IPA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 7 min; Wavelength: UV 220 / 254 nm; Retention time 1: 5.10 min; Retention time 2: 6.45 min; Sample solvent: EtOH-DCM = 1:1; Injection volume: 0.3 mL; Run number: 17. The faster eluting enantiomer, (3S)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carboxamide, was obtained as an off-white solid (20.1 mg, 35%) at 5.10 min: C 12 H 11 Cl2N3O2[M+H] + LCMS (ESI) calculated for: 300, 302 (3:2); found: 300, 302 (3:2); 1 H NMR (300 MHz, CD3OD) δ 7.40 (s, 1H), 7.10 (s, 1H), 3.87-3.64 (m, 3H), 3.64-3.53 (m, 1H), 2.47-2.34 (m, 1H), 2.31-2.16 (m, 1H). The slower eluting enantiomer, (3R)-5,6-dichloro-2-oxo-1H-spiro[indole-3,3'-pyrrolidine]-1'-carboxamide, was obtained as an off-white solid at 6.45 min (22.0 mg, 38%): C 12 H 11 Cl2N3O2[M+H] + LCMS (ESI) calculated for: 300, 302 (3:2); found: 300, 302 (3:2); 1 H NMR (300MHz, CD3OD) δ7.40(s,1H),7.10(s,1H),3.87-3.65(m,3H),3.64-3.54(m,1H),2.47-2.34(m,1H),2.31-2.18(m,1H).

[0512] Example 24. Evaluation of Kv1.3 potassium channel blocker activity This assay is used to evaluate the activity of the disclosed compounds as Kv1.3 potassium channel blockers.

[0513] cell culture CHO-K1 cells stably expressing Kv1.3 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, and G418 (500 μg / ml). Cells were grown in culture flasks at 37°C in a humidified incubator with 5% CO.

[0514] solution Cells were bathed 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. 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. The internal solution was 285 mOsm. All compounds were dissolved in 30 mM DMSO. Compound stock solutions were freshly diluted with the external solution to yield 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.

[0515] Voltage Protocol Currents were elicited by applying 100 ms depolarizing pulses from -90 mV (holding potential) to +40 mV at a frequency of 0.1 Hz. Control (no compound) and compound pulse trains for each compound concentration applied contained 20 pulses.

[0516] A 10-second pause was used between pulse trains (see Table A below).

[0517] [Table 12]

[0518] Patch clamp recording and compound application The automated patch-clamp platform Patchliner (Nanion Technologies GmbH) allowed for recording of whole-cell currents and application of compounds. Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) was used for data acquisition with an EPC10 patch-clamp amplifier (HEKA Elektronik Dr. Schulze GmbH). Data were sampled at 10 kHz without filtering. Passive leak currents were subtracted online using the P / 4 procedure (HEKA Elektronik Dr. Schulze GmbH). Increasing compound concentrations were applied consecutively to the same cell without washout between pulses. The total compound incubation time between pulse trains was within 10 s. Peak current inhibition was observed during compound equilibration.

[0519] Data analysis AUC and peak values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). 50 The last single pulse of the pulse train corresponding to a given compound concentration was used to determine the IC. The AUC and peak values ​​obtained in the presence of compound were normalized to the control values ​​in the absence of compound. Origin (OridinLab) was used to calculate the IC. 50 is the Hill formula: 化合物 / I 対照 =(100-A) / (1+([Compound] / IC 50 )nH) + A. IC 50 is the concentration at which current inhibition is half-maximal, [compound] is the applied compound concentration, A is the fraction of unblocked current, and nH is the Hill coefficient.

[0520] Example 25. Evaluation of hERG activity This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0521] hERG electrophysiology This assay is used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0522] cell culture CHO-K1 cells stably expressing hERG were grown in Ham's F-12 medium containing 10% heat-inactivated FBS, 1% penicillin / streptomycin, hygromycin (100 μg / ml), and glutamine containing G418 (100 μg / ml). Cells were grown in culture flasks at 37°C in a 5% CO2 humidified incubator.

[0523] solution Cells were bathed 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. 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. The internal solution was 285 mOsm. All compounds were dissolved in 30 mM DMSO. Compound stock solutions were freshly diluted with the external solution to yield 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.

[0524] 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. Control (no compound) and compound pulse trains for each compound concentration applied contained 70 pulses.

[0525] [Table 13]

[0526] Patch clamp recording and compound application The automated patch-clamp platform Patchliner (Nanion) allowed recording of whole-cell currents and application of compounds. Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) was used for data acquisition with an EPC10 patch-clamp amplifier (HEKA). Data were sampled at 10 kHz without filtering. Increasing compound concentrations were applied consecutively to the same cell without washout in between.

[0527] Data analysis AUC and PEAK values ​​were obtained using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). 50 The last single pulse of the pulse train corresponding to a given compound concentration was used to determine the IC. AUC and PEAK values ​​obtained in the presence of compound were normalized to control values ​​in the absence of compound. IC was calculated using Origin (OridinLab). 50 is the Hill formula: 化合物 / I 対照 =(100-A) / (1+([Compound] / IC 50 )nH) + A. IC 50 is the concentration at which current inhibition is half-maximal, [compound] is the applied compound concentration, A is the fraction of unblocked current, and nH is the Hill coefficient.

[0528] Table 1 provides a summary of the inhibitory activity of certain selected compounds of the present invention against the Kv1.3 potassium channel and the hERG channel.

[0529] [Table 14-1]

[0530] Table 14-2

[0531] Table 14-3

[0532] Table 14-4

[0533] Table 14-5

[0534] Table 14-6

[0535] Table 14-7

[0536] Table 14-8

[0537] Table 14-9

[0538] Table 14-10

[0539] Table 14-11

[0540] Table 14-12

[0541] Table 14-13

[0542] Table 14-14

[0543] Table 14-15

[0544] Table 14-16

[0545] Table 14-17

[0546] Table 14-18

[0547] Table 14-19

[0548] Table 14-20

[0549] Table 14-21

[0550] Table 14-22

[0551] [Table 14-23]

[0552] [Table 14-24]

[0553] [Table 14-25]

[0554] [Table 14-26] * Not tested. The inventions described in the original claims of this application are set forth below. [1] Formula I: [ka] (In the formula, X 1 、X 2 , and X 3 are each independently H, halogen, CN, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, OH, SH, alkoxy, alkoxy halide, alkylthio, or alkylthio halide; Or X 1 and X 2 and the carbon atoms to which they are attached, taken together, form a 5- or 6-membered aryl, or Or X 2 and X 3 and the carbon atoms to which they are attached, taken together, form a 5- or 6-membered aryl; Z is H, alkyl, halogenated alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogen, CN, CF 3 , OCF 3 , OR a , N.R. a R b , or NR a (C=O)R b and Y 1 does not exist or C(R 1 ) 2 and Y 2 But there is no C(R 1 ) 2 , C(R 1 ) 2 (C=O), C(R 1 ) 2 C(R 1 ) 2 , or C(R 1 ) 2 C(R 1 ) 2 (C=O), R 1 each occurrence independently represents H, halogen, alkyl, cycloalkyl, saturated heterocycle, aryl, heteroaryl, (CR 4 R 5 ) n3 OR c , or (CR 4 R 5 ) n3 NR c R d and R 2 is alkyl, heteroalkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, heteroaryl, (CR 4 R 5 ) n2 (C=O)R 3 , (CR 4 R 5 ) n2 (C=O)N(R 4 )R 3 , SO 2 R 3 , or SO 2 NR c R d and R 3 is independently H, alkyl, cycloalkyl, heterocycle, bicycloalkyl, spiroalkyl, heterobicycloalkyl, heterospiroalkyl, alkylaryl, alkylheteroaryl, aryl, or heteroaryl; R 4 and R 5 is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; R a and R b each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; Alternatively, R a and R b form a 3- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached, R c and R d each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; Alternatively, R c and R d form a 3- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached, each heterocycle contains 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S; X 1 、X 2 、X 3 , Z, R 1 、R 2 , or R 3 Each of the alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in the formula (I) can be, where applicable and valence permitting, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(═O)R c , COOR c , (CR 4 R 5 ) n3 OR c , (CR 4 R 5 ) n3 NR c R d , and (CR 4 R 5 ) n3 NR c (C=O)R d and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: n 1 is an integer between 0 and 4, n 2 is an integer between 0 and 4, n 3 is an integer of 0 to 4) or a pharmaceutically acceptable salt thereof. [2] X 1 、X 2 , and X 3 are each independently H, halogen, CN, alkyl, or alkyl halide. [3] X 1 、X 2 , and X 3 are each independently a cycloalkyl or a halogenated cycloalkyl. [4] X 1 、X 2 , and X 3 are each independently H, F, Cl, Br, CN, CH 3 , or CF 3 The compound according to [1] or 2, wherein [5] X 1 、X 2 , and X 3 are each independently H or Cl. [6] The compound according to any one of [1] to [5], wherein Z is H, halogen, alkyl, or alkyl halide. [7] Z is H, F, Cl, Br, or CH 3 , or CF 3 The compound according to any one of [1] to [5], wherein [8] The compound according to any one of [1] to [5], wherein Z is H or Cl. [9] Z is OR a or NR a R b The compound according to any one of [1] to [5], wherein

[10] R a and R b The compound according to any one of [1] to [5] and 9, wherein each occurrence of is independently H or alkyl.

[11] R a and R b The compound according to any one of [1] to [5] and 9, wherein each occurrence of is cycloalkyl or heterocycle.

[12] R a and R b The compound according to any one of [1] to [5] and 9, wherein each occurrence of is aryl or heteroaryl.

[13] Z, X 1 、X 2 , and X 3 The compound according to any one of [1] to

[12] , wherein at least two of the following are not H:

[14] Structural part:

change

change

[15] Structural part:

change

change

[16] Structural part:

change

change

[17] Structural part:

change

change

[18] Y 1 and Y 2 are each independently absent or C(R 1 ) 2 The compound according to any one of [1] to

[17] , wherein

[19] Y 1 does not exist and Y 2 is C(R 1 ) 2 The compound according to any one of [1] to

[18] , wherein

[20] Y 1 is C(R1 ) 2 and Y 2 is C(R 1 ) 2 The compound according to any one of [1] to

[18] , wherein

[21] Structural part:

change

change

[18] , having the structure:

[22] Structural part:

change

change

[18] , having the structure:

[23] R 1 The compound according to any one of [1] to

[22] , wherein at least one occurrence of is H, alkyl, or cycloalkyl.

[24] R 1 At least one occurrence of is a halogen, (CR 4 R 5 ) n3 OR c , or (CR 4 R 5 ) n3 NR c R d The compound according to any one of [1] to

[22] , wherein

[25] R 1 The compound according to any one of [1] to

[22] , wherein at least one occurrence of is a saturated heterocycle, an aryl, or a heteroaryl.

[26] R 1 At least one occurrence of is H or CH 3 The compound according to any one of [1] to

[22] , wherein

[27] The compound has formula Ia:

change

[28]

[27] The compound according to

[27] , wherein Z is H, halogen, alkyl, or alkyl halide.

[29] Z is H, F, Cl, Br, or CH 3 , or CF 3 The compound according to

[27] , wherein

[30] The compound according to

[27] , wherein Z is H.

[31] Z is CN, OR a , or NR a R b The compound according to

[27] , wherein

[32] R a and R b

[27] or 31, wherein each occurrence of is independently H or alkyl.

[33] R a and R b

[27] or 31, wherein each occurrence of is cycloalkyl or heterocycle.

[34] R a and R b

[27] or 31, wherein each occurrence of is aryl or heteroaryl.

[35] R 1 The compound according to any one of

[27] to

[34] , wherein at least one occurrence of is alkyl or cycloalkyl.

[36] R 1 At least one occurrence of is a halogen, (CR 4 R 5 ) n3 OR c , or (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[27] to

[34] , wherein

[37] R 1 The compound according to any one of

[27] to

[34] , wherein at least one occurrence of is a saturated heterocycle, an aryl, or a heteroaryl.

[38] n 1 The compound according to any one of

[27] to

[34] , wherein is 0 or 1.

[39] The compound has formula Ib:

change

[40]

[39] The compound according to

[39] , wherein Z is H, halogen, alkyl, or alkyl halide.

[41] Z is H, F, Cl, Br, or CH 3 , or CF 3 The compound according to

[39] , wherein

[42] The compound according to

[39] , wherein Z is H.

[43] Z is CN, OR a , or NR a R b The compound according to

[39] , wherein

[44] R a and R b

[39] or 43, wherein each occurrence of is independently H or alkyl.

[45] R a and R b 44. The compound according to

[39] or 43, wherein each occurrence of is cycloalkyl or heterocycle.

[46] R a and R b 44. The compound according to

[39] or 43, wherein each occurrence of is aryl or heteroaryl.

[47] R 1 The compound according to any one of

[39] to

[46] , wherein at least one occurrence of is alkyl or cycloalkyl.

[48] R 1 At least one occurrence of is a halogen, (CR 4 R 5 ) n3 OR c , or (CR 4 R 5 ) n3 NRc R d The compound according to any one of

[39] to

[46] , wherein

[49] R 1 The compound according to any one of

[39] to

[46] , wherein at least one occurrence of is a saturated heterocycle, an aryl, or a heteroaryl.

[50] n 1 The compound according to any one of

[39] to

[49] , wherein is 0 or 1.

[51] R 2 is alkyl, cycloalkyl, or heteroalkyl.

[52] R 2 is a heterocycle, an aryl, a heteroaryl, an alkylaryl, or an alkylheteroaryl.

[53] R 2 The compound according to any one of [1] to

[50] , wherein is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[54] R 2 But SO 2 R 3 or SO 2 NR c R d The compound according to any one of [1] to

[50] , wherein

[55] R 2 However, (CR 4 R 5 ) n2 OR c , (CR 4 R 5 ) n2 (CR 4 )((CR 4 R 5 ) n3 OR c ) 2 , (C=O)(CR 4 R 5 ) n2 OR c , (C=O)(CR 4 R 5 ) n2 (CR 4 )((CR 4R 5 ) n3 OR c ) 2 , (CR 4 R 5 ) n2 COOR c , (C=O)(CR 4 R 5 ) n2 NR c R d , or (CR 4 R 5 ) n2 NR c (C=O)R d The compound according to any one of [1] to

[50] , wherein

[56] R 2 However, (CR 4 R 5 ) n2 (C=O)R 3 or (CR 4 R 5 ) n2 (C=O)NR 3 R 4 The compound according to any one of [1] to

[50] , wherein

[57] R 3 each occurrence of is alkyl or cycloalkyl, each of which, if valence permits, is selected from halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , (CR 4 R 5 ) n3 NR c R d , or (CR 4 R 5 ) n3 NR c (C=O)R d The compound according to any one of [1] to

[50] and 56, which is optionally substituted with:

[58] R 3 is a heterocycle, aryl, or heteroaryl, each of which, if valence permits, is alkyl, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , (CR 4 R 5 ) n3 NR c R d , or (CR 4 R 5 ) n3 NR c (C=O)R d The compound according to any one of [1] to

[50] and 56, which is optionally substituted with:

[59] R 3 each occurrence of is alkylaryl or alkylheteroaryl, each of which, if valence permits, is alkyl, halogen, CN, oxo, C(═O)R c , COOR c , (CR 4 R 5 ) n3 OR c , (CR 4 R 5 ) n3 NR c R d , or (CR 4 R 5 ) n3 NR c (C=O)R d The compound according to any one of [1] to

[50] and 56, which is optionally substituted with:

[60] R 3 each occurrence of is a bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl, each of which, where valences permit, may be alkyl, halogen, CN, oxo, C(═O)R c , COOR c , (CR 4 R 5 ) n3 ORc , (CR 4 R 5 ) n3 NR c R d , or (CR 4 R 5 ) n3 NR c (C=O)R d The compound according to any one of [1] to

[50] and 56, which is optionally substituted with:

[61] R 4 and R 5

[60] The compound according to any one of [1] to

[60] , wherein each occurrence of is independently H, alkyl, cycloalkyl, or heterocycle.

[62] R 4 and R 5

[60] The compound according to any one of [1] to

[60] , wherein each occurrence of is independently aryl or heteroaryl.

[63] R c and R d

[60] The compound according to any one of [1] to

[60] , wherein each occurrence of is independently H, alkyl, or cycloalkyl.

[64] R c and R d

[60] The compound according to any one of [1] to

[60] , wherein each occurrence of is independently a heterocycle, an aryl, or a heteroaryl.

[65] n 2 and n 3

[64] The compound according to any one of [1] to

[64] , wherein each occurrence of is independently 0, 1, or 2.

[66] n 2 and n 3 The compound according to any one of [1] to

[64] , wherein each occurrence of is independently 3 or 4.

[67] The compound has the formula Ic:

change

[68]

[67] The compound according to

[67] , wherein Z is H, halogen, alkyl, or alkyl halide.

[69] Z is H, F, Cl, Br, or CH 3 , or CF 3 The compound according to

[67] , wherein

[70] The compound according to

[67] , wherein Z is H or Cl.

[71] R 1 The compound according to any one of

[67] to

[70] , wherein at least one occurrence of is H, alkyl, or cycloalkyl.

[72] n 1 The compound according to any one of

[67] to

[71] , wherein is 0 or 1.

[73] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , and (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[67] to

[72] , wherein the alkyl is optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[74] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , and (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[67] to

[72] , wherein the cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[75] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , and (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[67] to

[72] , wherein the heterocycle is optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[76] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , and (CR4 R 5 ) n3 NR c R d The compound according to any one of

[67] to

[72] , wherein each of the aryl and heteroaryl groups is optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[77] R 3 The compound according to any one of

[67] to

[72] , wherein is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[78] The compound has the formula Id:

change

[79]

[78] The compound according to

[78] , wherein Z is H, halogen, alkyl, or alkyl halide.

[80] Z is H, F, Cl, Br, or CH 3 , or CF 3 The compound according to

[78] , wherein

[81] The compound according to

[78] , wherein Z is H or Cl.

[82] R 1 The compound according to any one of

[78] to

[81] , wherein at least one occurrence of is H, alkyl, or cycloalkyl.

[83] n 1 The compound according to any one of

[78] to

[82] , wherein is 0 or 1.

[84] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , and (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[78] to

[83] , wherein the alkyl is optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[85] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , and (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[78] to

[83] , wherein the cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[86] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COORc , (CR 4 R 5 ) n3 OR c , and (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[78] to

[83] , which is a heterocycle optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[87] R 3 However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(=O)R c , COOR c , (CR 4 R 5 ) n3 OR c , and (CR 4 R 5 ) n3 NR c R d The compound according to any one of

[78] to

[83] , wherein each of the aryl and heteroaryl groups is optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[88] R 3 The compound according to any one of

[78] to

[83] , wherein is bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl.

[89] R 2 but,

change

change

change

[50] , wherein

[90] R 2 but,

change

[89] , wherein

[91] R 2 but,

change

[50] , wherein

[92] The compound according to [1], wherein the compound is selected from the group consisting of compounds 1 to 159 shown in Table 1.

[93] A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[92] and a pharmaceutically acceptable carrier or diluent.

[94] A method for treating a condition, comprising administering a therapeutically effective amount of at least one compound according to any one of [1] to

[92] or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition according to

[93] to a mammalian species in need of such treatment, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[95] The method according to

[94] , wherein the immunological disorder is transplant rejection or an autoimmune disease.

[96] The method according to

[94] , wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[97]

[94] The method according to

[94] , wherein the central nervous system disorder is Alzheimer's disease.

[98] 94. The method of claim 94, wherein the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontal diseases (parodontitits), or inflammatory neuropathies.

[99]

[94] The method according to

[94] , wherein the gastroenterological disorder is inflammatory bowel disease.

[0100] The method according to

[94] , wherein the metabolic disorder is obesity or type II diabetes.

[0101] The method according to

[94] , wherein the cardiovascular disorder is ischemic stroke.

[0102] The method according to

[94] , wherein the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0103] 94. The method of claim 94, 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 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.

[0104] The method according to

[94] , wherein the mammalian species is human.

[0105] A method for blocking the Kv1.3 potassium channel, comprising administering a therapeutically effective amount of at least one compound according to any one of [1] to

[92] or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition according to

[93] to a mammalian species in need of blocking the Kv1.3 potassium channel.

[0106] The method described in

[0105] , wherein the mammalian species is human.

Claims

1. Formula Ic: 【Chemistry 1】 (In the formula, Structural part: 【Transformation 8】 but, 【Chemistry 9】 having the structure R １ each occurrence of is independently H or alkyl; R ３ is alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl, and said alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, when valences permit, is alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(═O)R ｃ , COOR ｃ , (CR ４ R ５ ) ｎ３ OR ｃ , and (CR ４ R ５ ) ｎ３ NR ｃ R ｄ and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: R ４ and R ５ is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; R ｃ and R ｄ each occurrence is independently H, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; Or, R ｃ and R ｄ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycle, each heterocycle contains 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S; R １ Each alkyl in ３ Each of the alkyl, cycloalkyl, heteroalkyl, heterocycle, aryl, and heteroaryl in the formula (I) can be, where applicable and valence permitting, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, oxo, C(═O)R ｃ , COOR ｃ , (CR ４ R ５ ) ｎ３ OR ｃ , (CR ４ R ５ ) ｎ３ NR ｃ R ｄ , and (CR ４ R ５ ) ｎ３ NR ｃ (C=O)R ｄ and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: n １ is an integer from 0 to 4, n ３ is an integer of 0 to 4), or a pharmaceutically acceptable salt thereof.

2. n １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is 0 or 1.

3. R ３ However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(═O)R ｃ , COOR ｃ , (CR ４ R ５ ) ｎ３ OR ｃ , and (CR ４ R ５ ) ｎ３ NR ｃ R ｄ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group optionally substituted by 1 to 4 substituents each independently selected from the group consisting of:

4. R ３ However, if valence allows, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkyl halide, cycloalkyl halide, halogen, CN, oxo, C(═O)R ｃ , COOR ｃ , (CR ４ R ５ ) ｎ３ OR ｃ , and (CR ４ R ５ ) ｎ３ NR ｃ R ｄ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a heterocycle optionally substituted by 1 to 4 substituents each independently selected from the group consisting of:

5. the below described: or a pharmaceutically acceptable salt thereof.

6. The following formula:

2. The compound of claim 1, wherein:

7. The following formula:

2. The compound of claim 1, wherein:

8. The following formula:

2. The compound of claim 1, wherein:

9. The following formula:

2. The compound of claim 1, wherein:

10. The following formula:

2. The compound of claim 1, wherein:

11. The following formula:

2. The compound of claim 1, wherein:

12. The following formula:

2. The compound of claim 1, wherein:

13. The following formula:

2. The compound of claim 1, wherein:

14. 10. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

15. 10. A pharmaceutical composition for treating a condition selected from the group consisting of cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and kidney diseases, comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. 16. The pharmaceutical composition of claim 15, wherein the immunological disorder is an autoimmune disease selected from the group consisting of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

17. 16. The pharmaceutical composition of claim 15, wherein the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neuropathy.

18. 16. The pharmaceutical composition of claim 15, 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 neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

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