Arylmethylene heterocyclic compounds as kv1.3 potassium shaker channel blockers

Abstract

To provide a compound and a composition useful as pharmaceuticals as potassium channel blockers.SOLUTION: A compound of Formula (I) or a pharmaceutically acceptable salt thereof is described. Pharmaceutical compositions comprising the compound and a method of using the same are also described.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application was filed on October 7, 2019, the entire contents of which are incorporated herein by reference. This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 911,655, filed on 2004 / 01 / 11.

[0002] This patent disclosure contains material that is subject to copyright protection. The copyright owner reserves the right to modify, revise, or otherwise update this patent. to the reproduction of a patent document or patent disclosure, as it appears in the Patent and Trademark Office patent file or records. No objections are made to the use of this material, but any and all copyrights are otherwise reserved.

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

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

[0005] Voltage-gated Kv1.3 potassium (K + ) channel is a receptor for lymphocytes (T lymphocytes and B lymphocytes) It is expressed in lymphocytes, the central nervous system, and other tissues and is involved in neurotransmitter release, heart rate, and insulin secretion. Kv1.3 regulates numerous physiological processes, including phosphorylation, phosphorylation, and neuronal excitability. Nerves regulate membrane potential and thereby regulate calcitonin production in human effector memory T cells. Effector memory T cells can indirectly affect neuronal signaling. These include multiple sclerosis, type 1 diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. It is a mediator of several conditions. Upon activation, effector memory T cells express Kv1. Increases the expression of 3 channels in human B cells, both naive and early memory B cells. In the resting state, Kv1.3 channels are expressed in small numbers. Chronic memory B cells express a large number of Kv1.3 channels. le regulates calcium homeostasis, which is required for T cell receptor-mediated cell activation, gene transcription, and proliferation. (Panyi, G., et al., 2004, Trends Immunol., 565-569). Blockade of Kv1.3 channels in Molly T cells inhibits calcium signaling, cytokines, and It suppresses the production of interferon-γ, interleukin-2, and cell proliferation. Control.

[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, as in the case of rheumatoid arthritis and systemic lupus erythematosus, Treatment is generally palliative and can have severe side effects, including anti-inflammatory The need for more effective treatments is fueled by the increasing number of studies that address the etiology of autoimmune diseases. It selectively inhibits the function of effector memory T cells, which are known to These inhibitors are designed to block the immune response without compromising it. It is believed that effector memory T can improve autoimmune disease symptoms. TEM cells express a large number of Kv1.3 channels and their functions are investigated using these channels. In vivo, Kv1.3 channel blockers inhibit TEMs at sites of inflammation. Kv1.3 channel blockers paralyze the inflammatory process and prevent their reactivation in inflamed tissue. It does not affect the motility of immune and central memory T cells in lymph nodes. Inhibition of the function of these cells by selectively blocking 1.3 channels has minimal side effects. This offers the possibility of effective treatment of autoimmune diseases.

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

[0008] Therefore, compounds that are selective Kv1.3 channel blockers may be used as immunosuppressants or immunosuppressants. Kv1.3 channels are also potential therapeutic agents for treating obesity. and for enhancing peripheral insulin sensitivity in patients with type 2 diabetes These compounds are also considered therapeutic targets for the prevention of transplant rejection, as well as immunological (e.g. For example, they may also be used to treat autoimmune and inflammatory disorders.

[0009] Tubulointerstitial fibrosis is the progressive deposition of connective tissue in the renal parenchyma, leading to deterioration of renal function. It is involved in the pathology of chronic kidney disease, chronic renal failure, nephritis, and glomerular inflammation, and is a risk factor for end-stage renal failure. Overexpression of Kv1.3 channels in lymphocytes promotes proliferation and involved in the underlying pathology of these kidney diseases and contributing factors in the progression of tubulointerstitial fibrosis. This can lead to chronic inflammation and overstimulation of cell-mediated immunity. Inhibition of ATP channel currents suppresses renal lymphocyte proliferation and ameliorates the progression of renal fibrosis (Kazama I., et al., 2015, Mediators Inflamm., 1-12).

[0010] Kv1.3 channels are also involved in inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease. It also plays a role in gastroenterological disorders, including ulcerative colitis, caused by excess T Ulcerative colitis is a chronic IBD characterized by cellular infiltration and cytokine production. This can impair the quality of life and lead to life-threatening complications. High levels of Kv1 in CD4+ and CD8+ T cells in the affected mucosa Kv .3 channels have been implicated in the production of pro-inflammatory compounds in active UC. The 1.3 channel is thought to serve as a marker of disease activity, and pharmacological blockade , which may constitute a novel immunosuppressive strategy in UC. Current treatment regimens for UC, including anti-TNFα agents, are ineffective for many patients. (Hansen LK, et al., 2014, J. Crohns Colitis, 1378-1391). Crohn's disease is a type of IBD that can affect any part of the digestive tract. It is generally thought to be the result of intestinal inflammation caused by a T cell-driven process initiated by safe bacteria. Therefore, Kv1.3 channel inhibition may be utilized for the treatment of Crohn's disease. can.

[0011] In addition to T cells, Kv1.3 channels are also expressed in microglia, and here we demonstrate that this channel The IL-1 receptor is involved in inflammatory cytokine and nitric oxide production and microglia-mediated neuronal death. In humans, strong Kv1.3 channel expression is associated with Alzheimer's disease. CD68 in microglia in the frontal cortex and in multiple sclerosis brain lesions + Found on cells Kv1.3 channel blockers preferentially target detrimental pro-inflammatory microglial function It has been suggested that Kv1.3 channels can mediate the progression of stroke in rodents and humans. It is expressed on activated microglia in the mouse brain. Higher Kv1.3 channel current density in acutely isolated microglia from the infarcted hemisphere than in microglia is observed (Chen YJ, et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

[0012] Expression of Kv1.3 channels is elevated in microglia of human Alzheimer's disease brains. Kv1.3 channels are pathologically relevant microglial targets in Alzheimer's disease (Rangaraju S., et al., 2015, J. Alzheimers Dis., 797-808) Soluble AβOs enhance microglial Kv1.3 channel activity. Required for AβO-induced microglial pro-inflammatory activation and neurotoxicity. Kv1.3 channel Expression / activity of the ATPase inhibitors was measured in transgenic Alzheimer's disease animals and in human Alzheimer's disease. Pharmacological targeting of microglial Kv1.3 channels inhibits Kv1.3 expression in hippocampal synapses. may affect neural plasticity and reduce amyloid deposition in APP / PS1 mice Therefore, Kv1.3 channels may be a therapeutic target for Alzheimer's disease.

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

[0014] Kv1.3 channel expression regulates proliferation, apoptosis, and cell viability in multiple cell types. These processes are crucial for cancer progression. In this context, the Kv1.3 channel located in the inner mitochondrial membrane is a regulator of apoptosis. It can interact with Bax (Serrano-Albarras, A., et al., 2018, Expert Op pin. Ther. Targets, 101-105). Therefore, inhibitors of Kv1.3 channels have anti-cancer properties. It can be used as an agent.

[0015] Several with multiple disulfide bonds from spiders, scorpions, and sea anemones It is known that peptide toxins block Kv1.3 channels. A few selective and potent peptide inhibitors of NER have been developed. A synthetic derivative of stichodactyla toxin (shk) (shk-186) is Shk is also a highly sophisticated peptide toxin. It has demonstrated efficacy in preclinical models, It is currently in Phase I clinical trials for the treatment of psoriasis. Shk inhibits the proliferation of TEM cells. Shk inhibits the growth of multiple sclerosis, which can lead to improvement in animal models of multiple sclerosis. It also binds to closely related Kvi channel subtypes found in the CNS and heart. To avoid potential cardiotoxicity and neurotoxicity, selective inhibitors of Kv1.3 channels are recommended. Furthermore, small peptides such as shk-186 are rapidly cleared from the body after administration. This results in a short circulation half-life and frequent administration events. There is a need for the development of long-acting, selective Kv1.3 channel inhibitors to treat do. Summary of the Invention [Problem to be solved by the invention]

[0016] Therefore, there is still a need to develop novel Kv1.3 channel blockers as medicines. It is said that... [Means for solving the problem]

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

[0018] [ka] and as potassium channel blockers having the formula: Useful compounds are described. The compounds of formula I described herein inhibit Kv1.3 potassium. (K + These compounds block the ATP channel and can be used to treat a variety of conditions. Also described herein are pharmaceutical compositions and methods for administering these compositions. Methods using the compound are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment are useful as pharmaceutically active agents, and Cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders Several clinical uses include methods for treating cardiac disorders, cardiovascular disorders, kidney diseases, or a combination thereof. There is a way.

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

[0020] [ka] (In the formula, Z is OR a , N.R. a R b , or NR b (C=O)R a and; X1 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, cyclo alkenyl, or halogenated cycloalkyl; X2 is H, halogen, CN, alkyl, alkyl halide, cycloalkyl, or is a cycloalkyl halide; X3 is H, halogen, fluoroalkyl, or alkyl; Alternatively, X1 and X2 and the carbon atoms to which they are attached together may optionally forming an optionally substituted 6-membered aryl; or X2 and X3 and the carbon atoms to which they are attached together may optionally forming an optionally substituted 6-membered aryl; R3 is H, halogen, or alkyl; Alternatively, X1 and R3 and the carbon atoms to which they are attached together may optionally be forming an optionally substituted 6-membered aryl; R1 and R2 are each independently H, alkyl, (CR6R7) n4 ORa , (C R6R7) n4 NR a R b , (CR6R7) n4 NR a (C=O)R b , (CR6R7) n4 NR a SO2R b , or (CR6R7) n4 CONR a R b or R1 , R2 and the carbon atom to which they are attached together form a 3- to 5-membered carbocyclic ring; R4 is H, alkyl, halogenated alkyl, optionally substituted cycloalkyl, ( CR6R7) n4 OR c , (CR6R7) n4 (C=O)R c , (C=O)(CR6R7 ) n4 R c , (CR6R7) n4 COOR c , (CR6R7) n4 NR c (C=O)R d , (CR6R7) n4 (C=O)NR c R d , (C=O)(CR6R7) n4 NR c R d , (CR6R7) n4 (C=O)(C=O)NR c R d , (C=O)(CR6R7) n4 OR c , (CR6R7) n4 SO2R c , (CR6R7) n4 SO2NR c R d , optional optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heterocycle aryl, optionally substituted alkyl-aryl, optionally substituted alkyl -heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted aralkyl alkyl-cycloalkyl, or optionally substituted cycloalkyl-alkyl; each occurrence of R5 is independently H, alkyl, cycloalkyl, or oxo; Alternatively, two R5 groups, together with the carbon atoms to which they are attached, form a 3- to 7-membered forming an optionally substituted saturated carbocyclic ring; Alternatively, the two R5 groups are attached to different carbon atoms on the ring and together form a bond. or forming an alkyl chain containing 1 to 3 carbons; each occurrence of R6 and R7 is independently H, alkyl, or cycloalkyl; R a and R b Each occurrence independently represents H, alkyl, cycloalkyl, saturated heterocycle, a aryl, or heteroaryl; or R a and R b These are combined and together with the nitrogen atom, a nitrogen atom and each of the groups consisting of N, O and S. forming an optionally substituted heterocycle containing 0 to 3 additional selected heteroatoms; R c and R d each occurrence of is independently H, alkyl, each of which is independently halogen, O Alkyl, alkoxy, or alkoxy substituted with 1 to 4 substituents, R8 or N(R8)2. nyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, Optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl alkyl-aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted cycloalkyl-alkyl; or R c and R d These are combined The nitrogen atoms, together with the nitrogen atoms attached to them, are N, O, and S, respectively. forming an optionally substituted heterocycle containing 0 to 3 additional heteroatoms selected from the group death; Each occurrence of R8 is independently H, alkyl, or an optionally substituted heterocycle; Or two R8 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 including R9 is H, alkyl, halogen, or (CR6R7) n4 OR b and; X1, X2, X3, R1, R2, R3, R4, R5, R6, R7, R9, if applicable , R a , R b , R c , and R d Alkyl, cycloalkyl, spiroalkyl, bis(cycloalkyl) The alkyl, heterocyclic, aryl, and heteroaryl groups are substituted with alkyl, heterocyclic, aryl, and heteroaryl groups, where valence permits. , cycloalkyl, cycloalkyl halide, alkyl halide, halogen, CN, -(CH2) 0~2 OR8, N(R8)2, (C=O)C 1~4 Alkyl, (C=O)N (R8)2, and 1 to 4 substituents independently selected from the group consisting of oxo, are optionally replaced by each occurrence of n1 is independently, where valence allows, an integer from 0 to 3; each occurrence of n2 and n3 is independently an integer from 0 to 2; each occurrence of n4 is independently an integer from 0 to 3) is described.

[0021] In any one of the embodiments described herein, each occurrence of n2 and n3 is independently is an integer between 0 and 1.

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

[0023] [ka] but,

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

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

[0026] [ka] but,

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

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

[0029] [ka] but,

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

[0031] In any one of the embodiments described herein, at least one of R1 and R2 is H or alkyl.

[0032] In any one of the embodiments described herein, at least one of R1 and R2 The appearance of (CR6R7) n4 OR a , (CR6R7) n4 NR a R b , (CR6R7) n 4NR a (C=O)R b , (CR6R7) n4 NR a SO2R b , or (CR6R7) n4 CONR a R b is.

[0033] In any one of the embodiments described herein, at least one of R1 and R2 The occurrence of OR a or NR a R b is.

[0034] In any one of the embodiments described herein, R1, R2, and R3 are bonded together. The adjacent carbon atoms join together to form a 3- to 5-membered carbocyclic ring.

[0035] In any one of the embodiments described herein, R1 and R2 are each independently H, Me, OH, CH2OH, NH2, NHMe, NMe2, CH2NH2, CON H2, CONHMe2, CONMe2, NH(C=O)Me, NMe(C=O)Me,

[0036] [ka] is.

[0037] In any one of the embodiments described herein, R4 is H, alkyl, halogenated alkyl, or cycloalkyl.

[0038] In any one of the embodiments described herein, R4 is H, Me, or fluorinated ethylene. It's chill.

[0039] In any one of the embodiments described herein, R4 is (CR6R7) n4 OR c , (CR6R7) n4 COR c , (C=O)(CR6R7) n4 R c , (CR6R7) n 4COOR c , (CR6R7) n4 NR c (C=O)R d , (CR6R7) n4 (C=O )NR c R d , (CR6R7) n4 (C=O)(C=O)NR c R d , (C=O)(CR 6R7) n4 OR c , (CR6R7) n4 SO2R c , or (CR6R7) n4 SO2 NR c R d is.

[0040] In any one of the embodiments described herein, R4 is (CR6R7)2OR c , (C=O)R c , (C=O)(CR6R7) 1-2R c , COOR c , (CR6R7)1 -2 NR c (C=O)R d , (C=O)NR c R d , (CR6R7) n4 (C=O)(C =O)NR c R d , (C=O)(CR6R7) 1-2 OR c , SO2R c , or SO2 NR c R d is.

[0041] In any one of the embodiments described herein, R4 is (CH2)2OH, (CH 2)2OMe, (C=O)H, (C=O)Me, (C=O)CH2OH, (C=O)CH 2OMe, (C=O)Et, (C=O)Ph, (C=O)isopropyl, (C=O)NH 2, (C=O)NHMe, (C=O)NMe2, (C=O)CH2NH2, (C=O)C H2NHMe, (C=O)CH(OH)CH2OH, (C=O)CH(OMe)CH2O H, (C=O)CH(OH)CH2OMe, (C=O)(C=O)NMe2, (C=O) OMe, SO2Me, SO2Et, SO2CH2OH, SO2CH2OMe, SO2NH 2, SO2NHMe, or SO2NMe2.

[0042] In any one of the embodiments described herein, R4 is (C=O)R c , (C=O )(CR6R7) 1~2 R c , (C=O)(CR6R7) 1~2 OR c , or SO2R c and;R care H, alkyl, each independently halogen, OR8 and N(R8)2 alkyl, alkenyl, or the like substituted by 1 to 4 substituents selected from the group consisting of optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted ... optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-aryl aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl cycloalkyl, optionally substituted alkyl-cycloalkyl, and optionally substituted cycloalkyl-alkyl.

[0043] In any one of the embodiments described herein, R c or R d H, Me, Et ,

[0044] [ka] is.

[0045] In any one of the embodiments described herein, R c or R d but

[0046] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0047] In any one of the embodiments described herein, R c But if valence allows, Al Kill, halogen, CN, -(CH2) 0~2 OR8, N(R8)2, (C=O)N(R8 )2, and 1 to 4 substituents independently selected from the group consisting of oxo, cycloalkyl, spiroalkyl, or bicycloalkyl, each optionally substituted; It's a kill.

[0048] In any one of the embodiments described herein, R c But if valence allows, Al Kill, halogen, CN, -(CH2) 0~2 OR8, N(R8)2, (C=O)N(R8 )2, and 1 to 4 substituents independently selected from the group consisting of oxo, each optionally replaced by

[0049] [ka] is.

[0050] In any one of the embodiments described herein, R4 is an optionally substituted saturated Heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally optionally substituted alkyl-aryl, optionally substituted alkyl-heteroaryl; optionally substituted alkyl-heterocycle, optionally substituted cycloalkyl, optionally substituted cycloalkyl optionally substituted alkyl-cycloalkyl or optionally substituted cycloalkyl - alkyl.

[0051] In any one of the embodiments described herein, R4 is

[0052] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0053] In any one of the embodiments described herein, R4, when valence allows, is arylene. Kill, halogen, CN, -(CH2) 0~2 OR8, N(R8)2, (C=O)N(R8 )2, and 1 to 4 substituents independently selected from the group consisting of oxo, Optionally substituted cycloalkyl.

[0054] In any one of the embodiments described herein, R4, when valence allows, is arylene. Kill, halogen, CN, -(CH2) 0~2 OR8, N(R8)2, (C=O)N(R8 )2, and 1 to 4 substituents independently selected from the group consisting of oxo, each optionally replaced

[0055] [ka] is.

[0056] In any one of the embodiments described herein, R4 is

[0057] [ka]

[0058] [ka] or a tautomer thereof.

[0059] In any one of the embodiments described herein, at least one occurrence of R5 is H , alkyl or cycloalkyl.

[0060] In any one of the embodiments described herein, at least one occurrence of R5 is on That's the basic idea.

[0061] In any one of the embodiments described herein, two R5 groups are located on different carbon atoms on the ring. are attached to atoms that together form a bond or an alkyl chain containing 1 to 3 carbon atoms. Form.

[0062] In any one of the embodiments described herein, two R5 groups are bonded to together with the carbon atoms surrounding it form a 3- to 7-membered optionally substituted saturated carbocyclic ring .

[0063] In any one of the embodiments described herein, R a and R b At least one of are independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl It is.

[0064] In any one of the embodiments described herein, R a and R b However, these are combined The nitrogen atoms, together with the nitrogen atoms attached to them, are N, O, and S, respectively. forming an optionally substituted heterocycle containing 0 to 3 additional heteroatoms selected from the group do.

[0065] In any one of the embodiments described herein, each occurrence of R6 and R7 is independently is H or alkyl.

[0066] In any one of the embodiments described herein, R9 is H, alkyl, or halo. This is Gen.

[0067] In any one of the embodiments described herein, R9 is (CR6R7) n4 OR b is.

[0068] In any one of the embodiments described herein, R9 is H, F, or OH. .

[0069] In any one of the embodiments described herein, Z is OR a , N.R. a R b ,or NR b (C=O)R a is.

[0070] In any one of the embodiments described herein, Z is OH, OMe, NH, NH Me, or NMe2.

[0071] In any one of the embodiments described herein, Z is OH.

[0072] In any one of the embodiments described herein, X1 is H, halogen, fluoride, or It is either akyl or alkyl.

[0073] In any one of the embodiments described herein, X1 is H, F, Cl, Br, Me , CF3, or CF2Cl.

[0074] In any one of the embodiments described herein, X 1 is Me or Cl.

[0075] In any one of the embodiments described herein, X2 is H, halogen, fluoride, or It is either akyl or alkyl.

[0076] In any one of the embodiments described herein, X2 is H, F, Cl, Br, Me , CF3, or CF2Cl.

[0077] In any one of the embodiments described herein, X2 is Cl.

[0078] In any one of the embodiments described herein, X3 is H, F, Cl, Br, fluorine The alkyl group is a substituted alkyl group, or an alkyl group.

[0079] In any one of the embodiments described herein, X3 is H, F, Cl, or CF It is 3.

[0080] In any one of the embodiments described herein, the structural moiety

[0081] [ka] each of which is substituted by R3;

[0082] [ka] It has the following structure.

[0083] In any one of the embodiments described herein, R3 is H or alkyl.

[0084] In any one of the embodiments described herein, R3 is halogen.

[0085] In any one of the embodiments described herein, the compound has the structure of Formula II

[0086] [ka] (R 3’ each occurrence is independently H, halogen, or alkyl; n6 is an integer between 0 and 2. It has.

[0087] In any one of the embodiments described herein, R 3’ At least one occurrence of H or alkyl.

[0088] In any one of the embodiments described herein, R 3’ At least one occurrence of It is a halogen.

[0089] In any one of the embodiments described herein, at least one occurrence of R8 is H , alkyl, or an optionally substituted heterocycle.

[0090] In any one of the embodiments described herein, R8 is H, Me, Et, Pr, B u, or

[0091] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0092] In any one of the embodiments described herein, two R groups may be bonded to together with the nitrogen atom present, a nitrogen atom and a group consisting of N, O and S, respectively forming an optionally substituted heterocycle containing 0 to 3 additional heteroatoms selected from do.

[0093] In any one of the embodiments described herein, n1 is 0, 1, 2, or 3. do.

[0094] In any one of the embodiments described herein, n4 is 0, 1, or 2.

[0095] In any one of the embodiments described herein, R c or R d At least one of are independently selected from H, alkyl, halogen, OR and N(R) Alkyl or alkenyl substituted with 1 to 4 substituents selected from the group consisting of , optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl- Aryl, optionally substituted alkyl-heteroaryl, optionally substituted aralkyl alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted It is a cycloalkyl-alkyl.

[0096] In any one of the embodiments described herein, R c and R d However, these are combined The nitrogen atoms, together with the nitrogen atoms attached to them, are N, O, and S, respectively. forming an optionally substituted heterocycle containing 0 to 3 additional heteroatoms selected from the group do.

[0097] In any one of the embodiments described herein, R c or R d At least one of The occurrence of H, Me, Et,

[0098] [ka] is.

[0099] In any one of the embodiments described herein, R c or R d At least one of The emergence of

[0100] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0101] In any one of the embodiments described herein, R c or R d At least one of independently, alkyl, halogen, CN, -(CH2), when valence allows. 0~2 from the group consisting of OR8, N(R8)2, (C=O)N(R8)2, and oxo, respectively cycloalkyl, each optionally substituted with 1 to 4 independently selected substituents; alkyl, spiroalkyl, or bicycloalkyl.

[0102] In any one of the embodiments described herein, R c or R d At least one of independently, alkyl, halogen, CN, -(CH2), when valence allows. 0~2 from the group consisting of OR8, N(R8)2, (C=O)N(R8)2, and oxo, respectively each optionally substituted with 1 to 4 independently selected substituents

[0103] [ka] is.

[0104] In any one of the embodiments described herein, the compound is selected from compounds 1-338 in Table 1. is selected from the group consisting of:

[0105] In another aspect, at least one of the methods according to any one of the embodiments described herein. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition comprising the compound is described.

[0106] In yet another aspect, there is provided a method of treating a condition in a mammalian species in need thereof, comprising: a therapeutically effective amount of at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof to a mammalian species, wherein the condition is cancer. , immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, and a renal disease.

[0107] In any one of the embodiments described herein, the immunological disorder is graft rejection or It is an autoimmune disease.

[0108] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multifocal leukemia, or leukemia. If you have idiopathic sclerosis, systemic lupus erythematosus, or type 1 diabetes.

[0109] In any one of the embodiments described herein, the central nervous system (CNS) disorder is It's Zheimer's disease.

[0110] In any one of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

[0111] In any one of the embodiments described herein, the gastroenterological disorder is inflammatory bowel disease. be.

[0112] In any one of the embodiments described herein, the metabolic disorder is obesity or type II diabetes. It's a disease.

[0113] In any one of the embodiments described herein, the cardiovascular disorder is ischemic stroke. .

[0114] 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.

[0115] In any one of the embodiments described herein, the condition is cancer, transplant rejection, joint Rheumatism, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, Alzheimer's disease, inflammation Inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis inflammation, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and and combinations thereof.

[0116] In any one of the embodiments described herein, the mammalian species is human.

[0117] In yet another embodiment, a compound capable of blocking Kv1.3 potassium channels in a mammalian species in need thereof is provided. A method of treating a cancer, comprising administering a therapeutically effective amount of at least one of the embodiments described herein. administering a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof to a mammalian species. A method is described that includes:

[0118] In any one of the embodiments described herein, the mammalian species is human.

[0119] Any one of the embodiments disclosed herein may be combined with any other embodiment disclosed herein. Any one of the embodiments disclosed herein may be appropriately combined with the embodiments. Combinations of one with any other embodiment disclosed herein are expressly contemplated. The selection of one or more embodiments for a substituent may be combined with the selection of any other substituent. All of the above may be appropriately combined with one or more specific embodiment selections. Such combinations may be used in conjunction with any one or more embodiments of the applications described herein, or Any of the formulas described herein may be used. DETAILED DESCRIPTION OF THE INVENTION

[0120] definition The following are definitions of terms used herein. Unless otherwise indicated, The first definition provided for a group or term in applies to groups or terms throughout this specification. All technical and scientific terms used are as commonly understood by one of ordinary skill in the art. It has meaning.

[0121] The terms "alkyl" and "alk" refer to alkyl groups having 1 to 12 carbon atoms, preferably It refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to 6 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t- Butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl Pentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, The term "(C1-C4) alkyl" includes methyl, ethyl, 1 to 4 propyl, isopropyl, n-butyl, t-butyl, and isobutyl "Substituted alkyl" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to 10 carbon atoms. " denotes one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, the following: The groups include one or more of: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents), a halogeno group, such as an alkyl group having a CF3 group or a CCl3 group; (i.e., those that form ═O), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, ...cyano, nitro, cyano, cyano, cyano chloroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R.b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(= O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P( =O)2NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence independently represents hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl , alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independent R is hydrogen, alkyl, cycloalkyl, heterocycle, or aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e Each Occurrences independently represent alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl , heterocycle, or aryl). In some embodiments, alkyl, cycloalkyl, The groups themselves, such as alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl, are optional. It may be substituted with a selection.

[0122] The term "alkenyl" refers to an alkenyl group having 2 to 12 carbon atoms and at least one carbon-carbon bond. refers to a straight or branched chain hydrocarbon group containing a single double bond. Exemplary such groups include: The term "C2-C6 alkenyl" includes ethylenyl and allyl. , 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-di Methi-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-Hex-1-enyl, (E)-Pent-2-enyl, (Z)-Hex-2-enyl (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1- enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-3-enyl 2 to 6 carbon atoms and at least one carbon-carbon, such as benzo-1,3-dienyl "Substituted alkenyl" refers to any straight or branched chain hydrocarbon group containing a double bond. substituted at available points of attachment with one or more substituents, preferably 1 to 4 substituents; Exemplary substituents include, but are not limited to, one or more of the following groups: or more than one: hydrogen, halogen, alkyl, alkyl halide (i.e., a single Aryl groups with halogen or multiple halogen substituents such as CF3 groups or CCl3 alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(= O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(= O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C( =O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)2 NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a Each output The present invention is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkyl R is nyl, heterocyclic, or aryl; b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or the R b and R c teeth, together with the N to which they are attached, optionally form a heterocyclic ring; R e Each occurrence of is unique Alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl). The exemplary substituents may themselves be optionally substituted.

[0123] 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 group containing a carbon triple bond. Exemplary such groups include ethylene The term "C2-C6 alkynyl" includes ethynyl, propion ... nyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl , pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl A straight chain containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as or branched chain hydrocarbon groups. "Substituted alkynyl" refers to a substituted or branched chain hydrocarbon group having one or more substituted or branched chains at any available point of attachment. It refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: water halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case (those that form groups such as alkyl groups with CF3 or CCl3), cyano, nitro , oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cyclo Alkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(= O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(= O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , O.C.( =O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(= O)R a , or NR b P(=O)2R e (In the formula, R a Each occurrence of is independently hydrogen, alkyl aryl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl R b , R c and R d each occurrence is independently hydrogen, alkyl, cycloalkyl , heterocycle, aryl, or the R b and R c are the N to which they are bonded together optionally form a heterocyclic ring; R e Each occurrence is independently alkyl, cycloalkenyl, alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl) The exemplary substituents may themselves be optionally substituted.

[0124] The term "cycloalkyl" refers to a group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to a completely saturated cyclic hydrocarbon group having cyclopropyl " refers to cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a group having one or more substituents, preferably cycloalkyl, at any available point of attachment. It refers to a cycloalkyl group substituted with 1 to 4 substituents. Exemplary substituents include: These include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., mono-, di ... A single halogen or multiple halo substituent, in the latter case a CF3 group or a CCl3 group. alkyl groups having ═O, cyano, nitro, oxo (i.e., ═O ), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2 R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b Rc , C(= O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a ,OC(=O) NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P (=O)2R e (In the formula, R a Each occurrence is independently hydrogen, alkyl, cycloalkyl, alkoxy, R is cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c oh Yobi R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, or aryl , or the above R b and R c together with the N to which they are attached, and optionally Forming a heterocyclic ring; R e Each occurrence independently represents alkyl, cycloalkyl, alkenyl, cycloalkyl, (Alkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents themselves are any Exemplary substituents include spiro-linked or fused ring substituents. , especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (heterocycle fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or The above-mentioned cycloalkyl, cycloalkenyl, heterocycle and aryl also include fused aryl. The alkyl substituent may itself be optionally substituted.

[0125] The term "cycloalkenyl" refers to a group having 1 to 4 rings and 3 to 8 carbons per ring. refers to a partially unsaturated cyclic hydrocarbon group containing cyclobutenyl. Exemplary such groups include cyclobutenyl, ... cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" means any 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, the following: The groups include one or more of: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents), a halogeno group, such as an alkyl group having a CF3 group or a CCl3 group; (i.e., those that form ═O), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, ...cyano, nitro, cyano, cyano, cyano chloroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NRb R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(= O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P( =O)2NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence independently represents hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl , alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independent R is hydrogen, alkyl, cycloalkyl, heterocycle, or aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e Each Occurrences independently represent alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl , heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents include spiro-linked or fused ring substituents, particularly spiro-linked cycloaliphatic groups. alkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl; The above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may optionally be It may be substituted.

[0126] The term "aryl" refers to an alkyl group having 1 to 5 alkyl groups, such as phenyl, biphenyl, or naphthyl. It refers to a cyclic aromatic hydrocarbon group having an aromatic ring, especially a monocyclic or bicyclic group. When containing an aromatic ring (such as a bicyclic ring), the aromatic ring of the aryl group may be linked at a single point (e.g., , biphenyl) or condensed (e.g., naphthyl, phenanthrenyl, etc.). The term "synthetic aromatic ring" refers to two adjacent aromatic rings that have two carbon atoms in common. "Substituted aryl" refers to a molecular structure having an aromatic ring with at least one of the following rings at any available point of attachment: an aryl group substituted with one or more substituents, preferably 1 to 3 substituents; Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, In the case of a compound, a group such as a CF3 group or an alkyl group having CCl3 is formed), cyano , nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl , cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N R b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b Rc , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(= O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a Each occurrence of is independently hydrogen , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cyclo alkyl, heterocyclic, aryl, or the R b and R c These are combined to form together with the N optionally form a heterocyclic ring; R e each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl Exemplary substituents may themselves be optionally substituted. Exemplary substituents include: , a fused cyclic group, in particular a fused cycloalkyl, a fused cycloalkenyl, a fused heterocycle, or a fused and the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic and aryl groups. The substituent itself may be optionally substituted.

[0127] 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. , refers to aryl and heteroaryl groups linked by a single bond. In the form, the number of ring atoms in the heteroaryl and / or aryl rings is used to indicate the substituents. Specify the size of the aryl or heteroaryl ring. For example, 5,6-heteroaryl Hetero-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be specified as well.

[0128] The term "carbocycle" or "carbon cycle" refers to a ring of 1 to 4 carbon atoms. Fully saturated or partially saturated cyclic hydrocarbons containing 3 to 8 carbon atoms per ring group, or a ring having 1 to 5 aromatic rings, such as phenyl, biphenyl or naphthyl The term "carbocycle" refers to a cyclic aromatic hydrocarbon group, especially a monocyclic or bicyclic group. and cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined in The term "substituted carbocycle" refers to a ring that is substituted with one or more substituents at any available point of attachment. It refers to a carbocyclic ring or carbocyclic group substituted with a substituent, preferably 1 to 4 substituents. Suitable substituents include, but are not limited to, substituted cycloalkyl, substituted cycloalkenyl ...alkenyl, substituted cycloalkenyl, substituted cycloalkenyl, substituted cycloalkenyl, Exemplary substituted cycloalkynyl and substituted aryl include those described above. Suitable substituents include spiro- or fused ring substituents at any available point of attachment, particularly spiro- or fused ring substituents. spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (heteroaryl) cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl The above cycloalkyl, cycloalkenyl, heterocyclic and aryl substituents themselves are also included. The body may be optionally substituted.

[0129] The terms "heterocycle" and "heterocyclic" refer to a ring containing at least one carbon atom. including aromatic (i.e., "heteroaryl") groups having at least one heteroatom; Fully saturated, or partially or fully unsaturated cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered Each ring of a heterocyclic group is independently saturated or Each ring of a heterocyclic group containing a heteroatom may be partially or fully unsaturated. 1, 2, 3 or 4 hetero atoms selected from the group consisting of atoms, oxygen atoms and sulfur atoms atoms, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen The heteroatoms may optionally be quaternized. (The term "heteroarylium" refers to refers to a heteroaryl group that has a quaternary nitrogen atom and therefore a positive charge.) Heterocyclic groups are The ring may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetyl, and the like. nyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl , oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazo thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuran aryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepine pinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyra nyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholin 1,3-dioxolane and tetrahydro-1,1-dioxothienyl Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindo aryl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]ol Quinuclidinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzo Pyranyl, indolizinyl, benzofuryl, benzofurazanyl, dihydrobenzo[d]o Xazol, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl , indazolyl, pyrrolopyridyl, furopyridinyl (furo[2,3-c]pyridinyl, furo[2,3-c]pyridinyl, bi[3,2-b]pyridinyl or furo[2,3-b]pyridinyl, etc.), dihydroiso Indolyl, dihydroquinazolinyl (3,4-dihydro-4-oxoquinazolinyl, etc.) , triazinylazepinyl, tetrahydroquinolinyl, and the like. The monocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthrolyl, Examples include anthridinyl, xanthenyl, and the like.

[0130] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") are used interchangeably. substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents; refers to a heterocycle or heterocyclic group. Exemplary substituents include, but are not limited to, the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents) halo substituents, in the latter case groups such as alkyl groups bearing CF3 or CCl3 groups; (forming ═O), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cyclohexyl alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)NR 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 ) ORe , 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 (In the formula, R a each occurrence independently represents hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e Each output The present invention is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, (Heterocycle, or aryl). The exemplary substituents may themselves be optionally substituted. Exemplary substituents include spiro-bonded or fused ring substituents at any available point of attachment. , especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (heterocycle fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or The above-mentioned cycloalkyl, cycloalkenyl, heterocycle and aryl also include fused aryl. The alkyl substituent may itself be optionally substituted.

[0131] The term "oxo" refers to a ring that may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring.

[0132] [ka] The oxo substituent refers to a carbon atom on an aromatic group, e.g., an aryl or heteroaryl. When attached to a ring atom, the bonds on the aromatic ring may be rearranged to satisfy valence requirements For example, pyridines with a 2-oxo substituent are

[0133] [ka] may have the structure

[0134] [ka] Also included are the tautomeric forms thereof:

[0135] The term "alkylamino" refers to a group having the structure -NHR', where R' is as defined herein. hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl; Examples of alkylamino groups include, but are not limited to, methyl Amino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino amino, n-butylamino, tert-butylamino, neopentylamino, n-pentyl amino, hexylamino, cyclohexylamino, and the like.

[0136] The term "dialkylamino" refers to the structure -NRR', where R and R' are each independently, alkyl or substituted alkyl, cycloalkyl or substituted alkyl as defined herein; substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic. R and R' are diaryl The alkylamino moieties may be the same or different. Examples of dialkylamino groups include Examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methyl di(n-propyl)amino, di(isopropyl)amino, di(isopropyl)amino di(chloropropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di( Neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclo In certain embodiments, R and R' are linked to form A cyclic structure is formed. The resulting cyclic structure may be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolidinyl, Piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-triazinolyl and and tetrazolyl.

[0137] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0138] The term "substituted" refers to a molecule, molecular moiety, or substituent (e.g., a group disclosed herein). alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or is an aryl group or any other group) at any available point of attachment, if valence allows, Refers to embodiments substituted with one or more substituents, preferably 1 to 6 substituents Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case (those that form a group such as an alkyl group with a CF3 group or CCl3), cyano, nitrite b, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O) R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C( =O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P (=O)2NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a Each occurrence independently represents hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, R is aryl, alkynyl, heterocyclic, or aryl; b , Rc and R d Each occurrence of is independent is hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b Oh BiR c optionally form a heterocyclic ring together with the N to which they are attached; R e of Each occurrence independently represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl In the above exemplary substituents, alkyl, cyclo, or aryl are Groups such as alkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl The term "optionally substituted" refers to a molecule , a molecular moiety or substituent (e.g., alkyl, cycloalkyl, alkylaromatic alkyl ... alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl group or any other group) may be unsubstituted or substituted with one or more of the substituents described above. Refers to an embodiment.

[0139] Unless otherwise indicated, any heteroatom with unsatisfied valences is The compound has enough hydrogen atoms to satisfy the following:

[0140] The compounds of the present invention may form salts, and these salts are also within the scope of the present invention. Reference to the compounds of the present invention is understood to include reference to salts thereof unless otherwise indicated. As used herein, the term "salt" refers to a compound formed from inorganic and / or organic acids and bases. The acid and / or base salts formed are also shown. a basic moiety such as, but not limited to, pyridine or imidazole and a and acidic moieties such as carboxylic acids, zwitterions ("inner salts") are formed. and are included in the term "salts" as used herein. Although non-toxic, physiologically acceptable salts are preferred, other salts may also be used, e.g., in the preparation of Salts of the compounds of the invention are useful in isolation or purification steps that may be employed. The compounds described herein may be added in a medium such as a medium in which the salt precipitates or in an aqueous medium, for example, The compound is formed by reacting the compound with a suitable amount of acid or base, followed by freeze-drying. obtain.

[0141] Basic moieties such as, but not limited to, amines or pyridine or imidazole rings The compounds of the present invention, which contain a moiety, can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetate salts (with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid). (such as those formed together), adipates, alginates, ascorbates, asparagus Glycates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, and citrates Salt, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate Salt, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerol Phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodide phosphates, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates) , lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2- Naphthalenesulfonates), nicotinates, nitrates, oxalates, pectates, persulfates salts, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates Phosphate, pivalate, propionate, salicylate, succinate, sulfate (with sulfuric acid) (e.g., formed by the addition of thiocyanates, sulfonates, tartrates, thiocyanates, tosylates) toluenesulfonates, undecanoates, etc.

[0142] The present invention also provides a method for preparing phenolic or carboxylic acid-containing amines containing an acidic moiety, such as, but not limited to, a phenol or carboxylic acid. The compounds of formula (I) can form salts with a variety of organic and inorganic bases. Exemplary bases The reactive salts include ammonium salts, alkali metal salts (e.g., sodium salts, lithium salts, and potassium salts). salts), alkaline earth metal salts (e.g., calcium and magnesium salts), organic salts groups (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (formed by N,N-bis(dehydroabietyl)ethylenediamine), N-methyl N-methyl-D-glucamine, N-methyl-D-glycamide, salts with t-butylamine, and The basic nitrogen-containing group includes a salt with an amino acid such as arginine or lysine. Alkyl chlorides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides) dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates); Long chain halides (e.g., decyl chloride, bromide, and iodide, lauryl, myristyl, and and stearyl), aralkyl halides (e.g., benzyl bromide and phenethyl), etc. It can be quaternized with the agent

[0143] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as used herein refers to a compound that, when administered to a subject, undergoes metabolic or chemical processing. and the like, which undergo a chemical transformation to provide a compound of the invention, or a salt and / or solvate thereof. The solvates of the compounds of the present invention include, for example, hydrates.

[0144] The compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric forms (e.g., amines, methylsulfonates ... All such tautomeric forms are within the scope of the present invention. As used herein, any depiction of a compound is contemplated herein as part of the description. The structures shown also include their tautomeric forms.

[0145] All stereoisomers of the compounds, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbon atoms on various substituents) are contemplated within the scope of the present invention. The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers. or (e.g., as a pure or substantially pure optical isomer having a particular activity). ), e.g., as a racemate, or any other stereoisomer or other selected stereoisomer. The chiral centers of the present invention may be mixed with chiral isomers as defined by the International Union of Pure and Applied Chemistry (IUPA) C) It may have the S or R configuration as defined by the 1974 Recommendation. Racemic forms may be, e.g. For example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or chiral column chromatography. The individual light beams can be separated by physical methods such as chromatographic separation. Optical isomers can be obtained by, but not limited to, salt formation with an optically active acid followed by crystallization. It may be obtained from the racemate by any suitable method, including conventional methods.

[0146] After preparation, the compound of the present invention is preferably 90% by weight or more, for example 95% by weight or more, To obtain a composition containing 99% or more by weight of a compound (a "substantially pure" compound), The compound may be isolated and purified to form a complex, which may then be used or formulated as described herein. Such "substantially pure" compounds of the invention are also contemplated herein as part of the present invention. do.

[0147] All configurational variations of the compounds of the present invention, in admixture or in pure or substantially pure form. The definition of the compounds of this invention includes both cis (Z) alkene isomers and trans (E ) both alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings. It includes both isomers.

[0148] Throughout this specification, groups and their substituents are defined to provide stable moieties and compounds. It can be selected as follows.

[0149] Definitions of specific functional groups and chemical terms are described in more detail herein. For the purposes of this document, chemical elements are listed in the Periodic Table of the Elements (CAS v rsion, Handbook of Chemistry and Physics, 75th Edition, inside cover, identified according to Functional groups are generally defined as described therein. The rules, as well as specific functional moieties and reactivities, are described in "Organic Chemistry," by Thomas Sorrell. ell, University Science Books, Sausalito (1999), the entire contents of which are available at: It is incorporated herein by reference.

[0150] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention relates to cis and trans isomers, R- and S-enantiomers, diastereoisomers, (D)-isomer, (L)-isomer, racemic mixtures thereof, and other isomers thereof. All such compounds, including mixtures, are contemplated as being within the scope of the present invention. Asymmetric carbon atoms may be present in a substituent such as an alkyl group. Both the compounds and mixtures thereof are intended to be included in the present invention.

[0151] Isomeric mixtures containing any of a variety of isomeric ratios may be utilized in accordance with the present invention. For example, when combining only two isomers, 50:50, 60:40, 70:30, 80: :20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 10 All mixtures containing a 0:0 isomer ratio are contemplated by the present invention. It will be readily understood that similar ratios are contemplated for more complex isomeric mixtures.

[0152] The present invention also relates to compounds identical to those disclosed herein, except that one or more atoms are , atoms having atomic masses or mass numbers different from those normally found in nature The present invention also includes isotopically labeled compounds in which the compound is replaced by an isotopically labeled atom. Examples of isotopes that can be incorporated into objects include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, Isotopes of fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 1 5 N, 18 O. 17 O.31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl Compounds of the invention or compounds thereof that contain the aforementioned isotopes and / or other isotopes of other atoms may also be used. may also be an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. Certain isotopically labeled compounds of the present invention, e.g., , 3 H and 14 Those incorporating radioactive isotopes such as C are drugs and / or Useful in substrate tissue distribution assays. Tritiated isotopes, i.e. 3 H, and Carbon-14 isotope, i.e. 14 C is particularly preferred due to its ease of preparation and detectability. Furthermore, deuterium, i.e. 2 Substitution with heavy isotopes such as H leads to greater metabolic stability. Certain therapeutic benefits resulting from the use of steroids, such as increased in vivo half-life or reduced dosage requirements, Isotopic labeling can result in reduced demand and may therefore be preferred in some situations. Compounds generally allow for the substitution of non-isotopically labeled reagents with readily available isotopically labeled reagents. and by carrying out the procedures disclosed in the following schemes and / or examples. It can be manufactured.

[0153] For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis: Alternatively, it can be prepared by induction with an asymmetric auxiliary, where the resulting diastereoisomers Separation of the omeric mixture and cleavage of the auxiliary group to give the pure desired enantiomer; or 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 appropriate optically active acids or bases, and subsequently the methods of the art are known. The diatomaceous matter thus formed can be isolated by fractional crystallization or chromatographic means well known in the art. The stereomers are separated and the pure enantiomers are then recovered.

[0154] The compounds described herein may be substituted with any number of substituents or functional moieties. It will be understood that the term "substituted" generally refers to the term "optionally." The specified group may be used whether or not it is preceded by a , and whether or not the substituent is included in the formula of the present invention. refers to the replacement of a hydrogen radical in a given structure by the radical of a substituent that is present. When more than one position can be substituted with more than one substituent selected from the specified group, Substituents may be the same or different at all positions. The term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched substituents of organic compounds. Included are branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents. For purposes of this invention, heteroatoms such as nitrogen are used herein to satisfy the valence of the heteroatom. The organic compounds described herein may have hydrogen substituents and / or any permissible substituents. Furthermore, this invention is not limited in any manner by the permissible substituents of organic compounds. The combination of substituents and variables envisioned by the present invention is not intended to be limiting. The combination preferably results in the formation of a stable compound useful, for example, in the treatment of a proliferative disorder. The term "stable" as used herein preferably means a compound that allows for production. and for a period of time sufficient to be detected, preferably for the purposes detailed herein. refers to a compound that maintains its integrity for a period of time sufficient to be useful for its purpose.

[0155] As used herein, the terms "cancer," and equivalently, "tumor," refer to a host-originated tumor. Cancer refers to a condition in which abnormally replicating cells of a certain origin are present in a subject in detectable amounts. It can be a malignant or non-malignant cancer. Cancers or tumors include, but are not limited to, biliary tract cancers. Brain cancer; Breast cancer; Cervical cancer; Choriocarcinoma; Colon cancer; Endometrial cancer; Esophageal cancer; Gastric (ga stric) (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer ( melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. Cancers can be primary or metastatic. Other diseases may be associated with mutational changes in components of the Ras signaling pathway, The compounds disclosed herein can be used to treat these non-cancer diseases. Non-cancerous diseases such as neurofibromatosis, Leopard syndrome, Noonan syndrome, and Legius syndrome Costello syndrome; Cardio-facial-cutaneous syndrome; Hereditary gingival fibromatosis type 1; Autoimmune phosphodiesterase may include capillary malformations; and capillary malformations - cerebral arteriovenous malformations.

[0156] As used herein, an "effective amount" is the amount needed to achieve or promote a desired outcome. or any amount sufficient. In some instances, an effective amount is a therapeutically effective amount. , any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application will depend on the disease or condition being treated, the dosage being administered, Varies depending on factors such as the specific drug, subject size, or severity of the disease or condition Those skilled in the art can empirically determine the effective amount of a particular agent without undue experimentation. It is possible.

[0157] As used herein, the term "subject" refers to a vertebrate animal. In one embodiment, In one embodiment, the subject is a mammal or mammalian species. In another embodiment, the subject is a human. In embodiments, the subject may be, but is not limited to, a non-human primate, a laboratory animal, a livestock animal, a racehorse, a domestic animal, or a domesticated animal. Non-human vertebrates, including animals and non-domestic animals.

[0158] compound Novel compounds are described as Kv1.3 potassium channel blockers. Surprisingly, 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 the Kv1.3 potassium channel and does not block the hERG channel. Therefore, it has been found to have a favorable cardiovascular safety profile.

[0159] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof

[0160] [ka] (In the formula, Z is OR a , N.R. a R b , or NR b (C=O)R a and; X1 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, cyclo alkenyl, or halogenated cycloalkyl; X2 is H, halogen, CN, alkyl, alkyl halide, cycloalkyl, or is a cycloalkyl halide; X3 is H, halogen, fluoroalkyl, or alkyl; Alternatively, X1 and X2 and the carbon atoms to which they are attached together may optionally forming an optionally substituted 6-membered aryl; or X2 and X3 and the carbon atoms to which they are attached together may optionally forming an optionally substituted 6-membered aryl; R3 is H, halogen, or alkyl; Alternatively, X1 and R3 and the carbon atoms to which they are attached together may optionally be forming an optionally substituted 6-membered aryl; R1 and R2 are each independently H, alkyl, (CR6R7) n4 OR a , (CR 6R7) n4 NR a R b , (CR6R7) n4 NR a (C=O)R b , (CR6R7) n 4NR a SO2R b , or (CR6R7) n4 CONR a R b or R1, R2 and the carbon atoms to which they are attached together form a 3- to 5-membered carbocyclic ring; R4 is H, alkyl, halogenated alkyl, optionally substituted cycloalkyl, ( CR6R7) n4 OR c , (CR6R7) n4 (C=O)R c, (C=O)(CR6R7 ) n4 R c , (CR6R7) n4 COOR c , (CR6R7) n4 NR c (C=O)R d , (CR6R7) n4 (C=O)NR c R d , (C=O)(CR6R7) n4 NR c R d , (CR6R7) n4 (C=O)(C=O)NR c R d , (C=O)(CR6R7) n4 OR c , (CR6R7) n4 SO2R c , (CR6R7) n4 SO2NR c R d , optional optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heterocycle aryl, optionally substituted alkyl-aryl, optionally substituted alkyl -heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted aralkyl alkyl-cycloalkyl, or optionally substituted cycloalkyl-alkyl; each occurrence of R5 is independently H, alkyl, cycloalkyl, or oxo; Alternatively, two R5 groups, together with the carbon atoms to which they are attached, form a 3- to 7-membered forming an optionally substituted saturated carbocyclic ring; Alternatively, the two R5 groups are attached to different carbon atoms on the ring and together form a bond. or forming an alkyl chain containing 1 to 3 carbons; each occurrence of R6 and R7 is independently H, alkyl, or cycloalkyl; Ra and R b Each occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl aryl, or heteroaryl; or R a and R b are combined together with the nitrogen atom, a nitrogen atom and a group selected from the group consisting of N, O and S. forming an optionally substituted heterocycle containing 0 to 3 additional heteroatoms selected from the group consisting of: R c and R d each occurrence of is independently H, alkyl, each of which is independently halogen, OR 8 or N(R8)2, alkyl, alkenyl, or aryl substituted by 1 to 4 substituents. optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl -aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted alkyl- or R is a substituted cycloalkyl-alkyl; c and R d These are combined together with the nitrogen atom present, a nitrogen atom and a group consisting of N, O and S, respectively and forming an optionally substituted heterocycle containing 0 to 3 additional heteroatoms selected from ; Each occurrence of R8 is independently H, alkyl, or an optionally substituted heterocycle; Or two R8 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 including R9 is H, alkyl, halogen, or (CR6R7) n4 OR a and; Alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl, where valence permits, may be alkyl, cycloalkyl, halogenated cycloalkyl, or heteroaryl. Chloroalkyl, alkyl halide, halogen, CN, -(CH2) 0~2 OR8, N( R8)2, (C=O)C 1~4 alkyl, (C=O)N(R8)2, and oxo and optionally substituted with 1 to 4 substituents each independently selected from the group ; each occurrence of n1 is independently, where valence allows, an integer from 0 to 3; each occurrence of n2 and n3 is independently an integer from 0 to 2; each occurrence of n4 is independently an integer from 0 to 3) is described.

[0161] In some embodiments, each occurrence of n2 and n3 is independently an integer from 0 to 2. In one embodiment, n2 and n3 are each 0. In another embodiment, n2 and n3 are each 0. In yet another embodiment, n2 and n3 are each 2. In some embodiments, n2 and n3 are 0 and 1, respectively. In some embodiments, n2 and n3 are 0 and 2, respectively. n3 is 1 and 2, respectively.

[0162] In some embodiments, the structural motif

[0163] [ka] but,

[0164] [ka] wherein the various substituents are defined herein. In some embodiments, the structural motif

[0165] [ka] but,

[0166] [ka] wherein the various substituents are defined herein. In some embodiments, the structural motif

[0167] [ka] but,

[0168] [ka] wherein the various substituents are defined herein. It has the following structure.

[0169] In any one of the embodiments described herein, R a and R b Each occurrence of is independent and H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. In some embodiments, R a and R b At least one of the groups independently represents H, alkyl, or cycloalkyl. In other embodiments, R a and R b At least one of In other embodiments, Ra oh Yobi R b together with the nitrogen atom to which they are attached, form the nitrogen atom, and each Optionally, the heteroatoms may include 0 to 3 additional heteroatoms selected from the group consisting of N, O, and S. to form a heterocycle substituted with

[0170] In some embodiments, R1 and R2 are each H or alkyl. In some embodiments, R1 and R2 are both H. In some embodiments, at least one of R1 and R2 is At least one of Me, Et, propyl, isopropyl, n-butyl, isobutyl or In some embodiments, R and R are each alkyl, such as sec-butyl. and H and alkyl.

[0171] In some embodiments, at least one occurrence of R1 and R2 is (CR6R7) n4 O R a or (CR6R7) n4 NR a R b In some embodiments, R1 and R2 At least one occurrence of (CR6R7) 0~2 NR a R b NR a R b Non-limiting Typical examples are NH2, NHMe, NMe2, NHEt, NMeEt, NEt2, NH Pr, NMePr, NEtPr, NH(iso-Pr), and N(iso-Pr)2. In some embodiments, at least one occurrence of R1 and R2 is (CR6R7) 0~2 OR a OR a Non-limiting examples include OH, OMe, OEt, OPr, These include O-iso-Pr, OBu, O-tert-Bu, and O-sec-Bu. In some embodiments, at least one occurrence of R1 and R2 is OR. a or NR a R b is.

[0172] In some embodiments, at least one occurrence of R1 and R2 is (CR6R7) 0~2 NR a (C=O)R b , (CR6R7) n4 NR a SO2R b , or (CR6R7)0 ~2 CONR a R b NR a (C=O)R b Non-limiting examples include NH(C= O)Me, NMe(C=O)Me, NH(C=O)Et, NMe(C=O)Et, NEt (C=O)Et, NH(C=O)Pr, NMe(C=O)Pr, NEt(C=O)Pr, NH(C=O)(iso-Pr), NMe(C=O)(iso-Pr), and NEt(C= O) (iso-Pr). a R b Non-limiting examples include (C=O) NH2, (C=O)NHMe, (C=O)NMe2, (C=O)NHEt, (C=O)N MeEt, (C=O)NEt2, (C=O)NHPr, (C=O)NMePr, (C=O )NEtPr, (C=O)NH(iso-Pr), and (C=O)N(iso-Pr) Examples include:

[0173] In other embodiments, R1, R2, and the carbon atoms to which they are attached together represent In some specific embodiments, R1, R2, and these form a 3- to 5-membered carbocyclic ring. The carbon atoms to which they are attached together form cyclopropyl, cyclobutyl, or cyclopentyl. Form pentyl.

[0174] In some embodiments, R and R are each independently H, Me, OH, CHOH , NH2, NHMe, NMe2, CH2NH2, CONH2, CONHMe2, CONM e2, NH(C=O)Me, NMe(C=O)Me,

[0175] [ka] is.

[0176] In some embodiments, R4 is H, alkyl, halogenated alkyl, or cycloalkyl. In some specific embodiments, R4 is H, Me, CF3, or ethyl fluoride. is.

[0177] In other embodiments, R4 is (CR6R7) n4 OR c , (CR6R7) n4 COR c , (C=O)(CR6R7) n4 R c , (CR6R7) n4 COOR c , (CR6R7) n 4NR c (C=O)R d , (CR6R7) n4 (C=O)NR c R d , (C=O)(CR 6R7) n4 NR c R d , (CR6R7) n4 (C=O)(C=O)NR c R d , (C= O)(CR6R7) n4 OR c , (CR6R7) n4 SO2R c , or (CR6R7) n4 SO2NR c R d In some specific embodiments, n4 is 0. In typical embodiments, n4 is 1 or 2. In some specific embodiments, R4 is (C R6R7)2OR c , (C=O)R c , (C=O)(CR6R7) 1~2 R c , COOR c , (CR6R7) 1~2 NR c (C=O)R d , (C=O)NR c R d , (CR6R7 ) n4 (C=O)(C=O)NR c R d , (C=O)(CR6R7) 1~2 OR c , SO 2nd Round c , or SO2NR c R d In some specific embodiments, CR6R7 is C H2, CHMe, CMe2, CHEt, or CEt2. In this case, R4 is (CH2)2OH, (CH2)2OMe, (C=O)H, (C=O)Me, (C=O)CH2OH, (C=O)CH2OMe, (C=O)CH(OH)CH2OH, (C=O)CH(OMe)CH2OH, (C=O)CH(OH)CH2OMe, (C=O )Et, (C=O)Ph, (C=O)isopropyl, (C=O)NH2, (C=O)NH Me, (C=O)NMe2, (C=O)CH2NH2, (C=O)CH2NHMe, (C =O)(C=O)NMe2, (C=O)OMe, SO2Me, SO2Et, SO2CH2 OH, SO2CH2OMe, SO2NH2, SO2NHMe, or SO2NMe2 In other embodiments, R4 is (C=O)CH(OH)CH2OH, (C=O)CH(O Me)CHOH, or (C=O)CH(OH)CHOMe.

[0178] In other embodiments, R4 is (C=O)R c , (C=O)(CR6R7) 1~2 R c , ( C=O)(CR6R7) 1~2 OR c , or SO2R c and;R c is H, alkyl, 1 to 4 independently selected from the group consisting of halogen, OR8, and N(R8)2 alkyl, alkenyl, optionally substituted cycloal ... alkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, Optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-aryl, optionally substituted alkyl-aryl alkyl-heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, and optionally substituted cycloalkyl-alkyl is selected from the group consisting of:

[0179] In some embodiments, R c or R d H, Me, Et,

[0180] [ka] is.

[0181] In some embodiments, R c but

[0182] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0183] In some embodiments, R c However, when valence allows, alkyl, halogen, CN, -(C H2) 0~2 The group consisting of OR8, N(R8)2, (C=O)N(R8)2, and oxo each optionally substituted with 1 to 4 substituents independently selected from In other embodiments, the alkyl group is a cycloalkyl, a spiroalkyl, or a bicycloalkyl. R c However, when valence allows, alkyl, halogen, CN, -(CH2) 0~2 OR8, N (R8)2, (C=O)N(R8)2, and oxo; each optionally substituted by 1 to 4 substituents

[0184] [ka] is.

[0185] In still other embodiments, R4 is an optionally substituted saturated heterocycle, an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl- Aryl, optionally substituted alkyl-heteroaryl, optionally substituted aralkyl alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted In some specific embodiments, R4 is a cycloalkyl-alkyl group.

[0186] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0187] In still other embodiments, R4 is, where valences permit, alkyl, halogen, CN, - (CH2) 0~2 OR8, N(R8)2, (C=O)N(R8)2, and oxo Cyclic groups optionally substituted with 1 to 4 substituents each independently selected from the group consisting of In other embodiments, R4 is alkyl, halogen, when valence allows. , CN, -(CH2) 0~2 OR8, N(R8)2, (C=O)N(R8)2, and O and optionally substituted by 1 to 4 substituents independently selected from the group consisting of chloro, chloro, chloro, chloro, chloro, chloro; replaced with the

[0188] [ka] is.

[0189] In some embodiments, R8 is H or alkyl. In other embodiments, R8 is any In yet another embodiment, two R groups are bonded together to form a heterocycle. Together with the nitrogen atom to which it is bonded, it consists of a nitrogen atom and N, O and S, respectively. and optionally substituted heterocyclic rings containing 0 to 3 additional heteroatoms selected from the group Complete.

[0190] In some specific embodiments, R4 is

[0191] [ka]

[0192] [ka] or a tautomer thereof.

[0193] In some embodiments, R5 is H, alkyl, or cycloalkyl. In certain embodiments, R5 is H. In other specific embodiments, R5 is Me, Et, Pr , iso-Pr, Bu, iso-Bu, sec-Bu, or tert-Bu. In specific embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclopropyl. In another specific embodiment, R5 is oxo.

[0194] In other embodiments, two R5 groups, together with the carbon atoms to which they are attached, form: In yet another embodiment, two The R5 groups are attached to different carbon atoms on the ring and together form a bond or 1 to 3 Forming alkyl chains containing carbon.

[0195] In some embodiments, each occurrence of R6 and R7 is independently H or alkyl. In some specific embodiments, CR6R7 is CH2, CHMe, CMe2, CHEt, or is CEt2. In some specific embodiments, CR6R7 is CH2.

[0196] In some embodiments, R9 is H, alkyl, or halogen. , R9 is (CR6R7) n4 OR b In some specific embodiments, R9 is H, F , or OH.

[0197] In any one of the embodiments described herein, Z is OR a , N.R. a R b ,or NR b (C=O)R a In some embodiments, Z can be OH, OMe, NH, N HMe, or NMe2. In some embodiments, Z is OH.

[0198] In any one of the embodiments described herein, X1 is H, halogen, fluoride, or In some embodiments, X1 can be cycloalkyl or alkyl. In some embodiments, X is H, F, Cl, Br, Me, CF, or CF2Cl. In some embodiments, X1 is H, F, or Cl. In this embodiment, X1 is Me or Cl.

[0199] In any one of the embodiments described herein, X2 is H, halogen, fluoride, or In some embodiments, X2 can be H, F, Cl, Br, Me , CF, or CFCl. In some embodiments, X is Cl or Br. In some embodiments, X2 is Cl.

[0200] In any one of the embodiments described herein, X3 is H, F, Cl, Br, fluorine In some embodiments, X3 is H, F, Cl, or alkyl. It is CF3.

[0201] In some embodiments, the structural moiety

[0202] [ka] each of which is substituted by R3;

[0203] [ka] It has the following structure.

[0204] In some embodiments, the compound of formula I has the structure of formula II.

[0205] [ka] (wherein n6 is an integer of 0 to 2; R 3’ Each occurrence of is independently H, halogen, or a alkyl; other substituents are as defined herein. In some embodiments, R 3’ At least one occurrence of is H or alkyl Non-limiting examples of alkyl include Me, Et, propyl, isopropyl, n-butyl In other embodiments, R 3’ Few At least one occurrence is halogen. In some embodiments, n6 is 0. In some embodiments, n6 is 1. In some embodiments, n6 is 2.

[0206] In any one of the embodiments described herein, R3 is H, halogen, or alkoxy. In some embodiments, R3 is H. In other embodiments, R3 is Me, E t-, propyl, isopropyl, n-butyl, iso-butyl or sec-butyl In yet other embodiments, R3 is F, Cl, or Br.

[0207] In any one of the embodiments described herein, at least one occurrence of R8 is H , alkyl, or an optionally substituted heterocycle. , Me, Et, Pr, Bu, or

[0208] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0209] In another embodiment, the two R8 groups, together with the nitrogen atom to which they are attached, form: a nitrogen atom and 0 to 3 additional atoms each selected from the group consisting of N, O, and S; Forms an optionally substituted heterocycle containing a heteroatom.

[0210] In some embodiments, n1 is 0, 1, 2, or 3. In some embodiments, n1 is 0 or 1. In some embodiments, n4 is 0, 1, or 2. In some embodiments, n4 is 0 or 1. In some specific embodiments, n4 is 0 or 1. be.

[0211] In any one of the embodiments described herein, R c or R d At least one of are independently selected from H, alkyl, halogen, OR and N(R) Alkyl or alkenyl substituted with 1 to 4 substituents selected from the group consisting of , optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl- Aryl, optionally substituted alkyl-heteroaryl, optionally substituted aralkyl alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted It is a cycloalkyl-alkyl.

[0212] In some embodiments, R c and R d However, together with the nitrogen atom to which they are bonded, and a nitrogen atom and 0 to 3 additional atoms selected from the group consisting of N, O, and S. The heterocyclic ring may be an optionally substituted heterocyclic ring containing an additional heteroatom.

[0213] In some specific embodiments, R c or R d at least one occurrence of independently H, Me, Et,

[0214] [ka] is.

[0215] In some specific embodiments, R c or R dAt least one occurrence of independently

[0216] [ka] and the heterocycle, when valence permits, is selected from the group consisting of: Cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C 1~4 optionally substituted with alkyl .

[0217] In some specific embodiments, R c or R d At least one occurrence of If valence allows, alkyl, halogen, CN, -(CH2) 0~2 OR8, N(R8)2 , (C=O)N(R8)2, and oxo; cycloalkyl, spiroalkyl, each optionally substituted by four substituents; Or bicycloalkyl.

[0218] In some specific embodiments, R c or R d At least one occurrence of If valence allows, alkyl, halogen, CN, -(CH2) 0~2 OR8, N(R8)2 , (C=O)N(R8)2, and oxo; each optionally substituted with four substituents

[0219] [ka] is.

[0220] In some embodiments, the compound of Formula I consists of compounds 1-338 shown in Table 1 below. is selected from the group.

[0221] [Table 1-1]

[0222] [Table 1-2]

[0223] Preparation method Below are general synthetic schemes for preparing compounds of the present invention. The schemes are exemplary and may be used by one of skill in the art to prepare the compounds disclosed herein. It is not intended to limit the techniques that can be used to obtain this. Different methods will be apparent to those skilled in the art. Additionally, the various steps of the synthesis may be performed in an alternate sequence or order to give the desired compounds. The following reactions are illustrative of the preparation of some of the starting materials and compounds disclosed herein. These are examples of products, but are not limiting.

[0224] Schemes 1-9 below illustrate the synthesis of compounds of the present invention, such as compounds having the structure of Formula I or The present invention provides a method for the preparation of a compound of formula (I) of the present invention. Various modifications of these methods to achieve similar results will occur to those skilled in the art. In the following embodiments, the synthetic route is, for example, to obtain compounds I-4, I-6, I-4a, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-2 -6a, I-7, I-7b, I-10, I-10a and I-13 Other compounds of Formula I can be prepared using methods similar to those described in Schemes 1-9. or by using methods known in the art. The general synthetic routes described in Schemes 1-9 and the implementations described in the Examples section below. The examples illustrate the methods used in the preparation of the compounds described herein.

[0225] Compound I-4 was prepared from compound I-1a or I-1b as shown in Scheme 1. It is possible.

[0226] [ka]

[0227] Compounds I-1a, I-1b, I-2a, I-2b and I-2c are known in the art. As shown in Scheme 1, "Br / I " refers to a Br or I substituent, and PG refers to a protecting group. Non-limiting examples of protecting groups include: Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl or any known in the art suitable for use as a protecting group for OH or NH Other protecting groups are known in the art. Other substituents are defined herein. As shown in Figure 1, the intermediate ketone I-3 can be converted to the protected phenol I- in the presence of a Lewis acid. The Friedel-Crafts reaction of 1a with the appropriately protected acid chloride I-2a A non-limiting example of a Lewis acid is aluminum chloride III. Alternatively, aryl bromide or iodide I-1b can be reacted with, for example, isopropylmagnesium. chloride (R is isopropyl) to the corresponding Grignard reagent, or converted to the corresponding aryllithium reagent by treatment with butyllithium (S Step ii) The resulting organometallic reagent reacts with the Weinreb amide I-2b to give the ketone I- The ketone I-3 is reduced using a suitable reducing agent to form alcohol I-4. (Step v). Non-limiting examples of suitable reducing agents include NaBH4. Alternatively, the aryl bromide or iodide I-1b can be reacted with, for example, isopropyl Treatment with methylmagnesium chloride (R is isopropyl) affords the corresponding or by treatment with butyllithium to the corresponding aryllithium reagent The resulting organometallic reagent reacts with aldehyde I-2c to give benzylic alkane. The benzylic alcohol I-4 is oxidized with an oxidizing agent, e.g., methyl ... It can be oxidized to the ketone I-3 using Dess-Martin periodinane. The protecting groups of compound I-4 are selectively removed to give free NH and / or phenolic OH groups. The resulting compound having the formula: can be transformed into things.

[0228] As shown in Scheme 2, compounds I-1b, I-2d, or I-3 can be converted into compounds I- 6 can be prepared.

[0229] [ka]

[0230] Compounds I-1b or I-2d can be prepared by any method known in the art. Compound I-3 can be prepared by the method shown in Scheme 1. As shown in Scheme 2, "Br / I" refers to a Br or I substituent, and PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, and other alkoxy groups. Protection for the dicarbonyl group, dialkylaminocarbonyl, or OH or NH Other protecting groups known in the art are suitable for use as the protecting group. As defined herein, as shown in Scheme 2, Step i, a compound of Formula I (wherein R is Compounds (e.g., compound I-6) having a Lewis acid (e.g., titanium) In the presence of methyl methyl ether (methyl methyl ether tetraethoxide), ketone I-3 is reacted with an alkylsulfinimide, e.g., t -butylsulfinimide (i.e., R is alkyl, such as t-butyl) The ketone I-3 can be converted to sulfinyl imine I-5 by heating. It can be obtained by using a reducing agent such as sodium borohydride or diisobutyl hydride. Reduction of sulfinyl imine I-5 with aluminum (DIBAL) affords sulfinyl imine I-5. Imide I-6 is obtained (step ii). Single enantiomers of compound I-6 can be prepared by methods known in the art. Alternatively, the compound shown in step iii can be prepared by methods known in the art. To this end, a Grignard or organolithium reagent is formed from I-1b, and the resulting Grignard or organolithium reagent is then reacted with I-1b. HCl or organolithium reagents to form sulfinyl imines I-2d (as known in the art) (prepared from I-2c in Scheme 1) to give I-6 directly. Compound I-6 can be synthesized by the following procedure. The resulting compound having free NH and / or phenolic OH groups is It can be optionally converted to a compound of formula I using methods known in the art.

[0231] As shown in Scheme 3, compounds I-1d and I-2b, I-1d and I-2c, respectively, were synthesized. and I-2c, and I-1d and I-2d to give compounds I-3a, I-4a, and I-5a. -6a can be prepared.

[0232] [ka]

[0233] Compounds I-1d, I-2b, I-2c, and I-2d can be prepared by any of the methods known in the art. As shown in Scheme 3, PG represents a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, as a protecting group for aryl, dialkylaminocarbonyl, or OH or NH Other protecting groups known in the art are suitable for use. As shown in Scheme 3, Steps i, ii, or iii, A suitably protected phenol, such as dicarbamate I-1d, was prepared as shown in Scheme 3. As shown, the Weinreb amide I was activated by lithiation ortho to the carbamate. I-2b (step i), aldehyde I-2c (step ii) or sulfinyl imine I-2d (step iii) can then be reacted with compound I-4a and The protecting groups of I-6a are selectively removed to give a compound having free NH and / or phenolic OH groups. The resulting compound is optionally converted to a compound of formula I using methods known in the art. The ketone I-3a can be converted to ketone I-3b using a suitable reducing agent (e.g., NaBH4). The resulting alcohol can then be reduced to the corresponding alcohol (not shown). The protecting groups of the phenols are selectively removed to give phenols with free NH and / or phenolic OH groups. The resulting compound is optionally converted to a compound of formula I using methods known in the art. It is possible.

[0234] As shown in Scheme 4, compound I-3 can be converted into compounds I-4, I-3″, and I- 7 can be prepared.

[0235] [ka]

[0236] Compound I-3 can be prepared by the method shown in Scheme 1. PG refers to a protecting group, as shown in Figure 4. Non-limiting examples of protecting groups include Me, aryl, Alkyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or Other protecting groups known in the art that are suitable for use as protecting groups for OH or NH2 are Other substituents are defined herein. As shown in Scheme 4, For compounds of formula I (where R1 = R2 = H) (e.g., compound I-7), the ketone I- 3 can be converted to alcohol I-4 by a reducing agent (e.g., sodium borohydride; step i). The alcohol I-4 is then reduced to or reduction with a silane such as triethylsilane in the presence of an acid such as trifluoroacetic acid to give compound I-7 (step ii). When the nitrogen protecting group is Boc, The group is removed under these conditions to give the benzyl cyclic amine I-7. For compounds of interest, ketone I-3 can be substituted with an appropriate alkyl-Grignard reagent (e.g., R1 MeBr) to give the alcohol I-3' (step iii). As shown in step iv, alcohol I-3' was prepared by the procedure used in step ii. A similar procedure was used to remove the OH group by reduction with triethylsilane to give compound I-3 (If the nitrogen protecting group is Boc, the nitrogen protecting group can be converted under these conditions to The protecting groups of compounds I-3″ and I-7 are then selectively removed to give The free phenolic OH groups of the compound are optionally converted to a compound of the formula: It can be converted into compound I.

[0237] Compound I-7b was prepared from compounds I-8 and I-9 as shown in Scheme 5. It is possible.

[0238] [ka]

[0239] Compounds I-8, I-9a and I-9 can be prepared by any method known in the art. As shown in Scheme 5, PG refers to a protecting group. Typical examples include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialky Suitable for use as a protecting group for hydroxylaminocarbonyl, or OH or NH Other protecting groups known in the art include those described herein. As shown in Scheme 5, compounds of formula I (wherein R1 = R2 = H and n2 = n3 = 1) are Another route to prepare the compound is by palladium catalysis, e.g., tetrakistriphenylphosphine. Benzyl bromide I-8 was converted to pyridineboronic acid or boronic acid esters using palladium. Reaction of the benzylpyridine I-9 (where R is H or alkyl) with (Step i) Oxidation in the presence of a reducing agent (e.g., an acid (e.g., HCl) Reduction of pyridine I-10 with hydrogen on platinum afforded benzylpiperidine I-7b. Alternatively, vinyl boronate I-9a can be prepared in a similar manner (steps iii and i). v) can be used to obtain compound I-7b. The compound I-7b can then be used in steps I and iii. The resulting compound with free NH and phenolic OH groups is then selectively removed, as described in the art. It can be optionally converted to a compound of formula I using known methods.

[0240] Compound I-7 was prepared from compounds I-1b and I-11 as shown in Scheme 6. It is possible.

[0241] [ka]

[0242] Compounds I-11 and I-1b 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: Examples include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylamino groups, Suitable protecting groups for OH or NH2 are known in the art. Other protecting groups known in the art are included. Other substituents are defined herein. As shown in Figure 6, an alternative route to compounds of formula I (where R1 = R2 = H) is to use palladium as a catalyst. Exocyclic alkenyl cyclic amines I- using a palladium catalyst (e.g., Pd(dppf)Cl2) Hydroboration of 8 and the resulting boronate with bromo- or iodophenol I-1b The protecting groups of compound I-7 are then selectively removed to give the free NH and The resulting compounds having phenolic and / or phenolic OH groups can be prepared using methods known in the art. and optionally converted to a compound of formula I.

[0243] As shown in Scheme 7, compound I-7 was also prepared from compounds I-1b and I-12. It can be manufactured.

[0244] [ka]

[0245] Compounds I-12 and I-1b can be prepared by any method known in the art. As shown in Scheme 7, PG refers to a protecting group. Non-limiting examples of protecting groups include: Examples include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylamino groups, Suitable protecting groups for OH or NH2 are known in the art. Other protecting groups known in the art are included. Other substituents are defined herein. As shown in Figure 7, an alternative route to compounds of formula I (where R1 = R2 = H) is to prepare blue LE Tristrimethylsilylsilane, iridium catalyst, and nickel catalyst under irradiation with D light combinations (e.g., Ir[dF(CF3)ppy]2(dtbbpy)PF6 and and NiCl2) to prepare bromophenols I-1b and bromomethyl cyclic amines The photoredox reaction of I-12 was then carried out. The resulting compounds having free NH and / or phenolic OH groups can be prepared by methods known in the art. The method can be used to optionally convert to a compound of formula I.

[0246] Compound I-13 was prepared from compounds I-8 and I-2d as shown in Scheme 8. It is possible.

[0247] [ka]

[0248] Compounds I-8 and I-2d can be prepared by methods known in the art. As shown in Scheme 8, PG refers to a protecting group. Non-limiting examples of protecting groups include: , Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl groups hydroxybenzoates, or OH or NH2 protecting groups. Other protecting groups known in the art are included. Other substituents are defined herein. As shown, compounds of formula I having a substituent R9 can be prepared by cleaving a compound such as sodium hexamethyldisilazide. In the presence of any base, compounds containing electron-withdrawing groups (EWGs), such as esters or nitriles, Cyclic amine I-2d was reacted with benzyl bromide I-8 to give compound I-13. Any suitable base can be used in this reaction. Compound I The ester or nitrile group (or other electron-withdrawing group) of -13 is known in the art. The desired R group can then be converted to the R group within the range defined herein by the method described above. The protecting groups of the resulting compound having the desired R group are selectively removed to give a free NH and / or The resulting compound having a phenolic OH group can be optionally cleaved using methods known in the art. Optionally, the compound can be converted to a compound of formula I.

[0249] Compounds of formula I having other R1 and R2 substituents can be prepared by, for example, reductive amination, wit The Wig reaction followed by cyclopropanation or hydroboration affords ketone I-3. or to the corresponding bromide and displacement of the bromide with a nucleophile to form an alcohol. It can be synthesized from amine I-4.

[0250] As shown in Scheme 9, compounds I-1e and I-14 can be converted to compounds of formula (I), where R 1 is NH2, n2=1 and n3=1) (e.g., compound I-16 and I-17) can be prepared.

[0251] [ka]

[0252] Compounds I-14 and I-1e can be prepared by any method known in the art. As shown in Scheme 9, phenol I-1e and pyridine aldehyde I The three-component reaction of 14 and acetamide, optionally with all three components, was carried out without the use of a solvent. This is accomplished by heating with aluminum trichloride at room temperature to give the acetamide I-15. Pyridine was reduced to piperidine I-16 by hydrogenation over platinum chloride, and the resulting product was then hydrolyzed with acid to afford the piperidine I-17. Get Min I-17.

[0253] The reactions described in Schemes 1 to 9 can be carried out in a suitable solvent. Examples include, but are not limited to, acetonitrile, methanol, ethanol, dichloromethane, Examples of suitable olefins include ethanol, DMF, THF, MTBE, and toluene. The reaction may be carried out under an inert atmosphere, for example under nitrogen or argon, or The reaction can be carried out in a sealed tube. The reaction mixture can be heated in a microwave or at elevated temperatures. Suitable high temperatures include, but are not limited to, 40, 50, 60, 80, and 90 , 100, 110, 120°C or higher or the reflux / boiling temperature of the solvent used. Alternatively, the reaction mixture can be heated to a temperature below room temperature, e.g., 0, -10, -20, -30 The mixture can be cooled in a cooling bath at -40, -50, -78, or -90 °C. Remove the solvent. or organic solvent phase and optionally NaCl, NaHCO3 or The reaction is partitioned between one or more aqueous phases containing HCl or NH4Cl. The solvent of the organic phase can be removed by evaporation under reduced pressure, and the residue can be separated by silica gel column chromatography. The resulting residue can be purified using HPLC or HPLC.

[0254] Pharmaceutical Composition The present invention also provides a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable carrier.

[0255] In yet another aspect, the present invention provides a compound selected from the group consisting of compounds of formula I described herein. and a pharmaceutically acceptable carrier or diluent. A composition is provided.

[0256] In certain embodiments, the composition is a hydrate, solvate, or pharmaceutically acceptable salt of The compositions may be administered by any suitable route, including, but not limited to, oral and parenteral. It can be administered to a subject by

[0257] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutical agent that can be administered to a bodily organ. A fluid or substance involved in carrying or transporting from one organ or part of the body to another or pharmaceutically acceptable additives such as solid fillers, diluents, excipients, solvents or encapsulating materials. Each carrier must be compatible with the other ingredients of the formulation and must be 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 not harmful to the patient. Some examples of materials that can act as carriers include lactose, glucose, and sugars such as cornstarch and potato starch; Cellulose such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate Roasted syrup and its derivatives; powdered tragacanth; malt; gelatin; talc; cocoa butter and Suppository wax and other excipients; peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oils such as corn oil and soybean oil; glycols such as butylene glycol; glycerin, sorbitol Polyols such as ethanol, mannitol and polyethylene glycol; ethyl oleate esters such as ethyl acetate and ethyl laurate; agar; magnesium hydroxide and aluminum hydroxide buffers such as ammonium; alginate; pyrogen-free water; isotonic saline; Ringer's Ethyl alcohol; phosphate buffer; and other non-toxic compatible materials used in pharmaceutical preparations The term "carrier" refers to a natural substance with which the active ingredient is combined to facilitate application. The components of a pharmaceutical composition also refer to natural or synthetic organic or inorganic components having a desired pharmaceutical effect. The compounds of the present invention can be mixed with each other and with each other in a manner such that there is no interaction which would substantially impair the activity of the compounds. It is possible.

[0258] As noted above, certain embodiments of the pharmaceutical agent may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" in this respect refers to a compound of the present invention. The term "relatively non-toxic, inorganic and organic acid addition salts" refers to the final salts of the compounds of the present invention. The purified compounds of the invention may be prepared in situ during the isolation and purification process or in their free base form. Separately reacting the compound with an appropriate organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, and sulfate. , bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, tearate, laurate, benzoate, lactate, phosphate, tosylate, citrate , maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glutamate Examples include coheptonate, lactobionate, and lauryl sulfonate. See, for example, Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19. I want to be illuminated).

[0259] Pharmaceutically acceptable salts of the compounds include salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, conventional non-toxic salts or quaternary ammonium salts of such The salts include hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates, nitrates, etc. Salts derived from inorganic acids; and acetates, butyonic acid salts, succinates, glycolates, etc. Cholate, stearate, lactate, malate, tartrate, citrate, ascorbic acid Phosphate, palmitate, maleate, hydroxymaleate, phenylacetate, glucan glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate Salt, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, Included are salts prepared from organic acids such as oxalates, isothionic salts, and the like.

[0260] In other cases, compounds of the present invention may contain one or more acidic functional groups. Therefore, it is possible to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these examples refers to a pharmaceutically acceptable salt of the compound of the present invention. It refers to relatively non-toxic inorganic and organic base addition salts. These salts also refer to the final product of the compound. The purified compound may be converted to a suitable salt in situ during isolation and purification, or in its free acid form. groups, such as hydroxides, carbonates or bicarbonates of pharmaceutically acceptable metal cations, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include Lithium, sodium, potassium, calcium, magnesium and aluminum salts Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, pipette (See, e.g., Berge et al., supra).

[0261] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polybutylene oxide copolymer, and colorants, Release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants also may be added to the composition. can exist within.

[0262] Formulations of the present invention may be administered orally, nasally, topically (including buccal and sublingually), rectally, vaginally and / or intravenously. or those suitable for parenteral administration. The formulations may conveniently be presented in unit dosage form. The single agent may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be prepared in a dosage form will vary depending upon 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 Generally, this amount is the amount of compound that produces a therapeutic effect. About 1% to about 99% of the active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 99% The range is about 30%.

[0263] Methods for preparing these formulations or compositions include incorporating a compound of the invention into a carrier and optionally Generally, the formulations include the step of combining the compounds of the present invention with one or more accessory ingredients. uniformly and intimately associating the substance with a liquid carrier, or a finely divided solid carrier, or both; The product is then, if necessary, shaped into a shape.

[0264] The formulations of the present invention suitable for oral administration each contain a predetermined amount of the compound of the present invention as an active ingredient. Contains capsules, cachets, pills, tablets, lozenges (flavor-based, usually with sucrose and acacia or tragacanth), powder, granule form, or water as a solution or suspension in an aqueous or non-aqueous liquid, or in an oil-in-water or water-in-oil form As a liquid emulsion, or as an elixir or syrup, or as a trough Agents (inert bases, e.g., gelatin and glycerin, or sucrose and acacia) The compounds of the present invention may be in the form of a liquid or liquid formulation, such as a pharmaceutical preparation, a mouthwash, or the like. It may also be administered as a bolus, electuary, or paste.

[0265] The solid dosage forms of the present invention for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.) In the case of cereals containing sodium citrate or dicalcium phosphate, the active ingredient is one or more of the following: is mixed with a plurality of pharmaceutically acceptable carriers and / or any of the following: starch Fillers such as cellulose, lactose, sucrose, glucose, mannitol and / or silicic acid Fillers or extenders; e.g., carboxymethylcellulose, alginates, gelatin, polyethylene glycol binders such as vinylpyrrolidone, sucrose and / or acacia; Any water-retaining agent; agar, calcium carbonate, potato or tapioca starch, alginate , certain silicates, sodium carbonate, and sodium starch glycolate. disintegrants; dissolution retarders such as paraffin; absorption enhancers such as quaternary ammonium compounds; e.g. , cetyl alcohol, glycerol monostearate and polyethylene oxide-poly Wetting agents such as butylene oxide copolymers; absorbing agents such as kaolin and bentonite clays Ingredients: talc, calcium stearate, magnesium stearate, solid polyethylene glycol lubricants such as alcohol, sodium lauryl sulfate, and mixtures thereof; and colorants In the case of capsules, tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions can be prepared using sugars such as lactose or milk sugar, as well as high molecular weight polyethylene glycols. Such excipients are used as fillers in soft and hard-filled gelatin capsules. It can also be used as a

[0266] A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain a binder (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 may be prepared by blending, in a suitable machine, a powder moistened with an inert liquid diluent. It can be prepared by molding a mixture of powdered compounds.

[0267] Tablets of the pharmaceutical composition of the present invention, as well as other solid dosage forms, such as sugar-coated tablets, capsules, pills, The formulations and granules may optionally be scored or coated and shelled, Prepared with, for example, enteric coatings and other coatings well known in the pharmaceutical formulation arts These can also be used in various formulations, for example, with varying ratios of hydrochloride to provide a desired release profile. hydroxybutylmethylcellulose, other polymer matrices, liposomes and / or Formulated using microspheres to provide delayed or controlled release of the active ingredient therein These can be purified, for example, by filtration through a bacteria-retaining filter or immediately after use. of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium before use. These compositions may be sterilized by incorporating sterilizing agents into the formulation. They may also contain opacifying agents to deliver the active ingredient(s) only, or preferentially, to a certain part of the gastrointestinal tract. The composition may be a composition that releases the active ingredient, optionally in a delayed manner. Examples of materials include polymeric substances and waxes. Active ingredients may also be present in appropriate If the compound is formulated as a pharmaceutical composition, it can be in micro-encapsulated form with one or more of the above-mentioned excipients.

[0268] Liquid dosage forms for oral administration of the compounds of the present invention may include pharmaceutically acceptable emulsions, matrices, or the like. These include emulsions, solutions, suspensions, syrups and elixirs. In addition to the ingredients, liquid dosage forms may contain a liquid solvent commonly used in the art, such as water or other solvents. Inert diluents such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol ethylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil) (brown oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol Solubilizers such as fatty acid esters of cholesteryl and sorbitan, and mixtures thereof; Additionally, cyclodextrins such as hydroxybutyl-β-cyclodextrins may be included. Rhodextrins can be used to solubilize the compounds.

[0269] Besides inert diluents, the oral compositions can also include wetting agents, emulsifying and suspending agents, sweetening agents, Adjuvants such as flavorings, colorings, fragrances and preservatives may also be included.

[0270] The suspensions may contain, in addition to the active compound, e.g., ethoxylated isostearyl alcohol, polyisoprene, Polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum Umium metahydroxide, bentonite, agar and tragacanth, and mixtures thereof The formulation may contain suspending agents such as

[0271] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, and the like. These include steroids, creams, lotions, gels, solutions, patches and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives which may be required. The composition may be mixed with a preservative, buffer or propellant.

[0272] Ointments, pastes, creams and gels may be formulated to treat animals in addition to the active compounds of the present invention. Natural and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives Conductors, polyethylene glycol, silicone, bentonite, silicic acid, talc and oxide The composition may contain excipients such as zinc, or mixtures thereof.

[0273] Powders and sprays may contain, in addition to the compounds of this invention, lactose, talc, silicic acid, water, Aluminum oxide, calcium silicate and polyamide powder, or a mixture of these substances Sprays may contain excipients such as chlorofluorohydrocarbons and Further containing conventional propellants such as volatile unsubstituted hydrocarbons, e.g., propane and butane It is possible.

[0274] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms are made by dissolving or dispersing the pharmaceutical agent in a suitable medium. Absorption enhancers can be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or immobilizing the compound on a polymeric substrate. This can be controlled by dispersing it in a matrix or gel.

[0275] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention. .

[0276] Pharmaceutical compositions of the present invention suitable for parenteral administration may contain one or more compounds of the present invention in an amount sufficient to provide an antioxidant. any additives, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending agents. One or more pharmaceutically acceptable sterile isotonic aqueous solutions, which may contain clouding or thickening agents. or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile injectable solutions immediately before use. It is included in combination with a sterile powder that can be reconstituted into a liquid or dispersion.

[0277] In some cases, to prolong the drug's effect, it is necessary to increase the absorption of the drug from subcutaneous or intramuscular injection. This is desirable in liquid suspensions of crystalline or amorphous material with poor water solubility. This can be achieved by using a liquid. In this case, the rate of absorption of the drug depends on its dissolution rate, which This may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may occur. Depot injection is achieved by dissolving or suspending the drug in an oily vehicle. One strategy involves the use of polyethylene oxide-based polymers, where the vehicle is fluid at room temperature but solidifies at body temperature. This includes the use of polypropylene oxide copolymers.

[0278] Injectable depot forms are formulated in biodegradable polymers such as polylactide-polyglycolide. The drug is then mixed with the polymer to form a microcapsule matrix. The rate of drug release can be controlled depending on the ratio of the polymers to the total polymer and the nature of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(non- Depot injectable formulations also include drugs delivered in liposomes or other formulations that are compatible with body tissues. or by encapsulation in a microemulsion.

[0279] When the compounds of the present invention are administered as pharmaceuticals to humans and animals, they may, as such, Or, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient It may be administered as a pharmaceutical composition containing it in combination with a pharmaceutically acceptable carrier.

[0280] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, i.e., and administering the product and pharmaceutical composition simultaneously with one or more other desired therapeutic agents or medical procedures. It can be administered before or after the treatment for use in a combination regimen. The particular combination of therapeutic agents and / or procedures will depend on the compatibility of the desired therapeutic agents and / or procedures and Consider the desired therapeutic effect to be achieved for the same disorder. It will also be appreciated that this may be achieved (e.g., when a compound of the invention is administered simultaneously with another therapeutic agent). Non-limiting examples of additional therapeutic agents include biologic and small molecule anti-cancer agents, immunomodulatory agents, and the like. , immunosuppressants, anti-inflammatory drugs, anti-arthritic drugs, corticosteroids, antidiarrheals, anticoagulants, and antithrombotic agents.

[0281] The compounds of the present invention are administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by any other acceptable route. The compounds can be used to administer to mammals (e.g., humans, livestock, and The joints of domestic animals, racehorses, birds, lizards, and any other organisms that can tolerate the compounds. It can treat inflammation conditions.

[0282] The present invention also provides one or more pharmaceutical compositions filled with one or more ingredients of the pharmaceutical compositions of the present invention. Pharmaceutical packs or kits containing a number of containers are provided. Notification in the form prescribed by a government agency regulating the use or sale of the Such containers may optionally bear a notice reflecting approval by the Agency for manufacture, use, or sale for the may be attached.

[0283] Administration to subjects In yet another aspect, the present invention provides a method for treating a condition in a mammalian species in need thereof. and a therapeutic agent selected from the group consisting of a compound of formula I or a pharmaceutically acceptable salt thereof. The method includes administering to a mammalian species an effective amount of at least one compound, wherein the condition is selected from the group consisting of cancer, Immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiac The present invention provides a method for treating a vascular disorder, wherein the vascular disorder is selected from the group consisting of a vascular disorder, and a kidney disease.

[0284] In some embodiments, the cancer is biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, Cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasia, leukemia, lymphoma, liver Cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, From the group consisting of bowel cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer be selected.

[0285] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, or periodontitis. In some embodiments, the gastroenterological disorder is a claudication disorder, or an inflammatory neuropathy. Inflammatory bowel disease, such as ulcerative colitis or cholangitis.

[0286] In some embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis). (arthritis, multiple sclerosis, systemic lupus erythematosus, or type 1 diabetes). In an embodiment, the central nervous system (CNS) disorder is Alzheimer's disease.

[0287] In some embodiments, the metabolic disorder is obesity or type II diabetes. In some embodiments, the cardiovascular disorder is ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, renal failure, or pulmonary embolism. inflammation, or chronic renal failure.

[0288] In some embodiments, the mammalian species is human.

[0289] In some embodiments, the condition is cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic leukemia, Lupus erythematosus, type 1 diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neurological conditions inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic The disease is selected from the group consisting of chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0290] In yet another embodiment, a compound capable of blocking Kv1.3 potassium channels in a mammalian species in need thereof is provided. 1. A method for treating a cancer, comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof. Methods are described that include administering an acceptable salt to a mammalian species.

[0291] In some embodiments, the compounds described herein inhibit the activity of other potassium channels. or calcium or sodium channels with minimal off-target inhibitory activity Kv1.3 potassium channel inhibitors without any inhibitory or off-target activity. In some embodiments, the compounds described herein are Does not block the hERG channel and therefore has a favorable cardiovascular safety profile .

[0292] Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a particular outcome. Thus, small molecule compositions useful according to the methods of the present invention can be prepared in any suitable form suitable for pharmaceutical use. The composition can be formulated in a method.

[0293] The formulations of the present invention may contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and the like. A pharmaceutically acceptable solution that may routinely contain the bunt, and optionally other therapeutic ingredients. It is administered in liquid form.

[0294] For therapeutic use, the compound must be capable of being taken up by the appropriate target cells. An effective amount of the compound can be administered to a subject by any suitable method. "Administering" a composition can be accomplished by any means known to those skilled in the art. Routes of administration include, but are not limited to, oral, transdermal (e.g., via a patch), and parenteral. Injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.) or mucosal (intranasal, intratracheal) Injections include bolus or continuous infusion.

[0295] For example, pharmaceutical compositions according to the present invention are often administered intravenously, intramuscularly, or by other parenteral means. They can also be administered intranasally, by inhalation, topically, orally, or by It can also be administered as an implant and can even be used rectally or vaginally. Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous solutions or physiological solutions for injection or inhalation. Saline solution, microencapsulated, encochleated coated on fine gold particles, contained in liposomes, or sprayed It may be condensed, aerosolized, or in the form of pellets for implantation in the skin or scratched onto the skin. The pharmaceutical composition may also be in the form of granules, powders, tablets, powder ... tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with extended release of the active compound, disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweetening agents or solubilizing agents Excipients and additives and / or adjuvants such as agents are conventionally used as described above. The pharmaceutical composition is suitable for use in a variety of drug delivery systems. For a brief overview of the method, see Langer R (1990) Sc, incorporated herein by reference. See ience 249:1527-33.

[0296] 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 The effective dose can range from about 100 picomoles / kg to about 100 micromoles / kg. It is thought to be in the range of

[0297] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are suitable for injection or or other parenteral vials or ampoules. Solid dosage units are tablets, capsules, or The active ingredient, the method of administration, and the dosage form are tablets, powders, and suppositories. purpose (i.e., preventive or therapeutic), the nature and severity of the disorder, the age and physical condition of the patient Depending on the weight, different doses may be required. The administration of a given dose may be in the form of individual dose units. This can be done both by single administration at 25°C or by several units of smaller doses. Repeated and multiple administration of doses at daily, weekly or monthly intervals are also contemplated by the present invention.

[0298] The composition may be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, salts should be pharmaceutically acceptable, but Conveniently use pharmaceutically unacceptable salts to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: Contains: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p- Toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid , naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts are also Alkali metal or alkali salts such as sodium, potassium or calcium salts of carboxylic acid groups They can also be prepared as alkali earth salts.

[0299] Suitable buffers include acetic acid and salts (1-2% w / v); citric acid and salts (1-3% w / v); / v); boric acid and salts (0.5-2.5% w / v); and phosphoric acid and salts (0.8 Suitable preservatives include benzalkonium chloride (0.003-0.02%). 0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01 ~0.25% w / v) and thimerosal (0.004~0.02% w / v) .

[0300] Compositions suitable for parenteral administration include sterile aqueous preparations that can be isotonic with the blood of the recipient. Among the acceptable vehicles and solvents that may be conveniently included are water, Ringer's solution, phosphate buffered saline, and the like. Buffered saline and isotonic sodium chloride solution are also available. Additionally, sterile, fixed oils are often used as solvents. For this purpose, synthetic mono- or diglycerides have traditionally been used as suspending media. Any non-irritating, non-volatile mineral or non-mineral oil may be used, including oleic acid. Fatty acids, such as carboxylic acids, have found use in the preparation of injectables. Suitable carrier formulations for intravenous administration, etc., are available from Remington's Pharmaceutical Sciences, Mack Publishing shing Company, Easton, PA.

[0301] The compounds useful in the present invention may be delivered in mixtures of three or more such compounds. The composition may further include one or more adjuvants in addition to the combination of compounds. do.

[0302] A variety of routes of administration are available. The particular mode selected will, of course, depend on the particular mode selected. The compound, the age and general health of the subject, the particular condition being treated, and the therapeutic efficacy The methods of the present invention generally do not involve any clinically unacceptable harmful effects. Medically, it means any modality that produces an effective level of response without causing side effects. Any acceptable mode of administration may be used. Preferred modes of administration are discussed above. It can be done.

[0303] The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods involve 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 the copolymer is uniformly and intimately associated with both copolymers, and then, if necessary, shaping the product. It is prepared in this way.

[0304] Other delivery systems may include time-release, delayed-release or sustained-release delivery systems. Such a system avoids repeated administration of compounds and provides convenience to subjects and physicians. Many types of release delivery systems are available and known to those of skill in the art. These include poly(lactide-glycolide), copolyoxalates, polycaprolactones, and polyisocyanates. lactones, polyesteramides, polyorthoesters, polyhydroxybutyrates, and poly These include polymer-based systems such as PEG-400 and PEG-400 anhydrides. Clocapsules are described, for example, in U.S. Pat. No. 5,075,109. The system includes cholesterol, cholesterol esters and fatty acids or triglycerides, e.g. Sterol-containing lipids, such as mono-, di-, and triglycerides; hydrogel release systems systems; silastic systems; peptide-based systems; wax coatings; conventional Compressed tablets using binders and excipients of the present invention; partially fused implants; and other non-polymeric Specific examples include, but are not limited to, systems in which: (a) the agent of the present invention is Erosion systems contained in a matrix, e.g., U.S. Pat. No. 4,452,775. Those described in the specification, specifications of Nos. 4675189 and 5736152 and (b) diffusion systems in which the active ingredient permeates through the polymer at a controlled rate, e.g. For example, U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407 686. Furthermore, some of them are suitable for implantation. A pump-based hardware delivery system may be used.

[0305] Assay for efficacy of Kv1.3 potassium channel blockers In some embodiments, the compounds described herein are administered to Kv1.3 potassium channels. In some embodiments, the compounds described herein are tested for their activity against and testing its Kv1.3 potassium channel electrophysiology. The compounds described herein are tested for their hERG electrophysiology.

[0306] 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 in scope. Various modifications of and many further embodiments of the present invention are shown and described herein. In addition, the full contents of this document, including the examples below, and the references cited therein, Those skilled in the art will be aware of the foregoing with reference to the scientific and patent literature. The contents of the references listed are incorporated herein by reference to help illustrate the prior art. It should be further understood that the following examples are provided to illustrate various embodiments and their applications. contains important additional information, exemplification and guidance that can be adapted to the practice of this invention in the context of equivalents of the present invention. Has. [Example]

[0307] Examples 1-76 describe methods used in the synthesis of representative compounds of Formula I disclosed herein. Various intermediates are described.

[0308] [Example 1] Intermediate 1 (1-(4-(4,5-dichloro-2-hydroxybenzoyl)piperidine-1 -Il)ethanone)

[0309] [ka]

[0310] Step A: DC of 1-acetylpiperidine-4-carboxylic acid (2.00 g, 11.68 mmol) To a stirred solution of E (20 mL) was added SOCl2 (10 mL) dropwise at 0 °C under a nitrogen atmosphere. The reaction solution was allowed to warm to room temperature. After stirring at room temperature for an additional 1.5 hours, the resulting solution was evaporated under reduced pressure. Concentration under reduced pressure affords crude 1-acetylpiperidine-4-carbonyl chloride, which This was used in the next step without further purification.

[0311] Step B: 1-Acetylpiperidine-4-carbonyl chloride (0.39 g, 2.03 mmol) in DCE (20 mL) was added to 1,2-dichloro-4-methoxybenzoate at room temperature under a nitrogen atmosphere. After stirring for 5 minutes, anhydrous Al Cl3 (0.49 g, 3.73 mmol) was added in small portions under a nitrogen atmosphere at 0 °C. The reaction mixture was warmed to 50°C and stirred under nitrogen for 2 hours. After cooling to 0°C, The resulting mixture was quenched with ice water (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na2SO4, The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was eluted with DCM / MeOH (10 / 1). Purification by silica gel column chromatography gave the crude product as a dark yellow solid. The crude product was purified by preparative HPLC using the following conditions: Column: Sunfire Prep C18 OBD column, 10 μm, 19 × 250 mm; Phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 9 min 56%B to 64%B; Detector: UV 254 / 210 nm; Retention time: 6.98 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 1-(4-(4,5-dichloro- (2-hydroxybenzoyl)piperidin-1-yl)ethanone was an off-white solid The compound (85.6 mg, 16%) was obtained as follows: LCMS (ESI) C 14 H 15 Cl2NO3[M + H] + Calculation of Value: 316, 318 (3 : 2), Actual Value 316, 318 (3 : 2); 1 H NMR (300 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.94 (s, 1H), 7.22 (s, 1H), 4.31 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 13 .2 Hz, 1H), 3.69-3.54 (m, 1H), 3.21-3.03 (m, 1H), 2.75-2.58 (m, 1H), 1.96 (s, 3H) ), 1.86-1.71 (m, 2H), 1.53-1.18 (m, 2H).

[0312] [Example 2] Intermediate 2 ((4,5-dichloro-2-hydroxyphenyl)(piperidin-4-yl)methyl)methyl Thanon)

[0313] [ka]

[0314] Step A: 1-[4-[(4,5-dichloro-2-hydroxybenzoyl) [phenyl]carbonyl]piperidin-1-yl]ethan-1-one (0.15 g, 0. The mixture of 48 mmol) was stirred at 105°C for 4 hours. After cooling to room temperature, the resulting mixture The product was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Ram: XBridge Shield RP18 OBD column 19 x 250 mm, 10 μm; Mobile phase A: water containing 10 mmol / L NH4HCO3; Mobile phase B: ACN; flow rate : 25 mL / min; Gradient: 20% B to 60% B in 9 min; Detector: UV254 / 210 nm Retention time: 8.5 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give ( 4,5-Dichloro-2-hydroxyphenyl)(piperidin-4-yl)methanone is yellow Obtained as a solid (23.5 mg, 18%): LCMS (ESI) C 12 H 13 Cl2NO2[M + H] + of Calculated values: 274, 276 (3 : 2), Measured values: 274, 276 (3 : 2); 1 H NMR (300 MHz, DMSO-d6) δ 7 .85 (br, 1H), 7.57 (s, 1H), 6.67 (s, 1H), 3.96-3.76 (m, 1H).3.12 (d, J = 12.0 Hz , 2H), 2.83-2.62 (m, 2H), 1.81 (d, J = 13.1 Hz, 2H), 1.57-1.34 (m, 2H).

[0315] [Example 3] Intermediate 3 (tert-butyl 4-(amino(4,5-dichloro-2-methoxyphenyl) Methyl)piperidine-1-carboxylate trifluoroacetic acid

[0316] [ka]

[0317] Step A: tert-Butyl 4-(4,5-dichloro-2-hydroxybenzoyl)piperidine 1-carboxylate (1.00 g, 2.68 mmol) in DMF (10 mL) with stirring. The solution was treated with K2CO3 (0.74 g, 5.36 mmol) and CH 3I (0.75 g, 5.36 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at rt for 1 h. The resulting mixture was diluted with water (60 mL) and The combined organic layers were washed with brine (2 x 10 mL) and anhydrous Na The mixture was dried over SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with PE / EA (4 / 1 ), and purified by silica gel column chromatography eluting with tert-butyl ether. 4-(4,5-dichloro-2-methoxybenzoyl)piperidine-1-carboxylate The compound was obtained as a pale yellow solid (0.85 g, 83%): LCMS (ESI) C 18 H 23 Cl2NO4[M + H] + Calculated values: 388, 390 (3 : 2), measured values ​​388, 390 (3 : 2);

[0318] Step B: tert-Butyl 4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]pyridin Dissolve peridine-1-carboxylate (1.70 g, 4.38 mmol) in THF (20 mL To the stirred solution in HCl at 0°C, NaBH4 (0.25 g, 6.58 mmol) was added in small portions. After stirring for an additional 1.5 h, the reaction mixture was added with saturated aqueous NH4Cl (50 mL ) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 2 0 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 DCM / MeOH (30 / 1). Purification by HCl gave tert-butyl 4-((4,5-dichloro-2-methoxyphenyl)- (hydroxy)methyl)cyclohexane-1-carboxylate is off-white Obtained as a solid (1.40 g, 82%): LCMS (ESI) C 18 H 25 Cl2NO4[M + H] + plan Calculated: 390, 392 (3 : 2), Measured: 390, 392 (3 : 2); 1 H NMR (300 MHz, DMSO-d6) δ 7.4 1 (s, 1H), 7.19 (s, 1H), 5..22 (d, J = 5.0 Hz, 1H), 4.61 (t, J = 5.2 Hz, 1H), 4. 25 (d, J = 5.8 Hz, 1H), 3.99 (d, J = 5.8 Hz, 1H), 3.76 (s, 3H), 2.91-2.74 (m, 2H ), 1.84-1.71 (m, 2H), 1.35 (s, 9H), 1.32-1.01 (m, 3H).

[0319] Step C: tert-Butyl 4-[(4,5-dichloro-2-methoxyphenyl)(hydroxy) Methyl]piperidine-1-carboxylate (2.50 g, 6.41 mmol) in DCM To a stirred solution of 18 mL of HCl at 0°C, add PBr3 (3.50 g, 12.81 mmol) dropwise. After stirring for another hour, the reaction solution was added with saturated aqueous NaHCO3 (30 The mixture was quenched with EA (3×20 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Then, crude 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperazine was obtained. Lysine was obtained and used directly in the next step without further purification: LCMS (ES I C 13 H 16 BrCl2NO [M + H] + Calculated values: 352, 354, 356 (2:3:1), measured values: 352, 354, 35 6 (2 : 3 : 1).

[0320] Step D: 4-[Bromo(4,5-dichloro-2-methoxyphenyl)methyl]piperidine (2. 00g, 5.66mmol) and EtN (0.90g, 8.50mmol) in DCM (20 mL) at 0 °C. The solution in CM (5 mL) was added dropwise. After stirring at 0° C. for an additional 1 h, the resulting solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10 / 1). Purification by column chromatography gave tert-butyl 4-(bromo(4,5-dichloro-2- (Methoxyphenyl)methyl)piperidine-1-carboxylate was obtained as a yellow oil (0.3 0g, 12% over two steps: LCMS (ESI) C 18 H 24 BrCl2NO3[M + 1 - 56] + Calculated values: 396, 398, 400 (2 : 3 : 1), measured values: 396, 398, 400 (2 : 3 : 1);1 H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 6.95 (s, 1H), 5.15 (d, J = 9.4 Hz, 1H), 4.18 (d, J = 13.5 Hz, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.85 (s, 3H), 2.81-2.54 (m, 2H) , 2.27-2.02 (m, 2H), 1.48 (s, 9H), 1.32-0.97 (m, 3H).

[0321] Step E: tert-Butyl 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl) Piperidine-1-carboxylate (0.26 g, 0.58 mmol) in DMF (5 mL To the stirred solution in HCl at room temperature was added NaN3 (0.11 g, 1.74 mmol). The mixture was warmed to 100° C. and stirred for 16 h. The reaction mixture was diluted with water (30 mL) and The combined organic layers were washed with water (2 x 15 mL) and extracted with anhydrous N After drying over a2SO4, the filtrate was concentrated under reduced pressure to one-quarter of its volume. Used directly in the next step without further purification: LCMS (ESI) C 18 H 24 Cl2N4O3[M + H] + Calculated values: 415, 417 (3:2), measured values: 415, 417 (3:2).

[0322] Step F: tert-Butyl 4-[azido(4,5-dichloro-2-methoxyphenyl)methyl] Piperidine-1-carboxylate (0.20 g, 0.48 mmol) and PPh3( To a stirred solution of 0.25 g (0.96 mmol) of NH3·H in THF (2 mL) at room temperature 20 (1 mL, 28% in H20) was added dropwise. The reaction solution was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure. The residue was eluted with 30% ACN in water (+0.05% TFA). Purification by reverse phase chromatography gave tert-butyl 4-(amino(4, 5-Dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate trihydrate Fluoroacetic acid was obtained as a yellow oil (0.10 g, 45% over two steps): LCMS (ESI) C 18 H 26 Cl2N2O3[M + H] + Calculated value: 389, 391 (3:2), Measured value: 389, 391 (3: 2); 1 H NMR (300 MHz, CD3OD) δ 7.46 (s, 1H), 7.29 (s, 1H), 4.21-4.09 (m, 2H), 4. 05-3.93 (m, 1H), 3.86 (s, 3H), 2.82-2.53 (m, 1H), 2.20-2.06 (m, 2H), 1.95-1.83 ( m, 1H), 1.40 (s, 9H), 1.32-0.97 (m, 3H).

[0323] [Example 4] Intermediate 4 (1-(4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)phenyl)methyl) Peridine-1-yl)ethanone

[0324] [ka]

[0325] Step A: 1-[4-(4,5-dichloro-2-hydroxybenzoyl)piperidin-1-yl] To a stirred solution of ethan-1-one (1.00 g, 3.16 mmol) in DMF (10 mL) , K2CO3 (0.87 g, 6.33 mmol) and CH3I at room temperature under a nitrogen atmosphere. (0.90 g, 6.33 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 The resulting mixture was diluted with water (60 mL) at room temperature and diluted with EA (3×50 mL). The combined organic layers were washed with brine (2 × 10 mL) and anhydrous NaSO The mixture was dried over 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was washed with PE / EA (4 / 1). Purification by silica gel column chromatography with elution afforded 1-[4-(4,5 -Dichloro-2-methoxybenzoyl)piperidin-1-yl]ethan-1-one is pale yellow Obtained as a colored solid (1.00 g, 95%): LCMS (ESI) C 15 H 17 Cl2NO3[M + H] + of Calculated values: 330, 332 (3:2), Measured values: 330, 332 (3:2).

[0326] Step B: 1-[4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidine- 1-yl]ethan-1-one (0.70 g, 2.12 mmol) in MeOH (5 mL) To the stirred solution at 0 °C, NaBH4 (0.12 g, 3.18 mmol) was added in small portions. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with saturated NH4Cl at 0°C. The mixture was quenched with aqueous 1H2O (30 mL), extracted with EA (3 x 50 mL), and then diluted with anhydrous Na2SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in PE / EA (3 / 1). When purified by silica gel column chromatography, 1-(4-((4,5 -Dichloro-2-methoxyphenyl)(hydroxy)methyl)piperidin-1-yl) The thanone was obtained as a yellow oil (0.46 g, 66%): LCMS (ESI) C 15 H 19 Cl2NO 3[M + H] + Calculated values: 332, 334 (3:2), measured values: 332, 334 (3:2).

[0327] Step C: 1-[4-[(4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl]pi peridin-1-yl]ethan-1-one (0.46 g, 1.38 mmol) in DCM (5 To a stirred solution of 1 mL of HCl at 0°C was added PBr3 (0.75 g, 2.77 mmol) dropwise. After stirring at 0°C for 1 hour, the reaction solution was quenched with water (30 mL) at 0°C and EA (4 The combined organic layers were washed with brine (2×10 mL) and extracted with anhydrous N The mixture was dried over a2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE / EA (2 Purification by silica gel column chromatography eluting with 1-(4- (Bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidin-1-yl Ethanone was obtained as a yellow oil (50 mg, 10%): LCMS (ESI) C 15 H 18 BrCl2 NO2[M + H] + Calculated values: 394, 396, 398 (2 : 3 : 1), measured values ​​394, 396, 398 (2 : 3 : 1); 1 H NMR (300 MHz, CD3OD) δ 7.57 (s, 1H), 7.15 (s, 1H), 5.14 (dd, J = 9.5, 2.4 H z, 1H), 3.99-3.90 (m, 1H), 3.85 (s, 3H), 3.84-3.80 (m, 1H), 3.18-2.91 (m, 1H), 2 .69-2.45 (m, 1H), 2.38-2.17 (m, 2H), 2.05 (d, J = 15.0 Hz, 3H), 1.43-1.15 (m, 3H ).

[0328] Step D: 1-(4-(bromo(4,5-dichloro-2-hydroxyphenyl)methyl)piperidinyl To a solution of (benzo-1-yl)ethanone (50 mg, 0.13 mmol) in DMF (3 mL), At room temperature, NaN3 (26 mg, 0.40 mmol) was added. The reaction mixture was heated to 100 °C. The mixture was allowed to warm and stirred for 8 hours. After cooling to room temperature, the resulting mixture was diluted with water (20 mL) and Extracted with EA (3 x 25 mL). The combined organic layers were washed with brine (3 x 10 mL). The mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to one-quarter of its volume. The residue was used directly in the next step without further purification: LCMS (ESI) C 15 H 18 Cl2 NO2[M + H] + Calculated values: 357, 359 (3:2), measured values: 357, 359 (3:2).

[0329] Step E: 1-[4-[azido(4,5-dichloro-2-methoxyphenyl)methyl]piperidine -1-yl]ethan-1-one (0.10 g, 0.28 mmol) in THF (4 mL) The solution was added with PPh3 (0.15 g, 0.56 mmol) and NH3·H2O (1 mL of HCl (28%) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was eluted with 29% ACN in water (+0.05% TFA). Purification by reverse phase chromatography gave 1-(4-(amino(4,5-dichloro- 2-Methoxyphenyl)methyl)piperidin-1-yl)ethanone was obtained as a pale yellow solid (30 mg, 71% over two steps: LCMS (ESI) C 15 H 20 Cl2N2O2[M + H] + of Calculated values: 331, 333 (3 : 2), Measured values: 331, 333 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.4 7 (d, J = 1.9 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 4.60-4.40 (m, 1H), 3.99-3.82 (m , 2H), 3.81 (s, 3H), 3.17-2.89 (m, 1H), 2.66-2.44 (m, 1H), 2.15-1.78 (m, 5H), 1. 43-1.03 (m, 3H).

[0330] [Example 5] Intermediate 5 (N-((2-(allyloxy)-4,5-dichlorophenyl)(piperidine- 4-yl)methyl)-2-methylpropane-2-sulfinamide

[0331] [ka]

[0332] Step A: (4,5-Dichloro-2-hydroxyphenyl)(piperidin-4-yl)methanone( 17 g, 62.27 mmol) and Et3N (31.44 g, 0.31 mol) To a stirred solution of BocO (14.90 g, 68.21 mmol) in MgO (150 mL) at 0 °C l) was added in small portions. The reaction solution was warmed to room temperature and stirred at room temperature for 4 hours. The solution was quenched with water (300 mL) at room temperature and extracted with EA (3×300 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was carried on to the next step without further purification. Used directly for: LCMS (ESI) C 17 H 21 Cl2NO4[M + H] + Calculated values: 374, 376 (3:2), measured Values ​​374, 376 (3 : 2).

[0333] Step B: tert-Butyl 4-(4,5-dichloro-2-hydroxybenzoate) in DMF (200 mL) Benzoyl)piperidine-1-carboxylate (crude) and K2CO3 (33.2 To a stirred mixture of 14.0 g, 0.24 mmol) of allyl bromide (14.0 g, 0.24 mmol) was added at room temperature under a nitrogen atmosphere. 48 g, 0.12 mmol) was added dropwise. The reaction mixture was warmed to 40° C. and stirred for 12 hours. The resulting mixture was diluted with water (500 mL) and extracted with EA (2 x 500 mL). The combined organic layers were washed with brine (2 x 100 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 (5 / 1). Purification by column chromatography yielded tert-butyl 4-(2-(allyl) Oxy)-4,5-dichlorobenzoyl)piperidine-1-carboxylate is pale yellow Obtained as a solid (15.40 g, 64% over two steps): LCMS (ESI) C 20 H 25 Cl2 NO4[M + H] +Calculated values: 414, 416 (3 : 2), measured values: 414, 416 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.07 (s, 1H), 6.16-6.00 (m, 1H), 5.55-5.36 (m, 2H), 4.62 (d, J = 5.7 Hz, 2H), 4.18-4.08 (m, 2H), 3.41-3.32 (m, 1H), 2.94-2.74 (m, 2H), 1 .93-1.81 (m, 2H), 1.68-1.54 (m, 2H), 1.54 (s, 9H).

[0334] Step C: tert-Butyl 4-[4,5-dichloro-2-(propan-2-yl)methyl]propan-2-yl ... -en-1-yloxy)benzoyl]piperidine-1-carboxylate (8.80g , 21.24 mmol) and Ti(OEt)4 (21.51 g, 94.30 mmol) To the stirred mixture was added 2-methylpropane-2-sulfinamide ( The reaction mixture was warmed to 70°C. The mixture was stirred under a nitrogen atmosphere for 16 hours. The resulting mixture was cooled to room temperature and cooled to room temperature with water (200 mL). A solid formed and was filtered off. The filtrate was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give crude tert-butyl 4-((2-(azathioprine). (4,5-dichlorophenyl)((tert-butylsulfinyl)imino The crude product was further purified to give methyl piperidine-1-carboxylate. Used directly in the next step without further analysis: LCMS (ESI) C 24H 34 Cl2N2O4S [M + H] + Calculated value: 51 7, 519 (3 ​​: 2), actual values ​​517, 519 (3 ​​: 2); 1 H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 6.95 (s, 1H), 6.05-5.95 (m, 1H), 5.43-5.26 (m, 2H), 4.56 (d, J = 5.8 Hz, 2H), 4 .25-4.00 (m, 2H), 2.86-2.52 (m, 3H), 1.91-1.54 (m, 4H), 1.45 (s, 9H), 1.21 (s, 9 H).

[0335] Step D: tert-Butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)((t (ert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate (crude To a solution of NaBH4 (1.21 mL) in MeOH (80 mL) was added NaBH4 (1.21 mL) at 0°C under nitrogen atmosphere. g, 31.86 mmol) was added in small portions. After the addition, the reaction mixture was warmed to room temperature. The mixture was stirred under nitrogen atmosphere for 2 hours, and the resulting mixture was quenched with water (150 mL) at 0° C. The combined organic layer was washed with water (2 x 50 mL). The mixture was filtered and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in water ( Purified by reversed-phase chromatography eluting with 45% ACN in 0.05% TFA tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)( 1,1-Dimethylethylsulfinamido)methyl)piperidine-1-carboxylate was obtained as a yellow oil (6.58 g, 60% over two steps): LCMS (ESI) C 24 H 36 Cl2N2O4S [M + H] + Calculated values: 519, 521 (3 : 2), measured values ​​519, 521 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.51 (s, 1H), 7.15 (s, 1H), 6.19-6.03 (m, 1H), 5.52-5.29 (m , 2H), 4.67-4.58 (m, 2H), 4.30 (d, J = 9.1 Hz, 1H), 4.04 (dd, J = 35.2, 13.5 Hz, 2H), 2.84-2.50 (m, 2H), 2.14-1.87 (m, 2H), 1.46 (s, 9H), 1.30-1.05 (m, 3H), 1.2 3 (s, 9H).

[0336] Step E: tert-Butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(1, 1-Dimethylethylsulfinamido)methyl)piperidine-1-carboxylate(6 To a stirred solution of 0.58 g (12.68 mmol) in DCM (100 mL) at room temperature was added TFA (20 mL) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (200 The pH of the reaction mixture was adjusted to 9 with saturated aqueous NaHCO3 at 0°C. The aqueous layer was extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to reverse phase chromatography eluting with 35% ACN in water (+0.05% TFA). Purification of the compound yielded N-((2-(allyloxy)-4,5-dichlorophenyl)(piperazine). Lysin-4-yl)methyl)-2-methylpropane-2-sulfinamide is a pale yellow oil Obtained as a product (4.24 g, 80%): LCMS (ESI) C 19 H 28 Cl2N2O2S [M + H] + plan Calculated: 419, 421 (3 : 2), Measured: 419, 421 (3 : 2); 1 H NMR (300 MHz, DMSO-d6 + DO) δ 7.50 (s, 1H), 7.19 (s, 1H), 6.06-5.92 (m, 1H), 5.42-5.18 (m, 2H), 4.63-4.48 ( d, J = 4.8 Hz, 2H), 4.47-4.34 (d, J = 8.7 Hz, 1H), 3.38-3.14 (m, 2H), 2.84-2.65 (m, 2H), 2.20-2.05 (m, 1H), 1.96-1.82 (m, 1H), 1.42-1.18 (m, 3H), 0.97 (s, 9H).

[0337] [Example 6] Intermediate 6 ((S)-N-((R)-(2-(allyloxy)-4,5-dichlorophenyl) )(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide), Method A

[0338] [ka]

[0339] Step A: tert-Butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)piperidin Zinc-1-carboxylate (5.16 g, 12.45 mmol) and Ti(OEt) To a stirred solution of 4 (8.52 g, 37.36 mmol) in THF (50 mL) was added a nitrogen atmosphere. At room temperature, (S)-2-methylpropane-2-sulfinamide (1.67 g, 13. The reaction mixture was heated to 70°C and stirred for 36 hours. After that, the resulting solution was quenched with water (300 mL) at room temperature. A solid was formed. The mixture was filtered. The filtrate was extracted with EA (2 x 500 mL). The combined organic layers were washed with brine ( The mixture was washed with 2×100 mL of HCl and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was dried in a vacuum oven to give (S)-tert-butyl 4-((2 -(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl) Imino)methyl)piperidine-1-carboxylate was obtained as a pale yellow solid (6.00 g, 93 %) as follows: LCMS (ESI) C 24 H 34 Cl2N2O4S [M + H] + Calculated value: 517, 519 (3 ​​: 2) , Actual values ​​517, 519 (3 ​​: 2); 1 H NMR (300 MHz, CDCl3) δ 7.28 (s, 1H), 6.97 (s, 1H), 6.06-5.94 (m, 1H), 5.46-5.26 (m, 2H), 4.58 (d, J = 5.7 Hz, 2H), 4.23-4.01 (m, 2 H), 3.81-3.62 (m, 1H), 2.84-2.57 (m, 2H), 1.93-1.81 (m, 2H), 1.68-1.54 (m, 2H), 1.46 (s, 9H), 1.22 (s, 9H).

[0340] Step B: (S)-tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl )((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate A solution of 1.50 g (2.90 mmol) of methylpropanol in 10 mL of toluene was added under a nitrogen atmosphere. , DIBAL-H (4.35 mL, 4.35 mmol, After the addition, the reaction solution was stirred under a nitrogen atmosphere at -65°C for 3 hours. The resulting solution was quenched with water (20 mL) at −65° C., followed by saturated tartaric acid. The aqueous layer was diluted with aqueous potassium sodium chloride (200 mL). The combined organic layers were washed with water (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with 45% water (+0.05% TFA) Purification by reversed-phase chromatography eluting with ACN afforded tert-butyl 4-( (R)-(2-(allyloxy)-4,5-dichlorophenyl)((S)-1,1-dimethyl (ethyl ethyl sulfinamido)methyl)piperidine-1-carboxylate is a yellow oil The compound was obtained as a methylcellulose (0.78 g, 52%): LCMS (ESI) C 24 H 36 Cl2N2O4S [M + H] + Calculation of Values: 519, 521 (3 : 2), Actual values ​​519, 521 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.23 (s , 1H), 6.96 (s, 1H), 6.10-5.92 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.50-4.37 (m, 1H), 4.28-4.04 (m, 2H), 3.84-3.64 (m, 1H), 2.71-2.49 (m, 2H), 2.01-1.81 (m, 2H), 1.47 (s, 9H), 1.49-1.22 (m, 3H), 1.17 (s, 9H).

[0341] Step C: tert-Butyl 4-((R)-(2-(allyloxy)-4,5-dichlorophenyl) )((S)-1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxamide A stirred solution of carboxylate (16.00 g, 30.80 mmol) in DCM (120 mL) To the resulting solution, TFA (30 mL) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (200 mL). The pH of the reaction mixture was adjusted to 0°C with saturated aqueous NaHCO3. The pH was adjusted to 8 with the solution. The aqueous layer was extracted with EA (3 x 500 mL). The combined organic layers were Washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate The residue was concentrated under reduced pressure and diluted with 35% ACN in water containing 10 mmol / L NH4HCO3. Purification by reversed-phase chromatography eluting with (S)-N-((R)-(2- (Allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2 -Methylpropane-2-sulfinamide as a yellow oil (7.00 g, 46%) Obtained: LCMS (ESI) C 19 H 28 Cl2N2O2S [M + H] + Calculated values: 419, 421 (3:2), measured value 41 9, 421 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 6.98 (s, 1H), 6.10-5.97 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.49-4.37 (m, 1H), 4.88-3 .95 (m, 1H), 3.42-3.24 (m, 2H), 2.81-2.67 (m, 2H), 2.21-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.65-1.42 (m, 3H), 1.17 (s, 9H).

[0342] Intermediate 6 ((S)-N-((R)-(2-(allyloxy)-4,5-dichlorophenyl) )(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide), Method B

[0343] [ka]

[0344] Step A: 3,4-Dichlorophenol (100.00 g, 613.49 mmol) in DCM (1 To a stirred solution of 1,000 mL of Br2 (98.04 g, 613.4 mL) was added Br2 (98.04 g, 613.4 mL) at 0 °C under a nitrogen atmosphere. 9 mmol) was added dropwise. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was quenched with saturated aqueous NaSO (500 mL) at 0 °C. The extract was extracted with EA (6 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL). After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-3-(2-methyl-2-propanol)-2-one. Bromo-4,5-dichlorophenol was obtained as a yellow oil. The crude product was further purified. Used directly in the next step without further purification: 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H ), 7.15 (s, 1H).

[0345] Step B: 2-Bromo-4,5-dichlorophenol (50.00 g, 206.71 mmol) and and K2CO3 (57.14 g, 413.41 mmol) in DMF (500 mL) The solution was treated with 3-bromoprop-1-ene (37.51 g, 310. 0.06 mmol) was added dropwise. The reaction mixture was stirred at 40° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with water (1.5 L) and extracted with EA (3×0.5 L). The organic layer was washed with brine (4 x 0.5 L) and dried over anhydrous Na2SO4. After filtration The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE. Purification by HCl gave 1-bromo-4,5-dichloro-2-(prop-2-ene-1- (I)yloxy)benzene was obtained as a pale yellow oil (40.00 g, 61%): 1 HN MR (400 MHz, CDCl3) δ 7.65 (s, 1H), 6.98 (s, 1H), 6.12-6.06 (m, 1H), 5.60-5.29 (m, 2H), 4.69-4.57 (m, 2H).

[0346] Step C: 1-Bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene To a stirred solution of (30.00 g, 106.39 mmol) in THF (800 mL) was added under a nitrogen atmosphere. i-PrMgCl-LiCl (125 mL, 15 mL) was added at −15°C for 30 min under ambient conditions. 9.59 mmol, 1.3 M in THF) was added dropwise. The resulting mixture was heated under a nitrogen atmosphere. The mixture was stirred at −15° C. for an additional 0.5 hours. The resulting solution was added with t ert-Butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl [I]piperidine-1-carboxylate (33.67 g, 106.39 mmol) was added. After the addition, the reaction mixture was stirred at -15°C for 2 hours. The reaction was then cooled to -15°C with saturated N The mixture was quenched with aqueous HCl (100 mL) and extracted with EA (3×500 mL). The combined organic layer was washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel elution with PE / EA (1 / 2). Purification by column chromatography gave tert-butyl 4-[(R)-[4, 5-dichloro-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2 -Methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxy The compound was obtained as an off-white solid (34.00 g, 58%): LCMS (ESI) C 24 H 36 Cl2N2O4S [M + H] + Calculated values: 519, 521 (3 : 2), measured values ​​519, 521 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 7.17 (s, 1H), 6.18-6.03 (m, 1H), 5.49-5.31 (m , 2H), 4.62 (d, J = 5.2 Hz, 2H), 4.52 (d, J = 8.8 Hz, 1H), 4.13 (t, J = 10.0 Hz, 1H), 4.01 (d, J = 13.4 Hz, 1H), 2.70 (d, J = 35.8 Hz, 2H), 2.12 (d, J = 13.6 Hz , 1H), 2.01-1.88 (m, 1H), 1.46 (s, 9H), 1.36-1.19 (m, 3H), 1.13 (d, J = 1.4 Hz, 9H).

[0347] Step D: tert-Butyl 4-[(R)-[4,5-dichloro-2-( propane-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2 -sulfinyl]amino]methyl]piperidine-1-carboxylate (5.70 g, To a stirred mixture of 10.97 mmol of TFA (10 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 9 with saturated aqueous NaHCO3 at 0°C. The resulting mixture was extracted with EA (2 x 100 mL). The combined organic layers were The mixture was washed with ethanol (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was The crude product was concentrated under reduced pressure and the resulting solution was diluted with 40% AC in water containing 10 mmol / L NH4HCO3. Purification by reversed-phase chromatography eluting with N yields (S)-N-[(R)-[4 ,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidine- 4-yl)methyl]-2-methylpropane-2-sulfinamide was obtained as a yellow solid (3.5 0g, 68%): LCMS (ESI) C 19 H 28 Cl2N2O2S [M + H] + Calculated value: 419, 4 21 (3 : 2), actual values ​​419, 421 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 6.9 8 (s, 1H), 6.10-5.97 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.49- 4.37 (m, 1H), 4.88-3.95 (m, 1H), 3.42-3.24 (m, 2H), 2.81-2.67 (m, 2H), 2.21-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.65-1.42 (m, 3H), 1.17 (s, 9H).

[0348] [Example 7] Intermediate 7 (N-((2-hydroxynaphthalen-1-yl)(pyridin-4-yl)methyl)methyl) Acetamide

[0349] [ka]

[0350] Step A: Naphthalen-2-ol (3.50 g, 24.28 mmol), acetamide (1.7 2g, 29.13mmol) and pyridine-4-carbaldehyde (2.60g, 24. To a stirred mixture of AlCl3 (0.49 g, The reaction mixture was heated at 110°C under a nitrogen atmosphere. The mixture was stirred for 8 hours. After cooling to room temperature, the reaction mixture was quenched with water (60 mL). The extract was extracted with EA (3 x 50 mL). 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. The residue was purified by DC Purification was performed by silica gel column chromatography eluting with M / MeOH (8 / 1). N-[(2-hydroxynaphthalen-1-yl)(pyridin-4-yl)methyl] The acetamide was obtained as a yellow-green solid (1.00 g, 14%): LCMS (ESI) C 18 H1 6N2O2[M + H] + Calculated value: 293, measured value 293; 1 H NMR (400 MHz, CD3OD) δ 8.39 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.87 (t, J = 9.0 Hz, 2H), 7.54 (t, J = 7. 7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.29-7.24 (m, 3H), 7.21 (d, J = 8.6 Hz, 1H) , 2.10 (s, 3H).

[0351] [Example 8] Intermediate 8 (N-((2-(allyloxy)-4,5-dichlorophenyl)(piperidine- 4-yl)methyl)-2,2,2-trifluoroacetamidotrifluoroacetic acid

[0352] [ka]

[0353] Step A: tert-Butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(1, 1-Dimethylethylsulfinamido)methyl)piperidine-1-carboxylate(0 To a stirred solution of 0.50 g (0.96 mmol) in 1,4-dioxane (5 mL) at room temperature, Aqueous HCl (6N, 0.5 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The resulting solution was neutralized to pH 7 with saturated aqueous NaHCO3 solution and then concentrated under reduced pressure. The residue was subjected to reversed-phase chromatography eluting with 60% ACN in water containing 20 mmol / L NH4HCO3. Purification by chromatography gave tert-butyl 4-((2-(allyloxy)- 4,5-Dichlorophenyl)(amino)methyl)piperidine-1-carboxylate is brown Obtained as a colored oil (0.40 g, 90%): LCMS (ESI) C 20 H 28 Cl2N2O3[M + H] + Calculated values: 415, 417 (3:2), measured values: 415, 417 (3:2).

[0354] Step B: tert-Butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(amino) (2)methyl)piperidine-1-carboxylate (0.11 g, 0.27 mmol) and To a stirred solution of EtN (54 mg, 0.53 mmol) in DCM (3 mL) at 0 °C, TFAA (61 mg, 0.29 mmol) was added dropwise, and the reaction solution was stirred at 0° C. for 0.5 hours. The reaction solution was diluted with DCM (50 mL). The solution was washed with brine (2 x 20 mL). After filtration, the filtrate was concentrated under reduced pressure to give tert -butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(2,2,2-trimethylsilyl) (trifluoroacetamido)methyl)piperidine-1-carboxylate was obtained as a yellow solid (0 Obtained as 0.13g, 95%): LCMS (ESI) C 22 H 27 Cl2F3N2O4[M + H] + Calculated value: 51 1, 513 (3 : 2), actual values ​​511, 513 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.02 (s, 1H), 6.11-5.99 (m, 1H), 5.47-5.38 (m, 2H), 4.78 (t, J = 12.0 Hz, 1H), 4.86-4.57 (m, 2H), 4.31-3.93 (m, 2H), 2.75-2.48 (m, 2H), 2.01-1.91 (m, 1H), 1.83 -1.72 (m, 1H), 1.46 (s, 9H), 1.49-1.22 (m, 3H).

[0355] Step C: tert-Butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(2, 2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate(0. To a solution of 13 g (0.25 mmol) of HCl in 3 mL of DCM was added 3 mL of TFA at room temperature. The reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to give N- ((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl (2,2,2-trifluoroacetamide trifluoroacetic acid) was obtained as a yellow solid (0.10 g, 90%): LCMS (ESI) C 17 H 19 Cl2F3N2O2[M + H] + Calculated value: 411, 413 (3 : 2), measured values ​​411, 413 (3 : 2).

[0356] [Example 9] Intermediate 9 (1-(allyloxy)-2-bromo-3,4,5-trichlorobenzene)

[0357] [ka]

[0358] Step A: (3,4,5-trichlorophenyl)boronic acid (5.00 g, 22.20 mol) To a stirred solution in HF (15 mL) was added H2O2 (1.51 g, 44.39 mmol, 30%) and NaOH (1.78 g, 44.39 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was diluted with saturated aqueous Na2SO3 (10 mL) at room temperature. The mixture was quenched and acidified to pH 3 with aqueous HCl (1N). The residue was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (2 x 80 mL). The residue was washed and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography eluting with E / EA (5 / 1) 3,4,5-Trichlorophenol was obtained as a pale yellow solid (4.30 g, 95%). Was: 1 H NMR (300 MHz, CDCl3) δ 6.92 (s, 2H).

[0359] Step B: 3,4,5-Trichlorophenol (4.60 g, 23.30 mol) in AcOH (2 To a stirred solution of Br2 (3.70 g, 23.15 mcg) in 100 mL of HCl was added Br2 (3.70 g, 23.15 mcg) at room temperature under an argon atmosphere. After stirring for 6 h, the reaction was washed with saturated aqueous Na2SO3 (80 mL). It was quenched and extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (3 x 80 mL). The residue was washed with HCl (HCl), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20 / 1). Upon purification, 2-bromo-3,4,5-trichlorophenol was obtained as an off-white solid ( Obtained as 2.40g, 37%): 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.15 (s, 1H).

[0360] Step C: 2-Bromo-3,4,5-trichlorophenol (2.40 g, 8.69 mmol) and To a stirred solution of HCl and K2CO3 (2.40 g, 17.37 mmol) in DMF (15 mL) At room temperature, allyl bromide (1.26 g, 10.42 mmol) was added. The reaction was heated to 50°C. The reaction mixture was diluted with EA (80 mL) and water (80 mL). The combined organic layers were washed with brine (6×80 mL), then extracted with EA (3×80 mL). ) 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 (20 / 1). When prepared, 2-bromo-3,4,5-trichloro-1-(prop-2-en-1-yl) The hydroxybenzene was obtained as a pale yellow oil (1.80 g, 66%).

[0361] [Example 10] Intermediate 10 ((S)-tert-butyl 4-(((tert-butylsulfinyl)imide (Methyl)piperidine-1-carboxylate

[0362] [ka]

[0363] Step A: tert-Butyl 4-formylpiperidine-1-carboxylate (50.00 g, 0 0.23 mol) and (S)-2-methylpropane-2-sulfinamide (43.00 g, 0.35 mmol) in THF (300 mL) at room temperature under a nitrogen atmosphere. Ti(OEt)4 (187.00 g, 0.82 mol) was added dropwise. The reaction solution was placed in a nitrogen atmosphere. The resulting solution was stirred at room temperature for 4 hours under atmospheric pressure. The mixture was quenched with EA (3×300 mL) and extracted with EA (3×300 mL). The combined organic layers were washed with brine. (3×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure Concentration with HCl affords (S)-tert-butyl 4-(((tert-butylsulfinyl)isothiazolinone). (amino)methyl)piperidine-1-carboxylate was obtained as an off-white solid (67 g, 8 1%): LCMS (ESI) C 15 H 28 N2O3S [M + H] + Calculated value: 317, measured value 317; 1 H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 3.9 Hz, 1H), 4.09 (d, J = 13.4 Hz, 2H), 2 .97-2.82 (m, 2H), 2.62 (m, 1H), 1.90 (dd, J = 13.4, 3.6 Hz, 2H), 1.71-1.43 (m, 2 H), 1.47 (s, 9H), 1.20 (s, 9H).

[0364] [Example 11] Intermediate 11 (tert-butyl 4-(((tert-butylsulfinyl)imino)methyl) (I) piperidine-1-carboxylate

[0365] [ka]

[0366] Step A: tert-Butyl 4-formylpiperidine-1-carboxylate (20.00 g, 9 3.90 mmol) and 2-methylpropane-2-sulfinamide (17.00 g, To a stirred solution of Ti( OEt)4 (50.00 g, 0.18 mmol) was added dropwise. The reaction solution was heated under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 4 hours. ) and extracted with EA (3×500 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. Then, tert-butyl 4-(((tert-butylsulfinyl)imino)methyl) Piperidine-1-carboxylate was obtained as a pale yellow solid (24.00 g, 80%). LCMS (ESI) C 15 H 28 N2O3S [M + H] + Calculated value: 317, Measured value: 317.

[0367] [Example 12] Intermediate 12 ((S)-N-((1-((R)-2,2-dimethyl-1,3-dioxolane -4-carbonyl)piperidin-4-yl)methylene)-2-methylpropan-2-sulfonyl Finamide)

[0368] [ka]

[0369] Step A: tert-Butyl 4-formylpiperidine-1-carboxylate (9.00 g, 42 To a stirred solution of 1.20 mmol) in DCM (60 mL) at room temperature, TFA (30 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure. The product was used in the next step without further purification: LCMS (ESI) C6H 11 NO [M + H] + Calculated value: 114, Measured value: 114.

[0370] Step B: (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (8.37 g, 57.27 mmol) and HATU (21.77 g, 57.26 mmol) in DMF ( To a stirred solution in 150 mL of HCl was added piperidine-4-carbaldehyde ( (5.40 g, 47.72 mmol) and EtN (72.43 g, 0.72 mol) The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was quenched with water (100 mL) and extracted with EA (3×200 mL). The extract was washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. The liquid was concentrated under reduced pressure. The crude product was used in the next step without further purification: LC MS (ESI) C 12 H 19 NO4[M + H] + Calculated value: 242, Measured value: 242.

[0371] Step C: 1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl]piperidin Diazin-4-carbaldehyde (4.30 g, 17.82 mmol) and (S)-2-methyl Dipropane-2-sulfinamide (3.24 g, 26.73 mmol) in THF (40 To a stirred solution of Ti(OEt)4 (12.20 g, 53 mL) was added Ti(OEt)4 (12.20 g, 53 mL) at room temperature under a nitrogen atmosphere. 48 mmol) was added, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was diluted with EA (3×50 The combined organic layers were washed with brine (3×30 mL) and anhydrous Na2S The mixture was dried over O. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with PE / EA (1:3) When purified by silica gel column chromatography eluting with (S)-N-(( 1-((R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)piperidine -4-yl)methylene)-2-methylpropane-2-sulfinamide pale yellow oil (4.37g, 71%): LCMS (ESI) C 16 H 28 N2O4S [M + H] + Calculated value: 3 45, actual value 345. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 3.9 Hz, 1H), 4.91-4.77 (m, 1H), 4.36-4.12 (m, 2H), 4.11-3.94 (m, 1H), 3.16 (dt, J = 25.1, 12.4 Hz, 1H), 2.91-2.73 (m, 2H), 1.90 (d, J = 14.6 Hz, 2H), 1.56-1.40 (m, 1H), 1.39-1.25 (m, 8H), 1.11 (d, J = 1.3 Hz, 9H).

[0372] [Example 13] Intermediate 13 (2,2-dimethyl-1,3-dioxolane-4-carboxylic acid)

[0373] [ka]

[0374] Step A: KOH (2.10 g, 37.42 m) in HO (9 mL) and EtOH (18 mL) mol) at room temperature, -carboxylate (3.00 g, 18.73 mmol) was added in small portions. The mixture was stirred at room temperature for 2 hours, and the mixture was acidified to pH 4 with 10% aqueous H3PO4. The resulting mixture was extracted with EA (3×40 mL). The combined organic layers were washed with brine ( The solution was washed with 2×20 mL of HCl and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. Upon condensation, 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid was obtained as a colorless oil ( Obtained as 1.80g, 65%): 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 4.58-4.50 (m, 1H), 4.17 (t, J = 7.9 Hz, 1H), 4.05-3.89 (m, 1H), 1.37 (s, 3H), 1. 30 (s, 3H).

[0375] [Example 14] Intermediate 14 ((R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid)

[0376] [ka]

[0377] Step A: Dissolve KOH (3.50 g, 62.38 mmol) in HO (5 mL) and EtOH (10 methyl (4R)-2,2-dimethyl-1,3-dioxolatone Benzene-4-carboxylate (5.00 g, 31.22 mmol) was added in small portions. The reaction mixture was stirred at room temperature for an additional 2 h. The resulting mixture was diluted with H2O (10 mL). The mixture was diluted with EA (3× The combined organic layers were washed with brine (3×10 mL) and extracted with anhydrous Na After filtration, the filtrate was concentrated under reduced pressure to give (4R)-2,2-dimethyl-2,4-dichloro-1,4-dichloro ... Thio-1,3-dioxolane-4-carboxylic acid was obtained as a pale yellow oil (3.00 g, 66%) Obtained as: LCMS (ESI) C6H 10 O4 [M - H] + Calculated value: 145, measured value 145; 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (br, 1H), 4.59-4.50 (m, 1H), 4.27-4.10 (m, 1H), 4.00-3.9 1 (m, 1H), 1.45 (s, 3H), 1.38 (s, 3H).

[0378] [Example 15] Intermediate 15 (1,2-dichloro-3-iodo-4-methoxybenzene)

[0379] [ka]

[0380] Step A: 3,4-Dichlorophenol (50.00 g, 306.75 mmol), DMAP (7 4.95 g, 613.50 mmol) and EtN (62.08 g, 613.50 mmol) To a stirred solution of 1,2-dichloromethane (2,4-diethylamino) in DCM (500 mL) was added diethylcarbamate under nitrogen atmosphere at room temperature. C. methyl chloride (62.39 g, 460.12 mmol) was added dropwise. The reaction mixture was then heated under nitrogen The mixture was stirred at room temperature for 2 hours under atmospheric pressure, and the resulting mixture was diluted with water (300 mL) at room temperature. The combined organic layers were washed with brine (2 x 200 mL). The mixture was washed with HCl 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 (40 / 1) 3,4-Dichlorophenyl N,N-diethylcarbamate was obtained as a yellow oil (72 0.00g, 80%): LCMS (ESI) C 11 H 13 Cl2NO2[M + H] + Calculated value: 262, 264 (3 : 2), actual values ​​262, 264 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.42 (dq, J = 14.2, 7.2 Hz, 4H), 1.24 (dt, J = 14.8, 7.2 Hz, 6H).

[0381] Step B: Diethylpropylamine (DIPA, 42.46 g, 419.64 mmol) in THF (400 mL) was added to a solution of n-BuLi (29. 32 g, 457.79 mmol, 2.5 M in hexane) was added dropwise. After stirring, the resulting solution was added with 3,4-dichlorophenoxyethanol at -78°C for 20 minutes. N,N-diethylcarbamate (100.00 g, 381.49 mmol) in THF ( After the addition, the resulting mixture was heated at -78°C under a nitrogen atmosphere. The mixture was stirred for an additional 0.5 h. I2(1 A solution of 1.67 g (400.56 mmol) of methylpropanol in 50 mL of THF was added dropwise. The resulting mixture was stirred at −78° C. for an additional 2 hours. The resulting mixture was added to saturated NaCl solution at −78° C. The mixture was quenched with aqueous 2SO3 (300 mL) and extracted with EA (3 x 500 mL). The combined organic layer was washed with brine (2 x 200 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 (40 / 1). Purification by column chromatography yielded 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate was obtained as an off-white solid (117.00 g, 79%). Obtained by LCMS (ESI) C 11 H 12 Cl2INO2[M + H] + Calculated value: 388, 390 (3:2), measured value 388, 390 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 3.55 (q, J = 7.1 Hz, 2H), 3.42 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0382] Step C: 3,4-Dichloro-2-iodophenyl N,N-diethylcarbamate (65.80g To a stirred solution of 169.58 mmol) in MeOH (100 mL) at 0° C. was added NaOH ( A solution of 67.82 g (1695.75 mmol) in 200 mL of H2O was added. The resulting mixture was warmed to 50°C and stirred for 10 hours. The pH value of the solution was adjusted by adding an aqueous solution of HCl (1N). The reaction mixture was diluted with water (400 mL) at room temperature and diluted with EA (3×4 The combined organic layers were washed with brine (3×100 mL) and extracted with anhydrous N The mixture was dried over a2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE / EA (4 Purification by silica gel column chromatography eluting with 2,4-dimethyl-3,4-propanol (0 / 1) gave 3,4-dimethyl-3,4-propanol. Dichloro-2-iodophenol was obtained as a yellow oil (47.00 g, 96%). Ta: 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H ), 6.09 (s, 1H).

[0383] Step D: 3,4-Dichloro-2-iodophenol (100.00 g, 346.15 mmol) In a stirred solution of DMF (300 mL), CHCl (73.70 g) was added at room temperature under a nitrogen atmosphere. , 519.23 mmol) and K2CO3 (95.68 g, 692.31 mmol) The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The mixture was diluted with water (500 mL) and extracted with EA (3×600 mL). The solution was washed with 100 mL of lye (3 x 1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20 / 1). Purification by chromatography gave 1,2-dichloro-3-iodo-4-methoxybenzoate. Zene was obtained as an off-white solid (88.00 g, 84%): 1 H NMR (400 MH z, CDCl3) δ 7.44 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H).

[0384] [Example 16] Intermediate 16 (1-(allyloxy)-3,4-dichloro-2-iodobenzene)

[0385] [ka]

[0386] Step A: 3,4-Dichloro-2-iodophenol (25.00 g, 86.54 mmol) and and K2CO3 (35.88 g, 259.61 mmol) in DMF (100 mL) with stirring. 3-Bromoprop-1-ene (15.70 g, 129.81 mmol) was added to the solution at room temperature. The resulting mixture was warmed to 40°C and stirred under a nitrogen atmosphere for 4 hours. After that, the resulting mixture was diluted with water (300 mL) and EA (3×500 mL) at room temperature. The combined organic layers were washed with brine (3 x 500 mL) and anhydrous NaSO The mixture was dried over 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was washed with PE / EA (5 / 1). Purification by silica gel column chromatography with elution gave 1,2-dichloro- 3-Iodo-4-(prop-2-en-1-yloxy)benzene is a yellow solid (16. 00g, 50%) obtained as: 1 H NMR (400 MHz, CD3OD) δ 7.49 (d, J = 8.9 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.17-6.00 (m, 1H), 5.54 (dt, J = 17.3, 1.7 Hz, 1H ), 5.31 (dt, J = 10.7, 1.7 Hz, 1H), 4.65 (dd, J = 4.0, 2.3 Hz, 2H).

[0387] [Example 17] Intermediate 17 (tert-butyl 4-(1-(4,5-dichloro-2-methoxyphenyl) (vinyl)piperidine-1-carboxylate)

[0388] [ka]

[0389] Step A: Methyltriphenylphosphonium bromide (1.10 g, 3.09 mmol) in THF To a stirred solution of NaH (0.12 g, 3.09 mmHg) in 15 mL of HCl at 0 °C under a nitrogen atmosphere was added NaH (0.12 g, 3.09 mmHg). ol (60% in mineral oil) was added in small portions. The reaction mixture was allowed to warm to room temperature and stirred for 15 minutes. Then, tert-butyl 4-[(4,5-dichloro-2-methoxyphenyl)carbonyl] [carbonyl]piperidine-1-carboxylate (0.80 g, 2.06 mmol) A solution of F (3 mL) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for an additional 2 h. The resulting mixture was quenched with saturated aqueous NH4Cl (40 mL) and diluted with EA (3 × 1 The combined organic layers were washed with brine (3 x 20 mL) and anhydrous Na The mixture was dried over SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with PE / EA (5 / 1 ), and purified by silica gel column chromatography eluting with tert-butyl ether. 4-[1-(4,5-dichloro-2-methoxyphenyl)ethenyl]piperidine-1- The carboxylate was obtained as a pale yellow oil (0.50 g, 63%): LCMS (ESI) C 19 H 25 Cl2NO3[M + H] + Calculated values: 386, 388 (3 : 2), measured values ​​386, 388 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.18 (s, 1H), 7.14 (s, 1H), 5.18 (s, 1H), 4.99 (s, 1H), 4.17 -4.07 (m, 2H), 3.82 (s, 3H), 2.83-2.70 (s, 2H), 2.64-2.52 (m, 1H), 1.81-1.70 (m, 2H), 1.50-1.37 (s, 9H), 1.35-1.21 (m, 2H).

[0390] [Example 18] Intermediate 18 ((S)-N-((R)-(3,4-dichloro-2-fluoro-6-hydroxybenzoyl) (Piperidin-4-yl)methyl)-2-methylpropane-2-sulfine amide)

[0391] [ka]

[0392] Step A: 5-Bromo-1,2-dichloro-3-fluorobenzene (4.00 g, 16.40 mm A solution of i-PrM (50 mL) in THF (50 mL) was heated at -65 °C for 30 min under nitrogen atmosphere. gCl·LiCl (25 mL, 32.80 mmol, 1.3 M in THF) was added dropwise. After stirring for an additional 30 minutes, B(OMe)3 (2.56 g, 24.60 mmol) in THF (10 mL) was added dropwise at −65° C. After the addition, the reaction mixture was heated at −6 The mixture was stirred at 5° C. for 30 minutes, and the resulting mixture was quenched with water (100 mL) at −65° C. The combined organic layers were washed with brine (2 x 60 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 50% ACN in water containing 10 mmol / L NH4HCO3. Purification by filtration yielded (3,4-dichloro-5-fluorophenyl)boronic acid, which was then purified to give a yellow color. Obtained as a colored solid (0.36 g, 94%): LCMS (ESI) C6H4BCl2FO2[M - H] + plan Calculated: 207, 209 (3 : 2), Measured: 207, 209 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H).

[0393] Step B: (3,4-Dichloro-5-fluorophenyl)boronic acid (3 .60g, 18.66mmol) and KOH (4.19g, 74.71mmol, 4. To a stirred mixture of 2.54 g of H2O2 (74.71 eq.) was added HCl (2.54 g, 74.71 eq.) at room temperature under air. The reaction mixture was stirred at room temperature under air for 2 hours. The resulting mixture was quenched with saturated aqueous NaHSO3 (100 mL) at room temperature. The solution was then acidified to pH 4 with citric acid. The resulting mixture was diluted with EA (2×400 The combined organic layers were washed with brine (2 x 60 mL) and anhydrous Na2S The mixture was dried over O. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with PE / EA (2 / 1) Purification by silica gel column chromatography eluting with 3,4-dichloro -5-fluorophenol was obtained as a yellow solid (2.65 g, 70%): 1 H NMR (400 MHz, CDCl3) 6.83 (s, 1H), 6.64 (dd, J = 9.8, 2.8 Hz, 1H), 5.64 (s, 1H).

[0394] Step C: 3,4-Dichloro-5-fluorophenol (2.60 g, 14.36 mmol), E tN (4.36 g, 43.09 mmol) and DMAP (3.51 g, 28.73 m To a stirred solution of 1,2-diethylcarbamate (20 mol) in DCM (20 mL) was added diethylcarbamate under nitrogen atmosphere at room temperature. C. methyl-chloride (2.33 g, 17.24 mmol) was added dropwise to the mixture at room temperature under a nitrogen atmosphere. After stirring for 2 h, the reaction solution was quenched with water (130 mL) at room temperature and EA (2×2 The combined organic layers were washed with brine (2 x 50 mL) and anhydrous Na The mixture was dried over 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE / EA (6 / 1) and purified by silica gel column chromatography to give 3,4-dichloro-2 ... 5-fluorophenyl N,N-diethylcarbamate was obtained as an off-white solid (3 Obtained as 0.20g, 70%): LCMS (ESI) C 11 H 12 Cl2FNO2[M + H] + Calculated value: 280, 282 (3 : 2), actual values ​​280, 282 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 7 .00 (dd, J = 9.3, 2.6 Hz, 1H), 3.49-3.32 (m, 4H), 1.31-1.15 (m, 6H).

[0395] Step D: 3,4-Dichloro-5-fluorophenyl N,N-diethylcarbamate (0.50g A solution of 1.79 mmol) in 10 mL of THF was heated at -65°C for 10 minutes under a nitrogen atmosphere. Over a period of time, LDA (1.34 mL, 2.68 mmol, 2 M in THF) was added. After the addition, the reaction solution was stirred at −65° C. for 30 minutes, and then (S)-tert-butyl 4- (((tert-Butylsulfinyl)imino)methyl)piperidine-1-carboxylate A solution of methylpropanol (0.85 g, 2.68 mmol) in THF (5 mL) was added under a nitrogen atmosphere. The mixture was added dropwise over 10 minutes at 65°C. The mixture was stirred for an additional hour at -65°C under a nitrogen atmosphere. The resulting mixture was then quenched with water (30 mL) at −65° C. and diluted with EA (2×70 mL). The combined organic layers were washed with brine (2 x 10 mL) and extracted with anhydrous Na2SO4 After filtration, the filtrate was concentrated under reduced pressure to give crude tert-butyl 4-(( R)-(3,4-dichloro-6-((diethylcarbamoyl)oxy)-2-fluoro (phenyl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidine-1 The crude product was used in the next step without further purification. LCMS (ESI) C 26 H 40 Cl2FN3O5S [M + H] + Calculated value: 596, 598 (3:2), Measured value: 596, 598 (3 : 2).

[0396] Step E: tert-Butyl 4-((R)-(3,4-dichloro-6-((diethylcarbamoyl )oxy)-2-fluorophenyl)((S)-1,1-dimethylethylsulfinamine Dissolve methyl piperidine-1-carboxylate (crude) in MeOH (20 mL) To the solution was added NaOH (0.45 g, 11.32 mmol) in small portions at room temperature. The resulting mixture was warmed to 50° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was The resulting solution was diluted with water (20 mL) at room temperature and acidified to pH 4 with citric acid. The combined organic layers were washed with brine (2 x 10 mL). The residue was extracted with water (+ Purify by reverse phase chromatography eluting with 60% ACN in 0.05% TFA and tert-butyl 4-[(S)-(3,4-dichloro-2-fluoro-6-hydroxybenzoyl] (R)-2-methylpropane-2-sulfinyl)amino)methyl ] piperidine-1-carboxylate was obtained as a yellow solid (0.60 g, 68% over two steps) %) as follows: LCMS (ESI) C 21 H 31 Cl2FN2O4S [M + H] + Calculated value: 497, 499 (3:2 ), Actual values ​​497, 499 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 1.8 Hz, 1H), 4.59 (d, J = 8.2 Hz, 1H), 4.27-3.92 (m, 2H), 2.80-2.51 (m, 2H), 2.09-1.98 (m, 2H ), 1.54-1.46 (m, 3H), 1.45 (s, 9H), 1.20 (s, 9H).

[0397] Step F: tert-Butyl 4-[(S)-(3,4-dichloro-2-fluoro-6-hydroxy phenyl)([[(R)-2-methylpropane-2-sulfinyl]amino])methyl] To a solution of piperidine-1-carboxylate (crude) in DCM (10 mL) at room temperature, TFA (2 mL) was added dropwise, and the reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with saturated N The pH was adjusted to 8 with aqueous HCl and extracted with EA (2 × 80 mL). The organic layer was washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, The filtrate was concentrated under reduced pressure to give crude (R)-N-[(S)-(3,4-dichloro-2- ( [fluoro-6-hydroxyphenyl](piperidin-4-yl)methyl]-2-methylpropional Pan-2-sulfinamide was obtained as a pale yellow oil (0.40 g, 83%). The crude product was used directly in the next step without further purification: LCMS (ESI) C 16 H 23 Cl2 FN2O2S [M + H] + Calculated values: 397, 399 (3 : 2), measured values ​​397, 399 (3 : 2); 1 H NMR (400 M Hz, CD3OD) δ 6.76 (s, 1H), 4.28 (d, J = 7.6 Hz, 1H), 3.52-3.40 (m, 1H), 3.30-3. 20 (m, 1H), 3.03-2.80 (m, 2H), 2.55-2.40 (m, 1H), 2.38-2.22 (m, 1H), 1.59-1.37 ( m, 3H), 1.10 (s, 9H).

[0398] [Example 19] Intermediate 19 (Lithio(2R)-1-methyl-5-oxopyrrolidine-2-carboxylate) to)

[0399] [ka]

[0400] Step A: Ethyl (2R)-5-oxopyrrolidine-2-carboxylate (0.50 g, 3.1 To a stirred solution of 0.8 mmol) in THF (4 mL) was added NaH (0.2 5g, 6.36mmol, 60% in mineral oil) was added to the mixture, and the resulting mixture was incubated at 0°C for 10 minutes. Then, MeI (0.90 g, 6.36 mmol) was added to the mixture. The resulting mixture was stirred under a nitrogen atmosphere at 0° C. for 1 hour. The reaction was diluted with water (3 mL) at 0° C. The resulting mixture was diluted with DCM (30 mL) and water (30 mL), The aqueous layer was then extracted with DCM (3×30 mL). The combined organic layers were washed with brine (3×2 0 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. and ethyl (2R)-1-methyl-5-oxopyrrolidine-2-carboxylate was pale yellow. Obtained as a colored oil (0.22 g, 40%): LCMS (ESI) C8H 13 NO3[M + H] + plan Calculated value: 172 Measured value 172; 1 H NMR (400 MHz, CDCl3) δ 4.26 (q, J = 8.6, 7.9 Hz, 2H), 4 .18-4.08 (m, 1H), 2.89 (s, 3H), 2.58-2.29 (m, 3H), 2.16-2.05 (m, 1H), 1.44-1.30 (m, 3H).

[0401] Step B: Ethyl (2R)-1-methyl-5-oxopyrrolidine-2-carboxylate (0.1 To a stirred solution of LiOH·H2 (5 g, 0.95 mmol) in MeOH (2 mL) at room temperature, A solution of 0 (48 mg, 1.15 mmol) in HO (2 mL) was added. The reaction mixture The mixture was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure to give lithio(2R)-1-methylpropanol. ethyl-5-oxopyrrolidine-2-carboxylate was obtained as an off-white solid (0.15 g, crude), which was used directly in the next step without further purification. :LCMS (ESI) C6H9NO3[M + H] + Calculated value: 144, Measured value: 144.

[0402] [Example 20] Intermediate 20 (1-Bromo-5-chloro-4-cyclobutyl-2-methoxybenzene)

[0403] [ka]

[0404] Step A: 4-Chloro-3-iodophenol (3.00 g, 11.79 mL) in DMF (30 mL) A stirred mixture of KCO (3.26 g, 23.59 mmol) and KCO (3.26 g, 23.59 mmol) was added at room temperature. CHCl (2.51 g, 17.69 mmol) was added dropwise to the resulting mixture at room temperature. Stirred for 1 h. The reaction mixture was diluted with EA (50 mL) and water (100 mL). The solution was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (6 x 30 mL). The residue was washed with water, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography eluting with PE / EA (20 / 1). Upon filtration, 1-chloro-2-iodo-4-methylbenzene was obtained as a colorless oil (2.90 g, 92 %) was obtained as: 1 H NMR (400 MHz, CD3OD) δ 7.47-7.41 (m, 1H), 7.41-7.33 (m, 1H), 6.99-6.90 (m, 1H), 3.78 (s, 3H).

[0405] Step B: 1-chloro-2-iodo-4-methoxybenzene (1.00 g, 3.73 mmol) To a stirred solution in THF (5 mL) was added n-BuLi (2.2 mL) at −78 °C under a nitrogen atmosphere. , 5.59 mmol, 2.5 M solution in hexane) was added dropwise. The solution was heated under nitrogen atmosphere. The mixture was stirred at 78° C. for 30 minutes. Then, cyclobutanone (0.39 g, 5.59 mmol) was added to the solution. The resulting solution was stirred under a nitrogen atmosphere at -78°C for 1 hour. The mixture was quenched with saturated aqueous NH4Cl (3 mL). The mixture was diluted with water (30 mL) and the aqueous solution was then extracted with EA (3×30 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, and the residue was purified by silica gel elution with PE / EA (3 / 1). Purification by column chromatography gave 1-(2-chloro-5-methoxyphenyl) (I)cyclobutan-1-ol was obtained as a pale yellow oil (0.56 g, 71%) : 1 H NMR (400 MHz, CD3OD) δ 7.28 (dd, J = 8.7, 1.5 Hz, 1H), 6.96 (d, J = 3.0 Hz , 1H), 6.83 (dd, J = 8.7, 2.2 Hz, 1H), 3.81 (s, 3H), 2.75-2.63 (m, 2H), 2.50-2.3 7 (m, 2H), 2.23-2.12 (m, 1H), 1.78-1.66 (m, 1H).

[0406] Step C: 1-(2-chloro-5-methoxyphenyl)cyclobutan-1-ol (0.56 g, 2.63 mmol) and EtSiH (0.61 mg, 5.27 mmol) in DCM ( To a stirred solution of BF3·Et2O (0.75 g, 5.2 mL) was added BF3·Et2O (0.75 g, 5.2 mL) at room temperature under a nitrogen atmosphere. 7 mmol) was added. The solution was stirred at room temperature under nitrogen for 1 hour. The reaction was diluted with water ( The mixture was quenched with 5 mL of ethanol and concentrated under reduced pressure. The residue was eluted with PE / EA (20 / 1). Purification by silica gel column chromatography gave 1-chloro-2-cyclobutyl 4-Methoxybenzene was obtained as a colorless oil (0.49 g, 95%): 1 HN MR (400 MHz, CD3OD) δ 7.21 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 3.0 Hz, 1H), 6.74 (dd, J = 8.7, 3.0 Hz, 1H), 3.81 (s, 3H), 3.79-3.72 (m, 1H), 2.47-2.33 (m, 2H), 2 .19-1.97 (m, 3H), 1.92-1.81 (m, 1H).

[0407] Step D: 1-Chloro-2-cyclobutyl-4-methoxybenzene (0.48 g, 2.44 mmol) To a stirred solution of Br2 (0.43 g, 2.69 mmol) in HOAc (5 mL) at room temperature l) was added dropwise. The solution was stirred at room temperature for 1 hour. The reaction was diluted with saturated aqueous Na2SO3 (2m L) and diluted with EA (30 mL) and water (30 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous water. The mixture was dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE / EA( Purification by silica gel column chromatography eluting with 20 / 1 gave 1-bromo-2-(2-methyl-2-propanol)-2-(2-methyl-2-propanol). Bromo-5-chloro-4-cyclobutyl-2-methoxybenzene was obtained as a colorless liquid (0.60 g , 72%) was obtained as: 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 6.98 (s, 1H), 3.92 (s, 3H), 3.83-3.71 (m, 1H), 2.51-2.34 (m, 2H), 2.24-2.02 (m, 3H), 1.94-1.8 0 (m, 1H).

[0408] [Example 21] Intermediate 21 (1-bromo-5-chloro-4-fluoro-2-(prop-2-en-1-yl) (oxy)benzene)

[0409] [ka]

[0410] Step A: 4-Chloro-3-fluorophenol (2.00 g, 13.65 mmol) in DCM ( To a stirred solution in 15 mL of HCl at room temperature was added Br2 (2.62 g, 16.40 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction was diluted with saturated aqueous Na2SO3 at room temperature. (30 mL). The aqueous layer was extracted with EA (3 x 50 mL). The combined organic layers The residue was washed with brine (3×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate is concentrated under reduced pressure to give 2-bromo-4-chloro-5-fluorophenol as a pale yellow oil. This was carried on to the next step without further purification. Used directly on: 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 10.5 Hz, 1H).

[0411] Step B: 2-Bromo-4-chloro-5-fluorophenol (3.40 mL) in DMF (30 mL) g, 15.08 mmol) and K2CO3 (4.17 g, 30.17 mmol) To the mixture was added 3-bromoprop-1-ene (2.74 g, 22.65 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3×30 mL). The combined organic layers were Washed with brine (6 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (20 / 1). Purification by HPLC gave 1-bromo-5-chloro-4-fluoro-2-( (per-2-en-1-yloxy)benzene as a colorless oil (2.40 g, 60%) Obtained: 1 H NMR (400 MHz, CD3OD) δ 7.68 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 11.0 Hz, 1H), 6.14-6.02 (m, 1H), 5.50 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.6 Hz, 1H) ), 4.65 (d, J = 4.3 Hz, 2H).

[0412] [Example 22] Intermediate 22 (tert-butyl 8-[methoxy(methyl)carbamoyl]-3-azabicyclo[4.2.1.2]phenyl) Chloro[3.2.1]octane-3-carboxylate

[0413] [ka]

[0414] Step A: Methyl 3-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride (0. EtN (0.98 g, 9.72 mmol) in DCM To a stirred solution in (6 mL) at room temperature, add BocO (0.80 g, 3.65 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EA (20 mL) and water (30 mL). The aqueous solution was extracted with EA (3 x 20 mL). The combined organic layers were diluted with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure. When this is done, 3-tert-butyl 8-methyl 3-azabicyclo[3.2.1]octane- The 3,8-dicarboxylate was obtained as a yellow oil (0.65 g, crude), which Used directly in the next step without further purification: LCMS (ESI) C 14 H 23 NO4 [M + H - 15] + Calculated value: 255, measured value 255; 1 H NMR (400 MHz, CDCl3) δ 3.90 (d, J = 60.4 Hz, 1H), 3.79-3.60 (m, 4H), 3.17 (d, J = 41.4 Hz, 1H), 2.97-2.77 (m, 1H), 2.69-2.41 (m, 3H), 1.85-1.61 (m, 4H), 1.47 (d, J = 3.7 Hz, 9H).

[0415] Step B: 3-tert-butyl 8-methyl 3-azabicyclo[3.2.1]octane-3,8- A stirred solution of dicarboxylate (0.65 g, 2.41 mmol) in MeOH (5 mL) To the solution was added a solution of NaOH (0.19 g, 4.83 mmol) in water (2 mL) at room temperature. The reaction was stirred at 40°C for 1 hour. After cooling to room temperature, the resulting solution was diluted with EA (20 ml). The aqueous solution was acidified to pH 3 with citric acid and then diluted with water (30 mL). The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (2×20 mL). After filtration, the filtrate was evaporated under reduced pressure to give 3-( tert-Butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carbonyl The carboxylic acid was obtained as a yellow oil (0.70 g, crude), which could be further purified. Used directly in the next step without further analysis: LCMS (ESI) C 13 H 21 NO4[M + H -56] + Calculated value: 200, Actual value 200; 1 H NMR (400 MHz, CD3OD) δ 3.88 (d, J = 12.5 Hz, 1H), 3.68 (d, J = 13 .1 Hz, 1H), 3.32-3.13 (m, 1H), 3.05-2.75 (m, 3H), 2.73-2.36 (m, 2H), 1.89-1.74 ( m, 2H), 1.64-1.55 (m, 1H), 1.47 (s, 9H).

[0416] Step C: 3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane 8-carboxylic acid (0.70 g, 2.74 mmol), HOBt (0.56 g, 4.11 mmol), A stirred solution of EDCI (0.79 g, 4.11 mmol) and EDCI (0.79 g, 4.11 mmol) in DMF (6 mL) was The solution was diluted with N,O-dimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmHg) at room temperature. ol) and EtN (0.55 g, 5.48 mmol) were added. The reaction was stirred at room temperature for 1 The reaction was stirred for 6 h. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was Extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (6 x 10 mL). The residue was evaporated under reduced pressure and the resulting mixture was washed with PE Purification by silica gel column chromatography eluting with ethanol / EA (2 / 1) yielded tert-Butyl 8-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.2 .1]octane-3-carboxylate as a pale yellow oil (0.43 g, 53%) Obtained: LCMS (ESI) C 15 H 26 N2O4[M + H - 56] + Calculated value: 243, measured value 243; 1 H NMR (4 00 MHz, CDCl3) δ 3.91 (d, J = 47.8 Hz, 1H), 3.73 (d, J = 10.9 Hz, 3H), 3.69-3.3 9 (m, 2H), 3.21 (d, J = 12.8 Hz, 3H), 3.03-2.84 (m, 1H), 2.74 (d, J = 17.2 Hz, 1 H), 2.55-2.33 (m, 3H), 2.03-1.88 (m, 1H), 1.84-1.57 (m, 2H), 1.47 (d, J = 7.2 Hz , 9H).

[0417] [Example 23] Intermediate 23 ((S)-N-[(R)-(4-bromo-5-chloro-2-methoxyphenyl )([1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl]pi 2-Methyl-2-propane-2-sulfinamide)

[0418] [ka]

[0419] Step A: 3-Bromo-4-chlorophenol (5.00 g, 24.10 mL) in THF (50 mL) To a stirred mixture of K2CO3 (9.99 g, 72.31 mmol) and K2CO3 (9.99 g, 72.31 mmol), 40 At 40°C, MeI (10.26 g, 72.31 mmol) was added dropwise. The reaction mixture was stirred at 40°C. The mixture was stirred for 16 h, diluted with water (50 mL) and diluted with EA (3×100 mL). The combined organic layers were washed with brine (2 x 100 mL) and extracted with anhydrous Na2SO4 The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel elution with PE. Purification by column chromatography gave 2-bromo-1-chloro-4-methoxybenzoate. Benzene was obtained as a colorless oil (4.50 g, 84%): 1 H NMR (400 MHz, CD3 OD) δ 7.41 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 6.93 (dd, J = 8.9, 2. 9 Hz, 1H), 3.81 (s, 3H).

[0420] Step B: 2-Bromo-1-chloro-4-methoxybenzene (2.00 g, 9.03 mmol) To a stirred solution in DCM (20 mL) at room temperature was added AgOTf (2.55 g, 9.93 mmol) After the addition, I2 (2.52 g, 9.93 mmol) was added to the reaction mixture and mixed. The mixture was stirred at room temperature for 3 hours. The reaction was diluted with saturated aqueous Na2SO3 (50 mL) at room temperature. It was quenched and extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (3 x 50 mL). The residue was washed with HCl (HCl), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give 1-bromo-2-methyl-2-propanol. Bromo-2-chloro-4-iodo-5-methoxybenzene was obtained as an off-white solid (2.5 0g, 80%) obtained as: 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.04 (s, 1H), 3.89 (s, 3H).

[0421] Step C: 1-Bromo-2-chloro-4-iodo-5-methoxybenzene (10.00 g, 28. A solution of 79 mmol) in THF (20 mL) was heated at -90°C for 10 min under a nitrogen atmosphere. Then add n-BuLi (11.5 mL, 28.75 mmol, 2.5 M in hexane) dropwise. The solution was stirred at the same temperature for 30 minutes.

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0073] [ A solution of 9.10 g (28.79 mmol) in THF (10 mL) was added to the above solution at -90 °C. The addition was rapid (the reaction temperature rose from -90°C to -70°C). The reaction was stirred for an additional 1.5 h at 5° C. The reaction was washed with saturated aqueous NH4Cl (20 mL). The mixture was quenched and then diluted with water (100 mL). The aqueous phase was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. The mixture was dried and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with 10 mmol / L NH4HCO Purification by reversed-phase chromatography eluting with 60% ACN in water containing 4 gave te rt-Butyl 4-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)([[ (S)-2-Methylpropane-2-sulfinyl]amino])methyl]piperidine-1- The carboxylate was obtained as an off-white solid (12.40 g, 80%): LC MS (ESI) C 22 H 34 BrClN2O4S [M + H] + Calculated values: 537, 539 (2:3:1), measured values: 537, 539 (2 : 3 : 1); 1 H NMR (400 MHz, CD3OD) δ 7.43 (s, 1H), 7.30 (s, 1H), 4.44 (d, J = 8.9 Hz, 1H), 4.16 (d, J = 13.4 Hz, 1H), 4.01 (d, J = 13.1 Hz, 1H), 3.85 (s, 3H) , 2.84-2.57 (m, 2H), 2.17-2.05 (m, 1H), 2.02-1.84 (m, 1H), 1.545 (s, 9H), 1.30-1 .08 (m, 3H), 1.13 (s, 9H).

[0422] Step D: tert-Butyl 4-[(R)-(4-bromo-5-chloro-2-methoxyphenyl) ([[(S)-2-Methylpropane-2-sulfinyl]amino])methyl]piperidine A solution of 1-carboxylate (6.00 g, 11.19 mmol) in DCM (60 mL) was stirred. To the stirred solution was added TFA (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred at room temperature and neutralized with saturated aqueous NaHCO3 (50 mL). The extract was extracted with DCM (3 x 200 mL). The combined organic layers were concentrated under reduced pressure to give (S). -N-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)(piperidine-4 [-yl]methyl-2-methylpropane-2-sulfinamide was obtained as a yellow oil (4.6 The crude product was directly used in the next step without further purification. Used: LCMS (ESI) C 17 H 26 BrClN2O2S [M + H] + Calculated values: 437, 439 (2:3:1), measured Values ​​437, 439 (2 : 3 : 1); 1 H NMR (400 MHz, CD3OD) δ 7.45 (s, 1H), 7.35 (s, 1H), 4. 50 (d, J = 9.1 Hz, 1H), 3.90 (s, 3H), 3.47 (d, J = 12.8 Hz, 1H), 3.30-3.25 (m, 1 H), 3.01-2.80 (m, 2H), 2.42-2.33 (m, 1H), 2.19-2.06 (m, 1H), 1.57-1.28 (m, 3H), 1.14 (s, 9H).

[0423] Step E: (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (1.70 g, 11.63 mmol) and HATU (4.43 g, 11.65 mmol) in DMF (1 To a stirred solution of (S)-N-[(R)-(4-bromo-5-chloro-2-methyl-2-propanol]-2-one at room temperature was added 100 mL of HCl. -Methoxyphenyl)(piperidin-4-yl)methyl]-2-methylpropan-2-s Sulfinamide (3.40 g, 7.76 mmol) and EtN (2.36 g, 23. 29 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water ( The mixture was quenched with EA (60 mL) and extracted with EA (3 x 100 mL). The mixture was washed with ethanol (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with 70% ACN in water containing 10 mmol / L NH4HCO3. Purification by reverse phase chromatography with HCl gave (S)-N-[(R)-(4-bromo -5-chloro-2-methoxyphenyl)([1-[(4R)-2,2-dimethyl-1,3 -dioxolane-4-carbonyl]piperidin-4-yl])methyl]-2-methylpropane Pan-2-sulfinamide was obtained as an off-white solid (3.80 g, 86%). LCMS (ESI) C 23 H 34 BrClN2O5S [M + H] + Calculated values: 565, 567 (2:3:1), measured value 56 5, 567 (2 : 3 : 1); 1 H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 5.48-5.32 (dd, J = 33.5, 7.5 Hz, 1H), 4.59-4.37 (m, 2H), 4.20- 4.10 (m, 1H), 4.32-4.18 (m, 2H), 3.88 (d, J = 2.2 Hz, 3H), 3.20-2.90 (m, 1H), 2. 73-2.56 (m, 1H), 2.25-2.06 (m, 2H), 1.48-1.33 (m, 8H), 1.17-1.09 (m, 10H).

[0424] [Example 24] Intermediate 24 ((S)-N-[(R)-[4-bromo-5-chloro-2-(prop-2-enyl)methyl] (4R)-2,2-dimethyl-1,3-diphenyl-1-yloxy)phenyl Xolane-4-carbonyl]piperidin-4-yl])methyl]-2-methylpropane- 2-sulfinamide)

[0425] [ka]

[0426] Step A: 1-Bromo-2-chloro-4-iodo-5-methoxybenzene (47.00 g, 135 To a stirred solution of 0.30 mmol) in DCM (470 mL) was added BBr 3 (101.00 g, 405.90 mmol) was added dropwise. The reaction solution was heated under a nitrogen atmosphere. The reaction was stirred at room temperature for 20 hours. The reaction was quenched with water (500 mL) at 0° C. and EA (3 The combined organic layers were washed with brine (3 x 500 mL) and After filtration, the filtrate was concentrated under reduced pressure to give 5-bromo-4- Chloro-2-iodophenol was obtained as a pale yellow solid (45.50 g, 95%). This was used in the next step without further purification.

[0427] Step B: 5-Bromo-4-chloro-2-iodophenol (45.20 g, 141.59 mmol) To a stirred solution of 100 mL of KCO3 (39.1%) in DMF (100 mL) was added KCO3 (39.1%) at room temperature under a nitrogen atmosphere. 14g, 283.18mmol) and allyl bromide (29.12g, 240.70mmol) l) was added dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was diluted with water (200 mL). The resulting mixture was extracted with EA (3×200 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 purified by silica gel column elution with PE. Purification by chromatography gave 1-bromo-2-chloro-4-iodo-5-(propanol). (28.50 g, 54%) of propyl-2-en-1-yloxybenzene was obtained as a colorless oil. and obtained: 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.0 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 6.12-5.98 (m, 1H), 5.53 (dq, J = 17.2, 1.6 Hz, 1H), 5.37 (dq, J = 1 0.7, 1.4 Hz, 1H), 4.59 (dq, J = 4.6, 1.5 Hz, 2H).

[0428] Step C: 1-Bromo-2-chloro-4-iodo-5-(prop-2-en-1-yloxy)benzyl To a stirred solution of benzene (10.00 g, 26.78 mmol) in THF (250 mL) was added nitrogen. n-BuLi (10.71 mL, 26.78 mmol, hexane) was added at -100 °C under nitrogen atmosphere. After stirring at -100°C for 30 minutes under a nitrogen atmosphere, the mixture was cooled to 100°C and cooled to 100°C. t-Butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl] Piperidine-1-carboxylate (8.47 g, 26.7 mmol) in THF (40 m The resulting mixture was further heated at -100°C. The reaction was stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl (200 mL) at -100 °C. The aqueous layer was extracted with EA (3 x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 70% ACN in water (+0.05% TFA). Purification by HCl gave tert-butyl 4-[(R)-[4-bromo-5-chloro-2-(2-methyl-2-propanol]-2-yl]propanol]. -(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane -2-sulfinyl]amino])methyl]piperidine-1-carboxylate is pale yellow Obtained as an oil (10.00 g, 60%): LCMS (ESI) C 24 H 36 BrClN2O4S [M + H] + Calculated values: 563, 565 (2 : 3 : 1), measured values: 563, 565 (2 : 3 : 1); 1 H NMR (400 MHz, CD Cl3) δ 7.22 (s, 1H), 7.12 (s, 1H), 6.11-5.96 (m, 1H), 5.48-5.30 (m, 2H), 4.61-4 .55 (m, 2H), 4.46 (s, 1H), 4.24-4.02 (m, 2H), 2.74-2.47 (m, 2H), 2.03-1.77 (m, 2 H), 1.46 (s, 9H), 1.40-1.11 (m, 3H), 1.18 (s, 9H).

[0429] Step D: tert-Butyl 4-[(R)-[4-bromo-5-chloro-2-(prop-2-ene -1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl] Amino])methyl]piperidine-1-carboxylate (5.60 g, 9.96 mol) To a stirred solution of in DCM (50 mL) at room temperature was added TFA (10 mL) dropwise. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was neutralized with saturated aqueous NaHCO3 at room temperature. The aqueous layer was extracted with EA (3 x 100 mL). The combined organic layers were concentrated under reduced pressure to give (S)-N-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yl Oxy)phenyl](piperidin-4-yl)methyl]-2-methylpropan-2-sulfonyl Finamide was obtained as a pale yellow semi-solid (5.30 g, crude). Used directly in the next step without further purification: LCMS (ESI) C 19 H 28 BrClN2O2S [M + H] + Calculated values: 463, 465 (2 : 3 : 1), measured values: 463, 465 (2 : 3 : 1); 1 H NMR (400 MHz, CDC l3) δ 7.25 (s, 1H), 7.13 (s, 1H), 6.08-5.98 (m, 1H), 5.46-5.34 (m, 2H), 4.62-4. 51 (m, 2H), 4.45-4.36 (s, 1H), 4.25-4.18 (m, 1H), 3.49-3.34 (dd, J = 32.3, 12.9 Hz, 2H), 2.90-2.73 (m, 2H), 2.26-1.97 (m, 2H), 1.80-1.52 (m, 3H), 1.18 - 1.09 (s , 9H).

[0430] Step E: (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2.50 g, 17.13 mmol) and HATU (6.52 g, 17.13 mmol) in DMF (3 To a stirred solution of (S)-N-[(R)-[4-bromo-5-chloro-2-(2-methyl-2-propanol]-2-one] at room temperature was added 20 mL of HCl. -(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl] -2-methylpropane-2-sulfinamide (5.30 g, 11.42 mmol) and The reaction solution was stirred at room temperature for 1 hour. The resulting solution was quenched with water (60 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with 10 mmol / L NH4HCO3 Purification by reversed-phase chromatography eluting with 70% ACN in water containing (S)- N-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy) phenyl]([1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbo Nyl]piperidin-4-yl])methyl]-2-methylpropane-2-sulfinamide was obtained as an off-white solid (3.80 g, 54%): LCMS (ESI) C 25 H 36 BrC lN2O5S [M + H] + Calculated values: 591, 593 (2 : 3 : 1), measured values ​​591, 593 (2 : 3 : 1); 1 HNM R (400 MHz, CDCl3) δ 7.24 (d, J = 22.6 Hz, 1H), 7.12 (s, 1H), 6.07-5.97 (m, 1H) , 5.46-5.30 (m, 2H), 4.68-4.58 (m, 2H), 4.60-4.50 (m, 3H), 4.49-4.33 (m, 1H), 4. 21-4.01 (m, 2H), 3.92-3.88 (m, 1H) 3.09-2.82 (m, 1H), 2.56 (t, J = 12.7 Hz, 1H), 2.19-1.96 (m, 2H), 1.57-1.25 (m, 9H), 1.17 (d, J = 11.7 Hz, 9H).

[0431] [Example 25] Intermediate 25 ((S)-N-((R)-(2-(allyloxy)-5-chloro-4-methyl (Phenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfina Mid)

[0432] [ka]

[0433] Step A: 1,1 of 2-bromo-5-methylphenol (42.00 g, 224.56 mmol) To a stirred solution in 1,3,3,3-hexafluoropropan-2-ol (500 mL), NCS (31.00 g, 235.78 mmol) was added in small portions at room temperature under an air atmosphere. The reaction solution was heated to 50°C and stirred under air for 16 hours. The resulting solution was then concentrated under reduced pressure. The residue was purified by silica gel column eluted with PE / EA (50 / 1). Purification by gel column chromatography yielded 2-bromo-4-chloro-5-methyl Chilphenol was obtained as a pale yellow solid (47.00 g, 90%): 1 H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 6.93 (d, J = 0.8 Hz, 1H), 2.32 (d, J = 0.7 Hz, 3H).

[0434] Step B: 2-Bromo-4-chloro-5-methylphenol (31.0 mL) in DMF (300 mL) A stirred mixture of K2CO3 (39.00g, 0.28mol) and K2CO3 (39.00g, 0.14mol) Allyl bromide (29.00 g, 0.24 mol) was added dropwise to the mixture at room temperature under an air atmosphere. The reaction mixture was stirred at 40°C for 16 hours under air atmosphere. After cooling to room temperature, the obtained The mixture was diluted with water (300 mL) and extracted with EA (3×150 mL). The organic layer was washed with brine (6 x 100 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column eluting with PE / EA (100 / 1). Purification by column chromatography gave 1-bromo-5-chloro-4-methyl-2 -(prop-2-en-1-yloxy)benzene was obtained as a colorless oil (24.50 g, 66 %) was obtained as: 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.77 (s, 1H), 6.12- 6.02 (m, 1H), 5.50 (d, J = 17.3 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H), 4.63-4.56 (m , 2H), 2.34 (s, 3H).

[0435] Step C: 1-Bromo-5-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzyl To a stirred solution of benzene (29.00 g, 0.12 mol) in THF (900 mL) was added a nitrogen atmosphere. n-BuLi (48 mL, 0.12 mol, 2.5 M in hexane) at -90 °C under ambient temperature After stirring at -90°C for 40 minutes under a nitrogen atmosphere, tert-butyl 4-[[ (S)-2-Methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate A solution of carboxylate (35.57 g, 0.12 mol) in THF (80 mL) was heated under nitrogen The resulting mixture was purged with nitrogen and stirred at −90° C. for 20 minutes. The reaction was stirred under atmospheric pressure for an additional hour at −90° C. The reaction was diluted with saturated aqueous NH4Cl at −90° C. The reaction mixture was quenched with 100 mL of water. The reaction mixture was concentrated under reduced pressure to remove THF. The layers were extracted with EA (3 x 600 mL). The combined organic layers were washed with brine (3 x 200 mL). The mixture was washed with HCl and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was The product was purified by silica gel column chromatography eluting with PE / EA (1 / 1). tert-butyl 4-[(R)-[5-chloro-4-methyl-2-(propan-2-yl)methyl] (S)-2-methylpropane-2-sulfini [N-(2-amino)methyl]piperidine-1-carboxylate was obtained as a pale yellow oil (25.4 0g, 44%): LCMS (ESI) C 25 H 39 ClNOS [M + H] + Calculated value: 499, 50 1 (3 : 1), actual values ​​499, 501 (3 : 1); 1 H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 6.74 (s, 1H), 6.10-5.93 (m, 1H), 5.47-5.26 (m, 2H), 4.61-4.50 (m, 2H), 4.41-4.28 (m, 1H), 4.21-4.04 (m, 2H), 3.95-3.73 (m, 1H), 2.82-2.47 (m, 2H), 2.41 (s, 3H), 2.1 0-1.96 (m, 1H), 1.93-1.75 (m, 1H), 1.47 (s, 9H), 1.37-1.21 (m, 3H), 1.12 (s, 9H) .

[0436] Step D: tert-Butyl 4-[(R)-[5-chloro-4-methyl-2-(prop-2-ene -1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl] Amino])methyl]piperidine-1-carboxylate (48.00 g, 95.77 mm To a stirred solution of 1,2-diol) in DCM (380 mL) at room temperature was added TFA (96 mL) dropwise. The resulting mixture was stirred at room temperature for an additional hour. The mixture was basified to pH 8. The resulting mixture was extracted with EA (3 x 1 L). The combined organic layers The extract was washed with brine (3 x 300 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure to give (S)-N-[(R)-[5-chloro-4-methyl-2-(propanol) (2-prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2- Methylpropane-2-sulfinamide was obtained as a pale yellow oil (33.10 g, 88%). Obtained by LCMS (ESI) C 20 H 31 ClN2O2S [M + 1] + Calculated value: 399, 401 (3:1), measured value 3 99, 401 (3 : 1); 1 H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.75 (s, 1H), 6.08-5.9 3 (m, 1H), 5.44-5.21 (m, 2H), 4.60-4.47 (m, 2H), 4.34-4.22 (m, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.34 (d, J = 13.0 Hz, 1H), 2.88-2.72 (m, 2H), 2.34 (s, 3H), 2.12 (d, J = 10.5 Hz, 2H), 1.69-1.51 (m, 3H), 1.10 (s, 9H).

[0437] [Example 26] Intermediate 26 (N-[(1-acetylpiperidin-4-yl)(4,5-dichloro-2-methyl)methyl] (2-methylphenyl)methylidene]-2-methylpropane-2-sulfinamide

[0438] [ka]

[0439] Step A: 1-[4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidine- 1-yl]ethan-1-one (0.30 g, 0.91 mmol) and Ti(OEt) To a stirred solution of (0.41 g, 1.82 mmol) in THF (10 mL) under a nitrogen atmosphere, 2-methylpropane-2-sulfinamide (0.22 g, 1.82 mmol) at room temperature The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. After this time, the reaction was quenched with saturated aqueous NH4Cl (50 mL) at room temperature and EA (3 The combined organic layers were washed with brine (2×50 mL) and extracted with anhydrous N The mixture was dried over a2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE / EA (2 Purification by silica gel column chromatography eluting with N-[(1 -acetylpiperidin-4-yl)(4,5-dichloro-2-methoxyphenyl)methyl 6-[2-(2-phenyl-2-thiazolinone)-2-methylpropane-2-sulfinamide was obtained as a pale yellow oil (0.27 g, 6 8%) as follows: LCMS (ESI) C 19 H 26 Cl2N2O3S[M + H] + Calculated value: 433, 435 (3:2 ), actual values ​​433, 435 (3:2).

[0440] [Example 27] Intermediate 27 ((2R,3S)-3-(benzoyloxy)oxolane-2-carboxylic acid)

[0441] [ka]

[0442] Step A: (4R,5S)-5-(hydroxymethyl)oxolane-2,4-diol (15.0 To a solution of 100 ml of 1000 ml of HCl (1000 g, 111.83 mmol) in MeOH (130 mL) at 0° C., H2SO4 (1.49 mL, 27.95 mmol, 97%) in 20 mL of HCl was added. The reaction mixture was stirred at 0°C to room temperature for 16 hours. The mixture was adjusted to pH 7 with saturated aqueous NaHCO3. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column eluting with PE / EA (1 / 4). Purification by chromatography gave (2S,3R)-2-(hydroxymethyl)- 5-Methoxyoxolan-3-ol as a pale yellow oil (15.00 g, 91%) Obtained: 1 H NMR (400 MHz, DMSO-d6) δ 4.64 (t, J = 3.3 Hz, 1H), 4.52 (d, J = 5. 5 Hz, 1H), 4.48-4.44 (m, 1H), 3.80-3.73 (m, 1H), 3.57-3.52 (m, 2H), 3.52-3.46 (m , 1H), 3.24-3.22 (m, 3H), 1.87-1.80 (m, 1H), 1.53 (dt, J = 12.8, 4.0 Hz, 1H).

[0443] Step B: (2S,3R)-2-(hydroxymethyl)-5-methoxyoxolan-3-ol ( 5.00 g, 33.75 mmol) and bis(trimethylsilyl)trifluoroacetate A solution of the amide (17.37 g, 67.48 mmol) in ACN (5 mL) was heated at 80 °C for 5 h. After cooling to room temperature, EtSiH (19.62 g, 168.74 mmol) and TMSOTf (37.50 g, 168.72 mmol) were added at room temperature for 15 min. The resulting mixture was stirred at room temperature for an additional 16 hours. The reaction was quenched with water (30 mL) at 0 °C and purified with saturated aqueous NaHCO3. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with EA. Purification by column chromatography yielded (2S,3R)-2-(hydroxymethyl) (Cyclohexyl)oxolan-3-ol was obtained as a pale yellow semi-solid (1.40 g, 35%) : 1 H NMR (400 MHz, DMSO-d6) δ 4.93-4.77 (m, 1H), 4.71-4.54 (m, 1H), 3.82-3.67 ( m, 2H), 3.57 (td, J = 5.3, 2.9 Hz, 1H), 3.40-3.33 (m, 1H), 1.98-1.85 (m, 1H), 1. 74-1.63 (m, 1H).

[0444] Step C: (2S,3R)-2-(hydroxymethyl)oxolan-3-ol (1.30 g, 1 1.01 mmol) and imidazole (0.76 g, 11.12 mmol) in DMF ( To a stirred solution of 1.66 g (11.01 mmol) of TBDMSCl in 8 mL of HCl at room temperature was added The resulting solution was stirred at room temperature for 0.5 h. The reaction was diluted with EA (50 mL) and Diluted with water (50 mL). The aqueous solution was extracted with EA (2 x 50 mL). The combined organic layers The residue was washed with brine (3×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was purified by silica gel column chromatography eluting with PE / EA (2 / 1). Then, (2S,3R)-2-[[(tert-butyldimethylsilyl)oxy]methyl ]Oxolan-3-ol was obtained as a colorless oil (1.54 g, 60%): 1 HN MR (400 MHz, DMSO-d6) δ 4.88 (d, J = 4.2 Hz, 1H), 4.08-3.99 (m, 1H), 3.82-3.68 (m, 2H), 3.62-3.55 (m, 1H), 3.55-3.44 (m, 2H), 2.01-1.85 (m, 1H), 1.78-1.63 (m, 1H), 0.87 (s, 9H), 0.04 (d, J = 2.5 Hz, 6H).

[0445] Step D: (2S,3R)-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxy Solan-3-ol (0.82 g, 3.53 mmol) and benzoic acid (0.56 g, 4 To a stirred solution of Ph3P (1.85 g, 7.0001 mmol) in THF (8 mL) at room temperature was added Ph3P (1.85 g, 7.0001 mmol). 0.05 mmol) and DEAD (1.23 g, 7.06 mmol) were added. The resulting solution was stirred at room temperature for 1 h. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (3 × 30 The mixture was washed with 1 mL of PE / EA (6 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was diluted with PE / EA (6 mL). When purified by silica gel column chromatography eluting with 1), (2S, 3S )-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxolane-3-yl The benzoate was obtained as a colorless oil (1.00 g, 84%): 1 H NMR (400 MH z, CDCl3) δ 8.06 (dt, J = 8.2, 1.1 Hz, 2H), 7.66-7.55 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 5.72-5.59 (m, 1H), 4.20-4.01 (m, 1H), 4.01-3.81 (m, 1H), 3.96 (td, J = 8.7, 4.8 Hz, 1H), 3.91 (dd, J = 6.3, 2.0 Hz, 2H), 2.48-2.32 (m, 1H), 2.20-2.08 (m, 1H), 0.85 (s, 9H), 0.05--0.05 (m, 6H).

[0446] Step E: (2S,3S)-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxy Solan-3-ylbenzoate (0.50 g, 1.49 mmol) in THF (3 mL) To a stirred solution of TBAF (2.97 mL, 2.97 mL) in HOAc (0.1 mL) was added at room temperature. 0 mmol, 1M in THF) was added. The reaction was stirred at room temperature for 3 hours. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (2×30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was purified by silica gel column chromatography eluting with PE / EA (1 / 4). Purification by filtration yielded (2S,3S)-2-(hydroxymethyl)oxolane-3 -yl benzoate was obtained as a colorless oil (0.30 g, 91%): 1 H NMR (40 0 MHz, DMSO-d6) δ 7.96-7.91 (m, 2H), 7.68-7.62 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H ), 5.51-5.46 (m, 1H), 3.97-3.86 (m, 2H), 3.81-3.72 (m, 1H), 3.65-3.57 (m, 2H), 2 .40-2.29 (m, 1H), 2.02-1.93 (m, 1H).

[0447] Step F: (2S,3S)-2-(hydroxymethyl)oxolan-3-ylbenzoate (0. 34g, 1.53mmol) and (acetyloxy)(phenyl)-lambda-3-ioda Dissolve methyl methyl acetate (0.74 g, 2.30 mmol) in ACN (3 mL) and water (3 mL To the stirred solution in HCl at room temperature was added TEMPO (48 mg, 0.31 mmol). The mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with saturated aqueous Na2SO3 (10 mL). The mixture was quenched and concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EA (1 / 1). Purification by gel column chromatography yielded (2R,3S)-3-(benzoyl) (2-amino-2-pyroxy)oxolane-2-carboxylic acid was obtained as a colorless oil (0.20 g, 55%). was: 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.07-7.81 (m, 2H), 7.68 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.3 Hz, 2H), 5.93-5.64 (m, 1H), 4.69-4.51 (m, 1H), 4.17-3.84 (m, 2H), 2.38-2.23 (m, 1H), 2.20-2.02 (m, 1H).

[0448] [Example 28] Intermediate 28 (Lithio 4-methyl-5-oxomorpholine-2-carboxylate)

[0449] [ka]

[0450] Step A: Stirring isoserine (50.00 g, 475.77 mmol) in MeOH (300 mL) To the stirred mixture was added SOCl2 (41 mL, 570.97 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give methyl 3- Amino-2-hydroxypropanoate was obtained as an off-white solid (50.00 g, 71% ) obtained as: LCMS (ESI) C4H9NO3 [M + H] + Calculated value: 120, measured value 120; 1 H NMR (4 00 MHz, CD3OD) δ 4.50 (dd, J = 8.2, 4.0 Hz, 1H), 3.82 (s, 3H), 3.36-3.30 (m, 1H ), (dd, J = 13.0, 8.3 Hz, 1H).

[0451] Step B: Methyl 3-amino-2-hydroxypropanoate (22.50g, 188.89mm ol) and EtN (57.34 g, 566.66 mmol) in DCM (300 mL) To the stirred solution, chloroacetyl chloride (21.33 g, 188.89 mmol) was added at room temperature. ) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 2). When prepared, methyl 3-(2-chloroacetamido)-2-hydroxypropanoate turns yellow. Obtained as a colored solid (13.00 g, 35%): LCMS (ESI) C6H 10 ClNO4[M + H] + of Calculated values: 196, 198 (3 : 1), Measured values: 196, 198 (3 : 1); 1 H NMR (400 MHz, CDCl) δ 6.9 7 (s, 1H), 4.35 (t, J = 5.0 Hz, 1H), 4.08 (s, 2H), 3.84 (s, 3H), 3.79-3.62 (m, 2 H), 3.26 (s, 1H).

[0452] Step C: Methyl 3-(2-chloroacetamido)-2-hydroxypropanoate (5.00g To a stirred solution of 25.56 mmol) in THF (300 mL) under nitrogen atmosphere at room temperature, t-BuOK (5.74 g, 51.15 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the starting material was completely consumed, MeI (4.35 g, 30.65 mmol) was added. The reaction mixture was stirred at room temperature for an additional 2 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give methyl 4-Methyl-5-oxomorpholine-2-carboxylate was obtained as a pale yellow semi-solid (0.90 g, 20%): LCMS (ESI) C7H 11 NO4[M + H] + Calculated value: 174, Measured value: 174 ; 1 H NMR (400 MHz, CD3OD) δ 4.61 (dd, J = 7.5, 4.8 Hz, 1H), 4.30 (d, J = 16.5 H z, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.78 (s, 3H), 3.63 (dd, J = 6.2, 4.1 Hz, 2H), 2.98 (s, 3H).

[0453] Step D: Methyl 4-methyl-5-oxomorpholine-2-carboxylate (0.15 g, 0. To a stirred solution of LiOH HO (73 m A solution of 1.73 g of HCl in 1 mL of water was added to the reaction mixture. The reaction mixture was stirred at 40° C. for 1 hour. The reaction was concentrated under reduced pressure to give lithio 4-methyl-5-oxomorpholine-2- The carboxylate was obtained as an off-white solid (0.14 g, crude) which was Used directly in the next step without further purification: LCMS (ESI) C6H9NO4 [M + H] + of Calculated: 160, Measured: 160.

[0454] [Example 29] Intermediate 29 (tert-butyl 3-[methoxy(methyl)carbamoyl]-8-azabicyclo[4.2.1.2]phenyl) Chloro[3.2.1]octane-8-carboxylate

[0455] [ka]

[0456] Step A: Methyl 8-azabicyclo[3.2.1]octane-3-carboxylate (1.00g , 5.91 mmol) and EtN (1.20 g, 11.86 mol) in DCM (10 To a stirred solution of 1.6 mL of BocO (1.60 g, 7.33 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EA (50 mL) and water (50 mL). The isolated aqueous solution was extracted with EA (3 x 20 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. Then, 8-tert-butyl 3-methyl 8-azabicyclo[3.2.1]octane-3 The 8-dicarboxylate was obtained as a pale yellow oil (1.30 g, 99%): LC MS (ESI) C 14 H 23 NO4[M + H -15] + Calculated value: 255, measured value 255.

[0457] Step B: 8-tert-butyl 3-methyl 8-azabicyclo[3.2.1]octane-3,8- To a stirred solution of dicarboxylate (1.30 g, 4.83 mol) in MeOH (5 mL) At room temperature, a solution of NaOH (0.39 g, 9.65 mol) in H2O (0.5 mL) was added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 x 20 mL). The combined aqueous layers were diluted with citric acid. The mixture was acidified to pH 3 and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine ( The solution was washed with 10 mL of HCl (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. When condensed, it becomes (8-[(tert-butoxy)carbonyl]-8-azabicyclo[3.2. 1]octane-3-carboxylic acid) was obtained as a pale yellow oil (1.20 g, 97%). LCMS (ESI) C 13 H 21 NO4[M + Na] + Calculated value: 278, measured value 278; 1 H NMR (300 MHz, CDC l3) δ 4.40-4.21 (m, 2H), 2.94-2.79 (m, 1H), 2.06-1.98 (m, 2H), 1.98-1.84 (m, 2H ), 1.84-1.73 (m, 2H), 1.73-1.59 (m, 2H), 1.49 (s, 9H).

[0458] Step C: 8-[(tert-butoxy)carbonyl]-8-azabicyclo[3.2.1]octa 3-(2 ... To a stirred solution of 0.40 mmol) of CDI (0.91 g, 5 0.64 mmol) and N,O-methoxy(methyl)amine hydrochloride (0.69 g, 7.0 5 mmol) was added. The reaction was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1). Purification gave tert-butyl 3-[methoxy(methyl)carbamoyl]-8-azabicyclo[4.2.1.2]methyl- ... Chloro[3.2.1]octane-8-carboxylate was obtained as a pale yellow oil (1.10 g, 3 69% over the entire step): LCMS (ESI) C 15 H 26 N2O4[M + H - 56] + Calculation of Value: 243, Actual value 243; 1 H NMR (400 MHz, CDCl3) δ 4.40-4.23 (m, 1H), 3.82-3.76 (m, 1H), 3.76-3.71 (m, 3H), 3.35-3.21 (m, 1H), 3.19 (d, J = 2.6 Hz, 3H), 2.18-1.93 ( m, 4H), 1.81-1.56 (m, 4H), 1.56-1.44 (m, 9H).

[0459] [Example 30] Intermediate 30 (tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1 -carboxylate)

[0460] [ka]

[0461] Step A: 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (2.00g , 9.94 mmol) and CDI (1.80 g, 10.9 mmol) in DCM (10 m To a stirred solution of EtN (1.20 g, 11.93 mmol) and N,O at room temperature 1-Methoxy(methyl)amine hydrochloride (0.90 g, 14.91 mmol) was added to the reaction mixture. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (30 mL) at room temperature and added to E The combined organic layers were washed with brine (2×20 mL) and extracted with HCl (3×30 mL). The residue was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography eluting with tetrahydrofuran A (1 / 1) gave te rt-Butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate The compound was obtained as a pale yellow oil (2.10 g, 78%): LCMS (ESI) C 11 H 20 N2O4[M + H - 56] + Calculated value: 189, measured value 189; 1 H NMR (300 MHz, CD3OD) δ 4.14-3.99 (m, 4H ), 3.89-3.76 (m, 1H), 3.72 (s, 3H), 3.22 (s, 3H), 1.46 (s, 9H).

[0462] [Example 31] Intermediate 31 (tert-butyl 4-fluoro-4-[methoxy(methyl)carbamoyl] piperidine-1-carboxylate)

[0463] [ka]

[0464] Step A: 1-[(tert-butoxy)carbonyl]-4-fluoropiperidine-4-carvone acid (2.00 g, 8.09 mmol) and CDI (2.60 g, 16.18 mmol) in DCM (10 mL) at room temperature, l) and N,O-methoxy(methyl)amine hydrochloride (1.00 g, 16.18 mmol ) was added. The reaction solution was stirred at room temperature for 16 hours. The resulting solution was diluted with water (30 The combined organic layers were diluted with brine (2×2 mL) and extracted with EA (3×30 mL). 0 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1). Purification of the compound by tert-butyl 4-fluoro-4-[methoxy(methyl)carbamoyl ]piperidine-1-carboxylate was obtained as a colorless oil (1.50 g, 57%). LCMS (ESI) C 13 H 23 FN2O4[M + H - 56] + Calculated value: 235, measured value 235; 1 H NMR (400 M Hz, CDCl3) δ 4.01 (d, J = 13.5 Hz, 2H), 3.75 (s, 3H), 3.26 (s, 3H), 3.21-3.01 ( m, 1H), 2.06 (dd, J = 19.6, 10.9 Hz, 5H), 1.49 (s, 9H).

[0465] [Example 32] Intermediate 32 (Lithio 5-((tert-butoxycarbonyl)amino)-1,3,4-o oxadiazole-2-carboxylate)

[0466] [ka]

[0467] Step A: Ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (0.10 g, 0.64 mmol) and EtN (0.19 g, 1.91 mmol) in DMF (1 To a stirred solution of 1 mL of HCl at room temperature was added BocO (0.17 g, 0.76 mmol). The resulting solution was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in 10 ml Reversed-phase chromatography eluting with 55% ACN in water containing mol / L NH4HCO3 Purification by ethyl 5-[[(tert-butoxy)carbonyl]amino]-1 ,3,4-Oxadiazole-2-carboxylate was obtained as a pale yellow oil (0.10 g, 5 5%) as follows: LCMS (ESI) C 10 H 15 N3O5[M + H - 56] + Calculated value: 202, measured value: 20 2; 1 H NMR (400 MHz, DMSO-d6) δ 4.38 (q, J = 7.1 Hz, 2H), 1.46 (d, J = 3.1 Hz, 9 H), 1.32 (t, J = 7.1 Hz, 3H).

[0468] Step B: Ethyl 5-[[(tert-butoxy)carbonyl]amino]-1,3,4-oxazolidinyl Azole-2-carboxylate (0.16 g, 0.62 mmol) in MeOH (2 mL To a stirred solution of LiOH HO (78 mg, 1.87 mmol) in MeOH (3 mL ) in water, and a solution of LiOH HO (48 mg, 1.15 mmol) in HO (2 The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give lithio 5-((tert-butoxycarbonyl)amino)-1 ,3,4-Oxadiazole-2-carboxylate was obtained as an off-white solid (0.16 g, crude), which was used directly in the next step without further purification. :LCMS (ESI) C8H 11 N3O5[M + H] + Calculated value: 230, measured value 230; 1 H NMR (400 MHz, DMSO-d 6) δ 8.53 (s, 1H), 2.50 (s, 9H).

[0469] [Example 33] Intermediate 33 (3-iodo-1-(triphenylmethyl)-1H-pyrazole)

[0470] [ka]

[0471] Step A: 3-Iodo-1H-pyrazole (0.50 g, 2.59 mmol) in DCM (5 mL) To the stirred solution was added TrtCl (0.86 g, 3.09 mmol) and EtN( 0.52 g, 5.16 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel eluting with PE / EA (12 / 1). Purification by gel column chromatography gave 3-iodo-1-(triphenylmethyl) (ethyl)-1H-pyrazole was obtained as an off-white solid (0.60 g, 48%) Ta: 1 H NMR (400 MHz, CDCl3) δ 7.19-7.10 (m, 15H), 6.42 (d, J = 2.5 Hz, 2H).

[0472] [Example 34] Intermediate 34 (4-iodo-1-(triphenylmethyl)-1H-pyrazole)

[0473] [ka]

[0474] Step A: 4-Iodo-1H-pyrazole (0.50 g, 2.59 mmol) in DCM (5 mL) To the stirred solution was added TrtCl (0.86 g, 3.09 mmol) and EtN( 0.52 g, 5.16 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel eluting with PE / EA (10 / 1). Purification by gel column chromatography gave 4-iodo-1-(triphenylmethyl) (ethyl)-1H-pyrazole was obtained as an off-white solid (0.80 g, 64%) Ta: 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.45 (s, 1H), 7.40-7.35 (m, 9H), 7.07-7.00 (m, 6H).

[0475] [Example 35] Intermediate 35 (Lithio (S)-3-methoxy-2-(trityloxy)propanoate)

[0476] [ka]

[0477] Step A: Methyl (2S)-oxirane-2-carboxylate (2.00 g, 19.59 mmol) To a stirred solution of Mg(OSOCF)(3.1) in MeOH (15 mL) at room temperature The resulting mixture was stirred at 40°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography eluting with DCM / MeOH (10 / 1). Purification by silica gel column chromatography yielded methyl (2S)-2-hydroxybenzoate. 3-Methoxypropanoate was obtained as a pale yellow oil (1.50 g, 46%). LCMS (ESI) C5H 10 O4 [M + H] + Calculated value: 135, measured value 135; 1 H NMR (400 MHz, CDCl3) δ 4.34 (t, J = 3.4 Hz, 1H), 3.83 (s, 3H), 3.75-3.65 (m, 2H), 3.41 (s, 3H), 2.6 5 (brs, 1H).

[0478] Step B: Methyl (2S)-2-hydroxy-3-methoxypropanoate (0.70 g, 5.2 2 mmol) and DMAP (64 mg, 0.52 mmol) in pyridine (8 mL) To the stirred solution at room temperature was added TrtCl (1.60 g, 5.74 mmol). The solution was warmed to 80° C. and stirred for 24 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (3×3 0 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 (10 / 1). When purified by The noate was obtained as an off-white solid (0.80 g, 33%): 1 H NMR (400 MHz, DMSO-d6) δ 7.45-7.19 (m, 15H), 4.16 (t, J = 5.2 Hz, 1H), 3.53 (dd, J = 10. 6, 5.5 Hz, 1H), 3.32-3.27 (m, 1H), 3.23 (s, 3H), 3.21 (s, 3H).

[0479] Step C: Methyl (2S)-3-methoxy-2-(triphenylmethoxy)propanoate (0. To a stirred solution of LiOH H (80 g, 2.13 mmol) in MeOH (8 mL) at room temperature A solution of 20 (0.45 g, 10.63 mmol) in water (3 mL) was added. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give lithio(S)-3 -Methoxy-2-(trityloxy)propanoate (0.80 g, crude) was obtained. This was used directly in the next step without further purification: LCMS (ESI) C 23 H 22 O4 [M + Na] + Calculated value: 385, Measured value: 385.

[0480] [Example 36] Intermediate 36 (Lithium 1-oxo-1,2-dihydroisoquinoline-4-carboxylate) to)

[0481] [ka]

[0482] Step A: Methyl 1-oxo-2H-isoquinoline-4-carboxylate (0.20 g, 1.0 To a stirred solution of 100 mmol) in MeOH (2 mL) was added LiOH HO (84 mg A solution of 2.00 mmol) in water (3 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to give lithium 1-oxo-1,2-dihydroxide. 4-carboxylate (0.20 g, crude), which was further Used directly in the next step without further purification: LCMS (ESI) C 10 H7NO3[M - H] + Calculation of Value: 188, Measured 188.

[0483] [Example 37] Intermediate 37 (Lithium 5-cyano-6-oxo-1,6-dihydropyridine-3-carbohydrate) xylates)

[0484] [ka]

[0485] Step A: Methyl 5-ethynyl-6-oxo-1H-pyridine-3-carboxylate (0.18 g, 1.00 mmol) in MeOH (2 mL) at room temperature. A solution of 4 (84 mg, 2.00 mmol) in water (3 mL) was added. The mixture was stirred at 0° C. for 0.5 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give Lithium 5-cyano-6-oxo-1,6-dihydropyridine-3-carboxylate ( 0.20 g, crude) was obtained, which was used directly in the next step without further purification. LCMS (ESI) C7H4N2O3[M - H] + Calculated value: 163, Measured value: 163.

[0486] [Example 38] Intermediate 38 (N-[(R)-[4,5-dichloro-2-(prop-2-en-1-yl)methyl] 2,2,2-trifluoroacetophenone amide)

[0487] [ka]

[0488] Step A: tert-Butyl 4-[(R)-[4,5-dichloro-2-(prop-2-ene-1- (S)-2-methylpropane-2-sulfinyl)amino ])methyl]piperidine-1-carboxylate (0.50 g, 0.96 mmol) To a stirred solution in 4-dioxane (8 mL) at room temperature, aqueous HCl (4N, 2 mL) was added. The reaction solution was stirred at room temperature for 20 minutes. The reaction solution was added with saturated aqueous Na2CO3 at room temperature. The pH was adjusted to 8 with the solution. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layer was washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-[(R)-amino[4,5-di Chloro-2-(prop-2-en-1-yloxy)phenyl]methyl]piperidine-1 -carboxylate was obtained as a yellow oil (0.40 g, crude), which was further purified Used directly in the next step without purification: LCMS (ESI) C 20 H 28 Cl2N2O3[M + H] + plan Calculated value: 415, 417 (3:2), Measured value: 415, 417 (3:2).

[0489] Step B: tert-Butyl 4-[(R)-amino[4,5-dichloro-2-(prop-2-ene] -1-yloxy)phenyl]methyl]piperidine-1-carboxylate (0.40g , 0.96 mmol) and EtN (0.29 g, 2.89 mmol) in DCM (5 m To a stirred solution of 10 mL of TFAA was added at 0°C. The reaction solution was stirred at 0° C. for 0.5 h. The reaction mixture was diluted with DCM (50 mL) and water (30 mL). The aqueous solution was diluted with DCM (2 x 20 mL). The combined organic layers were The mixture was washed with ethanol (2 x 20 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Condensation gives tert-butyl 4-[(R)-[4,5-dichloro-2-(prop-2-enyl) (2,2,2-trifluoroacetamido)methyl]pi Peridine-1-carboxylate was obtained as a yellow oil (0.40 g, crude) This was used directly in the next step without further purification: LCMS (ESI) C 22 H 27 Cl2F3N2 O4[M + Na] + Calculated values: 533, 535 (3 : 2), measured values: 533, 535 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.02 (s, 1H), 6.12-5.98 (m, 1H), 5.48-5.39 (m, 2H), 4.77 (t, J = 9.7 Hz, 1H), 4.69-4.56 (m, 2H), 4.10 (d, J = 16.0 Hz, 2H), 2.75-2.48 (m , 2H), 2.08-1.97 (m, 1H), 1.78 (d, J = 13.3 Hz, 1H), 1.45 (s, 9H), 1.31-1.20 (m, 3H).

[0490] Step C: tert-Butyl 4-[(R)-[4,5-dichloro-2-(prop-2-ene-1- (2,2,2-trifluoroacetamido)methyl)piperidine A solution of 1-carboxylate (0.40 g, 0.78 mmol) in DCM (2 mL) was stirred. To the solution was added TFA (2 mL) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of water containing 10 mmol / L NH4HCO3. Purification by reversed-phase chromatography eluting with 0% ACN gave N-[(R)-[4 ,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidine- 4-yl)methyl]-2,2,2-trifluoroacetamide was obtained as a pale yellow solid (0.30 g, 76% over 3 steps): LCMS (ESI) C 17 H 19 Cl2F3N2O2[M + H] + Calculated values: 411, 413 (3:2), measured values: 411, 413 (3:2).

[0491] [Example 39] Intermediate 39 (Lithio 2-(oxetan-3-yloxy)acetate)

[0492] [ka]

[0493] Step A: NaH (12.65 g, 316.16 mmol, 60%) in THF (300 mL) To the stirred mixture was added oxetan-3-ol (19.52 g, 263 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 hours. To the above mixture, ethyl 2-bromoacetate (44.00 g, 2 63.47 mmol) was added dropwise. The reaction mixture was stirred at room temperature for another 2 hours. The mixture was quenched with water (200 mL) and extracted with EA (3×200 mL). The organic layer was washed with brine (30×100 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 (5 / 1). Purification by column chromatography gave ethyl 2-(oxetan-3-yloxy) ) acetate was obtained as a colorless oil (25.00 g, 59%): 1 H NMR (400 MH z, CDCl3) δ 4.79-4.72 (m, 2H), 4.72-4.67 (m, 2H), 4.67-4.59 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.05 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0494] Step B: Ethyl 2-(oxetan-3-yloxy)acetate (1.00 g, 6.24 mmol) l) To a stirred solution of 1H in THF (2 mL) and MeOH (2 mL) at 0 °C, LiOH H 2O (0.29 g, 6.89 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give lithio 2-(oxetan-3-yloxy)acetate. The ester was obtained as an off-white solid (0.70 g, crude) which was further purified. Used directly in the next step without further purification: 1 H NMR (400 MHz, D2O) δ 4.77-4.74 (m, 1H) , 4.71-4.68 (m, 2H), 4.59-4.53 (m, 2H), 3.79 (s, 2H).

[0495] [Example 40] Intermediate 40 (Lithio (R)-3-methoxy-2-(trityloxy)propanoate)

[0496] [ka]

[0497] Step A: Methyl (2R)-oxirane-2-carboxylate (1.00 g, 9.80 mmol) ) in MeOH (10 mL) at room temperature, Mg(OSO2CF3)2 (1.58 g, 4.90 mmol) was added. The resulting mixture was stirred at 40°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with DCM / MeOH (10 / 1). Purification by gel column chromatography yielded methyl (2R)-2-hydroxybenzoate. -3-methoxypropanoate was obtained as a pale yellow oil (0.90 g, 55%) :LCMS (ESI) CH 10 O4 [M + H] + Calculated value: 135, measured value 135; 1 H NMR (400 MHz, CDCl3) δ 4.33 (t, J = 3.7 Hz, 1H), 3.83 (d, J = 1.5 Hz, 3H), 3.76-3.65 (m, 2H), 3.41 ( d, J = 1.5 Hz, 3H), 2.91-2.39 (brs, 1H).

[0498] Step B: Methyl (2R)-2-hydroxy-3-methoxypropanoate (0.50 g, 3.7 3 mmol) and DMAP (46 mg, 0.37 mmol) in pyridine (4 mL) To the stirred solution at room temperature was added TrtCl (1.14 g, 4.10 mmol). The solution was stirred at 80° C. for 24 h. The resulting mixture was diluted with water (20 mL) and EA (3 The combined organic layers were washed with brine (3×20 mL) and extracted with anhydrous N The mixture was dried over a2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE / EA (1 Purification by silica gel column chromatography eluting with 0 / 1 gave methyl ( 2R)-3-Methoxy-2-(triphenylmethoxy)propanoate is off-white was obtained as a solid (0.60 g, 34%): 1 H NMR (400 MHz, DMSO-d6) δ 7.49-7. 09 (m, 15H), 4.16 (t, J = 5.2 Hz, 1H), 3.53 (dd, J = 10.6, 5.5 Hz, 1H), 3.32-3.2 7 (m, 1H), 3.23 (s, 3H), 3.21 (s, 3H).

[0499] Step C: Methyl (2R)-3-methoxy-2-(triphenylmethoxy)propanoate (0. To a stirred solution of LiOH H (60 g, 1.59 mmol) in MeOH (6 mL) was added LiOH H at room temperature. A solution of 20 (0.33 g, 7.97 mmol) in water (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give lithio(R)-3- Methoxy-2-(trityloxy)propanoate (0.80 g, crude) was obtained. This was used directly in the next step without further purification: LCMS (ESI) C 23 H 22 O4[M + N a] - Calculated value: 385, Measured value: 385.

[0500] [Example 41] Intermediate 41 (tert-butyl(1R,5S,6R)-6-[methoxy(methyl)carbamoyl]carbamate 3-azabicyclo[3.1.0]hexane-3-carboxylate)

[0501] [ka]

[0502] Step A: (1R,5S,6R)-3-[(tert-butoxy)carbonyl]-3-azabicyclo[4.2.1]methylpropional 2[3.1.0]hexane-6-carboxylic acid (0.50 g, 2.20 mmol), HOB t (0.45 g, 3.30 mmol) and EDCI (0.63 g, 3.30 mmol) in DMF (6 mL) at room temperature, N,O-dimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmol) and EtN (0.45 g, 4.40 mmol) The reaction solution was stirred at room temperature for 2 hours. The reaction was diluted with EA (30 mL) and water (30 The aqueous solution was extracted with EA (3×30 mL). The combined organic layers were diluted with EA (3×30 mL). The mixture was washed with ethanol (6 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 70% ACN in water (+0.05% TFA). Purification by HPLC gave tert-butyl(1R,5S,6R)-6-[methacrylate] [Oxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbo The xylate was obtained as a pale yellow oil (0.30 g, 45%): LCMS (ESI) C 13 H2 2N2O4[M + H - 56] + Calculated value: 215, measured value 215; 1 H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 3.72-3.64 (m, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.52-3.41 (m, 3H), 3.22 (s, 3H), 2.15-2.04 (m, 1H), 2.02-1.93 (m, 1H), 1.47 (s, 9H).

[0503] [Example 42] Intermediate 42 (tert-butyl 4-[methoxy(methyl)carbamoyl]-2-methylpiperidin Peridine-1-carboxylate)

[0504] [ka]

[0505] Step A: 2-Methylpyridine-4-carboxylic acid (2.00 g, 14.58 mmol) in MeOH To a stirred solution in (10 mL) at room temperature, PtO2 (0.40 g, 1.75 mmol) and HCl (6N, 1 mL) was added. The reaction was degassed three times under hydrogen and H2 (50 atm). The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 2 -methylpiperidine-4-carboxylate was obtained as a pale yellow oil (2.00 g, 96%). which was used directly in the next step without further purification: LCMS (ESI) C 8H 15 NO2[M + H] + Calculated value: 158, measured value 158; 1 H NMR (400 MHz, CD3OD) δ 3.51-3.43 ( m, 1H), 3.37 (s, 3H), 3.31-3.24 (m, 1H), 3.12-3.02 (m, 1H), 2.77 (tt, J = 12.4, 3.8 Hz, 1H), 2.30-2.16 (m, 2H), 1.77 (qd, J = 13.8, 4.3 Hz, 1H), 1.63-1.49 (m, 1 H), 1.37 (d, J = 6.5 Hz, 3H).

[0506] Step B: Methyl 2-methylpiperidine-4-carboxylate (2.0 mL) in DCM (10 mL) Stirring of EtN (2.57 g, 25.40 mmol) and EtN (2.57 g, 25.40 mmol) To the mixture was added BocO (4.16 g, 19.06 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour and the reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL). After filtration, the filtrate was concentrated under reduced pressure to give 1- tert-Butyl 4-methyl 2-methylpiperidine-1,4-dicarboxylate is pale yellow This was obtained as a colored oil (3.3 g, crude) which was carried on to the next step without further purification. LCMS (ESI) C 13 H 23 NO4[M + H - 56]+ Calculated value: 202 Measured value 202; 1 H NMR (400 MHz, CDCl3) δ 4.28-4.09 (m, 1H), 3.91-3.76 (m, 1H), 3.72 (s, 3H), 3. 11 (td, J = 13.1, 4.1 Hz, 1H), 2.76-2.51 (m, 1H), 2.10-1.86 (m, 3H), 1.85-1.69 ( m, 1H), 1.47 (s, 9H), 1.09 (d, J = 6.5 Hz, 3H).

[0507] Step C: 1-tert-butyl 4-methyl 2-methylpiperidine-1,4-dicarboxylate To a stirred solution of (3.30 g, 12.82 mmol) in MeOH (10 mL) at room temperature, N A solution of aOH (1.03 g, 25.75 mmol) in water (2 mL) was added. The mixture was stirred at 40°C for 1 hour. The reaction was diluted with water (50 mL). The aqueous solution was washed with citric acid. The mixture was acidified to pH 3 and then extracted with EA (3 x 50 mL). The mixture was washed with ethanol (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 23% ACN in water (+0.05% TFA). Purification by HPLC gave 1-[(tert-butoxy)carbonyl]-2-methyl Thiolpiperidine-4-carboxylic acid was obtained as a pale yellow semi-solid (2.20 g, 71%). LCMS (ESI) C 12 H 21 NO4[M + H -56] + Calculated value: 188, Measured value: 188.

[0508] Step D: 1-[(tert-butoxy)carbonyl]-2-methylpiperidine-4-carboxylic acid (1.80g, 7.40mmol), HOBt (1.50g, 11.10mmol) and To a stirred solution of EDCI (1.80 g, 11.10 mmol) in DCM (10 mL) was added At room temperature, N,O-dimethylhydroxylamine hydrochloride (1.08 g, 11.10 mmol) and EtN (1.50 g, 14.80 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and the aqueous solution was extracted with EA (3×50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure. The residue was eluted with PE / EA (4 / 1). Purification by silica gel column chromatography gave tert-butyl 4-[methacrylate] [Oxy(methyl)carbamoyl]-2-methylpiperidine-1-carboxylate is pale yellow Obtained as an oil (1.50 g, 71%): LCMS (ESI) C 14 H 26 N2O4[M + H] + plan Calculated value: 287 Measured value 287; 1 H NMR (400 MHz, CDCl3) δ4.04-3.92 (m, 1H), 3.89-3.81 (m, 1H), 3.71 (s, 3H), 3.21 (s, 3H), 3.20-3.10 (m, 1H), 2.88 (d, J = 10.4 Hz, 1H), 2 .01-1.90 (m, 1H), 1.90-1.76 (m, 2H), 1.73-1.60 (m, 1H), 1.49 (s, 9H), 1.19 (d, J = 6.4 Hz, 3H).

[0509] [Example 43] Intermediate 43a (tert-butyl 4-[4,5-dichloro-2-( (2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carbo xylate, racemic); Intermediate 43b (tert-butyl 4- containing trans isomer) [4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methyl ethyl piperidine-1-carboxylate, racemic)

[0510] [ka]

[0511] Step A: 1-Bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene To a stirred solution of (2.76 g, 9.78 mmol) in THF (10 mL) under a nitrogen atmosphere, At 0 °C, i-PrMgCl (4.86 mL, 9.72 mmol, 2 M solution in THF) was added dropwise. The reaction was stirred at 0°C for 30 minutes. Then, tert-butyl 4-[methoxy( methyl)carbamoyl]-2-methylpiperidine-1-carboxylate (1.40 g, 4.89 mmol) was added to the reaction mixture. The reaction mixture was stirred under nitrogen atmosphere at 0°C for 1 hour. The resulting mixture was quenched with saturated aqueous NH4Cl (5 mL) and water (30 mL) The aqueous solution was extracted with EA (3×30 mL). The combined organic layers were washed with brine ( The solution was washed with 2×30 mL of HCl and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1). Purification by tert-butyl 4-[4,5-dichloro-2-(propanediol)] [Benzyl-1-yloxy]benzoyl-2-methylpiperidine-1-carboxylate Yellow semisolid (0.50g, 24%): LCMS (ESI) C 21 H 27 Cl2NO4[M + H -56] + Calculated value of : 372, 374 (3 : 2), measured values ​​372, 374 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 10.3 Hz, 1H), 7.07 (s, 1H), 6.17-5.98 (m, 1H), 5.56-5.28 (m, 2H), 4.69-4.59 (m, 2H), 4.23-4.02 (m, 1H), 3.93-3.78 (m, 1H), 3.56-3.39 (m, 1H), 3.17-3.02 (m, 1H), 2.06-1.81 (m, 1H), 1.81-1.57 (m, 2H), 1.57-1.43 (m, 10H), 1.09 (d, J = 6.6 Hz, 3H). and tert-butyl 4-(4,5-dichloro-2-hydroxybenzoate) (2-methylpiperidine-1-carboxylate) was obtained as a pale yellow oil (1.00 g , 53%): LCMS (ESI) C 18 H 23 Cl2NO4[M + H - 56] + Calculated values: 332, 334 (3:2), Actual Observations 332, 334 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 12.30 (s, 1H), 7.79 (s, 1H), 7. 17 (s, 1H), 4.21-4.02 (m, 1H), 3.96 (dd, J = 14.0, 6.9 Hz, 1H), 3.50-3.37 (m, 1H ), 3.25-3.06 (m, 1H), 2.08-1.96 (m, 2H), 1.96-1.81 (m, 1H), 1.81-1.67 (m, 1H), 1 .53 (s, 9H), 1.20 (d, J = 6.4 Hz, 3H).

[0512] tert-Butyl 4-(4,5-dichloro-2-hydroxybenzoate) in DMF (5 mL) (2-methylpiperidine-1-carboxylate (1.00 g, 2.56 mmol) l) and K2CO3 (0.71 g, 5.15 mmol) at room temperature. Bromoprop-1-ene (0.47 g, 3.86 mmol) was added. The resulting mixture The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10 / 1). Purification of the product by tert-butyl 4-[4,5-dichloro-2-(prop-2-ene-1 -yloxy)benzoyl]-2-methylpiperidine-1-carboxylate is pale yellow Obtained as an oil (1.00 g, 90%). tert-Butyl 4-[4,5-dichloro 2-(2-(prop-2-en-1-yloxy)benzoyl)-2-methylpiperidine- The total amount of 1-carboxylate was 1.50 g (72%).

[0513] Step B: tert-Butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy) )benzoyl]-2-methylpiperidine-1-carboxylate (1.50 g, 3.51 (mmol) were separated under SFC using the following conditions: Column: CHIRALPAK IF, 2 × 25 cm, 5 μm; mobile phase A: CO2: 75%, mobile phase B: MeOH: 25% Flow rate: 40 mL / min; Detector: UV: 220 / 254 nm; Retention time: RT1:3.2 9 min;RT2:3.85 min.

[0514] The first peak at 3.29 min was obtained, from which the two cis enantiomers were isolated. rt-Butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoate [zoyl]-2-methylpiperidine-1-carboxylate was obtained as a pale yellow semi-solid (0.50 g , 45%): LCMS (ESI) C 21 H 27 Cl2NO4[M + H -56] + Calculated values: 372, 374 (3:2), measured A second peak at 3.85 min was isolated from which two tert-Butyl 4-[4,5-dichloro-2-(propionamidopropyl]-2,4-diol, containing the trans enantiomer (2-methyl-2-propen-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxamide The sylate was obtained as a pale yellow semi-solid (0.40 g, 36%): LCMS (ESI) C 21 H 27 Cl2NO4[M + H - 56] + Calculated: 372, 374 (3:2), found: 372, 374 (3:2).

[0515] [Example 44] Intermediate 44 ((2,3-dichloro-6-methoxyphenyl)(piperidin-4-yl)methyl)methyl ethanol trifluoroacetic acid)

[0516] [ka]

[0517] Step A: 3,4-Dichlorophenol (100.00 g, 613.49 mmol) in DCM (1 To a stirred solution of 1,000 mL of Br2 (98.04 g, 613.4 mL) was added Br2 (98.04 g, 613.4 mL) at 0 °C under a nitrogen atmosphere. 9 mmol) was added dropwise. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was quenched with saturated aqueous NaSO (500 mL) at 0 °C. The extract was extracted with EA (6 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL). After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-3-(2-methyl-2-propanol)-2-one. Mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (100 g, crude) was obtained as a yellow oil. The crude product was purified without further purification. It was used directly in the next step.

[0518] Step B: 2-Bromo-4,5-dichlorophenol and 2-bromo- Crude mixture of 3,4-dichlorophenol (32 g, 125.04 mmol, 1 equiv.) and and K2CO3 (54.9 g, 396.87 mmol, 3 equiv.) at 0 °C with MeI (16 The reaction mixture was stirred at 50°C for 4 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE. Purification by chromatography gave 2-bromo-3,4-dichloro-1-methoxybenzoate. Zene (8.7g, 25.7%) as a white solid: 1 H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 9.0, 1.1 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 3.92 (s, 3H), and 1-Br Bromo-4,5-dichloro-2-methoxybenzene (24.3 g, 71.77%) was obtained as a white solid: 1 H NMR (300 MHz, CDCl) δ 7.64 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H). Obtained.

[0519] Step C: 2-Bromo-3,4-dichloro-1-methoxybenzene (0.80 g, 3.13 mmol) To a solution of i-PrMgCl (2.0 mcg) in THF (8 mL) was added i-PrMgCl (2.0 mcg) under nitrogen atmosphere at 0°C. L, 19.76 mmol, 2M in THF) was added dropwise. The reaction solution was stirred at 0° C. for 0.5 h. Then, tert-butyl 4-formylpiperidine-1-carboxylate (0. A solution of 67 g (3.13 mmol) in THF (2 mL) was added dropwise at 0°C under a nitrogen atmosphere. After stirring at 0°C for an additional 0.5 h, the reaction mixture was warmed to room temperature and further stirred under a nitrogen atmosphere. The reaction was stirred for 0.5 h. The reaction was quenched with saturated aqueous NH4Cl (40 mL) and (2 x 40 mL). The organic layers were combined and dried over anhydrous Na2SO4. Filtration The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column eluting with PE / EA (3 / 2). Purification by column chromatography gave tert-butyl 4-[(2,3-dichloro- -6-methoxyphenyl)(hydroxy)methyl]piperidine-1-carboxylate Obtained as an off-white foam (1.00 g, 82%): LCMS (ESI) C 18 H 25 Cl2 NO4[M + Na] +Calculated values: 412, 414 (3 : 2), measured values: 412, 414 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 4.98 (d, J = 8.9 Hz, 1H), 4.21 (d, J = 13.5 Hz, 1H), 4.07 (d, J = 13.5 Hz, 1H), 3.92 (s, 3H), 2.7 0 (td, J = 12.9, 2.8 Hz, 1H), 2.59 (td, J = 12.8, 3.0 Hz, 1H), 2.17-1.97 (m, 2H) , 1.48 (s, 9H), 1.42-1.24 (m, 3H).

[0520] Step D: tert-Butyl 4-[(2,3-dichloro-6-methoxyphenyl)(hydroxy) Methyl]piperidine-1-carboxylate (0.50 g, 1.28 mmol) in DCM To a solution of 100 ml of HCl (5 mL) was added TFA (2 mL) at room temperature. The reaction solution was stirred at room temperature for 1 hour. The mixture was stirred and concentrated to give (2,3-dichloro-6-methoxyphenyl)(piperidine-4-yl) (III) Methanol trifluoroacetic acid was obtained as a colorless oil (0.60 g, crude). :LCMS (ESI) C 13 H 17 Cl2NO2[M + H] + Calculated value: 290, 292 (3:2), Measured value: 290, 292 (3: 2).

[0521] [Example 45] Intermediate 45 ((S)-N-((R)-(2-(allyloxy)-4-chloro-5-methyl (Phenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfina Mid)

[0522] [ka]

[0523] Step A: 3-Chloro-4-methylphenol (0.50 g, 3.51 mmol) in HOAc(5 To a stirred solution of Br2 (0.56 g, 3.51 mmol) in 1 mL of HCl was added Br2 (0.56 g, 3.51 mmol) at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was then diluted with saturated aqueous Na2SO3 (5 The mixture was quenched with EA (2×30 mL) and extracted with EA (2×30 mL). The combined organic layers were washed with saturated NaH The mixture was washed with aqueous CO3 (2 x 30 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1). Chromatographic purification gave 2-bromo-5-chloro-4-methylphenol. Obtained as an off-white solid (0.70 g, 90%): 1 H NMR (400 MHz, CDCl ) δ 7.33 (s, 1H), 7.06 (s, 1H), 5.46 (s, 1H), 2.30 (s, 3H).

[0524] Step B: 2-Bromo-5-chloro-4-methylphenol (0.70 g, to a stirred mixture of KCO (0.87 g, 6.32 mmol) and KCO (0.87 g, 6.32 mmol). At room temperature, 3-bromoprop-1-ene (0.50 g, 4.11 mmol) was added. The reaction mixture was warmed to 40° C. and stirred for 3 h. The reaction mixture was diluted with water (50 mL) and The combined organic layers were washed with brine (3 x 10 mL) and extracted with HCl (2 x 15 mL). The mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in PE. Purification by silica gel column chromatography using the 5-methyl-2-(prop-2-en-1-yloxy)benzene is off-white was obtained as a solid (0.45 g, 54%): 1 H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 6.90 (s, 1H), 6.12-6.02 (m, 1H), 5.58-5.40 (m, 1H), 5.40-5.30 (m, 1H), 4.59 (dt, J = 5.0, 1.6 Hz, 2H), 2.30 (s, 3H).

[0525] Step C: 1-Bromo-4-chloro-5-methyl-2-(prop-2-en-1-yloxy)benzyl To a stirred solution of benzene (0.43 g, 1.64 mmol) in THF (4 mL) was added a nitrogen atmosphere. Under conditions of -65 °C, n-BuLi (0.76 mL, 1.90 mmol, 2.5 M in hexane) After stirring for 30 minutes, tert-butyl 4-[[(S)-2-methylpropyl] Pan-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (0.4 A solution of 1000 mg of HCl (1.0 g, 1.26 mmol) in THF (2 mL) was added dropwise at -65°C under a nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for an additional 1 h. The reaction was diluted with saturated aqueous NH4Cl The resulting mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (2×30 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 (1 / 5). Purification by column chromatography yielded tert-butyl 4-((R)-2- (allyloxy)-4-chloro-5-methylphenyl)(((S)-tert-butylsulfonyl) (Isopropyl)amino)methyl)piperidine-1-carboxylate was obtained as a pale yellow oil (0 Obtained as 0.18g, 30%): LCMS (ESI) C 25 H 39 ClNOS [M + H] + Calculated value: 499 , 501 (3 : 1), Actual value 499, 501 (3 : 1); 1 H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.87 (s, 1H), 6.09-5.99 (m, 1H), 5.50-5.27 (m, 2H), 4.61-4.45 (m, 2H), 4.42-3.82 (m, 4H), 2.66-2.57 (m, 2H), 2.29 (s, 3H), 1.92-1.91 (m, 1H), 1.66 (s, 3H), 1.45 (s, 9H), 1.13 (s, 9H).

[0526] Step D: tert-Butyl 4-((R)-2-(allyloxy)-4-chloro-5-methylphenyl) Nyl)(((S)-tert-butylsulfinyl)amino)methyl)piperidine-1- To a stirred solution of carboxylate (0.18 g, 0.38 mmol) in DCM (4 mL), At room temperature, TFA (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. The resulting solution The mixture was neutralized with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3 x 20 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 to give (S)-N-((R)-(2-(allyloxy)-2-methylpropional). (4-chloro-5-methylphenyl)(piperidin-4-yl)methyl)-2-methyl Dipropane-2-sulfinamide was obtained as a pale yellow oil (0.10 g, 70%). LCMS (ESI) C 20 H 31 ClNOS [M + H] + Calculated value: 399, 401 (3:1), Measured value: 399, 40 1 (3 : 1).

[0527] [Example 46] Intermediate 46 (1-bromo-4,5-dichloro-3-fluoro-2-(prop-2-ene) 1-yloxy)benzene)

[0528] [ka]

[0529] Step A: 3-Chloro-2-fluorophenol (1.50 g, 10.23 mmol) in MeCN (60 mL) and TFA (1.00 mL) at room temperature under a nitrogen atmosphere, NCS( 1.37 g, 10.24 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EA (5 / 1). Purification by column chromatography gave 3,4-dichloro-2-fluorophenol The compound was obtained as an off-white solid (1.60 g, 86%): 1 H NMR (400 MHz, D MSO-d6) δ 10.64 (s, 1H), 7.27 (dd, J = 9.0, 2.1 Hz, 1H), 6.97 (t, J = 8.9 Hz, 1 H).

[0530] Step B: Ac of 3,4-dichloro-2-fluorophenol (1.60 g, 8.84 mmol) To a stirred solution of Br2 (1.55 g, 9.72 mmol) in OH (20 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (100 mL). The reaction mixture was then extracted with EA (2 x 50 mL). The organic phase was washed with saturated aqueous Na2SO3. solution (2 × 50 mL), saturated aqueous NaHCO3 (2 × 50 mL) and brine (2 × The solution was then dried over anhydrous Na2SO4. After filtration, the filtrate The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1). Purification by HPLC gave 6-bromo-3,4-dichloro-2-fluorophenone. The product was obtained as an off-white solid (1.80 g, 78%): 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 2.3 Hz, 1H).

[0531] Step C: 6-Bromo-3,4-dichloro-2-fluorophenol (1 mL) in DMF (20 mL) 0.80g, 6.97mmol) and K2CO3 (2.00g, 14.47mmol) To the stirred mixture was added 3-bromoprop-1-ene (1.26 g, 10.39 mmol) at room temperature. ) was added. The reaction was then stirred at 40° C. for 3 hours. The reaction mixture was diluted with water (80 mL) The combined organic layers were diluted with brine (3 × 30 mL) and extracted with EA (2 × 50 mL). ) and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give 1-bromo-2-methyl-2-propanol. Bromo-4,5-dichloro-3-fluoro-2-(prop-2-en-1-yloxy)benzyl N-benzoxanthate was obtained as a colorless liquid (1.70 g, 82%):1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.3 Hz, 1H), 6.18-6.03 (m, 1H), 5.47-5.37 (m, 1H), 5.32 (dd, J = 10.2, 1.5 Hz, 1H), 4.70-4.60 (m, 2H); 19 F NMR (376 MHz, CDCl3) δ -121.32.

[0532] [Example 47] Intermediate 47 (Lithio (R)-2-methoxy-3-(trityloxy)propanoate)

[0533] [ka]

[0534] Step A: Methyl (2R)-2,3-dihydroxypropanoate (0.50 g, 4.16 mmol) l) and (chlorodiphenylmethyl)benzene (3.50 g, 12.5 mmol) D To a stirred solution in CM (4 mL) at room temperature was added DMAP (30 mg, 0.25 mmol) and EtN (1.26 g, 12.5 mmol) was added in small portions. The resulting mixture The mixture was stirred at room temperature under a nitrogen atmosphere for 72 hours, diluted with water (20 mL), and The combined organic layers were washed with brine (3 x 5 mL) and extracted with EA (3 x 25 mL). The residue was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography eluting with methyl ... (2R)-2-methoxy-3-(triphenylmethoxy)propanoate is Obtained as an orange solid (0.10 g, 6%). 1H NMR (400 MHz, CDCl3) δ 7.37-7. 29 (m, 15H), 4.31 (t, J = 3.5 Hz, 1H), 3.91 (dd, J = 14.0, 3.6 Hz, 2H), 3.87 (s, 3H).

[0535] Step B: Methyl (2R)-2-hydroxy-3-(triphenylmethoxy)propanoate(0 A stirred solution of 0.50 g (1.38 mmol) and CHCl (1 mL) in EtO (5 mL) was To the solution, Ag2O (0.96 g, 4.14 mmol) was added in small portions at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The combined organic layers were diluted with brine (3 x 5 mL) and extracted with DCM (3 x 20 mL). 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 (6 / 1). Upon purification, methyl (2R)-2-methoxy-3-(triphenylmethoxy)propanoate was obtained. The compound was obtained as an off-white solid (0.40 g, 77%): LCMS (ESI) C 24 H2 4O4[M + Na] + Calculated value: 399, Measured value 399; 1 H NMR (400 MHz, CDCl3) δ 7.39-7.21 (m, 15H), 4.00-3.90 (m, 2H), 3.82 (s, 3H), 3.87-3.76 (m, 1H), 3.53 (s, 3H).

[0536] Step C: Methyl (2R)-2-methoxy-3-(triphenylmethoxy)methyl in MeOH (2 mL) ) propanoate (50 mg, 0.13 mmol) at room temperature. A solution of HO (9 mg, 0.4 mmol) in HO (1 mL) was added. The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure to give lithio(2R)-2-methoxy-3- (Triphenylmethoxy)propanoate (50 mg, crude) was obtained. Used directly in the next step without further purification: LCMS (ESI) C 23 H 22 O4[M + Na] + Calculated value: 385, Measured value: 385.

[0537] [Example 48] Intermediate 48 (Lithio(2S)-2-methoxy-3-(triphenylmethoxy)propanoic acid (Route)

[0538] [ka]

[0539] Step A: Methyl (2S)-2,3-dihydroxypropanoate (1.00 g, 8.32 mmol) l) and (chlorodiphenylmethyl)benzene (2.50 g, 9.16 mmol) D To a stirred solution in CM (10 mL) was added EtN (1.26 g, 12.5 mmol) and and DMAP (61 mg, 0.50 mmol) were added. The resulting mixture was stirred at room temperature for 16 The resulting mixture was diluted with water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with PE / EA (5 / 1). Purification by silica gel column chromatography gave methyl (2S)-2-hydrogen methyl ester. Triphenylmethoxy-3-(triphenylmethoxy)propanoate was obtained as an off-white solid (1.00 g, 33%) was obtained as: 1 H NMR (400 MHz, CDCl3) δ 7.49-7.39 (m, 5H), 7.33 ( dt, J = 6.9, 1.5 Hz, 5H), 7.33-7.22 (m, 5H), 4.32-4.27 (m, 1H), 3.80 (s, 3H), 3. 54-3.45 (m, 1H), 3.38 (dd, J = 9.4, 3.4 Hz, 1H).

[0540] Step B: Methyl (2S)-2-hydroxy-3-(triphenylmethoxy)propanoate(0 A stirred solution of 0.50 g (1.38 mmol) and CHCl (1 mL) in EtO (5 mL) was Add Ag2O (0.96 g, 4.14 mmol) to the solution in an air atmosphere at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (30 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (3×25 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 (6 / 1). Purification by column chromatography yielded methyl(2S)-2-methoxy-3- (Triphenylmethoxy)propanoate was obtained as an off-white solid (0.40 g, 77%). ) was obtained as: LCMS (ESI) C 24 H 24 O4[M + Na] + Calculated value: 399, Measured value 399; 1 H NMR (400 MHz, CDCl3) δ 7.49-7.42 (m, 6H), 7.36-7.25 (m, 6H), 7.29-7.21 (m, 3H), 3.9 7 (dd, J = 5.4, 4.0 Hz, 1H), 3.78 (s, 3H), 3.47 (s, 3H), 3.45-3.36 (m, 2H).

[0541] Step C: Methyl (2S)-2-methoxy-3-(triphenylmethoxy)propanoate (0. To a stirred solution of 20 g (0.53 mmol) of HCl in MeOH (3 mL) was added HCl at room temperature under an air atmosphere. Then, LiOH·HO (38 mg, 1.59 mmol) in HO (1 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to give lithiated methylcellulose. (2S)-2-Methoxy-3-(triphenylmethoxy)propanoate is off-white The crude product was carried on to the next step without further purification. Used directly in step C: LCMS (ESI) 23 H 22 O4[M + Na] + Calculated value: 385, Measured value: 385.

[0542] [Example 49] Intermediate 49 (tert-butyl 4-(1-(4,5-dichloro-2-methoxyphenyl) (2-oxoethyl)piperidine-1-carboxylate)

[0543] [ka]

[0544] Step A: (Methoxymethyl)triphenylphosphanium chloride (1 To a stirred mixture of nB Li (10.30 mL, 25.75 mmol, 2.5 M in hexane) was added dropwise. The resulting mixture was stirred at -78°C for 30 minutes under a nitrogen atmosphere. tert-Butyl 4-(4,5-dichloro-2-methoxybenzoyl) ) piperidine-1-carboxylate (2.00 g, 5.15 mmol) in THF (5 m The resulting mixture was stirred at -78°C for an additional 2 hours. The mixture was quenched with saturated aqueous NH4Cl (80 mL) at 0°C. The combined organic layers were washed with brine (3×20 mL) and extracted with anhydrous N The mixture was dried over a2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE / EA (1 When purified by silica gel column chromatography eluting with tert- Butyl 4-[1-(4,5-dichloro-2-methoxyphenyl)-2-methoxyethenyl ]piperidine-1-carboxylate was obtained as a pale yellow oil (1.60 g, 59%). LCMS (ESI) C 20 H 27 Cl2NO4[M + H] + Calculated values: 416, 418 (3:2), measured values: 416, 41 8 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 1.3 Hz, 1H), 6.91 (s, 1H), 5. 87 (d, J = 1.3 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 3H), 2.74-2.58 (m, 4H), 1.71-1.53 (m, 5H), 1.46 (d, J = 1.3 Hz, 9H).

[0545] Step B: tert-Butyl 4-[(E)-1-(4,5-dichloro-2-methoxyphenyl)- 2-Methoxyethenyl]piperidine-1-carboxylate (1.80 g, 4.32 mm To a stirred solution of 1,4-dioxane (10 mL) at 0° C. was added aqueous HCl (6 N, 10 mL) was added dropwise. The resulting mixture was then warmed to room temperature and stirred for 3 hours. The resulting mixture was concentrated under reduced pressure. The resulting crude mixture was carried on to the next step without further purification. Used directly for: LCMS (ESI) C 14 H 17 Cl2NO2[M + H] + Calculated values: 302, 304 (3:2), measured Values ​​302, 304 (3:2)

[0546] Step C: 2-(4,5-dichloromethane) in THF (15 mL) and saturated aqueous NaHCO3 (20 mL) Chloro-2-methoxyphenyl)-2-(piperidin-4-yl)acetaldehyde (1 To a stirred mixture of Boc2O (1.62 g, 7.50 g, 4.96 mmol) was added Boc2O (1.62 g, 7. 445 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was The combined organic layers were washed with brine (2 x 10 mL) and extracted with HCl (3 x 30 mL). After drying over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure to give tert-butyl 2-propanol. 4-[1-(4,5-dichloro-2-methoxyphenyl)-2-oxoethyl]piperidinyl The diazine-1-carboxylate was obtained as a pale yellow oil (1.30 g, 65%): LCMS (ESI) C 19 H 25 Cl2NO4[M + H] +Calculated value: 402, 404 (3:2), Measured value: 402, 404 (3:2 ); 1 H NMR (400 MHz, CDCl3) δ 9.68 (d, J = 1.6 Hz, 1H), 7.13 (s, 1H), 7.00 (s, 1 H), 4.04 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 3.67 (dd, J = 8.9, 1.7 Hz, 1H), 2.8 2-2.71 (m, 1H), 2.66 (t, J = 12.6 Hz, 1H), 2.36-2.21 (m, 1H), 1.89 (dt, J = 13.3 , 2.9 Hz, 1H), 1.67 (s, 1H), 1.45 (s, 9H), 1.41 (s, 1H), 1.26-1.16 (m, 1H), 1.10 -0.95 (m, 1H).

[0547] [Example 50] Intermediate 50 (tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl) (2-methylpropane-2-sulfinyl) phenyl)ethoxy]methoxy]phenyl [amino]methyl]-2,2-dimethylpiperidine-1-carboxylate)

[0548] [ka]

[0549] Step A: (Methoxymethyl)triphenylphosphanium chloride (1508 mg, 4.40 m A solution of n-BuLi (2. 5 mL, 38.46 mmol, 2.5 M in hexane) was added dropwise. The solution was stirred at 0°C for 1 hour. Then, tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate was added. A solution of carboxylate (1 g, 4.40 mmol) in THF (5 mL) was added under a nitrogen atmosphere. The mixture was added dropwise at -20°C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with saturated aqueous NH4Cl. The mixture was quenched with EA (30 mL) and extracted with EA (2 x 20 mL). The organic phase was washed with anhydrous Na The residue was purified by silica gel eluting with PE / EA (1 / 1). Purification by gel column chromatography yielded tert-butyl 4-(methoxyphenyl)- Methylidene)-2,2-dimethylpiperidine-1-carboxylate was obtained as a colorless oil (0 Obtained as 0.80g, 71%): LCMS (ESI) C 14 H 25 NO3[M + H] + Calculated value: 256, Actual Measurement 256; 1 H NMR (300 MHz, methanol) δ 5.97 (d, J = 24.0 Hz, 1H), 3.62-3.45 (m , 5H), 2.37-2.27 (m, 2H), 2.26-2.20 (m, 1H), 2.18 (s, 1H), 1.46 (d, J = 1.7 Hz, 9H), 1.38 (d, J = 2.7 Hz, 6H).

[0550] Step B: tert-Butyl 4-(methoxymethylidene)-2,2-dimethylpiperidine-1-carboxylate A solution of carboxylate (0.80 g, 3.13 mmol) in THF (10 mL) was added at room temperature. At this point, aqueous HCl (4N, 5 mL) was added, and the reaction mixture was stirred at 50° C. for 4 hours. The reaction mixture was then basified to pH 9 with saturated aqueous NaHCO3, followed by addition of Bo C2O (821 mg, 3.76 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (2 x 15 mL). The organic phase was dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1). Purification by chromatography gave tert-butyl 4-formyl-2,2-dimethyl Dipiperidine-1-carboxylate was obtained as a colorless oil (360 mg, 48%). LCMS (ESI) C 13 H 23 NO3[M + H] + Calculated value: 242, Measured value: 242.

[0551] Step c': 2-Bromo-4,5-dichlorophenol (31.00 g, 128.15 mmol) and and [2-(chloromethoxy)ethyl]trimethylsilane (32.00 g, 192.23 To a stirred solution of DIEA (49.70 g, 3 mmol) in DCM (100 mL) at room temperature 84.46 mmol) was added. The resulting mixture was stirred at room temperature for 5 hours. The reaction was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel eluting with PE / EA (50 / 1). Purification by gel column chromatography yielded [2-(2-bromo-4,5-dichloride] [chlorophenoxymethoxy]ethyl]trimethylsilane (44.00g, 83%) pale yellow 1H NMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.46 (s, 1H), 5.39 (s, 2H), 3.74 (t, J = 6.0 Hz, 2H), 0.79 (t, J = 6.0 Hz, 2H), -0.05 (s, 9H) .

[0552] Step C: [2-(2-bromo-4,5-dichlorophenoxymethoxy)ethyl]trimethylsilyl A solution of 1,3-dimethyl-2,4-trimethyl- ... In a nitrogen atmosphere, i-PrMgCl (0.2 mL, 1.61 mmol, T HF (2M) was added dropwise. The reaction mixture was stirred under nitrogen atmosphere at -10°C for 0.5 hours. tert-Butyl 4-formyl-2,2-dimethylpiperidine-1-carboxylate A solution of (300 mg, 1.24 mmol) in THF (3 mL) was heated at -10 The resulting solution was added dropwise at 100°C. The reaction mixture was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 2 hours. The resulting mixture was quenched with saturated aqueous NH4Cl (40 mL). The residue was extracted with EA (3 x 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, and After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EA (9 / 1). Purification by gel column chromatography gave tert-butyl 4-[(4,5- Dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)(hydro 2,2-dimethylpiperidine-1-carboxylate was obtained as a colorless oil ( Obtained as 0.20 g, 30%): LCMS (ESI) C 25 H 41 Cl2NO5Si [M + H] + Calculated value of: 534, 536 (3 : 2), Actual values ​​534, 536 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H ), 7.41 (s, 1H), 5.30 (s, 2H), 3.83-3.72 (m, 2H), 3.71-3.50 (m, 2H), 3.46-3.28 ( m, 1H), 1.97-1.89 (m, 1H), 1.84-1.73 (m, 2H), 1.71-1.65 (m, 1H), 1.52 (d, J = 4. 0 Hz, 6H), 1.49 (s, 9H), 1.40 (s, 2H), 0.04 (s, 9H).

[0553] Step D: tert-Butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]ethyl] [Oxy]methoxy]phenyl)(hydroxy)methyl]-2,2-dimethylpiperidine-1 To a solution of 1000 mg of 1-carboxylate (0.18 g, 0.34 mmol) in DCM (8 mL), At room temperature, Dess-Martin reagent (0.14 g, 0.34 mmol) was added in three portions. The reaction mixture was then stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous Na2SO3. The organic phase was dried over anhydrous Na2SO4 and then extracted with DCM (2 x 10 mL). After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-[(4,5-dichloro) b-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)carbonyl]- 2,2-Dimethylpiperidine-1-carboxylate was obtained as a colorless oil (0.16 g, crude). LCMS (ESI) C 25 H 39 Cl2NO5Si [M + H] + Calculated value: 532, 534 (3 : 2) , Actual values ​​532, 534 (3:2).

[0554] Step E: tert-Butyl 4-(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy] [Ci]methoxy]benzoyl)-2,2-dimethylpiperidine-1-carboxylate(0 To a solution of 2-methylpropane-2- Sulfinamide (44 mg, 360 mmol) and Ti(...

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 (In the formula, Z is OR a , NR a R b , or NR b (C═O)R a ; X 1 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, cycloalkenyl, or halogenated cycloalkyl; X 2 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl; X 3 is H, halogen, fluoroalkyl, or alkyl; or X 1 and X 2 and the carbon atom to which they are attached, taken together, form an optionally substituted 6-membered aryl; or X 2 and X 3 and the carbon atom to which they are attached, taken together, form an optionally substituted 6-membered aryl; R ３ is H, halogen, or alkyl; or X 1 and R 3 and the carbon atom to which they are attached, taken together, form an optionally substituted 6-membered aryl; R １ and R ２ are each independently H, alkyl, (CR ６ R ７ ) ｎ４ OR ａ , (CR ６ R ７ ) ｎ４ N.R. ａ R ｂ , (CR ６ R ７ ) ｎ４ N.R. ａ (C=O)R ｂ , (CR ６ R ７ ) ｎ４ N.R. ａ SO ２ R ｂ , or (CR ６ R ７ ) ｎ４ C.O.N.R. ａ R ｂ or R １ , R ２ and the carbon atoms to which they are attached, taken together, form a 3- to 5-membered carbocyclic ring; R ４ is H, alkyl, halogenated alkyl, optionally substituted cycloalkyl, (CR 6 R 7 ) n4 OR c, (CR ６ R ７ ) ｎ４ (C=O)R ｃ , (C=O)(CR ６ R ７ ) ｎ４ R ｃ , (CR ６ R ７ ) ｎ４ COOR ｃ , (CR ６ R ７ ) ｎ４ N.R. ｃ (C=O)R ｄ , (CR 6 R 7 ) n4 (C=O)NR c R d , (C=O) (CR 6 R 7 ) n4 NR c R d , (CR 6 R 7 ) n4 (C=O) (C=O) NR c R d , (C=O) (CR ６ R ７ ) ｎ４ OR ｃ , (CR ６ R ７ ) ｎ４ SO ２ R ｃ , (CR 6 R 7 ) n4 SO 2 NR c R d , optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted cycloalkyl-alkyl; R ５ each occurrence is independently H, alkyl, cycloalkyl, or oxo; Or two R's ５ groups, together with the carbon atom to which they are attached, form a 3- to 7-membered optionally substituted saturated carbocyclic ring; Or two R's ５ the groups are attached to different carbon atoms on the ring and taken together form a bond or an alkyl chain containing 1 to 3 carbons; R ６ and R ７ each occurrence is independently H, alkyl, or cycloalkyl; R ａ and R ｂ each occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R ａ and R ｂ together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O and S; R ｃ and R ｄ each occurrence of is independently selected from H, alkyl, each of which is independently selected from halogen, OR ８ Or N(R ８ ) ２ or R is an alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted cycloalkyl-alkyl, each of which is substituted with 1 to 4 substituents that are ｃ and R ｄ together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O and S; R ８ each occurrence of R is independently H, alkyl, or an optionally substituted heterocycle; or two R ８ groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; R ９ is H, alkyl, halogen, or (CR ６ R ７ ) ｎ４ OR ｂ and Where applicable, X 1 , X 2 , X 3 , R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ９ , R ａ , R ｂ , R ｃ , and R ｄ The alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl of the formula (I) are, where valences permit, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, -(CH ２ ) ０～２ OR ８ , N(R ８ ) ２ , (C=O)C １～４ Alkyl, (C=O)N(R ８ ) ２ and oxo; n １ each occurrence is independently an integer from 0 to 3, where valences permit; n ２ and n ３ each occurrence is independently an integer from 0 to 2; n ４ each occurrence is independently an integer from 0 to 3).

2. n ２ and n ３ 2. The compound of claim 1, wherein each occurrence of is independently an integer from 0 to 1.

3. Structural motif 【Chemistry 2】 but, 【Chemistry 3】 2. The compound of claim 1 having the structure:

4. Structural motif 【Chemistry 4】 but, 【Chemistry 5】 2. The compound of claim 1 having the structure:

5. Structural motif 【Chemistry 6】 but, 【Chemistry 7】 having the structure The compound of claim 1.

6. The compound of any one of claims 1 to 5, wherein at least one occurrence of R 1 and R 2 is H or alkyl.

7. R １ and R ２ At least one occurrence of (CR ６ R ７ ) ｎ４ OR ａ , (CR ６ R ７ ) ｎ４ N.R. ａ R ｂ , (CR ６ R ７ ) ｎ４ N.R. ａ (C=O)R ｂ , (CR ６ R ７ ) ｎ４ N.R. ａ SO ２ R ｂ , or (CR ６ R ７ ) ｎ４ C.O.N.R. ａ R ｂ 6. The compound according to claim 1 , wherein

8. R １ and R ２ At least one occurrence of OR ａ Or N.R. ａ R ｂ 8. The compound of claim 7, wherein

9. R １ , R ２ and the carbon atom to which they are attached, taken together, form a 3- to 5-membered carbocyclic ring.

10. R 1 and R 2 are each independently H, Me, OH, CH 2 OH, NH 2 , NHMe, NMe 2 , CH 2 NH 2 , CONH 2 , CONHMe 2 , CONMe 2 , NH(C═O)Me, NMe(C═O)Me, 【Chemistry 8】 6. The compound according to claim 1 , wherein 11. The compound of any one of claims 1 to 10, wherein R 4 is H, alkyl, halogenated alkyl, or cycloalkyl.

12. The compound of claim 11, wherein R 4 is H, Me, or ethyl fluoride.

13. R ４ But (CR ６ R ７ ) ｎ４ OR ｃ , (CR ６ R ７ ) ｎ４ C.O.R. ｃ , (C=O)(CR ６ R ７ ) ｎ４ R ｃ , (CR ６ R ７ ) ｎ４ COOR ｃ , (CR ６ R ７ ) ｎ４ N.R. ｃ (C=O)R ｄ , (CR 6 R 7 ) n4 (C=O)NR c R d , (CR 6 R 7 ) n4 (C=O) (C=O) NR c R d , (C=O) (CR ６ R ７ ) ｎ４ OR ｃ , (CR ６ R ７ ) ｎ４ SO ２ R ｃ 11. The compound of any one of claims 1 to 10, wherein the ring is (CR6R7)n4SO2NRcRd.

14. R ４ But (CR ６ R ７ ) ２ OR ｃ , (C=O)R ｃ , (C=O)(CR ６ R ７ ) １－２ R ｃ , COOR ｃ , (CR ６ R ７ ) １－２ N.R. ｃ (C=O)R ｄ , (C=O)NR c R d , (CR 6 R 7 ) n4 (C=O) (C=O) NR c R d , (C=O) (CR ６ R ７ ) １－２ OR ｃ , S.O. ２ R ｃ or SO2NRcRd.

15. R ４ (CH ２ ) ２ OH, (CH ２ ) ２ OMe, (C=O)H, (C=O)Me, (C=O)CH ２ OH, (C=O)CH ２ OMe, (C=O)Et, (C=O)Ph, (C=O)isopropyl, (C=O)NH2, (C=O)NHMe, (C=O)NMe2, (C=O)CH ２ N.H. ２ , (C=O)CH ２ NHMe, (C=O)CH(OH)CH ２ OH, (C=O)CH(OMe)CH ２ OH, (C=O)CH(OH)CH ２ OMe, (C=O)(C=O)NMe 2 , (C=O)OMe, SO ２ Me, SO ２ Et, SO ２ CH ２ OH, SO ２ CH ２ 15. The compound of claim 14 which is OMe, SO2NH2, SO2NHMe, or SO2NMe2.

16. R ４ (C=O)R ｃ , (C=O)(CR ６ R ７ ) １～２ R ｃ , (C=O)(CR ６ R ７ ) １～２ OR ｃ , or S.O. ２ R ｃ and R ｃ are H, alkyl, each independently a halogen, OR ８ and N(R ８ ) ２ selected from the group consisting of alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, and optionally substituted cycloalkyl-alkyl, 15. The compound of claim 14.

17. R ｃ Or R ｄ is H, Me, Et, 【Chemistry 9】 15. The compound of claim 14, wherein

18. R ｃ Or R ｄ but 【Chemistry 10】 wherein said heterocycle, when valences permit, is selected from the group consisting of one or more of cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH ２ , oxo, or (C=O)C １～４ 15. The compound of claim 14, optionally substituted with alkyl.

19. R ｃ Where valence permits, alkyl, halogen, CN, -(CH ２ ) ０～２ OR ８ , N(R ８ ) ２ , (C=O)N(R ８ ) ２ 15. The compound of claim 14, which is a cycloalkyl, spiroalkyl, or bicycloalkyl, each optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

20. R ｃ Where valence permits, alkyl, halogen, CN, -(CH ２ ) ０～２ OR ８ , N(R ８ ) ２ , (C=O)N(R ８ ) ２ and oxo, each optionally substituted with 1 to 4 substituents independently selected from the group consisting of 【Chemistry 11】 That is, 20. The compound of claim 19.

21. R ４ is an optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted cycloalkyl, optionally substituted alkyl-cycloalkyl, or optionally substituted cycloalkyl-alkyl.

22. R ４ but 【Chemistry 12】 wherein said heterocycle, when valences permit, is selected from the group consisting of one or more of cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH ２ , oxo, or (C=O)C １～４ 22. The compound of claim 21, optionally substituted with alkyl.

23. R ４ Where valence permits, alkyl, halogen, CN, -(CH ２ ) ０～２ OR ８ , N(R ８ ) ２ , (C=O)N(R ８ ) ２ 22. The compound of claim 21, which is cycloalkyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

24. R ４ Where valence permits, alkyl, halogen, CN, -(CH ２ ) ０～２ OR ８ , N(R ８ ) ２ , (C=O)N(R ８ ) ２ and oxo, each optionally substituted with 1 to 4 substituents independently selected from the group consisting of 【Chemistry 13】 That is, 24. The compound of claim 23.

25. R ４ but 【Chemistry 14-1】 【Chemistry 14-2】 or a tautomer thereof.

26. R ５ 26. The compound of any one of claims 1 to 25, wherein at least one occurrence of is H, alkyl or cycloalkyl.

27. ​​R ５ 26. The compound of any one of claims 1 to 25, wherein at least one occurrence of is oxo.

28. Two R ５ 26. The compound of any one of claims 1 to 25, wherein the groups are attached to different carbon atoms on the ring and, together, form a bond or an alkyl chain containing 1 to 3 carbons.

29. Two R ５ groups, together with the carbon atom to which they are attached, form a 3- to 7-membered, optionally substituted, saturated carbocyclic ring; 26. A compound according to any one of claims 1 to 25.

30. R ａ and R ｂ 30. The compound of any one of claims 1 to 29, wherein at least one of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

31. R ａ and R ｂ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O and S; 30. A compound according to any one of claims 1 to 29.

32. R ６ and R ７ 32. The compound of any one of claims 1 to 31, wherein each occurrence of is independently H or alkyl.

33. R ９ but 33. The compound of any one of claims 1 to 32, wherein R is H, alkyl, or halogen.

34. R 9 is (CR ６ R ７ ) ｎ４ OR ｂ 33. The compound according to any one of claims 1 to 32, wherein 35. The compound according to claim 34, wherein R 9 is H, F, or OH.

33. A compound according to any one of claims 1 to 32.

36. The compound of any one of claims 1 to 35, wherein Z is OR a , NR a R b , or NR b (C═O)R a .

37. The compound of claim 36, wherein Z is OH, OMe, NH 2 , NHMe, or NMe 2 .

38. The compound of claim 36, wherein Z is OH.

39. The compound of any one of claims 1 to 38, wherein X 1 is H, halogen, fluorinated alkyl or alkyl.

40. The compound of any one of claims 1 to 39, wherein X 1 is H, F, Cl, Br, Me, CF 3 , or CF 2 Cl.

41. The compound of claim 39, wherein X 1 is Me or Cl.

42. The compound of any one of claims 1 to 41, wherein X 2 is H, halogen, fluorinated alkyl or alkyl.

43. The compound of claim 42, wherein X2 is H, F, Cl, Br, Me, CF3, or CF2Cl.

44. The compound of claim 42, wherein X 2 is Cl.

45. The compound of any one of claims 1 to 44, wherein X 3 is H, F, Cl, Br, a fluorinated alkyl, or an alkyl.

46. ​​The compound of claim 45, wherein X 3 is H, F, Cl, or CF 3 .

47. Structural part 【Chemistry 15】 each of which is substituted by R 3 ; 【Chemistry 16】 36. The compound of any one of claims 1 to 35, having the structure:

48. R ３ 48. The compound of any one of claims 1 to 47, wherein is H or alkyl.

49. R ３ 48. The compound of any one of claims 1 to 47, wherein is halogen.

50. The structure of formula II: 【Chemistry 17】 each occurrence of R 3 ' is independently H, halogen, or alkyl; n 6 is an integer from 0 to 2.

39. The compound of any one of claims 1 to 38, having the formula:

51. The compound of claim 50, wherein at least one occurrence of R 3′ is H or alkyl.

52. The compound of claim 50, wherein at least one occurrence of R 3′ is halogen.

53. R ８ 53. The compound of any one of claims 1 to 52, wherein at least one occurrence of is H, alkyl, or an optionally substituted heterocycle.

54. R ８ is H, Me, Et, Pr, Bu, or 【Chemistry 18】 wherein said heterocycle, when valences permit, is selected from the group consisting of one or more of cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH ２ , oxo, or (C=O)C １～４ 54. The compound of claim 53, optionally substituted with alkyl.

55. Two R ８ groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O and S; 53. A compound according to any one of claims 1 to 52.

56. The compound of any one of claims 1 to 55, wherein n 1 is 0, 1, 2, or 3.

57. The compound of any one of claims 1 to 5, wherein n 4 is 0, 1, or 2.

58. R ｃ Or R ｄ at least one occurrence of is independently H, alkyl, each independently halogen, OR ８ and N(R ８ ) ２ 6. The compound of claim 1, which is an optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-aryl, optionally substituted alkyl-heteroaryl, optionally substituted alkyl-heterocycle, optionally substituted alkyl-cycloalkyl, or optionally substituted cycloalkyl-alkyl, substituted by 1 to 4 substituents selected from the group consisting of:

59. The compound of any one of claims 1 to 5, wherein R c and R d together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O and S.

60. R ｃ Or R ｄ At least one occurrence of is independently H, Me, Et, 【Chemistry 19】 That is, 6. A compound according to any one of claims 1 to 5. At least one occurrence of R c or R d independently represents 【Chemistry 20】 6. The compound of any one of claims 1 to 5, wherein said heterocycle is optionally substituted, where valences permit, with one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C═O)C 1-4 alkyl.

62. The compound of any one of claims 1 to 5, wherein at least one occurrence of R c or R d is independently a cycloalkyl, spiroalkyl, or bicycloalkyl, each optionally substituted, where valences permit, with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C═O)N(R 8 ) 2 , and oxo.

63. At least one occurrence of R c or R d is independently, where valences permit, each optionally substituted with 1 to 4 substituents each independently selected from the group consisting of alkyl, halogen, CN, —(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C═O)N(R 8 ) 2 , and oxo; 【Chemistry 21】 6. The compound according to claim 1 , wherein 64. The compound of claim 1, selected from the group consisting of compounds 1 to 338 in Table 1.

65. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 64 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

66. A method of treating a condition in a mammalian species in need thereof, comprising the step of administering to said mammalian species a therapeutically effective amount of at least one compound described in any one of claims 1 to 64, or a pharma- ceutically acceptable salt thereof, wherein said condition is selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and renal diseases.

67. The method of claim 66, wherein the immunological disorder is graft rejection or an autoimmune disease.

68. The method of claim 67, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

69. The method of claim 66, wherein the central nervous system (CNS) disorder is Alzheimer's disease.

70. The method described in claim 66, wherein the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

71. The method of claim 66, wherein the gastroenterological disorder is inflammatory bowel disease.

72. The method described in claim 66, wherein the metabolic disorder is obesity or type II diabetes.

73. The method of claim 66, wherein the cardiovascular disorder is ischemic stroke.

74. The method described in claim 66, wherein the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

75. The method of claim 66, wherein the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

76. The method of claim 66, wherein the mammalian species is human.

77. A method of blocking the Kv1.3 potassium channel in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound described in any one of claims 1 to 64, or a pharma- ceutically acceptable salt thereof.

78. The method of claim 76, wherein the mammalian species is human.

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