ARYL HETEROCYCLIC COMPOUNDS AS Kv1.3 POTASSIUM SHAKER CHANNEL BLOCKERS

Abstract

To provide Kv1.3 potassium shaker channel blockers.SOLUTION: An aryl heterocyclic compound represented, for example, by Formula (IV), or a pharmaceutically acceptable salt thereof, as a Kv1.3 potassium shaker channel blocker, is provided. Pharmaceutical compositions comprising the same and methods of using the same are also provided.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] This patent disclosure contains material that is subject to copyright protection. The copyright owner holds the U.S. Patent A facsimile reproduction of the patent document or patent disclosure as it appears in the Patent and Trademark Office patent file or records No objections are made to this document, but all rights are otherwise reserved.

[0003] (Incorporated by reference) All documents cited herein are incorporated by reference in their entirety.

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

[0005] Voltage-dependent Kv1.3 potassium (K + ) channels in lymphocytes (T and B lymphocytes), It is expressed in the central nervous system and other tissues and regulates neurotransmitter release, heart rate, insulin secretion, and Kv1.3 channels regulate numerous physiological processes, including neuronal excitability and mitochondrial function. It can regulate membrane potential and thereby calcium responses in human effector memory T cells. Effector memory T cells are a key player in multiple sclerosis, type I diabetes, and other neurodegenerative disorders. It is a mediator of several conditions, including urinary tract infections, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. Upon activation, effector memory T cells increase the expression of Kv1.3 channels. Among human B cells, naive and early memory B cells contain a small number of K In contrast, class-switched memory B cells express a large number of K Furthermore, Kv1.3 channels are involved in T cell receptor-mediated cell proliferation. Promotes calcium homeostasis, which is necessary for activation, gene transcription, and proliferation (Panyi, G. ,et al.,2004,Trends Immunol.,565-569). Blockade of Kv1.3 channels in effector memory T cells disrupts calcium signaling, suppresses ATP production, and inhibits ATP synthesis. Promotes cytokine production (interferon-gamma, interleukin 2) and cell proliferation. Suppress such activity.

[0006] Autoimmune diseases result from tissue damage caused by an attack from the body's own immune system. These diseases include multiple sclerosis and type 1 diabetes. It can affect a single organ or, in the case of rheumatoid arthritis and systemic lupus erythematosus, In some cases, multiple organs may be affected, such as in the case of rheumatoid arthritis. Treatment is generally More effective treatment is palliative with anti-inflammatory and immunosuppressive drugs, which may be associated with The need for a method to detect effector memory T cells, which are known to be involved in the pathogenesis of autoimmune diseases, is warranted. Drugs that can selectively inhibit cell functions are being searched for. may be able to ameliorate the symptoms of autoimmune diseases without compromising the protective immune response. Effector memory T cells (TEMs) express large numbers of Kv1.3 In vivo, Kv1.3 channels are expressed and their function is dependent on these channels. Channel blockers paralyze TEM at the site of inflammation, preventing its reactivation in inflamed tissue. v1.3 channel blockers inhibit the motility of naive and central memory T cells in lymph nodes. By selectively blocking Kv1.3 channels, these cells Inhibiting the function of offers the potential for effective therapy of autoimmune diseases with minimal side effects. do.

[0007] Multiple sclerosis (MS) is a condition that affects the central nervous system. It is caused by autoimmune damage to the central nervous system (CNS). MS is a disease that progresses rapidly and predictably, causing muscle weakness and paralysis that severely impacts the patient's quality of life. The disease progresses uncontrollably and ultimately leads to death. Kv1.3 channels have also been identified in autologous cells derived from MS patients. Highly expressed in reactive TEM (Wulff H., et al., 2003, J.Clin.Invest.,1703-1713, Rus H.,et al.,2 005, PNAS, 11094-11099). Animal models of MS show that Kv1.3 channels have been successfully treated with IL-1 blockers.

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

[0009] Tubulointerstitial fibrosis is the progressive deposition of connective tissue in the renal parenchyma, leading to a decline in renal function. It is involved in pathologies such as chronic kidney disease, chronic renal failure, nephritis, and glomerular inflammation, and is known to be involved in end-stage renal disease. Overexpression of Kv1.3 channels in lymphocytes is a common cause of these disorders. promotes the proliferation of tubulointerstitial fibrosis, which contributes to the underlying pathology of these kidney diseases. This leads to chronic inflammation and overstimulation of cell-mediated immunity, which are contributing factors to the disease. Inhibition of channel currents suppresses renal lymphocyte proliferation and ameliorates the progression of renal fibrosis (Kaza ma I.,et al.,2015,Mediators Inflamm.,1-1 2).

[0010] Kv1.3 channels are also involved in ulcerative colitis ("UC") and chronic obstructive pulmonary disease (COPD). Gastrointestinal diseases, including inflammatory bowel disease ("IBD"), such as Crohn's disease UC is characterized by excessive T cell infiltration and cytokine production. UC is a chronic IBD characterized by a high incidence of ulcerative colitis (UC), which can impair quality of life and become a life-threatening complication. CD4 and CD8 positive T cells in the inflamed mucosa of UC patients High levels of Kv1.3 channels in the cytoplasm may regulate the production of proinflammatory compounds in active UC. Kv1.3 channels are thought to function as markers of disease activity. Pharmacological blockade may constitute a new immunosuppressive strategy in UC. Current treatment options for UC include corticosteroids, salicylates, and anti-TNF-α agents. Treatment regimens are inadequate for many patients (Hansen LK, et al. l., 2014, J. Crohns Colitis, 1378-1391). Crohn's disease is a type of IBD that can affect any part of the digestive tract. The disease is the result of intestinal inflammation caused by a T cell-driven process initiated by normally harmless bacteria. Therefore, inhibition of Kv1.3 channels may be useful in the treatment of Crohn's disease. It is possible.

[0011] In addition to T cells, Kv1.3 channels are also expressed in microglia, and this channel is involved in the production of inflammatory cytokines and nitric oxide, and in microglia-mediated neuronal killing. In humans, microglia in the frontal cortex of patients with Alzheimer's disease and in brain lesions of MS CD68 + Strong Kv1.3 channel expression is observed in cells. Blocking agents may be able to preferentially target detrimental pro-inflammatory microglial functions. It is suggested that Kv1.3 channels mediate activated microglobulins in the infarcted rodent and human brains. Higher Kv1.3 channel current density was observed in the ventricular plexus of a mouse model of stroke. Microglia acutely isolated from the infarcted hemisphere were more abundant than those isolated from the contralateral hemisphere. observed in the rear (Chen YJ, et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

[0012] Expression of Kv1.3 channels is elevated in microglia in human Alzheimer's disease brains. Kv1.3 channels are microglial targets relevant to Alzheimer's disease pathology. This suggests that (Rangaraju S., et al., 2015, J. Alzhe Imers Dis., 797-808). Soluble AβOs inhibit the Kv1.3 receptor in microglia. Kv1.3 channels enhance the activity of AβO-induced microglial inflammation. Kv1.3 channel expression / activity is required for inducible activation and neurotoxicity. It is upregulated in transgenic Alzheimer's disease animals and human Alzheimer's disease brains. Pharmacological targeting of glial Kv1.3 channels affects synaptic plasticity in the hippocampus and A It may reduce amyloid deposition in PP / PS1 mice. Therefore, Kv1. The 3 channel may be a potential therapeutic target for Alzheimer's disease.

[0013] Kv1.3 channel blockers significantly contribute to the secondary expansion of infarction by activated microglia. It also helps improve the pathology of cardiovascular disorders such as ischemic stroke, which are associated with cardiovascular disease.

[0014] Expression of Kv1.3 channels regulates proliferation, apoptosis, and cell survival in multiple cell types. These processes are important for cancer progression. In this context, The Kv1.3 channel located in the inner mitochondrial membrane interacts with the apoptosis regulator Bax. can interact (Serrano-Albarras, A., et al., 2018, E Expert Opinion.Ther.Targets,101-105). Therefore, K Inhibitors of the v1.3 channel can be used as anticancer drugs.

[0015] Many peptide toxins with multiple disulfide bonds from spiders, scorpions, and sea anemones It is known that some of the Kv1.3 channels block the Kv1.3 channel. Several selective and potent peptide inhibitors have been developed. Synthetic derivatives of Stychodactyla toxin ("shk"), which possess the properties of 86, are currently at the forefront of peptide synthesis. Shk has demonstrated efficacy in preclinical models and is currently in Phase I trials for the treatment of psoriasis. Clinical trials are underway. Shk can suppress the proliferation of TEMs, making it a promising treatment for multiple sclerosis in animal models. Unfortunately, Shk is a protein found in the CNS and heart, a closely related It also binds to related Kvi channel subtypes, avoiding potential cardiotoxicity and neurotoxicity Therefore, selective inhibitors of Kv1.3 channels are needed. Small peptides are rapidly eliminated from the body after administration, resulting in short circulating half-lives and frequent administration. Therefore, long-acting selective Kv1 inhibitors for the treatment of chronic inflammatory diseases are There is a need to develop .3 channel inhibitors.

[0016] Therefore, there is still a need to develop novel Kv1.3 channel blockers as medicines. It is said that. Summary of the Invention

[0017] In one aspect,

[0018] [ka] Compounds useful as potassium channel blockers are described, having the structure The groups are defined herein. or compound IV, Kv1.3 potassium (K + ) channels can be blocked, Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions and methods of using these compositions described herein are intended to treat conditions in vitro. Such compounds, pharmaceutical compositions, and methods of treatment are useful in treating rheumatoid arthritis and rheumatoid arthritis in humans. The law covers immunological disorders, CNS disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, and cardiovascular disorders. and methods for treating kidney disease, kidney disease, or a combination thereof. It has many clinical uses.

[0019] In one embodiment, a compound of formula I, I', II, II', III, or IV or its Pharmaceutically acceptable salts are described,

[0020] [ka]

[0021] [ka] During the ceremony, Each Z is independently OR a and Each X1 is independently selected from H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; Each X2 is independently H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; Each X3 is independently H, halogen, CN, alkyl, cycloalkyl, halogen a cycloalkyl halide or an alkyl halide; Or alternatively, X1 and X2 and the carbon atoms to which they are attached together represent: forming an optionally substituted 5- or 6-membered aryl; or alternatively, X2 and X3 and the carbon atoms to which they are attached together represent: forming an optionally substituted 5- or 6-membered aryl; Each R1 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3 , OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a and Each R2 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3 , OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a Or Or alternatively, R1 and R2 together with the carbon atoms to which they are attached form a cycloalkyl group. forming a hydroxyalkyl or saturated heterocyclic ring, Each R3 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b ,also is NR b (C=O)R a and Each R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, (CR a R b ) n2 OR a , or (CR a R b ) n2 NR a R b Or Or alternatively, the two R groups, together with the atoms to which they are attached, form a 3- to 7-membered forming an optionally substituted cycloalkyl or heterocyclic ring of Each R5 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C= O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2 R a and Each R6 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle, alkylaryl, alkylaryl, or alkylheteroaryl; Each R7 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle, or alkylaryl, alkylaryl, or alkylheteroaryl; or alternatively, R6 and R7, together with the nitrogen atom to which they are attached, form a nitrogen atom, and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S and the heterocycle, when valence permits, may be alkyl, cycloalkyl, Cycloalkyl halides, alkyl halides, halogens, CN, OR8, -(CH2 ) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C ═O)R8, and 1 to 4 substituents independently selected from the group consisting of oxo. optionally substituted with Each R9 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C=O)Ra , (C= O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2 R a and R 10 each independently represents H, alkyl, cycloalkyl, heterocycle, aryl, is heteroaryl, alkylaryl, or alkylheteroaryl; A1 is aryl or heteroaryl; A2 is aryl or heteroaryl; R 12 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b , (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R 13 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b , (CR a R b ) n2 OR a , (C=O)NR aR b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R a and R b each independently represents H, alkyl, alkenyl, cycloalkyl, N a saturated heterocyclic ring containing 1 to 3 heteroatoms each selected from the group consisting of , O, and S; or alternatively, R a and R b are the results of Consists of a nitrogen atom and N, O, and S together with the carbon or nitrogen to which it is bonded cycloalkyl or heteroalkyl groups containing 0 to 3 additional heteroatoms, each selected from the group Forming a ring, X1, X2, X3, A1, A2, R1, R2, R3, R4, R5, R6, if applicable , R7, R9, R 10 , R 12 , R 13 , R a , or R b Alkyl and cycloalkyl , heterocycle, aryl, and heteroaryl are, where valence permits, alkyl, cyclo, Alkyl, cycloalkyl halide, alkyl halide, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, 1 to 4 substituents independently selected from the group consisting of NR8(C=O)R8 and oxo optionally substituted by a substituent, Each R8 is independently H, alkyl, or an optionally substituted heterocycle. or alternatively, the two R groups together with the nitrogen atom to which they are attached form a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; forming an optionally substituted heterocycle containing the atom, each m is independently 1, 2, or 3; each n1 independently, where valence allows, is an integer from 0 to 3; Each n2 is independently an integer of 0 to 3; n4 is an integer from 0 to 3, n5 is an integer of 0 to 3.

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

[0023] In any one of the embodiments described herein, each m is independently 2 or It is 3.

[0024] In any one of the embodiments described herein, one or more occurrences of m is 1 .

[0025] In any one of the embodiments described herein, the compound has the formula Ia, Ia', II a, IIa', IIIa, or IVa:

[0026] [ka]

[0027] [ka]

[0028] In any one of the embodiments described herein, the compound has the formula Ib, Ib', II b, IIb', IIIb, or IVb:

[0029] [ka]

[0030] [ka]

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

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

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

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

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

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

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

[0038] In any one of the embodiments described herein, each R5 is independently cyclohexyl. It is a substituted or unsubstituted alkyl or saturated heterocycle.

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

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

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

[0042] In any one of the embodiments described herein, each of R1 and R2 is independently and alkyl, halogen, cycloalkyl, or fluorine, optionally substituted with H, OR8. It is an alkyl fluoride.

[0043] In any one of the embodiments described herein, each of R1 and R2 is independently H, CH3, CH2CH3, CH2OH, CH2CH2OH, CH2OCH3, CH 2CH2OCH3, or

[0044] [ka] is.

[0045] In any one of the embodiments described herein, R1 and R2 are selected from H and H, H and and Me, Me and Me, H and Et, Me and Et, or Et and Et, H and CHO H, H and CH2CH2OH, H and CH2OCH3, H and CH2CH2OCH3, or is H and

[0046] [ka] is.

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

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

[0049] In any one of the embodiments described herein, each of R6 and R7 is independently H, alkyl, cycloalkyl, or heterocycle; The ring is halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 Optionally, one to two substituents each independently selected from the group consisting of OH is replaced by

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

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

[0052] In any one of the embodiments described herein, R6 and R7 are each independently selected from the group consisting of aryl, ... together with the nitrogen atom present, a nitrogen atom and a group each selected from the group consisting of N, O, and S. and forming a heterocycle containing 0 to 3 additional heteroatoms selected from the group consisting of 1 to 3, and the heterocycle may be any ring as long as valence allows. In the case of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, Halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8), (C=O)N(R 8) each independently selected from the group consisting of 2, (C=O)R8, NR8(C=O)R8, and oxo; The alkyl group is optionally substituted with 1 to 4 substituents selected from the following:

[0053] In any one of the embodiments described herein, R6 and R7 are each independently selected from the group consisting of aryl, ... together with the nitrogen atom attached thereto form a 4-, 5-, or 6-membered heterocyclic ring, alkyl, alkyl halides, halogens, CN, OH, and -(CH2) 1-2 From OH and optionally substituted with 1 to 2 substituents each independently selected from the group consisting of:

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

[0055] In any one of the embodiments described herein, the 4-, 5-, or 6-membered heterocycle is , OH and -(CH2) 1-2 1 to 2 substituents independently selected from the group consisting of OH It is substituted by a substituent.

[0056] In any one of the embodiments described herein, R6 and R7 are each independently selected from the group consisting of aryl, ... Together with the nitrogen atom present, it forms azetidine.

[0057] In any one of the embodiments described herein, R6 and R7 are each independently selected from the group consisting of aryl, ... Together with the nitrogen atom present, it forms pyrrolidine.

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

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

[0060] [ka] Each of these is independent of the other.

[0061] [ka] It has the following structure.

[0062] In any one of the embodiments described herein, each R9 is independently cyclohexyl. alkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkyl It is heteroaryl.

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

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

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

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

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

[0068] In any one of the embodiments described herein, R 10 Each of these is independently H , -CH3, -CH2OH, or -CH2CH2OH.

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

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

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

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

[0073] [ka]

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

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

[0076] [ka] is.

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

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

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

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

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

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

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

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

[0085] [ka] is.

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

[0087] In any one of the embodiments described herein, R 13 One or more occurrences of H be.

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

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

[0090] In any one of the embodiments described herein, one or more occurrences of Z is OH. be.

[0091] In any one of the embodiments described herein, each X is independently H, It may be a halogen, a fluorinated alkyl, or an alkyl.

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

[0093] In any one of the embodiments described herein, one or more occurrences of X1 is H. do.

[0094] In any one of the embodiments described herein, each X2 is independently H, It may be a halogen, a fluorinated alkyl, or an alkyl.

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

[0096] In any one of the embodiments described herein, one or more occurrences of X2 is Cl. be.

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

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

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

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

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

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

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

[0104] [ka] Each of these is independent of the other.

[0105] [ka] It has the following structure.

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

[0107] [ka] At least one occurrence of

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

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

[0110] [ka]

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

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

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

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

[0115] In any one of the embodiments described herein, at least one occurrence of Z is O R a is.

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

[0117] In any one of the embodiments described herein, at least one occurrence of Z is O It's H.

[0118] In any one of the embodiments described herein, R a or R b At least one of Each occurrence is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaromatic group. It's a reel.

[0119] In any one of the embodiments described herein, R a or Rb At least one of The occurrences may independently be H, Me, Et, Pr, or

[0120] [ka]

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

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

[0123] [ka] is.

[0124] In any one of the embodiments described herein, R a and R b are combined together with the nitrogen atom present, a nitrogen atom and a group each selected from the group consisting of N, O, and S. and 0 to 3 additional heteroatoms, forming an optionally substituted heterocycle.

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

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

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

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

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

[0130] In another aspect, at least one a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. , pharmaceutical compositions are described.

[0131] In yet another aspect, a method for treating a condition in a mammalian species in need thereof is provided. A method is described, comprising administering a therapeutically effective amount of at least one administering a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammalian species; The conditions include cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastroenterological disorders, The disease is selected from the group consisting of an environmental disorder, a metabolic disorder, a cardiovascular disorder, and a renal disease.

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

[0133] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, Multiple sclerosis, systemic lupus erythematosus, or type 1 diabetes.

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

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

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

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

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

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

[0140] In any one of the embodiments described herein, the condition is cancer, transplant rejection, arthritis, or the like. Uremic arthritis, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, Alzheimer's disease, inflammation 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 The compound is selected from the group consisting of:

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

[0142] In yet another embodiment, a mammalian species in need of Kv1.3 potassium channel blockade is The present invention relates to a method for blocking Kv1.3 potassium channels, the method comprising administering a therapeutically effective amount of the At least one compound according to any one of the embodiments described herein, or a pharmaceutical The method includes administering a therapeutically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammalian species.

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

[0144] Any one of the embodiments disclosed herein may be used in combination with any other embodiment disclosed herein. The present invention can be appropriately combined with any one of the embodiments disclosed herein. Combination with any other embodiment disclosed herein is expressly contemplated. In the formula, the selection of one or more embodiments for one substituent is not limited to the selection of any other substituent. The present invention can be suitably combined with the selection of one or more specific embodiments of the present invention. The combination may be any one or more of the uses described herein or any of the formulas described herein. This can be done in the embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0145] definition The following are definitions of terms used in this specification. The initial definitions provided in this document, individually or as part of another group, apply to all elements of this document, unless otherwise indicated. The term applies to the group or term throughout the specification. All technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art. It has meaning.

[0146] The terms "alkyl" and "alk" refer to alkyl groups having 1 to 12 carbon atoms, preferably refers to a straight or branched chain alkane (hydrocarbon) radical containing 1 to 6 carbon atoms. Examples: Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, -butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl Pentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, The term "(C1-C4) alkyl" refers to an alkyl group having one to four carbon atoms. alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and Refers to a straight or branched chain alkane (hydrocarbon) radical containing isobutyl. "A" group may have one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. refers to a substituted alkyl group. Exemplary substituents include one or more of the following groups: Examples include, but are not limited to: hydrogen, halogen (e.g., a single halogen substituent or multiple halogens) In the latter case, for example, an alkyl group having a group such as CF3 or CCl3 (forming cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloa alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2Re , P(=O)2R e , S(=O)2OR e , P( =O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S( =O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C (=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)O R e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O) 2NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (R a Each of Independently, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl R is a heterocyclic, heterocyclic, or aryl; b , R c , and R d each independently represents hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R b and R c Is that together with the N to which they are attached optionally form a heterocycle, Re Each of them is unique Specifically, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic In some embodiments, the alkyl, cycloalkyl, Groups such as alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be The isoform may be optionally substituted.

[0147] The term "alkenyl" refers to an alkyl group having 2 to 12 carbon atoms and at least one carbon-carbon bond. refers to a straight or branched chain hydrocarbon radical containing a double bond. Examples of such groups include ethylene The term "C2-C6 alkenyl" refers to an alkyl group having 2 to 6 carbon atoms. A straight or branched chain hydrocarbon radical containing at least one carbon-carbon double bond. C1, for example, 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-dimethybut-2-enyl, (Z)-pent-2-enyl, (E )-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-Hex-2-enyl, (E)-Hex-2-enyl, (Z)-Hex-1-enyl (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl "Substituted alkenyl" refers to any of the substituted alkenyls, substituted alkenyls, and (E)-hexo-1,3-dienyl. substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment; Exemplary substituents include one or more of the following groups, but are not limited to: These include, but are not limited to: hydrogen, halogen, alkyl, alkyl halide (i.e., mono-, di ... Alkyl groups with one or more halogen substituents such as CF3 or CCl3 cycloalkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, 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)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)O R e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O) 2NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (R a Each of Independently, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl R is a heterocyclic, heterocyclic, or aryl; b , R c , and R d each independently represents hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R b and R c Is that together with the N to which they are attached optionally form a heterocycle, R e Each of them is unique Specifically, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic cyclic, or aryl). Exemplary substituents are those which are themselves optionally substituted. Good too.

[0148] The term "alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms and at least one carbon-carbon bond. refers to a straight or branched chain hydrocarbon radical containing a triple bond. Exemplary groups include ethynyl The term "C2-C6 alkynyl" includes ethynyl, prop-1- ... Lop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, penta -2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl, etc. a straight or branched chain containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond "Substituted alkynyl" refers to a hydrocarbon radical having, at any available point of attachment, It refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents. Suitable 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 e.g., For example, cyano, nitro, oxy) forming a group such as CF3 or an alkyl group with CCl3 O (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkene Nyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2 Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NR bS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2 NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O) Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc , NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)R a, or NRbP(=O)2Re (wherein each of Ra is independently hydrogen, alkyl, cyclo alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d each independently represents hydrogen, alkyl, cycloalkyl, heterocycle , aryl, or the above R b and R c together with the N to which they are attached , optionally forming a heterocyclic ring, R e each independently represents alkyl, cycloalkyl , alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). The substituents may themselves be optionally substituted.

[0149] The term "cycloalkyl" refers to a completely alkyl group containing 1 to 4 rings and 3 to 8 carbons per ring. Refers to saturated cyclic hydrocarbon groups. "C3-C7 cycloalkyl" includes cyclopropyl, ... butyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Alkyl" refers to a group having one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include one or more of the following groups: These include, but are not limited to: hydrogen, halogen (e.g., single halogen substituents) or multiple halo substituents, in the latter case having, for example, groups such as CF3 or CCl3 (forming alkyl groups) cyano, nitro, oxo (i.e., =O), CF3, OCF3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, O Ra, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2O Re, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2 Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O )Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC (=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRd P(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re (Ra each independently represents hydrogen, alkyl, cycloalkyl, alkenyl, or cycloalkenyl , alkynyl, heterocycle, or aryl, and R b , R c , and R d Each of these is independent. and R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e Noso each independently represents an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkyl Exemplary substituents are those which are themselves optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked or fused ring substituents. spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (heteroaryl) cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl wherein the aforementioned cycloalkyl includes cycloalkenyl, heterocycle, and aryl groups. The substituents can themselves be optionally substituted.

[0150] The term "cycloalkenyl" refers to a group containing 1 to 4 rings and 3 to 8 carbons per ring. refers to a partially unsaturated cyclic hydrocarbon group. Exemplary such groups are cyclobutenyl, cyclopentenyl, "Substituted cycloalkenyl" includes cycloalkenyl, cyclopentenyl, cyclohexenyl, and the like. A cycloaliphatic 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: including but not limited to: hydrogen, halogen (e.g., with a single halogen substituent or multiple halo substituents); In the latter case, for example, a group such as CF3 or an alkyl group with CCl3 is formed. ) cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, a Alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(= O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2O Re, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2N RbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)N RbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NR dC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbR c, NRbC(=O)Ra, or NRbP(=O)Re (each of Ra independently represents Hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl, and R b , R c , and R d each independently represents hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R b and R c are combined together with the N optionally form a heterocycle, R e Each of these is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or alkenyl The exemplary substituents may themselves be optionally substituted. Illustrative substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl. , spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cyclo cycloalkenyl, fused heterocycle, or fused aryl, wherein The aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents are themselves optional. It can be selectively replaced.

[0151] The term "aryl" refers in particular to monocyclic aryls such as phenyl, biphenyl, or naphthyl. or a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, including a bicyclic group. When the aromatic ring of the aryl group contains an aromatic ring (e.g., a bicyclic ring), the aromatic ring of the aryl group can be attached at a single point. can be either substituted (e.g., biphenyl) or fused (e.g., naphthyl, phenanthyl) The term "fused aromatic rings" refers to two adjacent aromatic rings that are joined together by two carbon atoms. "Substituted aryl" refers to a molecular structure having two or more aromatic rings that share a common bond. Substituted at available points of attachment by one or more substituents, preferably 1 to 3 substituents. Exemplary substituents include one or more of the following groups: but are not limited to: hydrogen, halogen (e.g., a single halogen substituent or multiple halogens) In the latter case, for example, an alkyl group having a group such as CF3 or CCl3 (forming) cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkane alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa , S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(= O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(= O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C( =O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)OR e, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2 NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re (each of Ra is unique) In particular, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl , heterocycle, or aryl, and R b , R c , and R d Each of the groups may independently be hydrogen, a alkyl, cycloalkyl, heterocyclic, aryl, or the R b and R c are those optionally together with the N to which it is attached form a heterocycle, and R e Each of these is independent and alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle. , or aryl). Exemplary substituents include those which may themselves be optionally substituted. Exemplary substituents include fused ring groups, particularly fused cycloalkyl, fused cycloalkenyl, and the like. cycloalkyl, cycloalkenyl, fused heterocyclic, or fused aryl are also included. The heterocyclic, and aryl substituents may themselves be optionally substituted.

[0152] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups joined by a single bond. Similarly, the term "heteroaryl-aryl" refers to heteroaryls linked by a single bond. The term "aryl-heteroaryl" refers to a heteroaryl group and an aryl group. It refers to aryl and heteroaryl groups linked by a single bond. In this case, the number of ring atoms in the heteroaryl and / or aryl rings is determined by the aryl groups in the substituents. It is used to specify the size of an aryl or heteroaryl ring. For example, 5,6-heteroaryl Heteroaryl-aryl is a substituent in which a five-membered heteroaryl is attached to a six-membered aryl group. Other combinations and ring sizes can be specified similarly.

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

[0154] The terms "heterocycle" and "heterocyclic" refer to aromatic (i.e., "heteroaryl") rings. including cyclic groups (e.g., 3- to 7-membered, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic systems) fully saturated, or partially or fully unsaturated, which contain at least one carbon atom Each ring of the heterocyclic group is independently saturated or It may be partially or fully unsaturated. Each ring of a heterocyclic group containing a heteroatom may be a nitrogen atom. 1, 2, 3, or 4 hetero atoms selected from the group consisting of atoms, oxygen atoms, and sulfur atoms The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen The heteroatoms may be optionally quaternized. (The term "heteroarylium" refers to a heteroatom that is quaternized.) A heterocyclic group refers to a heteroaryl group that has a nitrogen atom and therefore a positive charge. The ring may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring. Heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazol ... Imidazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxa Zolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isoxazolinyl, thiazolidinyl, isoxazolyl, thiazolidin ... Azolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thiazole Enyl, oxazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxo 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexa Hydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridyl Dazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpho thiamorpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone , 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl. Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiamine, and the like. Azolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d] [1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3 -Dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydrobenzo[b][1,4]dioxinyl Hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, Indo Lysinyl, benzofuryl, benzofurazanyl, dihydrobenzo[d]oxazole, chloro monyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, Pyrrolopyridyl, furopyridinyl (e.g., furo[2,3-c]pyridinyl, furo[3, 2-b]pyridinyl] or furo[2,3-b]pyridinyl, etc.), dihydroisoindolinyl dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxoquinazolinyl), tri azinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups These include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, and phenanthryl. These include cinyl, xanthenyl, and the like.

[0155] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") are used interchangeably. Heterocyclic rings or rings substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. refers to a heterocyclic group. Exemplary substituents include one or more of the following groups: including but not limited to: hydrogen, halogen (e.g., with a single halogen substituent or multiple halo substituents); In the latter case, for example, a group such as CF3 or an alkyl group with CCl3 is formed. ) cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, a Alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(= O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2O Re, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2N RbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)N RbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NR dC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbR c, NRbC(=O)Ra, or NRbP(=O)Re (each of Ra independently represents Hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl, and R b , R c , and R d each independently represents hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R b and R c are combined together with the N optionally form a heterocycle, R e Each of these is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or alkenyl The exemplary substituents may themselves be optionally substituted. Illustrative substituents also include spiro-bonded or fused ring substituents at any available point of attachment. , especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (heterocycle cycloalkyl, fused cycloalkenyl, fused heterocycle, or cycloalkyl, cycloalkenyl, heterocyclic and aryl groups as described above, including fused aryl groups; The substituents may themselves be optionally substituted.

[0156] The term "oxo"

[0157] [ka] refers to a substituent, which may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring. When the substituent is attached to a carbon ring atom of an aromatic group, e.g., an aryl or heteroaryl group, In this case, the bonds on the aromatic ring may be rearranged to satisfy valence requirements. Pyridines with substituents are

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

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

[0160] The term "alkylamino" refers to a group having the structure -NHR', where R' is any of the groups defined herein. hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl as defined in the document; Examples of alkylamino groups include methylamino, ethylamino, and n-propyl. Amino, isopropylamino, cyclopropylamino, n-butylamino, tert- Butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino Examples include, but are not limited to, silamino.

[0161] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are , each independently alkyl or substituted alkyl, cycloalkyl, as defined herein; or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or R and R' are substituted aryl, heterocycle or substituted heterocycle in the dialkylamino moiety. Examples of dialkylamino groups include dimethylamino groups. 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 )amino, di(hexyl)amino, di(cyclohexyl)amino, etc. In certain embodiments, R and R' may be linked to form a cyclic structure. The resulting cyclic structure can be aromatic or non-aromatic. Examples of the resulting cyclic structure include: are aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazoline Examples include, but are not limited to, 1,2,4-triazolyl, and tetrazolyl. stomach.

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

[0163] The term "substituted" refers to a molecule, molecular moiety, or substituent (e.g., alkyl, cyclohexane, alkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl groups or any other group disclosed herein) may be substituted, if valence permits, with one or more substituents, preferably or refers to an embodiment in which 1 to 6 substituents are substituted at any available point of attachment. Illustrative substituents include, but are not limited to, one or more of the following groups: water halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case e.g., For example, cyano, nitro, o, etc., which form a group such as CF3 or an alkyl group with CCl3. xo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, cyclo Alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, S Ra, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P (=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S (=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O) ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O )2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re(Ra, respectively are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkyl nyl, heterocycle, or aryl; R b , R c , and R d each independently represents hydrogen , alkyl, cycloalkyl, heterocyclic, aryl, or the above R b and R c Ha, so together with the N to which they are attached, optionally form a heterocyclic ring, R e Each of Independently, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, poly In the aforementioned exemplary substituents, alkyl, cycloalkyl, Groups such as alkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl are The term "optionally substituted" refers to a molecule, molecule, or a group that is optionally substituted. The alkyl moiety or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl) an alkyl, alkynyl, heterocyclic, or aryl group, or any other group disclosed herein; , refers to embodiments which may or may not be substituted with one or more of the substituents described above.

[0164] Unless otherwise specified, heteroatoms with unsatisfied valences must have enough atoms to satisfy the valences. It is considered to have no additional hydrogen atoms.

[0165] The compounds of the present invention can form salts which are also within the scope of the present invention. Reference to a product is understood to include reference to salts thereof unless otherwise indicated. The term "salts" as used herein refers to acidic and / or organic salts formed with inorganic and / or organic acids and bases. Furthermore, when the compound of the present invention is pyridine or imidazole, etc., and a basic moiety such as, but not limited to, a phenol or a carboxylic acid. When both the hydroxyl group and the hydroxyl group contain acidic moieties, including but not limited to, zwitterions ("inner salts") may be formed. The term "salt" as used herein includes pharmaceutically acceptable (i.e., non-toxic) salts. Although non-toxic and physiologically acceptable salts are preferred, other salts may also be used, e.g., Salts of the compounds of the present invention are useful, for example, in the isolation or purification steps for obtaining the compounds described herein. a compound described in the document with an amount of acid or base, such as an equivalent amount, in a medium such that the salt precipitates, or It can be formed by reaction in an aqueous medium followed by freeze-drying.

[0166] a basic moiety such as, but not limited to, an amine or a pyridine or imidazole ring The compounds of the present invention, including: can form salts with a variety of organic and inorganic acids. Acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids, e.g., Trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, betaine Benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate Camphorate, camphorsulfonate, cyclopentanepropionate, diglycerides Conate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate sulphate, glycerophosphate, hemisulphate, heptanoate, hexanoate, salt acid salts, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates) Hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphtha naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates , oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate Salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfo toluenesulfonates, such as nitrates, tartrates, thiocyanates, and tosylates; Decanoate and the like.

[0167] The compounds of the present invention contain an acidic moiety such as, but not limited to, a phenol or a carboxylic acid. The compounds can form salts with a variety of organic and inorganic bases. Exemplary Base Salts Examples include alkali metal salts such as ammonium salts, sodium, lithium and potassium salts. , alkaline earth metal salts such as calcium and magnesium salts, benzathine, dicyclohexyl Silamine, hydrabamine (N,N-bis(dehydroabietyl)ethylenediamine and (synthesized), N-methyl-D-glucamine, N-methyl-D-glycamide, t-butylamine salts with organic bases (e.g., organic amines) such as amines, and salts with amino acids such as arginine and lysine; The basic nitrogen-containing group may be a lower alkyl halide (e.g., a chloride, bromides and chlorides (methyl, ethyl, propyl, and butyl), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., , chloride, bromide, and decyl chloride, lauryl, myristyl, and stearyl), halogenated alkyls Quaternary, along with agents such as raryl (e.g., benzyl bromide and phenethyl) and others It will be transformed.

[0168] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as used herein refers to a drug that, upon administration to a subject, undergoes metabolic or chemical processing. Compounds that undergo chemical transformation to produce compounds of the invention, or salts and / or solvates thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0169] The compounds of the present invention, and salts or solvates thereof, may be present in their tautomeric forms (e.g., amines, amine derivatives, etc.). All such tautomeric forms are within the scope of the present invention. As used herein, any depicted portion of a compound is contemplated herein as a moiety. The structures include their tautomeric forms.

[0170] All stereoisomers of the compounds, including enantiomeric and diastereomeric forms ( For example, those that may exist due to asymmetric carbon atoms on various substituents are within the scope of the present invention. It is contemplated that the individual stereoisomers of the compounds of the present invention may, for example, be substantially different from the other isomers. (e.g., pure or substantially pure optical isomers having a particular activity) as a racemate), or as a racemate, or any other selected stereoisomer The chiral centers of the present invention may be mixed with chiral compounds according to the International Union of Pure and Applied Chemistry (IUPAC) It may have the S or R configuration as defined by the 1974 Recommendations. , physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or chiral methods. The individual optical isomers can be separated by separation using column chromatography. The isomers can be obtained by conventional methods, such as, but not limited to, salt formation with an optically active acid followed by crystallization. The compound can be obtained from the racemate by any suitable method, including by conventional methods.

[0171] Following their preparation, the compounds of the present invention are preferably isolated and purified to a concentration of 90 wt. % or more, for example, 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 herein incorporated by reference as part of the present invention. It is intended in this regard.

[0172] All configurational isomers of the compounds of the present invention may be used in admixture or in pure or substantially pure form. The compounds of the present invention are defined as being in either the cis (Z) or trans ( E) Alkene isomers, as well as both cis and trans isomers of cyclic hydrocarbons or heterocycles. Contains.

[0173] Throughout this specification, groups and substituents thereof are chosen to provide stable moieties and compounds. It can be done.

[0174] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of this guide, chemical elements are listed in the Periodic Table of the Elements. s,CAS version,Handbook of Chemistry and Physics, 75 th The specific functional groups are identified in accordance with the back cover of this specification. Further, the general principles of organic chemistry and the specific functional moieties and reactions For details on reactivity, see "Organic Chemistry", Thomas Sorre ll,University Science Books,Sausalito(19 99), the entire contents of which are incorporated herein by reference.

[0175] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. and trans isomers, R and S enantiomers, diastereomers, (d)-isomers, (l) -All such compounds, including isomers, racemic mixtures thereof, and other mixtures thereof Additional asymmetric carbon atoms may be added to substituents, e.g., aryl, aryl, aryls ... All such isomers as well as mixtures thereof are included within the scope of the present invention. is intended to be included.

[0176] Isomeric mixtures containing any of a variety of isomeric ratios can be utilized in accordance with the present invention. For example, when only two isomers are combined, 50:50, 60:40, 70:50, 0:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99: All mixtures containing an isomer ratio of 1 or 100:0 are contemplated by the present invention. It will be readily understood that similar ratios are contemplated for more complex isomeric mixtures. Deaf.

[0177] The present invention also includes isotopically labeled compounds that are identical to the compounds disclosed herein, but One or more atoms have an atomic mass or mass number that differs from the atomic mass or mass number normally found in nature. The fact that the compound of the present invention is replaced by an atom having a molecular weight of 1.5 or less is a problem. Examples of isotopes that can be incorporated into objects include: 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 hydrogen such as Cl, Includes isotopes of carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine. The compounds of the present invention, or their enantiomers, diastereomers, etc., may contain other isotopes of other atoms. Tautomers, tautomers, or pharmaceutically acceptable salts or solvates thereof are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, 3 H and 14 Radioactive isotopes such as C Incorporated compounds are useful in drug and / or substrate tissue distribution assays. Tritiation, i.e. 3 H, and carbon-14, i.e., 14 C isotopes are those Particularly preferred for ease of preparation and detectability. 2 H, etc. Substitution with heavier isotopes may result in greater metabolic stability, e.g., increased in vivo half-life or may offer certain therapeutic benefits due to reduced dosage requirements, and therefore, Isotopically labeled compounds generally have a higher affinity for non-isotopically labeled reagents. By substituting readily available isotopically labeled reagents, the following schemes and / or procedures can be implemented: It can be prepared by carrying out the procedures disclosed in the examples.

[0178] For example, if a particular enantiomer of a compound of the invention is desired, it can be obtained by asymmetric synthesis. or by derivatization with a chiral auxiliary, and the resulting diastereoisomers The chromatomeric mixture is separated and the auxiliary group is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, In this case, diastereomeric salts are formed with an appropriate optically active acid or base, followed by fractionation. Diastereomers formed by crystallization or chromatographic means well known in the art The mers are resolved and the subsequent pure enantiomers are recovered.

[0179] It is understood that the compounds described herein may be substituted with any number of substituents or functional moieties. Generally, whether preceded by the term "optionally," The term "substituted" and the substituents contained in the formulae of this invention refer to the radicals of the particular substituent. refers to the replacement of hydrogen radicals in a given structure by aryl groups. If a position can be substituted with more than one substituent selected from a specified group, the substituents As used herein, "position" refers to a group of amino acids that are either the same or different at every position. The term "substituted" is intended to include all permissible substituents of organic compounds. In a broad respect, the permissible substituents include acyclic and cyclic, branched and unbranched substituents of organic compounds. This includes unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents. Therefore, heteroatoms such as nitrogen may be substituted with hydrogen and / or alkyl groups to satisfy the valence of the heteroatom. The present invention also provides compounds comprising any of the permissible substituents of organic compounds described herein. It is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably present in, for example, This results in the formation of stable compounds useful in the treatment of reproductive disorders. The term "stable" as used herein preferably refers to a compound that is stable enough to allow for manufacture and testing. for a period of time sufficient to be useful for the purposes detailed herein. refers to a compound that maintains its integrity for a period of time sufficient for

[0180] As used herein, the terms "cancer" and, equivalently, "tumor" refer to a heterogeneous tumor of host origin. Cancer refers to a condition in which constantly replicating cells are present in detectable amounts in a subject. It may be a non-malignant cancer. Examples of cancers or tumors include biliary tract cancer, brain cancer, breast cancer, and 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, kidney cancer Cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, and other carcinomas and sarcomas Cancers can be primary or metastatic. Diseases other than cancer include, but are not limited to: The disease may be associated with mutational alterations in components of the Ras signaling pathway. The compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases include neurofibromatosis, Leopard syndrome, Noonan syndrome, and Gius syndrome, Costello syndrome, cardio-facial-cutaneous syndrome, hereditary gingival fibromatosis type 1, autoimmune diseases Immune lymphoproliferative syndrome and capillary malformation-arteriovenous malformation may be mentioned.

[0181] As used herein, an "effective amount" is the amount needed to achieve or promote a desired result. or any amount sufficient. In some cases, an effective amount is a therapeutically effective amount. in any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application will vary depending on the disease or condition being treated, the particular This can vary depending on factors such as the agent, the size of the subject, or the severity of the disease or condition. The effective amount of a particular drug can be determined empirically without undue experimentation. Cut.

[0182] As used herein, the term "subject" refers to a vertebrate animal. 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 primate, a laboratory animal, a livestock animal, a racehorse, a domestic animal, and Non-human vertebrates include, but are not limited to, non-human animals and non-domestic animals.

[0183] compound Novel compounds are described that are Kv1.3 potassium channel blockers. Remarkably, the compounds disclosed herein exhibit potent Kv1.3 potassium channel inhibition. Furthermore, applicants have surprisingly discovered that the compounds disclosed herein exhibit the following properties: The compound selectively blocks Kv1.3 potassium channels and does not block hERG channels. They found that the compound has a low vasopressin-releasing activity and therefore a favorable cardiovascular safety profile.

[0184] In one embodiment, a compound of formula I, I', II, II', III, or IV, or Pharmaceutically acceptable salts of

[0185] [ka]

[0186] [ka] During the ceremony, Each Z is independently OR a and Each X1 is independently selected from H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; Each X2 is independently H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; Each X3 is independently H, halogen, CN, alkyl, cycloalkyl, halogen a cycloalkyl halide or an alkyl halide; Or alternatively, X1 and X2 and the carbon atoms to which they are attached together represent: forming an optionally substituted 5- or 6-membered aryl; or alternatively, X2 and X3 and the carbon atoms to which they are attached together represent: forming an optionally substituted 5- or 6-membered aryl; Each R1 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3 , OR a , S.R.a , halogen, NR a R b , or NR b (C=O)R a and Each R2 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3 , OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a Or Or alternatively, R1 and R2 together with the carbon atoms to which they are attached form a cycloalkyl group. forming a hydroxyalkyl or saturated heterocyclic ring, Each R3 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b ,also is NR b (C=O)R a and Each R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, halogen, CN, CF3 , OR a , (CR a R b ) n2 OR a , oxo, (C=O)R a , O(C=O)R a , ( C=O)OR a , or (CR a R b ) n2 NR a R b Or Or alternatively, the two R groups, together with the atoms to which they are attached, form a 3- to 7-membered forming an optionally substituted cycloalkyl or heterocyclic ring of Each R5 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C= O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2 R a and Each R6 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle, alkylaryl, alkylaryl, or alkylheteroaryl; Each R7 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle, or alkylaryl, alkylaryl, or alkylheteroaryl; or alternatively, R6 and R7, together with the nitrogen atom to which they are attached, form a nitrogen atom, and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S and the heterocycle, when valence permits, may be alkyl, cycloalkyl, Cycloalkyl halides, alkyl halides, halogens, CN, OR8, -(CH2 ) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C ═O)R8, and 1 to 4 substituents independently selected from the group consisting of oxo. optionally substituted with Each R9 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C= O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2 R a and R 10 each independently represents H, alkyl, cycloalkyl, heterocycle, aryl, is heteroaryl, alkylaryl, or alkylheteroaryl; A1 is aryl or heteroaryl; A2 is aryl or heteroaryl; R 12 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogens, (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R 13 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogens, (CR a R b ) n2 OR a , (C=O)NR a R b , (CRa R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R a and R b each independently represents H, alkyl, alkenyl, cycloalkyl, N a saturated heterocyclic ring containing 1 to 3 heteroatoms each selected from the group consisting of , O, and S; or alternatively, R a and R b are the results of Consists of a nitrogen atom and N, O, and S together with the carbon or nitrogen to which it is bonded cycloalkyl or heteroalkyl groups containing 0 to 3 additional heteroatoms, each selected from the group Forming a ring, X1, X2, X3, A1, A2, R1, R2, R3, R4, R5, R6, if applicable , R7, R9, R 10 , R 12 , R 13 , R a , or R b Alkyl and cycloalkyl , heterocycle, aryl, and heteroaryl are, where valence permits, alkyl, cyclo, Alkyl, cycloalkyl halide, alkyl halide, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, 1 to 4 substituents independently selected from the group consisting of NR8(C=O)R8 and oxo optionally substituted by a substituent, Each R8 is independently H, alkyl, or an optionally substituted heterocycle. or alternatively, the two R groups together with the nitrogen atom to which they are attached form a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; forming an optionally substituted heterocycle containing the atom, each m is independently 0, 1, 2, or 3; each n1 independently, where valence allows, is an integer from 0 to 3; Each n2 is independently an integer of 0 to 3; n4 is an integer from 0 to 3, n5 is an integer of 0 to 3.

[0187] In another embodiment, a compound of formula I, I', II, II', III, or IV, or and pharmaceutically acceptable salts thereof are described.

[0188] [ka]

[0189] [ka] During the ceremony, Each Z is independently OR a and Each X1 is independently selected from H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; Each X2 is independently H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; Each X3 is independently H, halogen, CN, alkyl, cycloalkyl, halogen a cycloalkyl halide or an alkyl halide; Or alternatively, X1 and X2 and the carbon atoms to which they are attached together represent: forming an optionally substituted 5- or 6-membered aryl; or alternatively, X2 and X3 and the carbon atoms to which they are attached together represent: forming an optionally substituted 5- or 6-membered aryl; Each R1 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3 , OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a and Each R2 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF3, OCF3 , OR a , S.R. a , halogen, NR a R b , or NR b (C=O)R a Or Or alternatively, R1 and R2 together with the carbon atoms to which they are attached form a cycloalkyl group. forming a hydroxyalkyl or saturated heterocyclic ring, Each R3 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, CN, CF3, OCF3, OR a , S.R. a , halogen, NR a R b ,also is NR b (C=O)R a and Each R4 is independently H, alkyl, cycloalkyl, saturated heterocycle, (CR a R b ) n2 OR a, or (CR a R b ) n2 NR a R b Or Or alternatively, the two R groups, together with the atoms to which they are attached, form a 3- to 7-membered forming an optionally substituted cycloalkyl or heterocyclic ring of Each R5 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C= O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2 R a and Each R6 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle, alkylaryl, alkylaryl, or alkylheteroaryl; Each R7 is independently H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle, or alkylaryl, alkylaryl, or alkylheteroaryl; or alternatively, R6 and R7, together with the nitrogen atom to which they are attached, form a nitrogen atom, and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S and the heterocycle, when valence permits, may be alkyl, cycloalkyl, Cycloalkyl halides, alkyl halides, halogens, CN, OR8, -(CH2 ) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C ═O)R8, and 1 to 4 substituents independently selected from the group consisting of oxo. optionally substituted with Each R9 is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C=O)R a , (C= O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2 R a and R 10 each independently represents H, alkyl, cycloalkyl, heterocycle, aryl, is heteroaryl, alkylaryl, or alkylheteroaryl; A1 is aryl or heteroaryl; A2 is aryl or heteroaryl; R 12 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogens, (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R 13 each independently represents H, alkyl, CN, CF3, OCF3, OR a , S.R. a , halogens, (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a and R a and R b each independently represents H, alkyl, alkenyl, cycloalkyl, N a saturated heterocyclic ring containing 1 to 3 heteroatoms each selected from the group consisting of , O, and S; or alternatively, R a and R b are the results of Consists of a nitrogen atom and N, O, and S together with the carbon or nitrogen to which it is bonded cycloalkyl or heteroalkyl groups containing 0 to 3 additional heteroatoms, each selected from the group Forming a ring, X1, X2, X3, A1, A2, R1, R2, R3, R4, R5, R6, if applicable , R7, R9, R 10 , R 12 , R 13 , R a , or R b Alkyl and cycloalkyl , heterocycle, aryl, and heteroaryl are, where valence permits, alkyl, cyclo, Alkyl, cycloalkyl halide, alkyl halide, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, 1 to 4 substituents independently selected from the group consisting of NR8(C=O)R8 and oxo optionally substituted by a substituent, Each R8 is independently H, alkyl, or an optionally substituted heterocycle. or alternatively, the two R groups together with the nitrogen atom to which they are attached form a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; forming an optionally substituted heterocycle containing the atom, each m is independently 0, 1, 2, or 3; each n1 independently, where valence allows, is an integer from 0 to 3; Each n2 is independently an integer of 0 to 3; n4 is an integer from 0 to 3, n5 is an integer of 0 to 3.

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

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

[0192] In some embodiments, the compound has formula Ia, Ia', IIa, IIa', III a, or IVa:

[0193] [ka]

[0194] [ka]

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

[0196] [ka]

[0197] In some embodiments, the compound has formula Ib, Ib', IIb, IIb', III b, or IVb:

[0198] [ka]

[0199] [ka]

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

[0201] [ka]

[0202] In some embodiments, at least one occurrence of R4 is H, CN, alkyl, cycloalkyl, aryl, heteroaryl, CF3, or OR a Some real In embodiments, at least one occurrence of R4 is selected from the group consisting of halogen, saturated heterocycle, alkyl, aryl, and the like. alkyl, heteroaryl, (CR a R b ) n2 OR a , oxo, (C=O)R a , O(C=O)R a , (C=O)OR a , or (CR a R b ) n2 NR a R b That is. In some embodiments, at least one occurrence of R is oxo, (C=O)R a O( C=O)R a , or (C=O)OR a In some embodiments, at least one of R4 At least one occurrence of (CR a R b ) n2 OR a In some embodiments, At least one occurrence of R4 is H or alkyl. Non-limiting examples of alkyl include: are methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl Examples of aryl include ethyl, pentyl, hexyl, heptyl, and octyl. In the formula (I), at least one occurrence of R4 is cycloalkyl. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. and cycloheptyl. In some embodiments, at least one of R One occurrence is a halogen. Non-limiting examples of halogens include F, Cl, Br, and I can be mentioned.

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

[0204] In some particular embodiments, at least one occurrence of R4 is selected from the group consisting of NH2, CH2 NH2, or CH2CH2NH2. In certain other embodiments, at least one of R4 is Another occurrence is OH, CH2OH, or CH2NH2.

[0205] In yet other embodiments, at least one occurrence of R4 consists of N, O, and S. optionally substituted 4-membered, 5-membered alkyl groups containing 1 to 3 heteroatoms each selected from the group In a further embodiment, at least one of R4 is a 1, 2, 3, or 4 membered heterocycle. The appearance is

[0206] [ka]

[0207] [ka] and the heterocycle, when valence allows, is selected from the group consisting of alkyl, , OH, oxo, or (C=O)C 1-4 In some embodiments, At least one occurrence of R4 is an N-containing heterocycle, and the heterocycle may be any N-containing heterocycle where valence allows. alkyl, OH, oxo, or (C=O)C 1-4 Optionally substituted by alkyl Non-limiting examples of N-containing heterocycles include:

[0208] [ka]

[0209] [ka] Examples include:

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

[0211] [ka]

[0212] [ka]

[0213] [ka] and a saturated heterocyclic ring or heteroaryl selected from the group consisting of: Heteroaryl, where valence allows, can be cyano, cycloalkyl, fluorinated alkyl, or the like. , fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1-4 Optionally substituted with alkyl.

[0214] In some particular embodiments, at least one occurrence of R4 is H, halogen, Alkyl, OR a , N.R. a R b or oxo. In other particular embodiments, R At least one occurrence of H, F, Cl, Br, Me, Et, Pr, iso-Pr, Bu , iso-Bu, sec-Bu, or tert-Bu. , at least one occurrence of R4 is OH, NH2, NHMe, NMe2, NHEt, NM eEt, NEt2, or oxo. In yet other particular embodiments, at least one of R4 is Any one occurrence of H, halogen, alkyl, OH, NH2, CN, CF3, or OCF In yet other specific embodiments, at least one occurrence of R4 is H, Me Or Et.

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

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

[0217] In some specific embodiments, at least one occurrence of n1 is 0 and R5 At least one occurrence of is H or alkyl. In some particular embodiments , at least one occurrence of n1 is 1, and at least one occurrence of R5 is H or It's Rukiru.

[0218] In some embodiments, each R5 is independently H, alkyl, cycloalkyl Aryl, aryl, heteroaryl, (C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , or SO2R a Some implementations In one embodiment, at least one occurrence of R5 is H, alkyl, or cycloalkyl. In some embodiments, at least one occurrence of R5 is aryl or heteroaryl. In some specific embodiments, at least one occurrence of R5 is C=O)R a , (C=O)(CR a R b ) n2 OR a , (C=O)(CR a R b )n2 N R a R b , or SO2R a In some particular embodiments, at least one of R5 is Another occurrence is (C=O)R a or (C=O)-(CR a R b ) 1-2 -OR a is In some particular embodiments, at least one occurrence of R5 is (C=O)-( CR a R b ) 1-2 -NR a R b or (C=O)NR a R b Some specific examples In embodiments, at least one occurrence of R5 is (C=O)NR a R b , (C=O)C H2NR a R b , or (C=O)CH2CH2NR a R b Some specific implementations In certain embodiments, at least one occurrence of R5 is H. In certain other embodiments, at least one occurrence of R is methyl. At least one occurrence is ethyl.

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

[0220] [ka] In other particular embodiments, each of R and R is independently H and H , H and Me, Me and Me, H and Et, Me and Et, Et and Et, H and CH2 OH, H and CH2CH2OH, H and CH2OCH3, H and CH2CH2OCH3, or H and

[0221] [ka] In yet another embodiment, the structural moiety -(CR1R2) m -Each of them is independent -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3) -, -CCH3(CH2CH3)-, -CH(CH2OH)-, -CH(CH2OCH3 )-, -CH2-CH2-, -CH(CH3)-CH2-, -CH2-C(CH3)2- ,

[0222] [ka] is selected from the group consisting of:

[0223] In some embodiments, at least one occurrence of R or R independently represents a cycloalkyl group. In some embodiments, the alkyl group is a saturated heterocycle, an aryl group, or a heteroaryl group. and at least one occurrence of R or R is independently CN, CF, OCF, OR a , S.R. a , N.R. a R b , or NR b (C=O)R a is.

[0224] In some embodiments, each of R6 and R7 is independently cycloalkyl or is a heterocycle, and the cycloalkyl or heterocycle is selected from halogen, CN, OH, OMe, -(C H2) 1-2 OMe, and -(CH2) 1-2 OH, each independently selected from the group consisting of In some embodiments, R Each of R6 and R7 is independently H or alkyl, and alkyl is selected from the group consisting of halogen, CN , OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 A group consisting of OH Optionally, the group is substituted with 1 to 2 substituents each independently selected from the following: In certain embodiments, each of R and R is independently H, —CH, —CH 2OH, -CH2CH2OH, or -CH2CH2CH2OH. In this embodiment, each of R6 and R7 independently is alkylaryl or alkylheteroaryl. aryl, and alkylaryl or alkylteteroaryl , halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 Optionally substituted with 1 to 2 substituents each independently selected from the group consisting of OH will be done.

[0225] In some embodiments, R6 and R7 together with the nitrogen atom to which they are attached and a nitrogen atom and 0 to 3 additional atoms selected from the group consisting of N, O, and S. and forming a heterocyclic ring containing an additional heteroatom, the heterocyclic ring being, where valences permit, alkyl, cyclohexane ... Chloroalkyl, cycloalkyl halide, alkyl halide, halogen, CN, OR 8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8) 2, 1 to 4 independently selected from the group consisting of NR8(C=O)R8, and oxo is optionally substituted by a substituent of

[0226] In some embodiments, R6 and R7 together with the nitrogen atom to which they are attached and the like form a 4-, 5-, or 6-membered heterocyclic ring, and the heterocyclic ring is preferably an alkyl, halogenated alkyl, or the like. Alkyl, halogen, CN, OH, and -(CH2) 1-2 each independently selected from the group consisting of OH Optionally substituted with 1 to 2 substituents selected from the following: 4-, 5- or 6-membered Non-limiting examples of heterocycles include azetidine, pyrrolidine, piperidine, and piperazine. In some particular embodiments, the 4-, 5-, or 6-membered heterocycle is OH and -(CH2) 1-2 1 to 2 substituents independently selected from the group consisting of OH In some particular embodiments, the substituted group is a 4-, 5-, or 6-membered heterocyclic group. An elementary ring is

[0227] [ka] is.

[0228] In certain embodiments, R6 and R7 are each independently selected from the nitrogen atom to which they are attached. together to form an azetidine which may be substituted by alkyl or OH. In other particular embodiments, R6 and R7 together with the nitrogen atom to which they are attached to form a pyrrolidine which may be substituted by alkyl or OH. In certain embodiments, R6 and R7 together with the nitrogen atom to which they are attached are to form a piperidine which may be substituted by alkyl or OH.

[0229] In certain embodiments, the structural moiety

[0230] [ka] At least one occurrence of

[0231] [ka]

[0232] [ka] It has the following structure.

[0233] In some embodiments, each R9 is independently selected from cycloalkyl, saturated heterocyclic alkyl, and the like. ring, aryl, heteroaryl, alkylaryl, or alkylheteroaryl In some embodiments, at least one occurrence of R is (C=O)R a , (C =O)(CR a R b ) n2 OR a , (C=O)(CR a R b ) n2 NR a R b , (C=O )NR a R b , or SO2R a In some particular embodiments, at least one of R9 At least one occurrence is H or alkyl. Non-limiting examples of alkyl include methyl, , ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentabutyl In certain other embodiments, the alkyl groups include ethyl, hexyl, heptyl, and octyl. At least one occurrence of R9 is H or CH3.

[0234] In embodiments, R 10 At least one occurrence of is cycloalkyl or heterocycle. The cycloalkyl or heterocyclic ring is not substituted with halogen, CN, OH, OMe, -(CH2) 1-2 OMe, and -(CH2) 1-2 1 to 2 independently selected from the group consisting of OH In some embodiments, R 10 Less Each occurrence is H or alkyl, where alkyl is halogen, CN, OH, OMe , -(CH2) 1-2 OMe, and -(CH2) 1-2 each independently from the group consisting of OH Optionally substituted with 1 to 2 selected substituents. , R 10 at least one occurrence of is each independently selected from the group consisting of halogen, CN, and OH It is alkyl which may be substituted by 1 to 2 substituents selected from the following: In certain embodiments, R 10 At least one occurrence of is H, -CH3, -CH 2OH, or -CH2CH2OH.

[0235] In some embodiments, A1 is each selected from the group consisting of N, O, and S. It is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms. In this case, A1 is

[0236] [ka]

[0237] [ka] and heteroaryl selected from the group consisting of: Alkyl, OH, oxo, or (C=O)C 1-4 Optionally substituted with alkyl can be.

[0238] In some embodiments, A1 is an N-containing heteroaryl, is alkyl, OH, oxo, or (C=O)C when valences allow. 1-4 Alkyl Non-limiting examples of N-containing heteroaryls include:

[0239] [ka]

[0240] [ka] Examples include:

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

[0242] [ka] In some particular embodiments, A1 is selected from the group consisting of:

[0243] [ka] is.

[0244] In some embodiments, A1 is a 7- to 11-membered bicyclic or an 8- to 16-membered tricyclic aryl or heteroaryl. Non-limiting examples of bicyclic or tricyclic rings include bicyclic and tricyclic rings. Phenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolinol benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, iso Quinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalyl furo[2,3-c]pyridinyl, indazolyl, pyrrolopyridyl, furopyridinyl (furo[2,3-c]pyridinyl) , furo[3,2-b]pyridinyl], or furo[2,3-b]pyridinyl, etc.), carba Examples include zolyl, phenanthrolinyl, acridinyl, and phenanthridinyl.

[0245] In some embodiments, A1 is

[0246] [ka]

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

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

[0249] [ka]

[0250] [ka] and heteroaryl selected from the group consisting of: Alkyl, OH, oxo, or (C=O)C 1-4 Optionally substituted with alkyl can be.

[0251] In some embodiments, A2 is an N-containing heteroaryl, is alkyl, OH, oxo, or (C=O)C when valences allow. 1-4 Alkyl Non-limiting examples of N-containing heteroaryls include:

[0252] [ka]

[0253] [ka]

[0254] [ka] Examples include:

[0255] In some embodiments, A2 is a 5- or 6-membered heterocycle or phenyl. In some embodiments, A2 is a 5-membered heteroaryl. In an embodiment, A2 is

[0256] [ka]

[0257] [ka] In some particular embodiments, A2 is selected from the group consisting of:

[0258] [ka] is.

[0259] In some embodiments, A2 is a 7- to 11-membered bicyclic or an 8- to 16-membered tricyclic aryl or heteroaryl. Non-limiting examples of bicyclic or tricyclic rings include bicyclic and tricyclic rings. Phenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolinol benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, iso Quinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalyl furo[2,3-c]pyridinyl, indazolyl, pyrrolopyridyl, furopyridinyl (furo[2,3-c]pyridinyl) , furo[3,2-b]pyridinyl], or furo[2,3-b]pyridinyl, etc.), carba Examples include zolyl, phenanthrolinyl, acridinyl, and phenanthridinyl.

[0260] In some embodiments, A2 is

[0261] [ka]

[0262] [ka] is selected from the group consisting of:

[0263] In some embodiments, R 12 each independently represents H, alkyl, CF3, or halogen. In embodiments, R 12 At least one occurrence of CN, CF 3, OCF3, OR a , or SR a In some embodiments, R 12 Few At least one occurrence of halogen, NR a R b , or NR b (C=O)R a How many? In some embodiments, R 12 At least one occurrence of OR a , S.R. a , or NR a R b In some embodiments, R 12 At least one occurrence of NR b ( C=O)R a In some embodiments, R 12 At least one occurrence of (CR a R b ) n2 OR a , (C=O)NR a R b , (CR a R b ) n2 NR a R b ,also (CR a R b ) n2 NR b (C=O)R a In some embodiments, R1 At least one occurrence of 2 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, R 12 At least one occurrence of is H, fluorinated alkyl or alkyl. In some embodiments, R 12 At least one occurrence of , H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3. In some particular embodiments, R 12 At least one occurrence of is H.

[0264] In some embodiments, R 13 each independently represents H, alkyl, CF3, or halogen. In some embodiments, R 13 At least one occurrence of CN, CF3, OCF3, OR a , or SR a In some embodiments, R 13 At least one occurrence of is a halogen, NR a R b , or NR b (C=O)R a Yes In some embodiments, R 13 At least one occurrence of OR a , S.R. a , or NR a R b In some embodiments, R 13 At least one occurrence of , N.R. b (C=O)R a In some embodiments, R 12 At least one of The appearance of (CR a R b ) n2 OR a , (C=O)NR a R b, (CR a R b ) n2 NR a R b , or (CR a R b ) n2 NR b (C=O)R a In some embodiments, R 13 At least one occurrence of is H, halogen, fluorinated alkyl, or alkyl In some embodiments, R 13 At least one occurrence of is H, fluorine In some embodiments, R 13 At least one of One occurrence is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3 In some particular embodiments, R 13 At least one occurrence of is H do.

[0265] In some embodiments, n4 is an integer from 0 to 3. In some embodiments, n4 is an integer from 1 to 3. In some embodiments, n4 is 0. In some embodiments, n4 is 1 or 2. n4 is 1.

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

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

[0268] In some embodiments, each X is independently H, halogen, CN, alkoxy, or methyl. alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, at least one occurrence of X1 is selected from H, halogen, fluorinated alkyl, aryl ... In some embodiments, at least one of X1 is alkyl, or alkyl. In another embodiment, at least one occurrence of X is H or halogen. In another embodiment, at least one of X1 is a fluorinated alkyl or alkyl. In some embodiments, at least one occurrence of X is cycloalkyl. Occurrences are H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, at least one occurrence of X1 is H, F, or Cl. In some embodiments, at least one occurrence of X is F or Cl. In some embodiments, at least one occurrence of X is H or Cl. In some embodiments, at least one occurrence of X is F. and at least one occurrence of X is Cl. At least one occurrence is CF or CFH. In some embodiments, X At least one occurrence of X is CF. At least one occurrence is H.

[0269] In some embodiments, each X2 is independently H, halogen, CN, alkane, or argon. alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, at least one occurrence of X2 is selected from H, halogen, fluorinated alkyl, aryl ... In some embodiments, at least one of X2 is alkyl, or alkyl. In another embodiment, at least one occurrence of X is H or halogen. In another embodiment, at least one of X2 is a fluorinated alkyl or alkyl. In some embodiments, at least one occurrence of X2 is cycloalkyl. Occurrences are H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, at least one occurrence of X2 is H, F, or Cl. In some embodiments, at least one occurrence of X2 is F or Cl. In some embodiments, at least one occurrence of X2 is H or Cl. In some embodiments, at least one occurrence of X2 is F. and at least one occurrence of X is Cl. At least one occurrence is CF or CFH. In some embodiments, X At least one occurrence of X is CF. At least one occurrence is H.

[0270] In some embodiments, each X3 is independently H, halogen, CN, alkoxy, or methyl. alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In some embodiments, at least one occurrence of X3 is H, halogen, alkyl, or an alkyl halide. In some embodiments, at least one of X3 The occurrence is H, halogen, fluorinated alkyl, or alkyl. In other embodiments, at least one occurrence of X is H or halogen. At least one occurrence of X is a fluorinated alkyl or alkyl. In embodiments, at least one occurrence of X is selected from the group consisting of H, F, Cl, Br, Me, CF2H , CF2Cl, or CF3. In some embodiments, at least one of X3 is H, F, or Cl. In some embodiments, at least one occurrence of X In some embodiments, at least one occurrence of X3 is F or Cl. occurrence is H or Cl. In some embodiments, at least one occurrence of X is F. In some embodiments, at least one occurrence of X is Cl. In some embodiments, at least one occurrence of X3 is CF3 or CF2H In some embodiments, at least one occurrence of X is CF. In some embodiments, at least one occurrence of X3 is H.

[0271] In an embodiment, at least one occurrence of R3 is H, alkyl, CF3, or halo. In an embodiment, at least one occurrence of R is cycloalkyl or saturated. In an embodiment, at least one occurrence of R is an aryl or heterocyclic ring. In an embodiment, at least one occurrence of R is CN, CF, OCF3, OR a , or SR a In an embodiment, at least one occurrence of R is halogen, NR a R b , or NR b (C=O)R a In some embodiments, and at least one occurrence of R3 is OR a , S.R. a , or NR a R b How many? In some embodiments, at least one occurrence of R3 is NR b (C=O)R a is. In some embodiments, at least one occurrence of R3 is selected from H, halogen, fluorinated In some embodiments, at least one of R3 is alkyl, or alkyl. occurrence is H, fluorinated alkyl, or alkyl. In some embodiments, R At least one occurrence of 3 is H, Me, Et, i-Pr, n-Bu, CF2H, CF2 In some particular embodiments, at least one of R3 is Cl, or CF3. The appearance is H.

[0272] In some embodiments, the structural moiety

[0273] [ka] At least one occurrence of

[0274] [ka]

[0275] [ka] It has the following structure.

[0276] In some embodiments, the structural moiety

[0277] [ka] At least one occurrence of

[0278] [ka] It has the following structure.

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

[0280] [ka]

[0281] [ka]

[0282] [ka] having the structure In the formula, R 11 each independently represents H, halogen, fluorinated alkyl, or alkyl and each n3 is independently an integer of 0 to 3.

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

[0284] In some embodiments, R 11 each independently represents H, a halogen, a fluorinated In some embodiments, R 11 At least one of occurrence of is H or halogen. In some embodiments, R 11 At least one of One occurrence of R1 is alkyl or fluorinated alkyl. At least one occurrence of 1 is H, Cl, Br, CF3, CHF2, or Me. In some embodiments, R 11 At least one occurrence of is H.

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

[0286] [ka]

[0287] [ka] and the heterocycle, when valence allows, is selected from the group consisting of alkyl, , OH, oxo, or (C=O)C 1-4 Optionally substituted with alkyl. In some embodiments, R a or R b At least one occurrence of is independently H or

[0288] [ka] is.

[0289] In some embodiments, R a and R b together with the carbon atoms to which they are attached and, where valence allows, alkyl, cycloalkyl, halogenated cycloalkyl, alkyl halides, halogens, CN, OR8, -(CH2) 0-2 OR8, N(R 8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo may be substituted with 1 to 4 substituents each independently selected from the group consisting of , forming a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, Ra and R b together with the nitrogen atoms to which they are attached and a nitrogen atom, and, where valence allows, alkyl, cycloalkyl, halogen, Cycloalkyl halides, alkyl halides, halogens, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R 8, and oxo, each substituted by 1 to 4 substituents independently selected from the group consisting of 0 to 3 additional hetero atoms each selected from the group consisting of N, O, and S, optionally and forming an optionally substituted heterocycle containing atoms. Non-limiting examples of heterocycles include:

[0290] [ka]

[0291] [ka] Examples include:

[0292] In some embodiments, alkyl, cycloalkyl, Heterocycle, aryl, and heteroaryl may be optionally substituted with alkyl, cycloalkyl, or cycloaliphatic groups, where valences permit. Alkyl, cycloalkyl halide, alkyl halide, halogen, CN, OR8, - (CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, N 1 to 4 substituents independently selected from the group consisting of R8(C=O)R8 and oxo In some embodiments, the alkyl groups in A1 and A2 are optionally substituted by a group. Aryl and heteroaryl are substituted with alkyl, cycloalkyl, halo, etc., where valences permit. Cycloalkyl halides, alkyl halides, halogens, CN, OR8, -(CH2)0 -2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O ) R8, and 1 to 4 substituents independently selected from the group consisting of oxo, In some embodiments, the alkyl, cycloalkyl, and cyclohexyl groups in R and R are optionally substituted. The alkyl, heterocyclic, aryl, and heteroaryl groups are substituted with alkyl, heterocyclic, and heterocyclic groups when valences permit. Cycloalkyl, cycloalkyl halide, alkyl halide, halogen, CN , OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N( R8)2, NR8(C=O)R8, and oxo; In some embodiments, R3 is optionally substituted with up to 4 substituents. The alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in In this case, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl , halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8 , (C=O)N(R8)2, NR8(C=O)R8, and oxo, each independently selected from the group consisting of In some embodiments, the alkyl group is optionally substituted with 1 to 4 substituents selected from the group consisting of: In the above, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in R4 is, where valences permit, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated Halogenated alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2 , (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo is optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: In some embodiments, alkyl, cycloalkyl, heterocycle, aryl, and and heteroaryl, where valences permit, may be alkyl, cycloalkyl, halogenated cycloalkyl, or heteroaryl. Chloroalkyl, alkyl halide, halogen, CN, OR8, -(CH2) 0-2 OR 8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo, optionally with 1 to 4 substituents each independently selected from the group consisting of In some embodiments, the alkyl, cycloalkyl, and cycloalkyl groups in R6 and R7 are substituted with The heterocycles, aryls, and heteroaryls may be optionally substituted with alkyls, cycloalkyls, and cyclohexyls, where valences permit. Cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8 , -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2 , NR8(C═O)R8, and 1 to 4 independently selected from the group consisting of oxo In some embodiments, the alkyl group in R is optionally substituted by a substituent. aryl, cycloalkyl, heterocycle, aryl, and heteroaryl are substituted or unsubstituted when valences permit; , alkyl, cycloalkyl, cycloalkyl halide, alkyl halide, halogen N, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C= O)N(R8)2, NR8(C=O)R8, and oxo, each independently selected from the group consisting of In some embodiments, the group is optionally substituted with 1 to 4 substituents selected from the group consisting of: , R 10 The alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in Where valency permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogen Alkyl chloride, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C From the group consisting of (=O)R8, (C=O)N(R8)2, NR8(C=O)R8, and oxo Optionally substituted with 1 to 4 substituents each independently selected from the following: In the embodiment, R 12 and R 13 The alkyl in the group is alkyl, if valence allows. Cycloalkyl, cycloalkyl halide, alkyl halide, halogen, CN , OR8, -(CH2) 0-2 OR8, N(R8)2, (C=O)R8, (C=O)N( R8)2, NR8(C=O)R8, and oxo; In some embodiments, R a Reach BiR b The alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl in Where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated Alkyl, halogen, CN, OR8, -(CH2) 0-2 OR8, N(R8)2, (C= From the group consisting of (C=O)R8, (C=O)N(R8), NR8(C=O)R8, and oxo Optionally substituted with 1 to 4 independently selected substituents.

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

[0294] In some embodiments, the compound of Formula I is selected from compounds 1-15 shown in Table 1 below. In some embodiments, the compound of formula I' is selected from the group consisting of the following Table In some embodiments, the compound is selected from the group consisting of compounds 16 to 30 shown in The compound of formula II is selected from the group consisting of compounds 1a to 15a shown in Table 3 below. In some embodiments, the compound of formula II' is Compound 1 shown in Table 4 below. In some embodiments, the compound of Formula III is selected from the group consisting of 6a to 30a. The compound is selected from the group consisting of compounds 1b to 15b shown in Table 5 below. In an embodiment, the compound of formula IV is selected from compounds 16b-30b shown in Table 6 below. The compounds listed in Tables 1-6 are selected from the group consisting of: are representative but non-limiting compounds of

[0295] [Table 1-1]

[0296] [Table 1-2]

[0297]

Table 2-1

[0298]

Table 2-2

[0299]

Table 3-1

[0300]

Table 3-2

[0301]

Table 4-1

[0302]

Table 4-2

[0303]

Table 5-1

[0304]

Table 5-2

[0305]

Table 6-1

[0306]

Table 6-2

[0307] Abbreviations

[0308] [Table 7]

[0309] Preparation method Below are general synthetic schemes for preparing compounds of the present invention. are exemplary and represent possible compounds that one of skill in the art can use to prepare the compounds disclosed herein. It is not meant to be limiting in any way, and different methods will be apparent to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternating sequence or order to provide the desired compounds. All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrative and are not intended to be limiting unless otherwise specified and are incorporated by reference. Some preparations of compounds are not intended to be limiting.

[0310] Schemes 1-3 below illustrate the synthesis of compounds of the present invention, e.g., compounds of Formulas I, I', II, II', II Synthetic routes that can be used to synthesize compounds having structure I or IV, or precursors thereof Various methods have been developed to achieve results similar to those of the present invention, as described below. Various modifications can be envisioned by those skilled in the art. In the following embodiments, the synthetic route is shown by way of example. and a compound having the structure of formula I, I', II, II', III, or IV, or a precursor thereof. The general synthetic routes are described using precursors as shown in Schemes 1-3 and in the examples below. The Examples provided in the section illustrate the methods used to prepare the compounds described herein.

[0311] Compound I-1, as shown in Scheme 1, can be prepared by any method known in the art. As shown in Scheme 1, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), Trimethylsilylethoxymethyl (SEM), allyl, A c, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, and OH or Other protecting groups known in the art are suitable for use as protecting groups for amine groups. The substituents are defined herein. It reacts with (S)-t-butylsulfinamide in the presence of a Lewis acid such as propoxide. The sulfinyl imine I-2S can be obtained by the addition of methyl 2-bromomethyl I-2S. The Reformatsky reaction with ethyl acrylate and zinc gave the R configuration at the benzylamine position. The sulfinamide is then removed by treatment with dilute acid to give I-3. to give amine I-4, which was reprotected as toluenesulfonamide I-5 under standard conditions. I-5 is reacted with a base such as sodium hydride in a polar aprotic solvent such as DMF. By reacting the compound with the pyrrolidine derivative and heating it at, for example, 100°C, the compound is obtained as a mixture of epimers at the ester position. The tosyl group is converted to ester I-6 by treatment with magnesium metal in methanol. The amine I-7 is then reprotected, e.g., with a Boc group, and an ester is added to give I-7. I-8 is reacted with a suitable amine such as R6R7NH and HATU to form I-8. and all protecting groups are removed under standard conditions. to give pyrrolidine amide I-9.

[0312] [ka] Compound I-10, shown in Scheme 2, can be prepared by any method known in the art. As shown in Scheme 2, PG denotes a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilyl Ethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, di alkylaminocarbonyl and OH protecting groups known in the art. Other protecting groups are included. Other substituents shown in Scheme 2 are as defined herein. As shown in Scheme 2, compound I-10 can be reacted with a base such as n-butyllithium to form a methyl group. Deprotonation using 1-t-butyl 2-ethyl(2S)-5-oxopyrrolidine- 1,2-dicarboxylate to form ketone I-11. Use a phenol with a halogen such as iodine or bromine next to the phenol, and Magnesium chloride / lithium chloride (Turbo Grignard) or n-butyllithium It can be metallated by metal-halogen exchange using agents such as organolithium reagents. TF Removal of the Boc group with A results in cyclization to the imine I-12. reduction to methyl ... The cis isomer is obtained by various methods or by using sodium borohydride. The pyrrolidine nitrogen can then be protected with a protecting group such as Boc to give pyrrolidine I-13. Protect and get I-14.

[0313] [ka]

[0314] Compound I-2R shown in Scheme 3 can be prepared by any method known in the art. As shown in Scheme 3, PG denotes a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilyl Ethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, di Alkylaminocarbonyl and other compounds of the art suitable for use as protecting groups for OH or amine groups Other protecting groups known in the art are included. Other substituents shown in Scheme 3 are also suitable for use herein. For compounds of formula I disclosed herein where R2 is H and m is 1, In this case, a pyrrolidine ring with an extended chain at C4 (see compound I-15 labeled at the 4-position) (I want to) can be obtained by the synthesis described in Scheme 3. As shown, benzenesulfinyl imine I-2R can be synthesized by the reaction of tetrakis(II) with tetrakis(III) in a solvent such as THF. In the presence of a palladium catalyst such as triphenylphosphine palladium, Cycloaddition with the precursor 2-((trimethylsilyl)methyl)-prop-2-enyl acetate The 2R-phenylpyrrolidine I-15 can be obtained by introducing a side chain at C4. One method for this is the reaction of methyl acylate and glycerol to form the unsaturated ester I-16. This is achieved by cross-metathesis using the second generation Rabbs catalyst. In solvents such as methanol I-16 can be hydrogenated over a catalyst such as platinum oxide to give I-17 as a mixture of epimers. Ester I-17 is hydrolyzed with an agent such as lithium hydroxide to give the resulting carboxylic acid with an amine R6R7NH and a coupling reagent such as HATU to give amide I-1 8 can be converted to 9 using standard methods. Removal of the protecting groups gave the amide I-19 as a mixture of isomers, which was purified by chromatography. An alternative route to I-19 is to convert the sulfinamide to 1-methyl-2-methyl-2-propanol with acid. 2R-phenylpyrrolidine I-1 was prepared by hydrolysis and reprotection with Boc anhydride. 5 is first converted to Boc-protected pyrrolidine I-20. I-20 is then reacted with ruthenium chloride or other suitable cations. Reaction with an oxidizing agent to form a diol, which can be derivatized in situ using sodium periodate Cleavage affords the ketone I-22. The Wittig reaction of I-22 with tate or similar reagents affords unsaturated esters similar to I-16. to give ester I-22, where R1 can be H, alkyl, etc. A catalyst such as platinum oxide Hydrogenation of I-22 over a catalyst affords the ester I-23 as a mixture of isomers. Hydrolysis of I-24 affords acid I-24, which can be further subjected to the same sequence of amide coupling and Deprotection converts to amide I-19.

[0315] [ka]

[0316] Either R1 or R2, or both, are not H, and m is 1. For compounds of formula I, the substitutions on the extension chain can be obtained by the synthesis described in Scheme 4. Compound I-23a shown in Scheme 4 can be prepared by reacting unsubstituted triphenylphosphine with 1-23a. from ketone I-21 by Wittig reaction with anilidene acetate or sulfonyl The amide can be obtained from I-17 by exchanging the amide with Boc. As indicated, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxide, Dimethyl (MOM), trimethylsilylethoxymethyl (SEM), allyl, Ac, Bo c, other alkoxycarbonyl groups, dialkylaminocarbonyl, and OH or amine groups Other protecting groups known in the art are suitable for use as protecting groups for Scheme 4. The other substituents shown in are defined herein. The alkylation of I-23a can be carried out by LD Formation of the enolate with a strong base such as A and reaction with a halide R1X gives I-23 The alkylation is carried out by reacting a second R2X, which may be the same or different. This can be repeated to give the geminal disubstituted ester I-23b. Cleavage, amide coupling, and deprotection affords the substituted amide I-19a.

[0317] [ka]

[0318] Compound I-24, shown in Scheme 5, can be prepared by any method known in the art. As shown in Scheme 5, PG denotes a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilyl Ethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, di Alkylaminocarbonyl and other compounds of the art suitable for use as protecting groups for OH or amine groups Other protecting groups known in the art are included. Other substituents shown in Scheme 5 are also suitable for use herein. Compounds of formula III disclosed herein, wherein R2 is H and m is 1, For the compound, the aryl or heteroaryl ring can be converted to a decarboxylated photoacid as shown in Scheme 5. It can be obtained by a redox reaction of iridium catalyst in DMSO under irradiation with blue light. Catalytic catalyst [4,4'-bis(t-butyl)-2,2'-bipyridine-κN 1 ,κN 1 ]bis[3 ,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN 1 ]Fe Ni κC-iridium hexafluorophosphate, nickel chloride DME complex, di(t -butyl)-4,4'-bipyridine, phthalimide, and t-butyl-tetramethylguanidine an optionally protected aryl halide A1X (where X is bromine or The reaction of I-24 with carboxylic acid I-24 (where I is iodine) results in the replacement of the carboxylic acid with the aryl ring A1. In turn, this affords I-25 after deprotection.

[0319] [ka]

[0320] Compound I-8, shown in Scheme 6, can be prepared by any method known in the art. As shown in Scheme 6, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilyl Ethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, dia and alkylaminocarbonyl, and compounds of the art suitable for use as protecting groups for OH or amine groups. Other protecting groups shown in Scheme 6 are also known in the art. The compound of formula I' disclosed herein, wherein R2 and R9 are H and m is 1, is defined as: For compounds with alternate orientations of the amide side chain, synthesis is provided as described in Scheme 6. As shown in Scheme 6, carboxylic acid I-8 can be obtained by the addition of In a solvent, ammonium chloride, a coupling agent such as HATU, and triethylamine This is converted to the primary amide I-26 by reaction with a base such as THF. I-26 is heated with a borane reducing agent (e.g., borane-methyl sulfide complex) in a tert-butyl solvent to give Reduction of I-26 to the primary amine I-27 is accomplished by affording I-27. In a solvent such as DMF, a coupling agent such as HATU and triethylamine are used. Using a base, amine I-27 can be converted to carboxylic acid R 10 Acylation with CO2H affords amide I Deprotection under standard conditions gives amide I-29, where R1 = H and R2 = H. To obtain compounds where R1 is a substituent such as an alkyl group, the acid I-8 is first Weinreb's amide coupling reaction was carried out using N,O-dimethylhydroxylamine under amide coupling conditions. I-30 is then treated with the Grignard reagent R1MgBr to give to give ketone I-31. The formation of the oxime of I-31 and the reaction, for example, over Raney nickel, Reduction by hydrogenation gives amine I-32, which can be acylated in the same manner as I-27. and deprotection to give I-29.

[0321] [ka]

[0322] Compound I-14, shown in Scheme 7, can be prepared by any method known in the art. As shown in Scheme 7, PG denotes a protecting group. Non-limiting examples of protecting groups include Me, methoxymethyl (MOM), trimethylsilyl Ethoxymethyl (SEM), allyl, Ac, Boc, other alkoxycarbonyl groups, di Alkylaminocarbonyl and other compounds of the art suitable for use as protecting groups for OH or amine groups Other protecting groups known in the art are included. Other substituents shown in Scheme 7 are also suitable for use herein. The compound of formula II disclosed herein, wherein R1 and R2 are H and m is 1, is defined as follows: Regarding the compound, a pyrrolidine ring with an extended chain at C5 (compound I-14 labeled at the 5-position) (see Scheme 7) can be obtained by the synthesis described in Scheme 7. 7. Ester I-14 can be converted to acetone using, for example, sodium borohydride. I-34 is then reacted with an agent such as tosyl chloride and triethyl alcohol I-34. The resulting tosylate is treated with a base such as an amine, and the resulting tosylate is reacted with tetrabutyl ether in a solvent such as DMF. Displacement by heating with ammonium cyanide to form nitrile I-35 Hydrolysis of I-35 with sodium hydroxide and hydrogen peroxide gave the primary amide I-36. which is then deprotected to give I-37. Further hydrolysis followed by reaction with the amine R6R7NH and a coupling reagent such as HATU The protecting group can be removed under standard conditions to give the substituted amide. to give amide I-37a.

[0323] [ka]

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

[0325] In yet another aspect, the present invention provides a compound of formula I, I', II, II', II at least one compound selected from the group consisting of compounds of formula I or IV, and a pharmaceutically acceptable salt thereof; and an acceptable carrier or diluent.

[0326] In certain embodiments, the composition is in the form of a hydrate, solvate, or pharmaceutically acceptable salt. The composition may be administered by any suitable route of administration, including, but not limited to, oral and parenteral administration. It can be administered to a subject by any route.

[0327] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutical involved in transporting or transferring substances from one organ or part of the body to another pharmaceutically acceptable additives such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials Each carrier refers to a material, composition, or vehicle that is compatible with the other ingredients of the formulation. It must be "acceptable" in the sense that it is safe and will not harm the patient. Some examples of materials that can serve as acceptable carriers include: sugars such as lactose, glucose, and sucrose; corn starch and potato Starches such as: sodium carboxymethylcellulose, ethylcellulose, and cellulose and its derivatives such as cellulose acetate; powdered tragacanth; malt; gelatin; Talc; excipients such as cocoa butter and suppository wax; peanut oil, cottonseed oil, safflower oil oils such as sesame oil, olive oil, corn oil, and soybean oil; glycols such as butylene glycol Recall: Polyesters such as glycerin, sorbitol, mannitol, and polyethylene glycol esters such as ethyl oleate and ethyl laurate; agar; magnesium hydroxide Buffers such as sodium and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic Saline solution; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other substances used in pharmaceutical preparations The term "carrier" refers to a substance in which the active ingredient is placed to facilitate application. The term "compound" refers to a natural or synthetic organic or inorganic ingredient with which the compound is combined. with the compounds of the present invention and with each other so that there is no interaction which would substantially impair the desired pharmaceutical efficiency. They can be mixed together.

[0328] As noted above, certain embodiments of the pharmaceutical agent are provided in the form of a pharmaceutically acceptable salt. In this respect, the term "pharmaceutically acceptable salt" refers to a relatively simple salt of a compound of the present invention. refers to non-toxic inorganic and organic acid addition salts, which are useful in the final isolation and purification of the compounds of this invention. The purified compounds of the invention in situ or separately in free base form are treated with a suitable organic or inorganic acid. and isolating the salt thus formed. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, and phosphate. , nitrate, acetate, valerate, oleate, palmitate, stearate, la Urate, benzoate, lactate, phosphate, tosylate, citrate, maleate tartrate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoside Examples of suitable hydroxybenzoates include butonate, lactobionate, and lauryl sulfonate. Berge et al., (1977) “Pharmaceutical Salts ", J. Pharm. Sci. 66:1-19 (incorporated herein by reference in its entirety). Please refer to the

[0329] Pharmaceutically acceptable salts of the subject compounds include, for example, chemically acceptable salts from non-toxic organic or inorganic acids. For example, conventional non-toxic salts or quaternary ammonium salts of such compounds may be used. Salts are derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid. and salts of acetic acid, butionic acid, succinic acid, glycolic acid, stearic acid, Acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydro Maleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid , 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane Included are salts prepared from organic acids such as disulfonic acid, oxalic acid, isethionic acid, and the like.

[0330] In other cases, the compounds disclosed herein may contain one or more acidic functional groups, Thus, it is possible to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salt" refers to a compound disclosed herein. These salts also refer to the relatively non-toxic inorganic and organic base addition salts of the compounds. and either in situ during purification or separately with the purified compound in free acid form, by precipitation with a pharmaceutically acceptable metal cation. A suitable base such as a hydroxide, carbonate, or bicarbonate of thiol; or by reacting with 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 the formation of base addition salts include ethylamine, diethylamine, Amine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. See, for example, Berge et al. (supra).

[0331] Sodium lauryl sulfate, magnesium stearate, polyethylene oxide-polyb Wetting agents, emulsifiers, lubricants, colorants, release agents, coatings, etc. Nutrients, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the composition. do.

[0332] The formulations of the present invention may be administered orally, nasally, topically (including buccal and sublingually), rectally, vaginally, and / or intravenously. The formulations may conveniently be presented in unit dosage form and may be administered by pharmacy. It may be prepared by any method known in the art. The amount of active ingredient that can be produced will depend on the host treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form generally will be This will be the amount of the composition that produces a therapeutic effect. Generally, out of 100%, this amount is the active ingredient. About 1% to about 99%, preferably about 5% to about 70%, most preferably about 10% to about 3% of the ingredients It will be in the 0% range.

[0333] Methods for preparing these formulations or compositions include incorporating a compound of the invention into a carrier and optionally a Generally, the formulations include bringing a compound of the invention into association with a liquid carrier. and then, if desired, uniformly and intimately associating the carrier with the carrier or finely divided solid carrier, or both. and by shaping the product.

[0334] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (commonly Usually uses a flavor base of sucrose and acacia or tragacanth), powder, granules or a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid As a solid emulsion, or as an elixir or syrup, or as a troche (gelatin and / or Each of the compounds of the present invention is contained in a predetermined amount as an active ingredient in the form of a mouthwash or the like. The product may also be administered as a bolus, electuary, or paste.

[0335] The solid dosage forms of the present invention for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules) ), the active ingredient is sodium citrate or dicalcium phosphate, and / or or mixed with one or more pharmaceutically acceptable carriers such as any of the following: starch, Fillers such as lactose, sucrose, glucose, mannitol, and / or silicic acid bulking agents or fillers; e.g., carboxymethylcellulose, alginate, gelatin, polysaccharides Binders such as polyvinylpyrrolidone, sucrose, and / or acacia; glycerol Humectants such as agar, calcium carbonate, potato or tapioca starch, algin Acids, certain silicates, sodium carbonate, and sodium starch glycolate Disintegrants; solution retardants such as paraffin; absorption enhancers such as quaternary ammonium compounds; e.g. For example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-poly Wetting agents such as butylene oxide copolymers; absorbents such as kaolin and bentonite clays Sorbents: Talc, calcium stearate, magnesium stearate, solid polyethylene lubricants such as 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. The composition may contain excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols. The excipients can also be used as fillers in soft and hard-filled gelatin capsules. .

[0336] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made without the use of binders (e.g., gelatin or hydroxybutylmethylcellulose). lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate), or cross-linked sodium carboxymethylcellulose), surfactants or dispersants Molded tablets can be prepared by mixing the powdered compound moistened with an inert liquid diluent. can be made by molding in a suitable machine.

[0337] The pharmaceutical compositions disclosed herein may be in the form of tablets, as well as sugar-coated tablets, capsules, pills, and granules. Any other solid dosage form may optionally be coated with enteric coatings and other suitable coatings as are well known in the pharmaceutical arts. providing or preparing with coatings and shells such as cellulose acetate and other coatings; These can also be formulated to provide sustained or controlled release of the active ingredient therein, e.g. Different ratios of hydroxypropyl methylcellulose to provide desired release profiles They may be formulated using cellulose, other polymer matrices, liposomes, and / or microspheres. They can be purified by, for example, filtration through a bacteria-retaining filter or by rinsing with sterile water immediately before use. or in the form of a sterile solid composition that can be dissolved in any other sterile injectable medium. These compositions may also be optionally made impermeable. It may contain a brightening agent, which allows the active ingredient to be delivered only or preferentially in a certain part of the digestive tract. Optionally, the composition may be of a delayed release type. Examples of embedding compositions include polymeric substances and waxes. The active ingredient can also be embedded in the capsule, where appropriate. In this case, the compound may be in the form of a microcapsule with one or more of the above-mentioned excipients.

[0338] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, These include microemulsions, solutions, suspensions, syrups, and elixirs. In addition, liquid dosage forms may contain inert diluents commonly used in the art, e.g. , water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, Cole, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol Recall: 1,3-butylene glycol, oils (specifically cottonseed oil, peanut oil, cocoa Oils: peanut oil, wheat germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and sorbitan fatty acid esters, and In addition, cyclodextrins such as hydroxybutyl-β- Cyclodextrins can be used to solubilize the compounds.

[0339] Besides inert diluents, the oral compositions can also include additives such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and the like. The composition may contain adjuvants such as flavoring agents, fragrances, and preservatives.

[0340] Suspensions may contain, in addition to the active compound, suspending agents, such as ethoxylated isostearyl alcohols. sorbitol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and Tragacanth, as well as mixtures thereof may also be included.

[0341] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, and the like. These include formulations, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be incorporated into a pharmaceutical composition containing a pharmaceutically acceptable carrier, and any preservatives, buffers, or It may be mixed with a propellant under sterile conditions.

[0342] Ointments, pastes, creams, and gels may contain, in addition to the active compounds of the invention, excipients, e.g. For example, animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cereals Lubricant derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0343] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, Silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or any of these substances In addition, the spray may contain a mixture of chlorofluorohydrocarbons, as well as It may contain certain common propellants such as volatile unsubstituted hydrocarbons such as butane and propane. good.

[0344] Transdermal patches have the additional advantage of providing controlled delivery of the compounds disclosed herein to the body. Such dosage forms have the advantage that they can be prepared by dissolving or dispersing the drug in a suitable medium. Absorption enhancers are used to increase the flux of a drug across the skin. Such flux rates can be used to provide a flow-controlling membrane or to control the rate of release of compounds. The hydroxyl group can be controlled by either dispersing it in a polymer matrix or in a gel. Cut.

[0345] Ophthalmic formulations, eye ointments, drops, powders, solutions and the like are also considered to be within the scope of this invention. It is planned.

[0346] Pharmaceutical compositions of the present invention suitable for parenteral administration include one or more compounds of the present invention in one or more a pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, or emulsion; Alternatively, sterile powders (containing antioxidants, Buffers, bacteriostats, or blood or suspending agents or growth enhancers of the intended recipient of the formulation. The viscosity agent may contain a solute that renders the viscosity isotonic.

[0347] In some cases, absorption of the drug from a subcutaneous or intramuscular injection is used to prolong the drug's effect. This is because the liquid phase of crystalline or amorphous materials with poor water solubility is This can be achieved by using a suspension. The rate of absorption of the drug is then determined by its dissolution rate. Depending on the amount of crystalline solids, the amount of crystalline solids may vary, depending on the size and crystalline form of the crystals. Alternatively, parenterally administered dosage forms may be used. Delayed absorption of is accomplished by dissolving or suspending the drug in an oil vehicle. One injection strategy involves using polyethyleneoxy methylcellulose, in which the vehicle is liquid at room temperature and solidifies at body temperature. This includes the use of a polypropylene oxide copolymer.

[0348] Injectable depot forms are formulated in biodegradable polymers such as polylactide-polyglycolide. It is made by forming a microencapsulated matrix of the compound in a polymer. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(orthoesters). Injectable depot formulations also include liposomal or steroid formulations that are compatible with body tissue. are also prepared by entrapment of drugs in microemulsions.

[0349] When the compounds of the present invention are administered as pharmaceuticals to humans and animals, they may be administered as such. or, for example, 0.1% in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition containing up to 99.5% (more preferably, 0.5% to 90%) of an active ingredient. may be given as follows.

[0350] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy. The compounds and pharmaceutical compositions may be administered simultaneously with or prior to one or more other desired therapeutic agents or medical procedures. The characteristics of the therapies (therapeutic agents or procedures) used in the combination regimen The specific combination will depend on the compatibility of the desired therapeutic agent and / or treatment and the desired outcome that will be achieved. The desired therapeutic effect will be taken into account. It will also be understood that this may be achieved (e.g., the compounds of the present invention may be administered simultaneously with another anti-cancer agent). (can be administered to

[0351] The compounds of the present invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by any other acceptable route. The compounds can be administered to mammals (e.g., humans, domestic animals, and domesticated animals) by any suitable means. Treating arthritic conditions in livestock, racehorses, birds, lizards, and other organisms that are resistant to the compound can be used to

[0352] The present invention also includes one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the present invention. If necessary, such containers may contain pharmaceutical or biological products. and (b) provide notice in a form prescribed by a government agency that regulates the manufacture, use, or sale of a pharmaceutical product. The notification may be linked to the agency's approval for manufacture, use, or sale for human administration. Reflects.

[0353] Administration to subjects In yet another aspect, the present invention provides a method for treating a condition in a mammalian species in need thereof. 1. A method of treating a patient comprising administering to a patient a therapeutically effective amount of a compound of Formula I, I', II, II', III, or IV or a pharmaceutically acceptable salt thereof. or a pharmaceutical composition thereof to a mammalian species, wherein the condition is cancer, immunological disorders, CNS disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and renal diseases The method is selected from the group consisting of:

[0354] In some embodiments, the cancer is biliary tract cancer, brain cancer, breast cancer, cervical cancer, trophoblast cancer, Cancer, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, epithelial Internal tumors, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer , pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

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

[0356] In some embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, MS, systemic lupus erythematosus, or type 1 diabetes). In embodiments, the CNS disorder is Alzheimer's disease.

[0357] In some embodiments, the metabolic disorder is obesity or type II diabetes. In some embodiments, the cardiovascular disorder is ischemic stroke. The kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

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

[0359] In some embodiments, the condition is cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis , systemic lupus erythematosus, type 1 diabetes mellitus, Alzheimer's disease, inflammatory skin conditions, inflammation Neuropathy, psoriasis, spondylitis, periodontal disease, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke , chronic kidney disease, nephritis, chronic renal failure, and combinations thereof. .

[0360] In yet another embodiment, a mammalian species in need of Kv1.3 potassium channel blockade is A method for blocking Kv1.3 potassium channels is described, the method comprising administering a therapeutically effective amount of a compound of formula At least one compound of I, I', II, II', III, or IV, or a drug thereof The method includes administering a physiologically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammalian species.

[0361] In some embodiments, the compounds described herein inhibit the Kv1.3 potassium channel It is selective in blocking potassium channels, as opposed to other potassium channels, or calcium channels. have minimal off-target inhibitory activity against ATP or sodium channels, or In some embodiments, the compounds described herein inhibit the hERG channel It does not block the vasopressin receptor and therefore has a desirable cardiovascular safety profile.

[0362] Some embodiments of the present invention involve administering an effective amount of the composition to a subject to achieve a particular result. Thus, small molecule compositions useful according to the methods of the present invention include those for pharmaceutical use. The formulation can be carried out in any manner suitable for the purpose.

[0363] The formulations of the present invention may contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, ajuva, The drug is administered in a pharmaceutically acceptable solution, which may routinely contain the agent, and optionally other therapeutic ingredients. It is given.

[0364] For therapeutic use, an effective amount of the compound is administered to a subject in need thereof so that the compound is taken up by the appropriate target cells. The pharmaceutical composition of the present invention can be administered to a subject by any method that allows the subject to receive the compound. "Administering" a composition can be accomplished by any means known to those skilled in the art. Specific routes of administration include oral, transdermal (e.g., via patch), parenteral injection (subcutaneous, intradermal), , intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucous membranes (intranasal, intratracheal, inhalation, rectal, Injections include, but are not limited to, intravaginal injections. Injections can be bolus or continuous infusion. It is possible.

[0365] For example, pharmaceutical compositions according to the present invention may be administered intravenously, intramuscularly, or by other parenteral means. They are often administered intranasally, by inhalation, topically, orally, or by implant. It can also be administered by rectal or vaginal administration. Suitable preparation forms include, for example, aqueous solutions or saline solutions for injection or inhalation, microencapsulated solutions, and the like. , encochleated, coated on fine gold particles, contained in liposomes, nebulized , aerosol, pellets for implantation into the skin, or dried onto a sharp object to damage the skin Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro) capsules, etc. capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or active compounds The formulation may contain a disintegrant, a binder, a coating agent, excipients and additives and / or auxiliaries such as swelling agents, lubricants, flavorings, sweeteners or solubilizers The pharmaceutical compositions are used in various drug delivery systems. For a brief review of current drug delivery methods, see Langer R (1 990) Science 249:1527-33 (incorporated herein by reference in its entirety). See the section on "Integrated Component Attributes" for more information.

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

[0367] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are suitable for injection or Other parenteral vials or ampoules. Solid dosage units include tablets, capsules, powders, etc. The treatment of patients involves determining the activity of the compound, the method of administration, and the purpose of administration (i.e. , prevention or treatment), depending on the nature and severity of the disorder, the age and weight of the patient, different doses The administration of a given dose may be a single administration in the form of individual dosage units, or several doses. This can be done both in the form of smaller dose units. Repeated and multiple administration of doses at specific intervals of months apart are also contemplated by the present invention. do.

[0368] The composition can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicines, salts must be pharmaceutically acceptable, but Unacceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include those derived from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, 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 Such salts include, but are not limited to, those prepared from calcium carbonate. Alkali metal salts or alkali salts such as sodium, potassium, or calcium salts of the carboxylic acid group It can be prepared as an earth salt.

[0369] Suitable buffering agents include: acetic acid and salt (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 and salt (0.8-2% w / v). Suitable preservatives include: benzal chloride ammonium (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01 to 0.25% w / v); and thimerosal (0.004 to 0. 02% w / v).

[0370] Compositions suitable for parenteral administration may be prepared as sterile aqueous preparations that can be isotonic with the blood of the recipient. Among the acceptable vehicles and solvents that are conveniently included are water, Ringer's solution, and phosphate-buffered saline. Water and isotonic sodium chloride solution are also suitable as solvents or suspending media. For this purpose, synthetic monoglycerides or diglycerides have traditionally been used. Any non-irritating fixed mineral or non-mineral oil may be used, including oleic acid. The fatty acids find use in the preparation of injectables: subcutaneous, intramuscular, intraperitoneal, intravenous. Suitable carrier formulations for administration of such drugs are available from Remington's Pharmaceuticals. l Sciences,Mack Publishing Company,Easto n, PA, which is incorporated herein by reference in its entirety.

[0371] Compounds useful in the present invention may be delivered in mixtures of three or more such compounds. The mixture may further comprise one or more adjuvants in addition to the combination of compounds. It is possible.

[0372] A variety of routes of administration are available. The particular mode selected will, of course, depend on the particular mode selected. The specific compound, the age and general health of the subject, the particular condition being treated, and the therapeutic effect. The dosage required will depend on the dosage. Generally, the methods of the present invention are carried out using a medically acceptable Any mode of administration that provides effective levels of the drug without causing clinically unacceptable side effects. The administration can be carried out using any mode that results in a desired response. It is discussed in the article.

[0373] The compositions may conveniently be presented in unit dosage form and may be administered by any of the methods well known in the art of pharmacy. All methods include bringing the compound into association with a carrier which constitutes one or more accessory ingredients. Generally, the compositions comprise a compound in a liquid carrier, a finely divided solid carrier, or both. and then, if necessary, shaping the product. will be done.

[0374] Other delivery systems include time-release, delayed release, or sustained release. Such systems may include a multiple-dose (multiple-dose) delivery system. This can avoid the need for a wide range of release agents, thereby improving convenience for both the patient and the physician. Delivery systems are available and known to those skilled in the art. They include poly(lactide- glycolide), copolyoxalate, polycaprolactone, polyesteramide, polyol These include polymer-based systems such as hydroxyesters, polyhydroxybutyrate, and polyanhydrides. Drug-containing microcapsules of the aforementioned polymers are disclosed, for example, in U.S. Pat. ,109. Delivery systems also include non-polymeric systems such as: cholesterol sterols, such as cholesterol, cholesterol esters, and fatty acids, or mono-, di-, and lipids, including neutral fats such as triglycerides; hydrogel release systems; silastic systems; Peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients partially fused implants, etc. Specific examples include, but are not limited to: Not limited to: (a) U.S. Patent Nos. 4,452,775 and 4,675,189 and those described in US Pat. No. 5,736,152, wherein the agent of the present invention is a matrilineal (b) an erosion system contained in the form of a box; and (b) a method for manufacturing a erosion system as described in U.S. Pat. Nos. 3,854,480 and 5,480. Controlled ion exchange reactions, such as those described in US Pat. Nos. 5,133,974 and 5,407,686, are also possible. Diffusion systems where the active ingredient permeates through the polymer at a controlled rate. Additionally, pump-based hardware delivery systems Delivery systems are available, some of which are suitable for implantation.

[0375] Assay for efficacy of Kv1.3 potassium channel blockers In some embodiments, the compounds described herein inhibit the Kv1.3 potassium channel In some embodiments, the compounds described herein are tested for their activity against the The compounds described are tested for their Kv1.3 potassium channel electrophysiology. In some embodiments, the compounds described herein have the ability to inhibit their hERG electrophysiology. will be tested for.

[0376] equivalent The following representative examples are intended to help illustrate the present invention and are not intended to limit the scope of the invention. It is not intended to be, and should not be construed as, limiting the scope. As such, various modifications of the invention and many of its aspects in addition to those shown and described herein are contemplated. Further embodiments are described in the examples and by reference to the scientific and patent literature cited herein below. The contents of these references will be clear to those skilled in the art from the full content of this document, including the present application. , which are incorporated herein by reference to help describe the state of the art. The following examples are provided to illustrate the practice of the present invention in its various embodiments and equivalents thereof. It contains important additional information, examples, and guidance that can be adapted to your implementation. [Example]

[0377] Examples 1-11 are compounds of Formula I, I', II, II', III, or I Various intermediates used in the synthesis of representative compounds of V are described. Example 1. Intermediate 1a ((R)-N-[[2,3-dichloro-6-(methoxymethoxy)methyl] )phenyl]methylidene]-2-methylpropane-2-sulfinamide) and Intermediate 1 b((S)-N-[[2,3-dichloro-6-(methoxymethoxy)phenyl]methylide methylpropane-2-sulfinamide)

[0378] [ka]

[0379] Step A: 2,3-Dichloro-6-(methoxymethoxy)benzaldehyde in THF (20 mL) (2.00 g, 8.51 mmol) and (R)-2-methylpropane-2-sulfone To a stirred solution of amide (1.55 g, 12.8 mmol) was added Ti(OEt)4 (5.82 g (25.52 mmol) was added at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 16 hours. It was then quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EA (3 / 1). Purification by gel column chromatography gave ((R)-N-[[2,3-dichloro -6-(methoxymethoxy)phenyl]methylidene]-2-methylpropane-2-sulf C (vinamide) was obtained as a pale yellow oil (2.60 g, 81%): 13 H 17 Cl2NO3 S[M+H] + LCMS (ESI) calculated: 338, 340 (3:2) Found: 338, 340(3:2); 1 H NMR(300MHz,CDCl3)δ 8.91(s,1H ),7.49(d,J=9.0Hz,1H),7.13(d,J=9.0Hz,1H), 5.23(s,2H), 3.48(s,3H), 1.31(s,9H). (S) Enantiomer The mer intermediate 1b was synthesized using (R)-2-methylpropane-2-sulfinamide. It was prepared in the same manner.

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

[0381] [ka] Step A: (R)-N-[[2,3-dichloro-6-(methoxymeth)oxy] 10.0g of phenylmethylidene-2-methylpropane-2-sulfinamide , 29.6 mmol) and 2-[(trimethylsilyl)methyl]prop-2-ene-1- To a stirred solution of phenylalanine acetate (8.26 g, 44.4 mmol) was added Pd(PPh3)4( To the reaction mixture was added 3.42 g (2.96 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 20 h, quenched with water (100 mL) and extracted with EA (3×150 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with PE / EA (3 / 1). The compound was purified by silica gel column chromatography to give (2R)-2-[2,3-dichloro-2,4-diphenyl-2,5-diphenyl-1,3-diphenyl-2,4-diphenyl-2,5 ... Chloro-6-(methoxymethoxy)phenyl]-4-methylidene-1-[(R)-2-methyl [Cyclopropylpropane-2-sulfinyl]pyrrolidine was obtained as a pale yellow oil (7.30 g, 60 %):C 17 H 23 Cl2NO3S[M+H] + LCMS (ESI) calculated value: 392, 394(3:2) Actual value 392,394(3:2); 1 H NMR (400 MHz, CD Cl3)δ 7.34(d,J=8.9Hz,1H),7.11(d,J=9.1Hz, 1H),5.70-5.57(m,1H),5.20-5.09(m,2H),4.99 -4.91(m,2H),4.37(d,J=13.9Hz,1H),3.89(d,J =13.9Hz,1H),3.49(s,3H),3.07-2.94(m,1H),2 .80-2.70(m,1H),1.09(s,9H).

[0382] Step B: (2R)-2-[2,3-dichloro-6-(methoxymeth)oxy]- ... (R)-2-methylpropane-2-sulfinyl]-4-methylidene-1-[(R)-phenyl]-4-methylidene-1-[(R)-2-methylpropane-2-sulfinyl] To a stirred solution of [methyl]pyrrolidine (7.30 g, 18.6 mmol) was added aqueous HCl (4 N, 5 mL) was added dropwise at room temperature. The resulting reaction solution was stirred at room temperature for 1 hour and saturated aqueous NaHC The mixture was basified to pH 8 with O3 and extracted with EA (3 x 100 mL). The mixture was washed with ethanol (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was treated with BocO (6.25 g, 28.6 m) in DCM (60 mL). mol) and TEA (5.31 mL, 38.2 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was eluted with PE / EA (5 / 1). Purification by silica gel column chromatography gave tert-butyl (2R)-2 -[2,3-Dichloro-6-(methoxymethoxy)phenyl]-4-methylidenepyrrolidine C was obtained as a pale yellow oil (7.30 g, 89%). 18 H 23 Cl2NO4[M+H] + LCMS (ESI) calculated value: 388,390 (3:2) Found Value 388,390(3:2); 1 H NMR (400 MHz, CDCl) δ 7.32 (d,J=8.9Hz,1H),7.02(d,J=9.0Hz,1H),5.73-5 .55(m,1H),5.21(d,J=7.1Hz,1H),5.11(d,J=7. 0Hz,1H),5.05-4.93(m,2H),4.23-4.13(m,2H), 3.45(s,3H),3.11-3.00(m,1H),2.82-2.73(m,1 H), 1.17(s,9H).

[0383] Step C: tert-Butyl (2R)-2-[2 ,3-Dichloro-6-(methoxymethoxy)phenyl]-4-methylidenepyrrolidine-1 To a stirred mixture of NaIO4 (1 2.1 g, 56.4 mmol), HO (60 mL), 2,6-lutidine (4.03 g, 37.6 mmol), and RuCl3·H2O (0.420 g, 1.88 mmol) were added to the chamber. The resulting reaction mixture was stirred for 1 h and then saturated aqueous NH4HCO3 (200 ml) The mixture was quenched with EA (3×200 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1). Purification by tert-butyl (2R)-2-[2,3-dichloro-6-(methoxyphenyl)-2-methyl-2-propanol] [(Dimethoxy)phenyl]-4-oxopyrrolidine-1-carboxylate was obtained as a pale yellow oil. Obtained (5.60g, 69%): C 17 H 21 Cl2NO5[M+H-56] + LCM S(ESI) calculated value: 334,336 (3:2) observed value 334,336 (3:2); 1 H NMR(300MHz,CDCl3)δ 7.55-7.31(m,1H),7.02 (dd,J=20.2,8.4Hz,1H),6.12-5.89(m,1H),5.2 0-5.08(m,2H),4.00-3.88(m,2H),3.45-3.37(m ,3H),3.15(dd,J=18.8,11.1Hz,1H),2.61-2.48 (m,1H), 1.28(s,9H).

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

[0385] [ka] Step A: tert-Butyl (2R)-2-[2,3-dichloro-6-( methoxymethoxy)phenyl]-4-oxopyrrolidine-1-carboxylate(0.8 00g, 2.05mmol) and ethyl 2-(triphenylphosphanylidene)acetate (1 A mixture of 1.07 g (3.07 mmol) of 1,000 sulphite was stirred at 110°C for 16 hours. After that, the resulting mixture was concentrated under reduced pressure. The residue was eluted with PE / EA (3 / 1). Purification by silica gel column chromatography gave tert-butyl (2R,4Z )-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy) (2-oxoethylidene)pyrrolidine-1-carboxylate was obtained as a colorless oil (0 0.840g, 80%):C 21 H 27 Cl2NO6[M+H] + LCMS (ESI) measurement Calculated value: 460,462 (3:2) Measured value: 460,462 (3:2); 1 H NMR (40 0MHz, CDCl3)δ 7.36-7.29(m,1H),7.04-6.98(m ,1H),5.78-5.74(m,1H),5.19-5.14(m,1H),5.1 2-5.02(m,1H),4.77-4.58(m,2H),4.46-4.32(m ,1H),4.27-4.19(m,2H),3.40(d,J=5.7Hz,3H), 3.36-3.19(m,1H),2.92-2.73(m,1H),1.35-1.2 9(m,3H),1.23-1.18(m,9H).

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

[0387] [ka] Step A: tert-Butyl (2R,4Z)-2-[2,3-dichloro- 6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxoethylidene)pi To a stirred mixture of loridine-1-carboxylate (0.620 g, 1.35 mmol), PtO2 (0.130 g, 0.550 mmol) was added at room temperature, and the reaction mixture was heated under reduced pressure. The mixture was degassed with 1.5 atm, purged with hydrogen three times, and stirred at room temperature for 2 hours under a hydrogen atmosphere (1.5 atm). The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 5 mL). Concentration under reduced pressure gave tert-butyl (2R)-2-[2,3-dichloro-6-(methoxy [Methoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxamide The carboxylate was obtained as a pale yellow oil (0.600 g, 87%): 21 H 29 Cl2NO 6[M+H] + LCMS (ESI) calculated: 462, 464 (3:2) Found: 462, 464(3:2); 1 H NMR(300MHz,CDCl3)δ 7.34-7.29 (m,1H),7.06-6.97(m,1H),5.57-5.39(m,1H),5 .31-5.07(m,2H),4.23-4.11(m,2H),4.01-3.68 (m,1H),3.57-3.08(m,4H),2.91-2.58(m,1H),2 .55-2.20(m,3H),2.161.76(m,1H),1.331.24(m ,3H),1.15(d,J=2.4Hz,9H).

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

[0389] [ka] Step A: tert-Butyl(2R)-2-(2,3-dichloro-6-(methoxymethoxy)phenyl) (2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate ( 13.0 g) was separated by preparative SFC under the following conditions: Column: OptiChir al-C9-5, 3×25cm, 5μm; Mobile phase A: CO2, Mobile phase B: MeOH(+0 1% 2M NH3-MeOH); Flow rate: 250 mL / min; Gradient: Isocratic 4% B; column temperature: 35°C; back pressure: 100 bar; wavelength: 220 nm; retention time 1:2 .80 minutes; Holding time 2: 3.40 minutes; Sample solvent: MeCN / MeOH=4 / 1; Injection amount: 2 mL; Runs: 75. Faster eluting enantiomer at 2.80 min, tert- Butyl(2R,4S)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl] -4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (intermediate 4a) was obtained as a pale yellow oil (9.44 g, 73% yield): C 21 H 29 Cl2NO6[ M+H] + LCMS (ESI) calculated: 462,464 (3:2) Found: 462,46 4(3:2); 1 H NMR(300MHz,CDCl3)δ 7.31(d,J=9. 0Hz,1H),7.02(d,J=8.9Hz,1H),5.45(t,J=8.8H z,1H),5.27-5.07(m,2H),4.16(q,J=7.1Hz,2H) ,3.95(dd,J=10.3,7.2Hz,1H),3.53-3.43(m,3H ),3.14(t,J=10.5Hz,1H),2.71-2.56(m,1H),2. 55-2.38(m,3H),1.86(q,J=11.6Hz,1H),1.28(t , J = 7.1 Hz, 3H), 1.14 (s, 9H). The slower eluting energy at 3.40 min tert-butyl(2R,4R)-2-[2,3-dichloro-6-(methoxy) [2-(2-methoxy)phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate The carboxylate (intermediate 4b) was obtained as a pale yellow oil (1.33 g, 10% yield): C2 1H 29 Cl2NO6[M+H] + LCMS (ESI) calculated value: 462,464 (3: 2) Actual value 462,464 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.31(d,J=8.7Hz,1H),7.02(d,J=8.9Hz,1H),5. 45(t,J=8.9Hz,1H),5.30-5.07(m,2H),4.16(q, J=7.1Hz,2H),3.95(dd,J=10.3,7.3Hz,1H),3.5 2-3.45(m,3H),3.14(t,J=10.5Hz,1H),2.72-2. 58(m,1H),2.44(dt,J=13.8,6.5Hz,3H),1.86(q ,J=11.7Hz,1H),1.28(t,J=7.1Hz,3H),1.13(s, 9H).

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

[0391] [ka] Step A: tert-Butyl (2R)-2-[2 ,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-ox (isoethyl)pyrrolidine-1-carboxylate (1.50 g, 3.24 mmol) To the solution was added LiOH (0.230 g, 9.73 mmol) at room temperature. Stir for 2 h, acidify with saturated aqueous citric acid to pH 2, dilute with water (50 mL), and add EA( The combined organic layers were washed with brine (3 x 50 mL) and After filtration, the filtrate was concentrated under reduced pressure to give [(5R)-1-(te rt-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl [Nyl]pyrrolidin-3-yl]acetic acid was obtained as an off-white solid (1.20 g, 85 %):C 19 H 25 Cl2NO6[M+H] + LCMS (ESI) calculated value: 434.4 36(3:2) Actual value 434,436(3:2); 1 H NMR (300 MHz, CDC) l3)δ 7.32(d,J=8.9Hz,1H),7.03(d,J=8.9Hz,1 H),5.60-5.36(m,1H),5.36-5.06(m,2H),4.01( dd,J=10.3,7.3Hz,1H),3.56-3.43(m,4H),3.18 (t,J=10.5Hz,1H),2.78-2.34(m,3H),1.88(q,J =11.5Hz,1H),1.15(s,9H).

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

[0393] [ka] Step A: tert-Butyl (2R,4S)- in HO (0.4 mL) and MeOH (2 mL) 2-[2,3-Dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy- 2-oxoethyl)pyrrolidine-1-carboxylate (0.550 g, 1.19 mmol) To a stirred solution of 1) was added LiOH (85.0 mg, 3.54 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was acidified to pH 6 with citric acid, followed by The combined organic layers were washed with brine (3 x 30 mL). The mixture was filtered and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give [(3S,5R )-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxy Methoxy)phenyl]pyrrolidin-3-yl]acetic acid was obtained as a white solid (0.450 g , 87%):C 19 H 25 Cl2NO6[M+H] + LCMS (ESI) calculated value: 43 4,436(3:2) Actual value 434,436(3:2); 1 H NMR (400 MHz, CDCl3)δ 7.32(d,J=8.9Hz,1H),7.03(d,J=8.9H z,1H),5.47(t,J=9.0Hz,1H),5.32-5.08(m,2H) ,4.01(dd,J=10.3,7.3Hz,1H),3.48(s,3H),3.1 8(t,J=10.5Hz,1H),2.67(d,J=7.2Hz,1H),2.62 -2.38(m,3H),1.88(q,J=11.6Hz,1H),1.22(d,J =53.9Hz,9H).

[0394] Example 8. Intermediate 6a ((ethyl(3S,5R)-5-[2,3-dichloro-6-(methyl)methyl] [4-(4-methylbenzensulfonyl)phenyl]-1-(4-methoxymethoxy)phenyl carboxylate) and intermediate 6b ((ethyl (3R,5R)-5-[2,3-dichloro -6-(methoxymethoxy)phenyl]-1-(4-methylbenzenesulfonyl)pyrrol cin-3-carboxylate)

[0395] [ka] Step A: (S)-N-[[2,3-dichloro- 6-(Methoxymethoxy)phenyl]methylidene]-2-methylpropane-2-sulfonyl amide (1.00 g, 2.96 mmol) and 2-(bromomethyl)prop-2-ene To a stirred mixture of ethyl acetate (1.71 g, 8.87 mmol) and Zn (0.580 g, 8. The reaction mixture was stirred for 5 minutes and then diluted with water (20 mL). The combined organic layers were diluted with brine (2×30 mL) and extracted with EA (3×30 mL). ) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. by reversed-phase chromatography eluting with 45% ACN in water (+10 mM NH4HCO3). The product was purified by HPLC to give (4R)-4-[2,3-dichloro-6-(methoxymethoxy)phenyl]propanol. phenyl]-2-methylidene-4-[[(S)-2-methylpropane-2-sulfinyl] Ethyl aminobutanoate was obtained as a pale yellow oil (1.40 g, 94%): 19 H 27 C l2NO5S[M+H] + LCMS (ESI) calculated value: 452,454 (3:2) Found value 452,454(3:2); 1 H NMR (300 MHz, CD3OD) δ 7.41 -7.36(m,1H),7.19-7.13(m,1H),6.08(d,J=1.4 Hz,1H),5.47(d,J=9.9Hz,1H),5.38-5.31(m,2H ),5.29-5.11(m,1H),4.22-4.09(m,2H),3.56(s ,3H),3.20-3.01(m,2H),1.29(q,J=6.8Hz,3H), 1.12(s,9H).

[0396] Step B: (4R)-4-[2,3-dichloro-6-(methoxy)methyl]propanol in MeOH (10.50 mL) (S)-2-methylpropane-2-sulfonyl)phenyl]-2-methylidene-4-[[(S)-2-methylpropane-2-sulfonyl To a stirred solution of ethyl [alfinyl]amino]butanoate (1.56 g, 3.45 mmol), Aqueous HCl (2M, 3.50 mL) was added at room temperature. The reaction mixture was stirred for 1 hour and saturated It was basified to pH 8 with aqueous NaHCO3 and extracted with EA (3 x 20 mL). The layer was washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate The residue was concentrated under reduced pressure. A solution of TsCl (0.660 g) was added to a solution of DCM (10 mL). , 3.45 mmol), DMAP (0.110 g, 0.86 mmol), and TEA (1 0.00 mL, 7.18 mmol) was added at room temperature. The resulting solution was stirred for 2 hours and The combined organic layers were diluted with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1). (4R)-4-[2,3-dichloro-6-(methoxymethoxy)phenyl] Ethyl [4-(4-methylbenzenesulfonamido)-2-methylidenebutanoate] Obtained as a yellow solid (1.10 g, 76%): C 22 H 25 Cl2NO6S[M+Na] + LCMS (ESI) calculated: 524,526 (3:2) Found: 524,526 (3: 2); 1 H NMR(400MHz,CDCl3)δ 7.57-7.51(m,2H) ,7.14(d,J=9.0Hz,1H),7.07-7.02(m,2H),6.82 (d,J=9.1Hz,1H),6.22(d,J=1.2Hz,1H),5.94(d ,J=10.9Hz,1H),5.60(q,J=1.1Hz,1H),5.30-5. 25(m,1H),5.25-5.18(m,2H),4.18(q,J=7.1Hz, 2H),3.57(s,3H),3.00-2.90(m,1H),2.73-2.64 (m,1H),2.31(s,3H),1.30(t,J=7.1Hz,3H).

[0397] Step C: (4R)-4-[2,3-dichloro-6-(methoxymethoxy) Ethyl [phenyl]-4-(4-methylbenzenesulfonamido)-2-methylidenebutanoate To a stirred solution of 1.2g of ethanol (0.600g, 1.19mmol), NaHCO3 (53.0mg, 0.12 The reaction mixture was stirred at 110° C. for 16 hours. The resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 3 / 1). Purification by (ethyl (5R)-5-[2,3-dichloro-6-(methoxymeth)oxy] [(4-phenyl)-1-(4-methylbenzenesulfonyl)pyrrolidine-3-carboxylate C isomer 1) as a pale yellow solid (0.150 g, 24%): 22 H 25 Cl2NO 6S[M+H] + LCMS (ESI) calculated: 502, 504 (3:2) Found: 502 ,504(3:2); 1 H NMR(300MHz,CDCl3)δ 7.73-7.6 1(m,2H),7.37-7.28(m,3H),7.04-6.91(m,1H), 5.52-5.38(m,1H),5.22-5.02(m,2H),4.16(q,J =7.1Hz,2H),4.14-4.01(m,1H),3.78(t,J=11.2 Hz,1H),3.59-3.46(m,4H),2.79-2.60(m,1H),2 .50-2.38(m,4H), 1.26(t,J=7.1Hz,3H), and (ethyl (5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]-1-(4- Methylbenzenesulfonyl)pyrrolidine-3-carboxylate isomer 2) pale yellow solid (0.29 g, 46%) as: C 22 H 25 Cl2NO6S[M+H] + LCM S(ESI) calculated value: 502,504 (3:2) observed value 502,504 (3:2); 1 H NMR(300MHz,CDCl3)δ 7.65(d,J=7.8Hz,2H),7 .32(d,J=8.9Hz,1H),7.25(d,J=7.8H,2H),7.02 (d,J=9.0Hz,1H),5.60-5.47(m,1H),5.27-5.05 (m,2H),4.00-3.85(m,4H),3.55(s,3H),3.26-3 .15(m,1H),2.63-2.47(m,1H),2.43(s,3H),2.3 9-2.24(m,1H),1.22(t,J=7.1Hz,3H).

[0398] Example 9. Intermediate 7 (methyl(5R)-5-[2,3-dichloro-6-(methoxymeth)amino]-2,4-dichloro-1,3-dimethyl ... [4-(4-methyl-2-phenyl)-2-pyrrolidine-3-carboxy] rate)

[0399] [ka] According to the procedure described in Example 8, substituting methyl 2-(bromomethyl)prop-2-enoate The methyl ester was prepared by the following procedure. The product was used in the next step without separating the isomers. Used.

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

[0401] [ka] Step A: (5R)-5-[2,3-dichloro-6-(methoxymeth)amino]- ... [4-(4-methyl-2-phenyl)-1-(4-methyl-2-phenyl)-pyrrolidine-3-carboxylic acid] To a stirred solution of methyl (9.00 g, 18.4 mmol) was added Mg (6.72 g, 276 mmol). The reaction mixture was stirred for 2 hours and then HCl (1N, 50 mL) was added in small portions at room temperature. ) to pH 5, stirred for 10 min, and acidified to pH 7 with saturated aqueous NaHCO3 (50 mL). The mixture was neutralized and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×10 0 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give ( 5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-3 Methyl-carboxylate was obtained as a pale yellow oil (6.00 g, 78%): C 14 H 17 Cl2 NO4[M+H] + LCMS (ESI) calculated: 334, 336 (3:2) Found: 33 4,336(3:2).

[0402] Step B: (5R)-5-[2,3-dichloro-6-(methoxymeth)amino]- ... Methyl 2-(2-hydroxyphenyl)pyrrolidine-3-carboxylate (4.00 g, 11.9 mmol) To a stirred solution of 2.42 g of HCl and TEA (23.9 mmol), BocO (5.22 g, 23.9 mmol) was added dropwise under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (100 mL) and extracted with EA (3×80 mL). The mixture was washed with ethanol (4 x 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% EA in PE. The first eluted component, 1-(tert-butyl)3-methyl (3R,5 R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1, The 3-dicarboxylate (intermediate 8b) was obtained as a pale yellow oil (1.20 g, 23%): C 19 H 25 Cl2NO6[M+H] + LCMS (ESI) calculated value: 434,436 ( 3:2) Actual value 434,436 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.33(d,J=9.0Hz,1H),7.05(d,J=9.0Hz,1H), 5.49(t,J=9.1Hz,1H),5.30-5.14(m,2H),4.02( dd,J=10.4,8.0Hz,1H),3.75(s,3H),3.72-3.64 (m,1H),3.48(s,3H),3.23-3.11(m,1H),2.60-2 0.37 (m, 2H), 1.15 (s, 9H). The second eluting component, 1-(tert-butyl )3-methyl(3S,5R)-5-(2,3-dichloro-6-(methoxymethoxy)phenyl (nyl)pyrrolidine-1,3-dicarboxylate (Intermediate 8a) was obtained as a pale yellow solid. (1.8g, 35%):C 19 H 25 Cl2NO6[M+H] + LCMS (ESI) measurement Calculated: 434,436 (3:2) Found: 434,436 (3:2). Trans isomer, 1 -(tert-butyl)3-methyl(3S,5R)-5-(2,3-dichloro-6-(methyl) (2,3-trimethoxyphenyl)pyrrolidine-1,3-dicarboxylate (1.80 g, 4 The resulting eluate (0.11 mmol) was re-purified by preparative SFC using the following conditions: Column: CH IRALPAK IF, 3 x 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 50 mL / min; Gradient: Isocratic 15% B; Column temperature: 35°C; Back pressure: 100 bar; Wavelength: 220 nm; Retention time: 9 0.98 min; Sample solvent: MeOH-preparative; Injection volume: 0.5 mL. Fractions containing the desired product The fractions were collected and concentrated under reduced pressure to give 1-(tert-butyl)3-methyl(3S,5R)- 5-(2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1,3-di The carboxylate was obtained as a pale yellow oil (1.20 g, 66%): C 19 H 25 Cl2N O6 [M+H] + LCMS (ESI) calculated: 434, 436 (3:2) Found: 434 ,436(3:2). 1 H NMR(400MHz,CDCl3)δ 7.32(d,J =8.9Hz,1H),7.03(d,J=9.2Hz,1H),5.59(t,J=8 .1Hz,1H),5.28-5.08(m,2H),4.00(d,J=11.0Hz ,1H),3.79-3.75(s,4H),3.49(s,3H),3.26-3.1 8(m,1H),2.64(t,J=9.7Hz,1H),2.33-2.20(m,1 H), 1.15(s,9H).

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

[0404] [ka] Step A: 1-tert-Butyl 3-methyl ( 3S,5R)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine To a stirred mixture of benzophenone-1,3-dicarboxylate (0.200 g, 0.460 mmol) LiOH·H2O (39.0 mg, 0.920 mmol) was added to the reaction mixture at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. l (49.0 mg, 0.920 mmol) and HATU (0.350 g, 0.920 mm To a stirred mixture of 1000 mg of TEA (93.0 mg, 0.920 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, dissolved in MeOH (0.5 mL) and diluted with water (+0.05 Purification by reverse phase chromatography eluting with 45% ACN in 1% TFA gave tertiary t-Butyl(2R,4S)-4-carbamoyl-2-[2,3-dichloro-6-(methoxy)

[0039] (Dimethoxy)phenyl]pyrrolidine-1-carboxylate (Intermediate 9a) was reacted with 1,000 sachets of ... (0.150g, 77%): 18 H 24 Cl2N2O5[M+H] + LCM S(ESI) calculated value: 419,421 (3:2) observed value 419,421 (3:2); 1 H NMR(400MHz,CDCL3)δ 7.33(d,J=8.9Hz,1H),7 .03(d,J=9.0Hz,1H),5.83-5.53(m,3H),5.27-5 .11(m,2H),4.01-3.72(m,2H),3.49(s,3H),3.1 7-3.08(m,1H),2.71-2.60(m,1H),2.36-2.25(m ,1H),1.16(s,9H). 1-tert-butyl 3-methyl(3R,5R)-5 -[2,3-Dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1,3-dica Carboxylate (0.200 g, 0.460 mmol) was used in the same manner (R,R ) Diastereomeric intermediate 9b was prepared. 18 H 24 Cl2N2O5[M+H] + of LCMS(ESI) calculated: 419,421 (3:2); 1 H NMR (400 MHz, CDCl3)δ 7.33(d,J=8.9Hz,1H),7.07-7.02(m,1 H),5.61-5.39(m,3H),5.31-5.18(m,2H),4.01( t,J=9.2Hz,1H),3.77-3.65(m,1H),3.49(s,3H) ,3.07-2.94(m,1H),2.58-2.41(m,2H),1.16(s, 9H).

[0405] Examples 12-20 illustrate compounds of Formula I, I', II, II', III, or The synthesis of a representative compound of IV is described.

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

[0407] [ka] Step A: tert-Butyl (2R)-2-[2, 3-Dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxo Stirring of ethyl)pyrrolidine-1-carboxylate (0.600 g, 1.30 mmol) To the mixture, LiOH·H2O (0.110 g, 2.60 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The composition contained HATU (0.740 g, 1.95 mmol), TEA (0.54 mL, 3.8 9 mmol), and NH4Cl (0.140 g, 2.60 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 h, dissolved in MeOH (1 mL) and water (+0.05% TF A) was purified by reverse phase chromatography eluting with 40% ACN in (2R)-4-(carbamoylmethyl)-2-[2,3-dichloro-6-(methoxymethyl) methoxy)phenyl]pyrrolidine-1-carboxylate was obtained as a pale yellow solid (0. 240g, 38%):C 19 H 26 Cl2N2O5[M+H] + LCMS (ESI) measurement Calculated value: 433,435 (3:2) Measured value: 433,435 (3:2); 1 H NMR (30 0MHz, CDCl3)δ 7.35-7.29(m,1H),7.07-6.97(m ,1H),5.56-5.33(m,2H),5.29-5.01(m,1H),4.0 4-3.68(m,1H),3.48(s,3H),3.28-3.09(m,1H), 2.93-2.57(m,1H),2.57-2.20(m,2H),2.13-1.7 8(m,2H), 1.15(s,9H).

[0408] Step B: tert-Butyl (2R)-4-(carbamoylmethyl)-2- in DCM (2 mL) [2,3-Dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxy To a stirred solution of ethyl acetate (0.240 g, 0.55 mmol), add BBr (0.5 mL) to the chamber. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0°C with MeOH (3 mL). The residue was diluted with 30% A in water (+10 mM NH4HCO3) and concentrated under reduced pressure. Purification by reverse-phase chromatography eluting with CN gave 2-[(5R)-5-(2, 3-Dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]acetamide Obtained as a white solid (96.0 mg, 59%): C 12 H 14 Cl2N2O2[M+ H] + LCMS (ESI) calculated value: 289,291 (3:2) Found value: 289,291 ( 3:2); 1 H NMR(400MHz,CD3OD)δ 7.18(d,J=8.8H z,1H),6.59(dd,J=8.9,1.1Hz,1H),5.01-4.89( m,1H),3.50-3.37(m,1H),2.92-2.83(m,1H),2. 76-2.59(m,2H),2.46-2.32(m,2H),1.55-1.43( m,1H).

[0409] Step C: 2-[(5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidine-3 [-yl]acetamide (96.0 mg, 0.330 mmol) was subjected to the following conditions: Separation was performed by preparative chiral HPLC: Column: CHIRALPAK IH, 2 x 25 cm , 5μm; Mobile phase A: Hex(+0.5%2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 25 min; Wavelength: 220 / 254nm; Retention time 1: 16.45 minutes; Retention time 2: 22.00 minutes; Trial Solvent: EtOH-HPLC; Injection volume: 1.2 mL; Run number: 8. The faster eluting enantiomer, 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxybenzoate] The product was purified under the following conditions to give [hydroxyphenyl]pyrrolidin-3-yl]acetamide. Purification was performed by preparative HPLC using: Column: SunFire Prep C18 OBD Column, 19×150mm, 5μm 10nm; Mobile phase A: Water (+0.0 5% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10% B in 6.8 min 30% B, 30% B; Wavelength: 210 nm; Retention time: 4.30 min. The fractions containing 2-[(3S,5R)-5-(2,3-dichloro- 6-hydroxyphenyl)pyrrolidin-3-yl]acetamide as an off-white solid Compound 31 (57.2 mg, 42%) was obtained by 12 H 14 Cl2N2O2[M+ H] + LCMS (ESI) calculated value: 289,291 (3:2) Found value: 289,291 ( 3:2); 1 H NMR(400MHz,CD3OD)δ 7.47(d,J=8.9H z,1H),6.93(d,J=8.9Hz,1H),5.30(dd,J=11.6, 7.0Hz,1H),3.67(dd,J=11.3,7.7Hz,1H),3.38( d,J=10.9Hz,1H),2.90-2.78(m,1H),2.58(dd,J =15.2,6.2Hz,1H),2.52-2.42(m,2H),2.21-2.1 0(m,1H). The slower eluting enantiomer, 2-[(3R,5R )-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]aceto The amide was obtained. The product was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD Column, 19×150mm, 5μm 10nm; Mobile phase A: Water (+0.05%TFA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 10% B to 30% B, 30% B in 6.8 min; Wavelength: 210 nm; Hold Time : 4.35 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give 2-[(3R ,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl] Acetamide (compound 32) was obtained as a purple solid (10.8 mg, 8%): C 12 H1 4Cl2N2O2[M+H] + LCMS (ESI) calculated: 289,291 (3:2) Actual value 289,291 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7. 47(d,J=8.9Hz,1H),6.93(d,J=8.9Hz,1H),5.36 (t,J=9.1Hz,1H),3.84(dd,J=11.4,7.0Hz,1H), 3.23(dd,J=11.4,8.3Hz,1H),3.18-3.02(m,1H) ,2.61-2.41(m,3H),2.24-2.13(m,1H).

[0410] tert-Butyl(2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]phenyl Nyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate or is tert-butyl(2R)-2-[3,4-dichloro-6-(methoxymethoxy)phenyl] nyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate, Starting from the corresponding amine, which was available from commercial sources, compound 31 was synthesized. The following compounds in Table 7A were prepared in a manner similar to that described above.

[0411] [Table 8-1]

[0412] [Table 8-2]

[0413] tert-Butyl (2R,4S)-2-[2,3-dichloro-6-(methoxymethoxy) )phenyl]-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate Starting from the amine and the corresponding amine, which was available from commercial sources, compound 31 was synthesized. The following compounds in Table 7B were prepared in a manner similar to that described for .

[0414] [Table 9-1]

[0415] [Table 9-2]

[0416] [Table 9-3]

[0417] [Table 9-4]

[0418] [Table 9-5]

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

[0420] [ka] Step A: tert-Butyl (2R)-2-[2,3-dichloro-6-( methoxymethoxy)phenyl]-4-oxopyrrolidine-1-carboxylate(0.3 00g, 0.770mmol) and 2-(triphenylphosphanylidene)propanoic acid ethyl ester A mixture of 1,2-dimethyl-3,4-trimethylsilyl (0.420 g, 1.15 mmol) was stirred at 110° C. for 24 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was diluted with PE / EA (3 / 1) The compound was purified by silica gel column chromatography eluting with tert-butyl ( 2R,4Z)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-( 1-Ethoxy-1-oxopropan-2-ylidene)pyrrolidine-1-carboxylate was obtained as a pale yellow oil (0.270 g, 67%): C 22 H 29 Cl2NO6[M+H] + LCMS (ESI) calculated: 474,476 (3:2) Found: 474,476 (3: 2); 1 H NMR(300MHz,CDCl3)δ 7.32(dd,J=9.1,3 .3Hz,1H),7.00(dd,J=8.9,4.9Hz,1H),5.84-5. 62(m,1H),5.18-5.02(m,2H),4.63(s,1H),4.38 -4.14(m,3H),3.74-2.66(m,5H),1.89(d,J=21. 7,1.9Hz,3H),1.40-1.26(m,3H),1.21(s,9H).

[0421] Step B: tert-Butyl (2R) in MeOH (3 mL) and aqueous HCl (6 M, 0.3 mL) ,4Z)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1- Ethoxy-1-oxopropan-2-ylidene)pyrrolidine-1-carboxylate(0 To a stirred mixture of PtO2 (41.0 mg, 0.18 0 mmol) was added at room temperature. The reaction mixture was degassed under reduced pressure, purged twice with hydrogen, and The mixture was stirred under nitrogen atmosphere (1.5 atm) for 6 hours. The resulting mixture was filtered, and the filter cake was The residue was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC ( PE / EA 2 / 1) to obtain tert-butyl (2R)-2-[2,3-dichloro-2,4-diphenyl-2,5-diphenyl-1,2 ... Chloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-1-oxopropane (2-phenyl-2-yl)pyrrolidine-1-carboxylate was obtained as a pale yellow oil (0.170 g , 69%):C 22 H 31 Cl2NO6[M+H-56] + LCMS (ESI) calculated value of :420,422(3:2)Actual value 420,422(3:2); 1 H NMR (300M Hz, CDCl3)δ 7.33-7.29(m,1H),7.06-6.98(m,1 H),5.54-5.38(m,1H),5.31-5.08(m,2H),4.23- 4.07(m,2H),3.98-3.80(m,1H),3.53-3.44(m,3 H),3.31-3.05(m,1H),2.50-2.34(m,3H),2.00- 1.84(m,1H),1.31-1.22(m,6H),1.14(d,J=1.8H z,9H).

[0422] Step C: tert-Butyl (2R)-2-[2, 3-Dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-1-oxo propan-2-yl)pyrrolidine-1-carboxylate (0.170 g, 0.360 m To a stirred mixture of 1000 mol of LiOH HO (30.0 mg, 0.710 mmol) was added The reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The product was diluted with HATU (0.200 g, 0.530 mmol), TEA (72.0 mL, 0 0.710 mmol) and NH4Cl (38.0 mg, 0.710 mmol) were added at room temperature. The reaction mixture was stirred for 2 hours and eluted with 40% ACN in water (+0.05% TFA). The compound was purified by reverse phase chromatography to give tert-butyl (2R)-4-(1-carboxylate). (2,3-dichloro-6-(methoxymethoxy)phenyl)-2-[2,3-dichloro-6-(methoxymethyl)phenyl]pyridin Roridin-1-carboxylate was obtained as a pale yellow solid (0.130 g, 73%): C 20 H 28 Cl2N2O5[M+H] + LCMS (ESI) calculated value: 447,449 ( 3:2) Actual value 447,449 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.35-7.29(m,1H),7.06-6.98(m,1H),5.49-5 .40(m,1H),5.27-5.01(m,2H),3.98-3.87(m,1H ),3.49(s,3H),3.33-3.09(m,1H),2.49-2.36(m ,2H),2.31-2.19(m,2H),1.32-1.25(m,3H),1.1 3(d, J = 11.3 Hz, 9 H).

[0423] Step D: tert-Butyl (2R)-4-(1-carbamoylethyl)- in DCM (2 mL) 2-[2,3-Dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carbohydrate To a stirred mixture of 1,2-dihydroxybenzoates (0.130 g, 0.290 mmol) in 1,2-dihydroxybenzoates (0.5 The reaction mixture was stirred at room temperature for 2 hours and quenched with MeOH (3 mL). The mixture was thawed, basified to pH 8 with saturated aqueous NaHCO3 and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Purified: Column: SunFire Prep C18 OBD Column, 19x 150mm, 5μm 10nm; Mobile phase A: water (+0.05%TFA), mobile phase B: AC N; flow rate: 25 mL / min; gradient: 10% B to 30% B in 6.8 min; wavelength: 210 nm; Retention time 1: 5.67 min, retention time 2: 6.80 min. At 5.67 min, a chromatogram containing the desired product was obtained. The fractions containing 2-[(3S,5R)-5-(2,3-dichloro- 6-hydroxyphenyl)pyrrolidin-3-yl]propanamide isomer 1 C was obtained as a light brown solid (22.8 mg, 18%). 13 H 16 Cl2N2O2[M+H] + LCMS (ESI) calculated: 303,305 (3:2) Found: 303,305 (3: 2); 1 H NMR(400MHz,CD3OD)δ 7.47(d,J=8.8Hz, 1H),6.93(d,J=8.9Hz,1H),5.30(dd,J=11.6,7. 0Hz,1H),3.62(dd,J=11.3,7.7Hz,1H),3.40(t, J=11.2Hz,1H),2.74-2.61(m,1H),2.58-2.48(m ,1H),2.39-2.30(m,1H),2.22(q,J=11.9Hz,1H) , 1.26 (d, J = 6.9 Hz, 3H). The fractions containing the desired product were collected at 6.80 min. The mixture was collected and concentrated under reduced pressure to give 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxybenzoyl) ((2-hydroxyphenyl)pyrrolidin-3-yl)propanamide isomer 2, an off-white solid (5.60 mg, 4.6%) as: C 13 H 16 Cl2N2O2[M+H] + L CMS (ESI) calculated value: 303.305 (3:2) Measured value 303.305 (3:2); 1 H NMR(400MHz,CD3OD)δ 7.47(d,J=8.9Hz,1H) ,6.93(d,J=8.8Hz,1H),5.31(dd,J=11.7,6.9Hz ,1H),3.54(dd,J=11.3,7.8Hz,1H),3.41(t,J=1 0.9Hz,1H),2.74-2.61(m,1H),2.54-2.42(m,2H ),2.16(q,J=11.9Hz,1H),1.27(d,J=7.0Hz,3H) .

[0424] tert-Butyl(2R)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]phenyl Starting from [4-oxopyrrolidine-1-carboxylate], compound 45 was prepared. The following compounds in Table 7C were prepared in a manner similar to that described above.

[0425] [Table 10]

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

[0427] [ka] Step A: tert-Butyl (2R,4S)-4-carbamoyl-2-[2 ,3-Dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate To a stirred solution of BH3-Me2S (0.140 g, 0.360 mmol) The reaction mixture was stirred for 70 minutes at room temperature under a nitrogen atmosphere. The mixture was stirred at RT for 4 h, quenched with MeOH (1 mL) at RT, and concentrated under reduced pressure to give tert-Butyl(2R,4S)-4-(aminomethyl)-2-[2,3-dichloro-6 -(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate was obtained as a colorless oil. (60.0 mg, 41%), which was used in the next step without purification: C 18 H 26 Cl2N2O4[M+H] + LCMS (ESI) calculated values: 405,407 (3: 2) Actual measured value: 405,407 (3:2).

[0428] Step B: tert-Butyl (2R,4S)-4-(aminomethyl)-2- in DMF (2 mL) [2,3-Dichloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxy acetate (60.0 mg, 0.150 mmol) and glycolic acid (23.0 mg, 0.3 To a stirred solution of 1000 mmol of HATU (0.120 g, 0.300 mmol) and TE A (30.0 mg, 0.300 mmol) was added at room temperature. The reaction mixture was stirred for 2 hours. The resulting solution was diluted with 48% MeOH (1 mL) in water (+0.05% TFA). Purification by reverse phase chromatography eluting with ACN afforded tert-butyl (2R, 4S)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-[(2- Hydroxyacetamido)methyl]pyrrolidine-1-carboxylate was obtained as a colorless oil. (50.0 mg, 72.9%). 20 H 28 Cl2N2O6[M+H] + LCMS (ESI) Calculated value: 463,465 (3:2) Found value: 463,465 (3:2).

[0429] Step C: tert-Butyl (2R,4R)-2-[2,3-dichloro] in MeOH (0.4 mL) 2-hydroxyacetamidomethyl-6-(methoxymethoxy)phenyl]-4-[(2-hydroxyacetamido)methyl A stirred solution of 1,2-dihydroxybenzoylpyrrolidine-1-carboxylate (50.0 mg, 0.110 mmol) To the solution, concentrated HCl (0.8 mL) was added at room temperature. The reaction mixture was stirred for 2 hours and then cooled under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD Column, 19×150mm, 5μm ;Mobile phase A: water (+10mM NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; Gradient: 30% B to 40% B, 40% B in 4.5 min; Wavelength: 210 nm; Retention time: 4.35 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give N-{[(3S ,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl] Methyl}-2-hydroxyacetamide was obtained as an off-white solid (16.9 mg , 49%):C 13 H 16 Cl2N2O3[M+H] + LCMS (ESI) calculated value: 3 19,321(3:2) Actual value 319,321(3:2); 1 H NMR (400 MHz) ,CD3OD)δ 7.18(d,J=8.8Hz,1H),6.58(d,J=8.8 Hz,1H),4.99(t,J=8.4Hz,1H),4.01(s,2H),3.4 1-3.34(m,3H),2.90(dd,J=10.7,6.8Hz,1H),2. 72-2.51(m,1H),2.34-2.24(m,1H),1.92-1.80( m,1H).

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

[0431] [Table 11]

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

[0433] [ka] Step A: tert-Butyl (2R,4Z)-2-[2,3-dichloro-6-(2R,4Z)- ... -(methoxymethoxy)phenyl]-4-(2-methoxy-2-oxoethylidene)pyrro To a stirred mixture of lysine-1-carboxylate (0.300 g, 0.670 mmol), CuI (0.260 g, 1.34 mmol) and SiMe3Cl (0.290 g, 2.6 9 mmol) was added dropwise under a nitrogen atmosphere at 0° C. The reaction was stirred at room temperature for 1 hour, and then The mixture was cooled to 60° C. CH3MgBr (4 mL, 4.03 mmol, 1 M in THF) was added to 5 The reaction solution was stirred at -60°C for an additional 3 hours until it reached room temperature. It was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. The filtrate was then concentrated under reduced pressure. The residue was dissolved in 70% ACN in water (+0.05% TFA). The compound was purified by reverse phase chromatography to give tert-butyl (2R)-2-[2 ,3-dichloro-6-(methoxymethoxy)phenyl]-4-(2-methoxy-2-ox (isoethyl)-4-methylpyrrolidine-1-carboxylate was obtained as a tan oil (0. 180g, 58%):C 22 H 31 Cl2NO6[M+H] + LCMS (ESI) calculation of Value: 476,478(3:2) Actual value 476,478(3:2); 1 H NMR (400 MHz, CDCl3)δ 7.32(d,J=9.0Hz,1H),7.04(d,J= 9.0Hz,1H),5.63-5.46(m,1H),5.30-5.07(m,2H ),4.23-4.11(m,2H),3.76-3.57(m,1H),3.55-3 .26(m,4H),2.52-2.39(m,2H),2.16-2.06(m,2H ),1.44-1.21(m,6H),1.15(d,J=4.6Hz,9H).

[0434] Step B: tert-Butyl (2R)-2-[2, 3-Dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy-2-oxo Ethyl)-4-methylpyrrolidine-1-carboxylate (0.180g, 0.380m To a stirred solution of 18.0 mg of LiOH (0.760 mmol) was added at room temperature. The reaction was stirred for 1 h and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and ATU (0.220g, 0.570mmol), NH4Cl (0.100g, 1.89m mol) and TEA (76.0 mg, 0.760 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for another 1 h, diluted with EA (20 mL) and water (20 mL), and diluted with EA (3×2 The combined organic layers were washed with brine (2 x 20 mL) and anhydrous Na After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with water (+0.05% T Purification by reverse phase chromatography eluting with 50% ACN in FA gave tert- Butyl (2R)-4-(carbamoylmethyl)-2-[2,3-dichloro-6-(methoxy)methyl] (Dimethoxy)phenyl]-4-methylpyrrolidine-1-carboxylate as a yellow oil Obtained (0.110g, 65%): C 20 H 28 Cl2N2O5[M+H] + LCMS( ESI) Calculated value: 447,449 (3:2) Measured value: 447,449 (3:2); 1 HN MR(400MHz,CDCl3)δ 7.33(dd,J=9.0,3.0Hz,1H ),7.07-6.99(m,1H),5.80-5.46(m,1H),5.29-5 .07(m,2H),3.63(d,J=10.3Hz,1H),3.54-3.43( m,4H),2.53-1.87(m,4H),1.43-1.31(m,3H),1. 15(s,9H).

[0435] Step C: tert-Butyl (2R)-4-(carbamoylmethyl) in MeOH (2.00 mL) )-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-methylpyrrolyl To a stirred solution of 1,2-dihydroxybenzoyl-1-carboxylate (0.100 g, 0.220 mmol), concentrated HCl (2.00 mL) was added at room temperature. The reaction was stirred for 1 hour and concentrated under reduced pressure. Purification was performed by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD Column, 19×150mm, 5μm; Mobile phase A: Water (+10mM NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% in 5.5 min B to 50% B, 50% B; wavelength: 210 nm; retention time: 5.2 min. The fractions containing 2-[5R-(2,3-dichloro-6-hydroxybenzoyl)methyl]-2-methyl-1,2-dihydro-2,3-dihydro-2,4 ... [(3-methyl-2-phenyl)pyrrolidin-3-yl]acetamide as an off-white solid (35.0 mg, 52%) as: C 13 H 16 Cl2N2O2[M+H] + LC MS(ESI) calculated: 303,305 (3:2) found 303,305 (3:2); 1 H NMR(400MHz,CD3OD)δ 7.17(dd,J=8.9,1.1Hz ,1H),6.59(dd,J=8.9,1.2Hz,1H),5.08-4.99(m ,1H),3.21(d,J=11.3Hz,1H),3.09-2.95(m,1H) ,2.66-2.29(m,3H),1.78-1.54(m,1H),1.28(d, J = 5.8 Hz, 3H).

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

[0437] [ka] Step A: A stirred solution of i-PrNH (0.180 g, 1.95 mmol) in THF (1 mL) n-BuLi (0.9 mL, 2.27 mmol, 2.5 M in hexane) was added to the After 30 minutes, tert-butyl (2R)- 2-[2,3-Dichloro-6-(methoxymethoxy)phenyl]-4-(2-ethoxy- 2-Oxoethyl)pyrrolidine-1-carboxylate (0.300g, 0.650mm The reaction solution was stirred at -78°C for 30 minutes, and CH3I (0.9 20 g, 6.49 mmol) was added, and the reaction mixture was stirred at −78° C. for an additional 2 h. The resulting mixture was quenched with saturated aqueous NH4Cl (20 mL) at room temperature to give EA (3 The combined organic layers were washed with brine (3×30 mL) and extracted with anhydrous N After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2R) -2-[2,3-dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy (1-oxopropan-2-yl)pyrrolidine-1-carboxylate was obtained as a yellow oil (0.330 g, crude), which was used directly in the next step without purification: C 22 H 31 Cl2NO6[M+H] + LCMS (ESI) calculated value: 476,478 (3:2 ) Actual measured value: 476,478 (3:2).

[0438] Step B: A stirred solution of i-PrNH (0.210 g, 2.08 mmol) in THF (1 mL) n-BuLi (1 mL, 2.43 mmol, 2.5 M in hexane) was added to the solution under a nitrogen atmosphere. After 30 min, tert-butyl (2R)-2- [2,3-Dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (0.330 g, 0.6 The reaction solution was stirred under a nitrogen atmosphere at -78°C for 30 minutes. The mixture was stirred and CH3I (0.980 g, 6.93 mmol) was added. The reaction mixture was placed under a nitrogen atmosphere. The mixture was stirred at −78° C. for an additional 2 hours under air. The resulting mixture was diluted with saturated aqueous NH4Cl (20 ml) The mixture was quenched by the addition of EA (3×30 mL) at room temperature and extracted with EA (3×30 mL). The organic layer was washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure. The residue was dissolved in 50% ACN in water (+20 mM NH4HCO3). Purification by reverse phase chromatography eluting with tert-butyl (2R)-2-[ 2,3-Dichloro-6-(methoxymethoxy)phenyl]-4-(1-ethoxy-2-methyl (1-oxopropan-2-yl)pyrrolidine-1-carboxylate was obtained as a yellow oil. (0.150g, 47% over two steps): C 23 H 33 Cl2NO6[M+H ] + LCMS (ESI) calculated: 490,492 (3:2) Found: 490,492 (3 :2); 1 H NMR(300MHz,CDCl3)δ 7.35-7.30(m,1H ),7.09-6.98(m,1H),5.56-5.34(m,1H),5.29-5 .05(m,2H),4.16(q,J=7.1Hz,2H),3.80-3.63(m ,1H),3.55-3.27(m,4H),2.85-2.47(m,1H),2.4 0-1.92(m,1H),1.73-1.53(m,1H),1.32-1.20(m ,9H),1.19-1.08(m,9H).

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

[0440] Step D: 2-[(5R)-1-(tert-butoxycarbonyl)-5- [2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidin-3-yl]-2 -methylpropanoic acid (0.300 g, 0.650 mmol) and HATU (0.370 g To a stirred solution of 1,2-dimethyl-3-(2,4-dimethyl-2,6-dimethyl-1,7-dimethyl-2,8-dimethyl-1,9-dimethyl-2,9-dimethyl-2,8 ... NH4Cl (69.0 mg, 1.30 mmol) was added at room temperature. The reaction mixture was stirred for 3 h. It was stirred, diluted with water (20 mL) and extracted with EA (3×20 mL). The mixture was washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was Concentration under reduced pressure gave tert-butyl(2R)-4-(1-carbamoyl-1-methylethyl) (2,3-dichloro-6-(methoxymethoxy)phenyl)pyrrolidine-1- The carboxylate was obtained as a yellow oil (0.300 g, crude), which was carried on without purification. Used directly in step C 21 H 30 Cl2N2O5[M+H] + LCMS(ES) I) Calculated value: 461,463 (3:2) Measured value: 461,463 (3:2).

[0441] Step E: tert-Butyl (2R)-4-(1-carbamoyl-1-methyl)methylpropional in MeOH (3 mL) (ethylethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine To a stirred solution of benzophenone-1-carboxylate (0.300 g, crude) was added concentrated HCl (3 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. Purification was performed by preparative HPLC using the following conditions: Column: SunFire Prep C 18 OBD Column, 19×150mm, 5μm 10nm; Mobile phase A: Water (+ 0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 20% in 6.8 min B to 20%B, 20%B; detector UV: 210 nm; retention time 1: 6.27 min, retention time Intermediate 2: 7.58 min. The faster eluting enantiomer, 2-[(3R,5R )-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-2- Methylpropanamide (compound 51) was obtained as a purple solid (6.00 mg, 3 steps) 2.3% over the entire range):C 14 H18 Cl2N2O2[M+H] + LCMS (ESI) Calculated value: 317,319 (3:2) Measured value 317,319 (3:2); 1 H NMR(4 00MHz,CD3OD)δ 7.46(d,J=8.9Hz,1H),6.93(d, J=8.9Hz,1H),5.26(t,J=9.4Hz,1H),3.70(dd,J =11.4,7.8Hz,1H),3.49-3.41(m,1H),3.02-2.8 7(m,1H),2.42-2.24(m,2H),1.30(d,J=3.1Hz,6 H). The slower eluting enantiomer, 2-[(3S,5R)-5-(2 ,3-dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-2-methylpropane The amide (compound 52) was obtained as an off-white solid (10.6 mg, 3 steps). (over 4.0%):C 14 H 18 Cl2N2O2[M+H] + LCMS (ESI) measurement Calculated value: 317,319 (3:2) Measured value: 317,319 (3:2); 1 H NMR (40 0MHz,CD3OD)δ 7.45(d,J=9.0Hz,1H),6.92(d,J =8.9Hz,1H),5.27(dd,J=10.3,8.2Hz,1H),3.69 -3.56(m,1H),3.49(dd,J=11.4,8.4Hz,1H),2.8 8-2.74(m,1H),2.39-2.25(m,2H),1.30(d,J=4. 8Hz,6H).

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

[0443] [ka] Step A: 1,2-Dichloro-4-methoxybenzene (2.00 g, 11 To a stirred solution of n-BuLi (6.78 mL, 16.9 mmol, hexahydrate) A 2.5M solution of 5-(2.5M HCl) was added dropwise under a nitrogen atmosphere at -78°C. After stirring for 30 minutes, THF (5 1-tert-Butyl 2-ethyl(2S)-5-oxopyrrolidine-1,2 The resulting solution was added with 2-dicarboxylate (4.36 g, 17.0 mmol). The mixture was stirred for 1 hour, quenched with saturated aqueous NH4Cl (10 mL) at 0°C, and water (50 mL The combined organic layers were diluted with brine (3 × 30 mL) and extracted with EA (3 × 40 mL). L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography eluting with PE / EA (3 / 1). (2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,3- Ethyl dichloro-6-methoxyphenyl-5-oxopentanoate is an off-white solid (1.26 g, 25%) as: C 19 H 25 Cl2NO6[M+Na] + LCM S(ESI) calculated value: 456,458 (3:2) observed value 456,458 (3:2); 1 H NMR(400MHz,CDCl3)δ 7.43(d,J=8.9Hz,1H),6 .81(d,J=8.9Hz,1H),5.13(d,J=8.4Hz,1H),4.3 8-4.29(m,1H),4.24(qd,J=7.1,2.3Hz,2H),3.8 3(s,3H),3.00-2.78(m,2H),2.37-2.24(m,1H), 2.15-2.00(m,1H),1.46(s,9H),1.31(t,J=7.1H z,3H).

[0444] Step B: (2S)-2-[(tert-butoxycarbonyl)amino] in DCM (12 mL) Ethyl 5-(2,3-dichloro-6-methoxyphenyl)-5-oxopentanoate (1 To a stirred solution of 1.20 g (2.76 mmol) of 1,2-dimethyl-2,4-trimethyl-1,4-trimethyl ...1,4-trimethyl-2,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4 The mixture was stirred at 40°C for 3 h and then diluted to pH 4.0 with saturated aqueous NaHCO3 (20 mL) at 0°C. The mixture was neutralized to 7 and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ( 2S)-5-(2,3-dichloro-6-methoxyphenyl)-3,4-dihydro-2H- Ethyl pyrrole-2-carboxylate was obtained as a yellow oil (1.20 g, crude), which was purified Used directly in the next step without further purification: 14 H 15 Cl2NO3[M+H] + LC MS(ESI) calculated: 316,318 (3:2) found: 316,318 (3:2) 1 H NMR(300MHz,CDCl3)δ 7.42(d,J=8.9Hz,1H), 6.80(d,J=8.9Hz,1H),5.02-4.88(m,1H),4.27( q,J=7.1Hz,2H),3.81(s,3H),3.06-2.76(m,2H) ,2.46-2.25(m,2H),1.33(t,J=7.1Hz,3H).

[0445] Step C: (2S)-5-(2,3-dichloro-6-methoxyphenyl)- in EA (12 mL) Ethyl 3,4-dihydro-2H-pyrrole-2-carboxylate (1.20 g, 3.76 mm To a stirred solution of PtO2 (0.172 g, 0.759 mmol) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (1.5 atm) for 2 hours. The resulting mixture was filtered. The filter cake was washed with EA (3×20 mL). The filtrate was concentrated under reduced pressure and the residue was Purified by reversed-phase chromatography eluting with 37% ACN in water (+0.05% TFA). (2S,5R)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine Ethyl 2-carboxylate trifluoroacetate was obtained as a yellow oil (0.800 g, 2-step purification). (67% across the group):C 14 H 17 Cl2NO3[M+H] + LCMS (ESI) calculated value of :318,320(3:2)Actual value 318,320(3:2); 1 H NMR (400M Hz, CDCl3)δ 7.52(d,J=9.0Hz,1H),6.90(d,J=9 .0Hz,1H),5.47-5.34(m,1H),4.79(d,J=10.7Hz ,1H),4.46-4.30(m,2H),4.03(s,3H),2.84-2.5 9(m,1H),2.47-2.27(m,2H),2.27-2.13(m,1H), 1.40(t,J=7.2Hz,3H).

[0446] Step D: (2S,5R)-5-(2,3-dichloro-2,4-dihydroxybenzoate) in THF (8 mL) and HO (2 mL) ethyl (6-methoxyphenyl)pyrrolidine-2-carboxylate (0.800 g, 2.51 To a stirred solution of Boc (0.422 g, 5.03 mmol) and NaHCO3 (0.422 g, 5.03 mmol) 2O (0.690 g, 3.02 mmol) was added at room temperature. The reaction mixture was stirred for 2 hours. The mixture was diluted with water (20 mL) and extracted with EA (3×20 mL). The mixture was washed with ethanol (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was concentrated and eluted with 67% ACN in water (+10 mmol / L NH4HCO3). The compound was purified by reverse phase chromatography to give 1-tert-butyl 2-ethyl (2S ,5R)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dica The carboxylate was obtained as a yellow oil (0.400 g, 38%): 19 H 25 Cl2NO 5[M+H] + LCMS (ESI) calculated: 418, 420 (3:2) Found: 418, 420(3:2); 1 H NMR(300MHz,CDCl3)δ 7.38-7.30 (m,1H),6.76(d,J=8.9Hz,1H),5.49-5.34(m,1H ),4.60-4.44(m,1H),4.34-4.16(m,2H),3.79(s ,3H),2.49-2.10(m,4H),1.49-1.09(m,12H).

[0447] Step E: 1-tert-Butyl 2-ethyl(2S,5R)-5-(2, 3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (0. To a stirred solution of NaBH4 (0.720 g, 19.1 mmol) The reaction mixture was stirred for 4 hours and quenched with water (10 mL). The combined organic layers were washed with brine (3 x 30 mL). The residue was washed with water, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Reversed-phase chromatography eluted with 62% ACN in water (+10 mmol / L NH4HCO3). The product was purified by filtration to give tert-butyl(2R,5S)-2-(2,3-dichloro- 6-Methoxyphenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate was obtained as a colorless oil (0.200 g, 56%): C 17 H 23 Cl2NO4[M+H] + LCMS (ESI) calculated: 376,378 (3:2) Found: 376,378 (3:2) ); 1 H NMR(300MHz,CDCl3)δ 7.36(d,J=8.9Hz,1 H),6.80(d,J=8.9Hz,1H),5.38(t,J=8.4Hz,1H) ,4.32-4.16(m,1H),3.99-3.89(m,1H),3.86(s, 3H),3.81-3.67(m,1H),2.27-2.04(m,3H),1.89 -1.74(m,1H),1.14(s,9H).

[0448] Step F: tert-Butyl (2R,5S)-2-(2,3-dichloro-6) in DCM (3 mL) -methoxyphenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate( 0.200g, 0.530mmol) and TEA (0.110g, 1.06mmol) To the stirred solution, TsCl (0.200 g, 1.06 mmol) was added at room temperature. The mixture was stirred for 16 hours and concentrated under reduced pressure. The residue was purified by column chromatography eluting with PE / EA (3 / 1). Purification by silica gel column chromatography yielded tert-butyl (2R,5S) -2-(2,3-dichloro-6-methoxyphenyl)-5-{[(4-methylbenzenesulfonyl) (sulfonyl)oxy]methyl}pyrrolidine-1-carboxylate was obtained as a colorless oil (0 .160g, 57%):C 24 H 29 Cl2NO6S[M+H] + LCMS (ESI) Calculated value: 530,532 (3:2) Measured value 530,532 (3:2); 1 H NMR(3 00MHz, CDCl3)δ 7.89-7.81(m,2H),7.38(d,J=8 .1Hz,2H),7.33(d,J=9.1Hz,1H),6.74(d,J=8.8 Hz,1H),5.30(t,J=8.8Hz,1H),4.35-4.06(m,3H ),3.74(s,3H),2.47(s,3H),2.20-2.07(m,2H), 2.07-1.93(m,2H),1.20(d,J=74.1Hz,9H).

[0449] Step G: tert-Butyl (2R,5S)-2-(2,3-dichloro-6)- -Methoxyphenyl)-5-{[(4-methylbenzenesulfonyl)oxy]methyl}pi To a stirred solution of loridine-1-carboxylate (0.140 g, 0.26 mmol), u4NCN (0.280 g, 1.06 mmol) was added at room temperature. The reaction mixture was heated to 80°C. The mixture was stirred at rt for 16 h, diluted with water (30 mL) and extracted with EA (3×30 mL). The organic layer was washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was dissolved in water (+10 mmol / L NH4HCO3)7 Purification by reverse phase chromatography eluting with 0% ACN gave tert-butyl(2 S,5R)-2-(cyanomethyl)-5-(2,3-dichloro-6-methoxyphenyl) Pyrrolidine-1-carboxylate was obtained as a pale yellow oil (50.0 mg, 49%): C 18 H 22 Cl2N2O3[M-56] + LCMS (ESI) calculated value: 329,331 (3:2) Actual value 329,331(3:2); 1 H NMR (300 MHz, CDCl3 )δ 7.36(d,J=8.9Hz,1H),6.78(d,J=8.9Hz,1H) ,5.41-5.30(m,1H),4.38-4.27(m,1H),3.80(s, 3H),3.17-3.03(m,1H),2.73(dd,J=16.5,10.0H z,1H),2.34-2.02(m,4H),1.11(s,9H).

[0450] Step H: tert-Butyl (2S,5R)- in MeOH (1 mL) and HO (0.2 mL) 2-(cyanomethyl)-5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine- 1-carboxylate (50.0 mg, 0.130 mmol) and NaOH (16.0 m To a stirred solution of HO (13.0 mg, 0.390 mmol) ) was added at room temperature. The reaction mixture was stirred for 4 hours and washed with saturated aqueous Na2SO3 (2 mL) The mixture was quenched at RT, diluted with water (20 mL), and extracted with EA (3 x 20 mL) respectively. The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in water (+10 mmol / L NH Purification by reverse phase chromatography eluting with 40% ACN in CO3 was performed to obtain tert -butyl(2S,5R)-2-(carbamoylmethyl)-5-(2,3-dichloro-6- (Methoxyphenyl)pyrrolidine-1-carboxylate was obtained as a yellow oil (30.0 ml g, 57%):C 18 H 24 Cl2N2O4[M+H] + LCMS (ESI) calculated values ​​of: 403,405(3:2)Actual value: 403,405(3:2).

[0451] Step I: tert-Butyl (2S,5R)-2-(carbamoylmethyl) in DCM (1 mL) -5-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate To a stirred solution of 1000 mg (50.0 mg, 0.120 mmol) of BBr3 (0.190 g, 0.7 The resulting mixture was stirred at 40° C. for 4 hours and water (2 mL The residue was purified by preparative HPLC using the following conditions: Purification was performed using: Column: XBridge Prep OBD C18 Column, 19 ×250mm, 5μm; Mobile phase A: water (+10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 20% B to 50% B, 50% B in 5.2 min; Detector: UV 254 / 220 nm; retention time: 5.08 min. Fractions containing the desired product The fractions were collected and concentrated under reduced pressure to give 2-[(2S,5R)-5-(2,3-dichloro-6- Hydroxyphenyl)pyrrolidin-2-yl]acetamide was obtained as a pale yellow solid (4 .00mg, 18%):C 12 H 14 Cl2N2O2[M+H] + LCMS (ESI) Calculated value: 289,291 (3:2) Measured value 289,291 (3:2); 1 H NMR(4 00MHz,CD3OD)δ 7.20(d,J=8.8Hz,1H),6.60(d, J=8.8Hz,1H),4.93-4.91(m,1H),3.78-3.70(m, 1H),2.59-2.55(m,2H),2.48-2.37(m,1H),2.22 -2.11(m,1H),1.86-1.66(m,2H).

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

[0453] [ka] Step A: Nickel chloride DME complex (5.00 mg, 0.02 mmHg) in DMSO (1 mL) A solution of dtbpy (6.00 mg, 0.02 mmol) and dtbpy (6.00 mg, 0.02 mmol) was added to 6 After stirring at 0°C for 30 minutes, solution A was obtained. Meanwhile, [(3S,5R )-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6-(methoxy methoxy)phenyl]pyrrolidin-3-yl]acetic acid (Intermediate 5a) (0.100 g, 0. 23 mmol), tert-butyl 4-iodopyrazole-1-carboxylate (0. 100g, 0.35mmol), 2-tert-butyl-1,1,3,3-tetramethyl Guanidine (59.0 mg, 0.35 mmol), 2,3-dihydro-1H-isoindo Ir[dF(CF3)] A solution of [ppy]2(dtbpy)PF6 (3.00 mg, 0.002 mmol) was heated under nitrogen The mixture was stirred at room temperature under a nitrogen atmosphere for 5 minutes to obtain solution B. Then, solution A was added to solution B and the mixture was stirred under a nitrogen atmosphere for 5 minutes to obtain solution B. The final reaction mixture was irradiated with a blue LED at room temperature for 5 hours, and then diluted with water (20 ml). The combined organic layers were diluted with brine (3 x 20 mL) and extracted with EA (3 x 20 mL). The residue was washed with 1 mL of HCl and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The fraction was subjected to reverse phase chromatography eluting with 30% ACN in water (+0.05% TFA). Purify the product to obtain tert-butyl 4-{[(3R,5R)-1-(tert-butoxy) (carbonyl)-5-[2,3-dichloro-6-(methoxymethoxy)phenyl]pyrrolidine {benzo-3-yl}methyl}pyrazole-1-carboxylate was obtained as a yellow oil (40. 0mg, 31%):C 26 H 35 Cl2N3O6[M+H] + LCMS (ESI) calculation of Value: 556,558 (3:2) Actual value: 556,558 (3:2).

[0454] Step B: tert-Butyl 4-{[ (3R,5R)-1-(tert-butoxycarbonyl)-5-[2,3-dichloro-6 -(methoxymethoxy)phenyl]pyrrolidin-3-yl]methyl}pyrazole-1-carboxylate A solution of carboxylate (40.0 mg, 0.07 mmol) was stirred at room temperature for 2 hours and then reduced The residue was concentrated under reduced pressure and diluted with 40% ACN in water (+10 mmol / L NH4HCO3). The compound was purified by reverse phase chromatography eluting with 3,4-dichloro-2-[(2R ,4R)-4-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-yl]phenol C was obtained as an off-white solid (12.3 mg, 55%): 14 H 15 Cl2N3 O[M+H] + LCMS (ESI) calculated value 312,314 (3:2) found value 312,3 14(3:2): 1 H NMR(400MHz,CD3OD)δ 7.45(s,1H) ,7.37(s,1H),7.18(d,J=8.8Hz,1H),6.59(d,J= 8.9Hz,1H),4.95-4.92(m,1H),3.38-3.34(m,1H ),2.93(dd,J=11.1,8.2Hz,1H),2.74-2.68(m,2 H)),2.65-2.51(m,2H),1.64-1.48(m,1H).

[0455] Starting from intermediate 5a and the corresponding heteroaryl halide, compound 54 In a manner similar to that described, the following compounds in Table 7E were prepared.

[0456] [Table 12]

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

[0458] [ka] Step A: Bis(propan-2-yl)amine (0.853 g, 8.44 mL) in THF (10 mL) To a stirred solution of n-BuLi (3.94 mL, 9.84 mmol) in hexane 2.5 M) was added dropwise under a nitrogen atmosphere at −78° C. After stirring for 30 minutes, THF (10 ml) tert-Butyl (2R,4S)-2-[2,3-dichloro-6-(methoxymethyl) [2-ethoxy-2-oxoethyl]-4-(2-ethoxy-2-phenyl)pyrrolidine-1-carbo The xylate (1.30 g, 2.81 mmol) was added dropwise over 20 minutes. Stir for 30 minutes. After stirring, bromo(methoxy)methane (1.76 g, 14.1 m mol) was added. The resulting reaction mixture was stirred for 2 h and saturated aqueous NH4Cl (30 m The mixture was quenched with EA (3×50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (3× 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography eluting with 78% ACN in water (+10 mmol / L NH4HCO3). Purification by chromatography gave tert-butyl(2R,4S)-2-(2,3 -dichloro-6-(methoxymethoxy)phenyl)-4-(1-ethoxy-3-methoxy (1-oxopropan-2-yl)pyrrolidine-1-carboxylate was obtained as a yellow oil (0.550g, 38%):C 23 H 33 Cl2NO7[M+H] + LCMS(ES) I) Calculated value: 506,508 (3:2) Measured value 506,508 (3:2); 1 H NMR (300MHz, CDCl3)δ 7.29(d,J=9.28Hz,1H),7.00 (d,J=8.95Hz,1H),5.53-5.33(m,1H),5.29-5.0 6(m,2H),4.26-4.08(m,2H),4.00-3.70(m,1H), 3.69-3.51(m,1H),3.51-3.28(m,7H),3.28-3.0 6(m,1H),2.73-2.22(m,3H),2.04-1.76(m,1H), 1.43-1.02(m,12H).

[0459] Step B: tert-Butyl (2R,4S)-2-[2,3-dichloro- 6-(methoxymethoxy)phenyl]-4-(1-ethoxy-3-methoxy-1-oxo propan-2-yl)pyrrolidine-1-carboxylate (0.550 g, 1.09 mm To a stirred solution of LiOH HO (91.2 mg, 2.17 mmol) and HO (2 mL) was added at room temperature. The reaction was stirred for 3 hours and concentrated under reduced pressure. The residue was diluted with DMSO. Dissolve HATU (0.619 g, 1.63 mmol), NH4Cl (8 7.1 mg, 1.63 mmol), and TEA (0.329 g, 3.26 mmol) were added. The resulting reaction mixture was stirred for 1 h, diluted with water (20 mL), and diluted with EA (3×20 The combined organic layers were washed with brine (3×20 mL) and anhydrous Na2S The mixture was dried over O. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with water (+0.05% TF A) Purification by reverse phase chromatography eluting with 45% ACN yielded tert-butyl ether. (2R,4S)-4-(1-carbamoyl-2-methoxyethyl)-2-[2,3-diamino-2-methyl- Chloro-6-(methoxymethoxy)phenyl]pyrrolidine-1-carboxylate Obtained as an oil (0.420 g, 81%)21 H 30 Cl2N2O6[M+H] + LC MS(ESI) calculated: 477,479 (3:2) found 477,479 (3:2); 1 H NMR(300MHz,CDCl3)δ 7.34-7.27(m,1H),7.0 0(dd,J=9.09,4.29Hz,1H),6.52-5.83(m,2H),5 .65-5.34(m,1H),5.34-5.01(m,2H),3.99-3.84 (m,1H),3.79-3.51(m,1H),3.46-3.26(m,4H),3 .27-3.08(m,4H),2.67-2.26(m,3H),2.07-1.79 (m,1H), 1.48-0.94(m,9H).

[0460] Step C: tert-Butyl (2R,4S)-4-(1-carbamoyl)- in MeOH (1 mL) 2-Methoxyethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl] To a stirred solution of pyrrolidine-1-carboxylate (0.150 g, 0.314 mmol) Aqueous HCl (1 mL, 4 M) was added at room temperature. The reaction mixture was stirred for 1 hour and then heated under reduced pressure. Concentrated. The residue was purified by preparative HPLC using the following conditions: Column: Su n Fire Prep C18 OBD Column, 19×150mm, 5μm 10nm; Mobile phase A: Water (+0.05%TFA), Mobile phase B: ACN; Flow rate: 20mL / gradient: 18% B to 23% B in 5 min; detector: UV 254 / 220 nm; hold The isomer eluting faster at 3.85 min, 2 at 5.65 min. -[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pyrrolidine- 3-yl]-3-methoxypropanamide isomer 1 was obtained as an off-white solid (8 .50mg, 6%):C 14 H 18 Cl2N2O3[M+H] + LCMS (ESI) measurement Calculated value: 333,335 (3:2) Measured value: 333,335 (3:2); 1 H NMR (40 0MHz,CD3OD)δ 7.44(d,J=8.90Hz,1H),6.91(d, J=8.91Hz,1H),5.24(dd,J=11.49,7.08Hz,1H), 3.66-3.59(m,2H),3.54(dd,J=9.53,5.76Hz,1H ),3.41(t,J=11.04Hz,1H),3.36(s,3H),2.74-2 0.64 (m, 2H), 2.39-2.19 (m, 2H). Eluting later at 5.65 min Isomer, 2-[(3S,5R)-5-(2,3-dichloro-6-hydroxyphenyl)pi [Rolidin-3-yl]-3-methoxypropanamide isomer 2 was obtained as an off-white solid. Obtained (12.1 mg, 9%): C 14 H 18 Cl2N2O3[M+H] + LCMS( ESI) Calculated value: 333,335 (3:2) Measured value: 333,335 (3:2); 1 HN MR(400MHz,CD3OD)δ 7.45(dd,J=8.92,0.85Hz, 1H),6.91(d,J=8.92Hz,1H),5.27(dd,J=11.64, 6.85Hz,1H),3.67-3.54(m,2H),3.54-3.45(m,2 H),3.34(s,3H),2.79-2.62(m,2H),2.50-2.36( m, 1H), 2.21 (q, J = 11.86 Hz, 1H).

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

[0462] [ka] Step A: tert-Butyl (2R,4S)-4-(1-carbamoyl)-2H-acetate in DCM (3 mL) -methoxyethyl)-2-[2,3-dichloro-6-(methoxymethoxy)phenyl]pi To a stirred solution of loridine-1-carboxylate (0.270 g, 0.566 mmol), BBr3 (1.42 g, 5.66 mmol) was added at room temperature. The reaction mixture was stirred for 1 hour. The mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was subjected to preparative Purified by HPLC: Column: Sun Fire Prep C18 OBD C olumn, 19×150mm, 5μm 10nm; Mobile phase A: Water (+0.05%TFA ), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 13% B to 24% B in 5 min, 2 4% B; Detector: UV 254 / 220 nm; Retention time 1: 4.51 min, Retention time 2: 4 .91 min. The faster eluting isomer, 2-[(3S,5R)-5-(2,3 -dichloro-6-hydroxyphenyl)pyrrolidin-3-yl]-3-hydroxypropane The amide isomer 1 was obtained as an off-white solid (18.6 mg, 8%): 13 H1 6Cl2N2O3[M+H]+ LCMS (ESI) calculated value: 319,321 (3:2) Actual value 319,321 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7. 47(d,J=8.89Hz,1H),6.92(d,J=8.93Hz,1H),5. 26(dd,J=11.52,7.00Hz,1H),3.84(dd,J=10.85 ,6.51Hz,1H),3.77-3.64(m,2H),3.45(t,J=11. 37Hz,1H),2.81-2.66(m,1H),2.61-2.53(m,1H) ,2.42-2.32(m,1H),2.27(q,J=11.89Hz,1H). 4. The slower eluting isomer, 2-[(3S,5R)-5-(2,3-dichloro-6 -hydroxyphenyl)pyrrolidin-3-yl]-3-hydroxypropanamide isomers 2 was obtained as an off-white solid (16.6 mg, 7%): C 13 H 16 Cl2N2O 3[M+H] + LCMS (ESI) calculated: 319, 321 (3:2) Found: 319, 321(3:2); 1 H NMR(400MHz,CD3OD)δ 7.44(d,J= 8.90Hz,1H),6.91(d,J=8.89Hz,1H),5.28(dd,J =11.63,6.84Hz,1H),3.85-3.71(m,2H),3.58-3 .42(m,2H),2.86-2.71(m,1H),2.60-2.39(m,2H ), 2.20(q,J=11.98Hz,1H).

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

[0464] [Table 13]

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

[0466] cell culture CHO-K1 cells stably expressing Kv1.3 were cultured in 10% heat-inactivated FBS, 1 mM Contains sodium pyruvate, 2 mM L-glutamine and G418 (500 μg / ml) Cells were grown in DMEM containing 0.1% EDTA. Cells were grown in culture flasks at 37°C in a humidified atmosphere of 5% CO2. were grown in a culture vessel.

[0467] solution Cells were incubated in 140 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM Mg The cells were bathed in an extracellular solution containing Cl2, 5 mM glucose, and 10 mM HEPES. pH adjusted to 7.4 with H. 295-305 mOsm. The internal solution was 50 mM KCl, Contains 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES. pH adjusted to 7.2 with KOH. 285 mOsm. All compounds were added at 30 mM D Compound stock solutions were freshly diluted in external solution to give 30 nM, 100 nM, The concentrations were 1 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. The highest content of DMSO (0.3%) was present at 100 μM.

[0468] Voltage Protocol Depolarizing pulses of 100 ms from -90 mV (holding potential) to +40 mV were administered at 0.1 Hz. Currents were evoked by applying the compound at a frequency of 100 Hz. (none) and compound pulse trains contained 20 pulses.

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

[0470] [Table 14]

[0471] Patch clamp recording and compound application Automated patch clamp platform Patchliner (Nanion) Whole-cell current recording and compound application were performed using a cytotoxicity assay (CRISPR) using the cytotoxicity assay (CRISPR) for the detection of cytotoxicity. This is now possible with the EPC10 patch clamp amplifier (HEKA Elektronik Dr. Schulze GmbH together with Patchmaster software (HE KA Elektronik Dr. Schulze GmbH) was used for data acquisition. The data was sampled at 10 kHz without filtering. The flow is performed according to the P / 4 procedure (HEKA Elektronik Dr. Schulze GmbH ) were subtracted online. The total compound input until the next pulse train was applied consecutively to the same cell without any pulse input. Incubation times were within 10 seconds. Peak current inhibition was observed during compound equilibration. It was.

[0472] Data analysis AUC and peak values ​​were measured using Patchmaster (HEKA Elektronik Dr. Schulze GmbH). 50 To determine the The last single pulse in the pulse train corresponding to the compound concentration was used. UC and peak values ​​were normalized to control values ​​in the absence of compound. OridinLab) to detect IC 50 is the Hill formula: 化合物 / I 対照 =(1 00-A) / (1+([Compound] / IC 50 )nH)+A IC 50 is the concentration at which the current inhibition is half-maximal, and [compound] is the applied compound concentration. where A is the fraction of unblocked current and nH is the Hill coefficient.

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

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

[0475] cell culture CHO-K1 cells stably expressing hERG were cultured in 10% heat-inactivated FBS, 1% penicillin-containing medium. Cholecystocin / streptomycin, hygromycin (100 μg / ml) and G418 (1 The cells were grown in Ham's F-12 medium containing glutamine (000 μg / ml). They were grown in Lasco at 37°C in a 5% CO2 humidified incubator.

[0476] solution Cells were incubated in 140 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM Mg The cells were bathed in an extracellular solution containing Cl2, 5 mM glucose, and 10 mM HEPES. pH adjusted to 7.4 with H. 295-305 mOsm. The internal solution was 50 mM KCl, Contains 10 mM NaCl, 60 mM KF, 20 mM EGTA, and 10 mM HEPES. pH adjusted to 7.2 with KOH. 285 mOsm. All compounds were added at 30 mM D Compound stock solutions were freshly diluted in external solution to give 30 nM, 100 nM, The concentrations were 1 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. The highest content of DMSO (0.3%) was present at 100 μM.

[0477] Voltage Protocol The voltage protocol (see Table B) consisted of a 300 ms depolarization to +20 mV (to stimulate cardiac activity). (similar to the plateau phase of the potential kinetics), followed by a 300 ms repolarization to -50 mV (to induce a tail current) ), and the voltage change during cardiac action potential with a final step to a holding potential of -80 mV The pulse frequency was 0.3 Hz. The control (no compound) and compound pulse trains for each compound concentration contained 70 pulses. .

[0478] [Table 15]

[0479] Patch clamp recording and compound application Automated patch clamp platform Patchliner (Nanion) This allowed for the recording of whole-cell currents and the application of compounds. A HEKA amplifier was used together with Patchmaster software (HEKA Ele A ktronik (Dr. Schulze GmbH) was used to acquire the data. The signal was sampled at 10 kHz without filtering. Successive applications were made to the same cell without any washout in between.

[0480] Data analysis AUC and PEAK values ​​were measured using Patchmaster (HEKA Elektronik IC was obtained using the IC 50 To determine The last single pulse of the pulse train corresponding to a given compound concentration was used. The resulting AUC and PEAK values ​​were normalized to the control values ​​in the absence of compound. IC using oridin (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 concentration at which current inhibition is half-maximal, where A is the fraction of unblocked current, and nH is the Hill coefficient.

[0481] Table 7 shows specific selections of the present invention for Kv1.3 potassium channel and hERG channel. A summary of the inhibitory activity of selected compounds is provided.

[0482] [Table 16-1]

[0483] [Table 16-2]

[0484] [Table 16-3]

[0485] [Table 16-4]

[0486] [Table 16-5]

[0487] [Table 16-6]

[0488] [Table 16-7] * Not tested.

Claims

1. A compound of Formula I, I', II, II', III, or IV, or a pharmaceutically acceptable salt thereof. A salt that can be used in the present invention. 【Chemical 1】 【Chemistry 2】 During the ceremony, Each Z is independently OR ａ and X １ each independently represents H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; X ２ each independently represents H, halogen, CN, alkyl, cycloalkyl, halogen cycloalkyl halide or alkyl halide; X ３ each independently represents H, halogen, CN, alkyl, cycloalkyl, halogen a cycloalkyl halide or an alkyl halide; Or alternatively, X １ and X ２ and the carbon atoms to which they are attached, taken together, forming an optionally substituted 5- or 6-membered aryl; Or alternatively, X ２ and X ３ and the carbon atoms to which they are attached, taken together, forming an optionally substituted 5- or 6-membered aryl; R １ each independently represents H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF ３ , OCF ３ , OR ａ , S.R. ａ , halogen, NR ａ R ｂ , or NR ｂ (C=O)R ａ and R ２ each independently represents H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, CN, CF ３ , OCF ３ , OR ａ , S.R. ａ , halogen, NR ａ R ｂ , or NR ｂ (C=O)R ａ Or Or alternatively, R １ and R ２ together with the carbon atoms to which they are attached form cyclohexyl forming a hydroxyalkyl or saturated heterocyclic ring, R ３ each independently represents H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, CN, CF ３ , OCF ３ , OR ａ , S.R. ａ , halogen, NR ａ R ｂ ,also is NR ｂ (C=O)R ａ and R ４ each independently represents H, alkyl, cycloalkyl, saturated heterocycle, (CR ａ R ｂ ) ｎ２ OR ａ , or (CR ａ R ｂ ) ｎ２ NR ａ R ｂ Or Or alternatively, two R ４ The groups, together with the atoms to which they are attached, have 3 to 7 members. forming an optionally substituted cycloalkyl or heterocyclic ring of R ５ each independently represents H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C═O)R ａ , (C= O)(CR ａ R ｂ ) ｎ２ OR ａ 、(C=O)(CR ａ R ｂ ) ｎ２ NR ａ R ｂ 、or SO ２ R ａ and R ６ each independently represents H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle alkylaryl, alkylaryl, or alkylheteroaryl; R ７ each independently represents H, alkyl, cycloalkyl, heterocycle, aryl, heterocycle or alkylaryl, alkylaryl, or alkylheteroaryl; Or alternatively, R ６ and R ７ together with the nitrogen atom to which they are attached, form a nitrogen atom, and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S and the heterocycle, when valence permits, is selected from alkyl, cycloalkyl, cycloalkyl halide, alkyl halide, halogen, CN, OR ８ , -(C H ２ ) ０－２ OR ８ 、N(R ８ ) ２ 、(C=O)R ８ 、(C=O)N(R ８ ) ２ 、NR ８ (C=O)R ８ and 1 to 4 substituents each independently selected from the group consisting of oxo, and optionally replaced by R ９ each independently represents H, alkyl, cycloalkyl, saturated heterocycle, aryl, Heteroaryl, alkylaryl, alkylheteroaryl, (C═O)R ａ , (C= (O)(CR ａ R ｂ ) ｎ２ OR ａ 、(C=O)(CR ａ R ｂ ) ｎ２ NR ａ R ｂ 、又はSO ２ R ａ and R １０ each independently represents H, alkyl, cycloalkyl, heterocycle, aryl, is heteroaryl, alkylaryl, or alkylheteroaryl; A １ is aryl or heteroaryl, A ２ is aryl or heteroaryl, R １２ each independently represents H, alkyl, CN, CF ３ , OCF ３ , OR ａ , S.R. ａ , halogen, NR ａ R ｂ , (CR ａ R ｂ ) ｎ２ OR ａ , (C═O)NR ａ R ｂ , (CR ａ R ｂ ) ｎ２ NR ａ R ｂ , or (CR ａ R ｂ ) ｎ２ NR ｂ (C=O)R ａ and R １３ each independently represents H, alkyl, CN, CF ３ , OCF ３ , OR ａ , S.R. ａ , halogen, NR ａ R ｂ , (CR ａ R ｂ ) ｎ２ OR ａ , (C═O)NR ａ R ｂ , (CR ａ R ｂ ) ｎ２ NR ａ R ｂ , or (CR ａ R ｂ ) ｎ２ NR ｂ (C=O)R ａ and R ａ and R ｂ each independently represents H, alkyl, alkenyl, cycloalkyl, N a saturated heterocyclic ring containing 1 to 3 heteroatoms each selected from the group consisting of , O, and S; or alternatively, R ａ and R ｂ are the results of Consists of a nitrogen atom and N, O, and S together with the carbon or nitrogen to which it is bonded. cycloalkyl or heteroalkyl containing 0 to 3 additional heteroatoms each selected from the group Forming a ring, If applicable, X １ , X ２ , X ３ , A １ , A ２ , R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ９ , R １０ , R １２ , R １３ , R ａ , or R ｂ The alkyl, cycloalkenyl, alkyl, heterocycle, aryl, and heteroaryl are substituted with alkyl, cycloalkyl, cyclohexyl ... Chloroalkyl, cycloalkyl halide, alkyl halide, halogen, CN, OR ８ 、-(CH ２ ) ０－２ OR ８ 、N(R ８ ) ２ 、(C=O)R ８ 、(C=O)N(R ８ ) ２ , N.R. ８ (C=O)R ８ and 1 to 4 independently selected from the group consisting of oxo and optionally substituted by a substituent of R ８ Each of is independently H, alkyl, or an optionally substituted heterocycle. or alternatively, two R ８ The groups, together with the nitrogen atom to which they are attached, a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; forming an optionally substituted heterocycle containing the atom, each m is independently 1, 2, or 3; n １ each independently, where valences allow, is an integer from 0 to 3; n ２ are each independently an integer from 0 to 3; n ４ is an integer from 0 to 3, n ５ is an integer of 0 to 3, or a pharmaceutically acceptable salt thereof.

2. R ４ each independently represents H, alkyl, cycloalkyl, saturated heterocycle, (CR ａ R ｂ ) ｎ２ NR ａ R ｂ , or (CR ａ R ｂ ) ｎ２ OR ａ and R ５ Each of the , H, alkyl, cycloalkyl, or saturated heterocycle.

3. 3. The compound of claim 1 or 2, wherein each m is independently 2 or 3.

4. 3. The compound of claim 1 or 2, wherein one or more occurrences of m is 1.

5. The compound has the formula Ia, Ia', IIa, IIa', IIIa, or IVa: 【Chemistry 3】 【Chemistry 4】 2. The compound of claim 1 having the structure:

6. The compound has the formula Ib, Ib', IIb, IIb', IIIb, or IVb: 【Chemistry 5】 【Chemistry 6】 2. The compound of claim 1 having the structure:

7. R ４ one or more occurrences of is H, alkyl, cycloalkyl, or OR ａ A claim 7. The compound according to any one of claims 1 to 6.

8. R ４ 8. The compound of claim 7, wherein one or more occurrences of is H or alkyl.

9. R ４ One or more occurrences of may be H or CH ３ 9. The compound according to claim 7 or 8, wherein

10. R ４ One or more occurrences of may be a saturated heterocycle, (CR ａ R ｂ ) ｎ２ OR ａ , or (CR ａ R ｂ ) ｎ２ NR ａ R ｂ The compound according to any one of claims 1 to 6,

11. n １ 11. The method of claim 1, wherein one or more occurrences of is 1. Compound.

12. n １ 11. The method of claim 1, wherein one or more occurrences of Compound.

13. R ５ each independently is H, alkyl, cycloalkyl, or saturated heterocycle; The compound according to any one of claims 1 to 12.

14. R ５ is independently a cycloalkyl or a saturated heterocycle. The compound according to any one of claims 1 to 4.

15. R ５ and each of the following is independently H or alkyl: The compound described.

16. R ５ each independently represents H or CH ３ 16. The compound of claim 15, wherein:

17. R １ and R ２ each independently represents a cycloalkyl, a saturated heterocycle, an aryl, a heterocyclic group, Aryl, alkylaryl, alkylheteroaryl, CN, CF ３ , OCF ３ , OR ａ , S.R. ａ , halogen, NR ａ R ｂ , or NR ｂ (C=O)R ａ Claims 1 to 16 The compound according to any one of claims 1 to 4.

18. R １ and R ２ each independently represents H, OR ８ alkyl, halo, Any one of claims 1 to 16, wherein the alkyl group is halogen, cycloalkyl, or fluorinated alkyl. The compound described in

19. R １ and R ２ each independently represents H, CH ３ , C.H. ２ CH ３ , C.H. ２ OH, CH ２ CH ２ OH、CHH ２ OCH ３ 、H ２ CH ２ OCH ３ 、 or 【Chemistry 7】 19. The compound of claim 18, wherein:

20. R １ and R ２ is H and H, H and Me, Me and Me, H and Et, Me and Et, Et and Et, H and CH ２ OH, H and CH ２ CH ２ OH, H and CH ２ OCH ３ , H and CH ２ CH ２ OCH ３ , or H and 【Chemistry 8】 19. The compound of claim 18, wherein:

21. Structural part - (CR １ R ２ ) ｍ - is independently -CH ２ -, -CH(CH ３ ) -、-C(CH ３ ) ２ -、-CH(CH ２ CH ３ )-、-CH(CH ２ OH)-、-CH (CH ２ SO ３ )-、-CH ２ -CH ２ -、-CH(CH ３ )-CH ２ -、-CH ２ - C(CH ３ ) ２ -、 【Chemistry 9】 3. The compound of claim 1 or 2, selected from the group consisting of:

22. R ６ and R ７ each independently is H, alkyl, cycloalkyl, or heterocycle; The alkyl, cycloalkyl, and heterocycle are not halogen, CN, OH, OMe, -(C H ２ ) １－２ OMe, and -(CH ２ ) １－２ OH, each independently selected from the group consisting of 22. The compound according to claim 1, optionally substituted by one to two substituents selected from the group consisting of aryl, aryloxy ... The compound described.

23. R ６ and R ７ each independently is H or alkyl, and said alkyl is halogen; optionally substituted with 1 to 2 substituents each independently selected from the group consisting of CN, CN, and OH; 23. The compound of claim 22, which is optionally substituted.

24. R ６ and R ７ each independently represents H, —CH ３ , -CH ２ OH, -CH ２ CH ２ O H, or -CH ２ CH ２ CH ２ 24. The compound of claim 22 or 23, wherein:

25. R ６ and R ７ together with the nitrogen atom to which they are attached, form a nitrogen atom, as well as N a heterocycle containing 0 to 3 additional heteroatoms each selected from the group consisting of , O, and S; and the heterocycle may, where valences permit, be alkyl, cycloalkyl, halogenated, Cycloalkyl, alkyl halide, halogen, CN, OR ８ , -(CH ２ ) ０－２ O R ８ 、N(R ８ ) ２ 、(C=O)N(R ８ ) ２ 、(C=O)R ８ 、NR ８ (C=O)R ８ and oxo, optionally selected from 1 to 4 substituents The compound of any one of claims 1 to 21, wherein the compound is optionally substituted.

26. R ６ and R ７ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered and forming a heterocyclic ring of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, OH, and -(CH ２ ) １－２ 1 to 2 substituents independently selected from the group consisting of OH; 26. The compound of claim 25, optionally substituted with a substituent.

27. The 4-, 5-, or 6-membered heterocycle is selected from the group consisting of azetidine, pyrrolidine, piperidine, and pyridine.

27. The compound of claim 26 which is perazine.

28. The 4-, 5-, or 6-membered heterocycle is selected from the group consisting of OH and —(CH ２ ) １－２ A group consisting of OH The compound according to claim 27, which is substituted by 1 to 2 substituents each independently selected from Compound.

29. R ６ and R ７ together with the nitrogen atom to which they are attached to form azetidine 29. The compound of claim 28,

30. R ６ and R ７ together with the nitrogen atom to which they are attached to form pyrrolidine 27. The compound of claim 26,

31. R ６ and R ７ each independently is alkylaryl or alkylheteroaryl; The compound according to any one of claims 1 to 21.

32. structural part 【Chemistry 10】 Each of these is independent, 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 The compound of any one of claims 1 to 21, having the structure:

33. R ９ each independently represents a cycloalkyl, a saturated heterocycle, an aryl, or a heteroaryl.

22. Any one of claims 1 to 21, wherein the aryl is alkyl, alkylaryl, or alkylheteroaryl. Item 1. The compound according to item 1.

34. R ９ each independently represents (C═O)R ａ , (C=O)(CR ａ R ｂ ) ｎ２ OR ａ , (C=O)(CR ａ R ｂ ) ｎ２ NR ａ R ｂ , (C═O)NR ａ R ｂ , or SO ２ R ａ Yes The compound according to any one of claims 1 to 21.

35. R ９ Each of the groups is independently H or alkyl. The compound described.

36. R ９ each independently represents H or CH ３ 36. The compound of claim 35, wherein:

37. R １０ each independently is H, alkyl, cycloalkyl, or heterocycle; The alkyl, cycloalkyl, and heterocycle may be halogen, CN, OH, OMe, —(CH ２ ) １－２ OMe, and -(CH ２ ) １－２ 1 to 1, each independently selected from the group consisting of OH Any of claims 1 to 21 and 33 to 36, optionally substituted with two substituents. The compound according to any one of claims 1 to 4.

38. R １０ is alkyl, and said alkyl is selected from the group consisting of halogen, CN, and optionally substituted with 1 to 2 substituents each independently selected from the group consisting of OH 38. The compound of claim 37,

39. R １０ each independently represents H, —CH ３ , -CH ２ OH, or -CH ２ CH ２ OH 39. The compound of claim 37 or 38, wherein:

40. A １ is a 5- or 6-membered aryl or heteroaryl, 3. The compound according to claim 1.

41. A １ but, 【Chemistry 14】 41. The compound of claim 40, selected from the group consisting of:

42. A １ but, 【Chemistry 15】 41. The compound of claim 40, selected from the group consisting of:

43. A １ but, 【Chemistry 16】 43. The compound of claim 40 or 42, wherein:

44. R １２ each independently is H, halogen, fluorinated alkyl, or alkyl , the compounds according to claims 1 to 21 and 40 to 43.

45. R １２ 45. The compound of claim 44, wherein one or more occurrences of is H.

46. A ２ is a 5- or 6-membered aryl or heteroaryl, 3. The compound according to claim 1.

47. A ２ but, 【Chemistry 17】 47. The compound of claim 46, selected from the group consisting of:

48. A ２ but, 【Chemistry 18】 47. The compound of claim 46, selected from the group consisting of:

49. A ２ but, 【Chemistry 19】 49. The compound of claim 46 or 48, wherein:

50. R １３ each independently is H, halogen, fluorinated alkyl, or alkyl , the compounds according to claims 1 to 21 and 46 to 49.

51. R １３ 51. The compound of claim 50, wherein one or more occurrences of is H.

52. Each Z is independently OH or O(C １ -C ４ alkyl) The compound according to any one of claims 1 to 4.

53. 53. The compound of claim 52, wherein each Z is independently OMe, OEt, or OH. thing.

54. 54. The compound of claim 52 or 53, wherein one or more occurrences of Z is OH.

55. X １ each independently is H, halogen, fluorinated alkyl, or alkyl; 55. A compound according to any one of claims 1 to 54.

56. X １ each independently represents H, F, Cl, Br, Me, CF ２ H, C.F. ２ Cl, or CF ３ 56. The compound of claim 55, wherein:

57. X １ 57. The compound of claim 55 or 56, wherein one or more occurrences of is H.

58. X ２ each independently is H, halogen, fluorinated alkyl, or alkyl; 58. A compound according to any one of claims 1 to 57.

59. X ２ each independently represents H, F, Cl, Br, Me, CF ２ H, C.F. ２ Cl, or CF ３ 59. The compound of claim 58, wherein:

60. X ２ 60. The compound of claim 58 or 59, wherein one or more occurrences of is Cl.

61. X ３ each independently is H, halogen, fluorinated alkyl, or alkyl; 61. The compound of any one of claims 1 to 60.

62. X ３ each independently represents H, F, Cl, Br, Me, CF ２ H, C.F. ２ Cl, or CF ３ 62. The compound of claim 61, wherein:

63. X ３ 63. The compound of claim 61 or 62, wherein one or more occurrences of is Cl.

64. R ３ each independently represents H, alkyl, CF ３ , OR ａ , S.R. ａ , halogen, NR ａ R ｂ , or NR ｂ (C=O)R ａ The compound according to any one of claims 1 to 63, thing.

65. R ３ each independently is H, halogen, fluorinated alkyl, or alkyl; 65. The compound of claim 64.

66. R ３ 66. The compound of claim 64 or 65, wherein one or more occurrences of is H.

67. structural part 【Chemistry 20】 Each of these is independent, 【Chemical 21】 【Chemical 22】 52. The compound of any one of claims 1 to 51, having the structure:

68. structural part 【Chemical 23】 At least one occurrence of 【Chemistry 24】 52. The compound of any one of claims 1 to 51, having the structure:

69. The compound is represented by formula Ic, Ic', Id, Id', IIc, IIc', IId, IId' , IIIc, IIId, IVc, or IVd: 【Chemistry 25】 【Chemical 26】 【Chemical 27】 having the structure In the formula, R １１ are independently H, halogen, or alkyl; n ３ 2. The compound of claim 1, wherein each of is independently an integer from 0 to 3.

70. n ３ 70. The compound of claim 69, wherein each of is independently 0, 1, or 2.

71. R １１ 70. The compound of claim 69, wherein each of is independently H or alkyl.

72. R １１ 70. The compound of claim 69, wherein at least one occurrence of is halogen.

73. At least one occurrence of Z is OR ａ 70. The compound of claim 69, wherein:

74. 70. The compound of claim 69, wherein at least one occurrence of Z is OH, OMe, or OEt. compound.

75. 70. The compound of claim 69, wherein at least one occurrence of Z is OH.

76. R ａ or R ｂ At least one occurrence of independently selected from H, alkyl, cycloalkyl, saturated 76. The compound according to claim 1, wherein the aryl is a heterocyclic ring, an aryl, or a heteroaryl. Compound.

77. R ａ or R ｂ at least one occurrence of is independently H, Me, Et, Pr, or 【Chemical formula 28】 and wherein said heterocycle, if valence permits, is selected from the group consisting of: OH, oxo, or (C=O)C １－４ optionally substituted with alkyl 77. The compound of claim 76.

78. R ａ or R ｂ At least one occurrence of is H, Me or 【Chemical 29】 78. The compound of claim 76 or 77, wherein:

79. R ａ and R ｂ together with the nitrogen atom to which they are attached, form a nitrogen atom, as well as N substituted or substituted alkyl groups containing 0 to 3 additional heteroatoms each selected from the group consisting of , O, and S; 76. The compound according to any one of claims 1 to 75, which forms an optionally heterocyclic ring.

80. R ８ each independently represents H, alkyl, or alkyl, halogen, or OH; The compound according to any one of claims 1 to 79, which is an optionally substituted heterocycle. thing.

81. R ８ 81. The compound of claim 80, wherein each of is independently H or alkyl.

82. R ８ 82. The compound of claim 80 or 81, wherein each of is independently H or Me.

83. 10. The method of claim 1, wherein the compound is selected from the group consisting of compounds 31 to 79 shown in Table 7. The compound described in

84. The compound is selected from the group consisting of compounds 1 to 15 shown in Table 1, compounds 16 to 20 shown in Table 2, and compounds 17 to 21 shown in Table 3. Compounds 1a to 15a shown in Table 3, compounds 16a to 30a shown in Table 4, compounds 17a to 18a shown in Table 5, and compounds 16b to 30b shown in Table 6. The compound of claim 1.

85. At least one compound according to any one of claims 1 to 84 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

86. 1. A method of treating a condition in a mammalian species in need thereof, comprising administering a therapeutically effective amount of 85. At least one compound according to any one of claims 1 to 84 or a pharmaceutically acceptable salt thereof. and administering to said mammalian species a salt thereof, wherein said condition is cancer, an immunological disorder, Central nervous system disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and kidney disorders The method of claim 1, wherein the method is selected from the group consisting of:

87. 87. The method of claim 86, wherein the immunological disorder is transplant rejection or an autoimmune disease.

88. The autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

87. The method of claim 86, which is a urinary disease.

89. 87. The method of claim 86, wherein the central nervous system disorder is Alzheimer's disease.

90. The inflammatory disorders include inflammatory skin conditions, arthritis, psoriasis, spondylitis, periodontal disease (parodontitis), 87. The method of claim 86, wherein the neuropathic inflammatory disorder is a neuropathic inflammatory disorder.

91. 87. The method of claim 86, wherein the gastroenterological disorder is inflammatory bowel disease.

92. 87. The method of claim 86, wherein the metabolic disorder is obesity or type II diabetes.

93. 87. The method of claim 86, wherein the cardiovascular disorder is ischemic stroke.

94. 87. The method of claim 86, wherein the kidney disease is chronic kidney disease, nephritis, or chronic renal failure. Law.

95. The condition is cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus , Type 1 diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, dental Periodontal disease, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, 87. The method of claim 86, wherein the anti-inflammatory drug is selected from the group consisting of nephritis, chronic renal failure, and combinations thereof. How to post.

96. 87. The method of claim 86, wherein the mammalian species is human.

97. In mammalian species requiring blockade of the Kv1.3 potassium channel, 85. A method for blocking sodium channels comprising administering to a subject a therapeutically effective amount of any one of claims 1 to 84. administering to said mammalian species at least one compound of the invention or a pharmaceutically acceptable salt thereof. A method, comprising:

98. 98. The method of claim 97, wherein the mammalian species is human.

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